**Part 6**

## **Prevention and Management of Osteoporosis**

408 Osteoporosis

Witzke, K.A. & Snow, C.M. (2000). Effects of plyometric jump training on bone mass in

Wyshak, G. & Frisch, R.E. (1994). Carbonated beverages, dietary calcium, the dietary

*Adolescent Health,* Vol. 15, No. 3, (May 1994), pp. 210-215

2000), pp. 1051-1057

adolescent girls. *Medicine and Science in Sports and Exercise,* Vol. 32, No. 6, (June

calcium/phosphorus ratio, and bone fractures in boys and girls. *Journal of* 

**21** 

*Spain* 

**Osteoporosis, Nutrition and Adolescence** 

Osteoporosis is a worldwide health problem characterized by low bone mineral density and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures. Skeletal bone is maintained by the continuous process of bone remodeling by osteoclasts, cells that break down bone, and osteoblasts, cells that rebuild bone. An imbalance between bone resorption and accrual derives to overall bone loss, which in time leads to osteoporosis (Schettler & Gustafson, 2004). After the third decade of life, the bone mass naturally declines approximately 1-2% per year in women, and 0.3-1% per year in men, leading to losses of 30-50% of their initial bone mass in women and 20-30% in men during their lifetime (Riggs & Melton, 1986). As a consequence, both men and women may develop osteoporosis, maybe the most common chronic disability of postmenopausal women. However, osteoporosis should not be considered solely as adult disease, since bone health must be a lifelong concern, with special focus on the adolescent years (Schettler & Gustafson, 2004). In this sense, Kreipe (1992) suggested that "senile osteoporosis is a

Osteoporosis in adolescence may be a primary or secondary consequence of diseases or disorders genetic but, in addition, it may be induced by erroneous lifestyle habits, including poor dietary habits, insufficient exposure to sunlight and low physical activities (Campos et al., 2003). The primary forms of osteoporosis in adolescents are relatively rare, and some of them are familiar or genetically determined. In this group may be included the osteogenesis imperfecta, a form of osteoporosis because of bone fragility which is characterized by weak bones that fracture easily, and the idiopathic juvenile osteoporosis, a rare disease associated with a negative calcium balance and characterized by repeated fractures (Bianchi, 2007). The secondary forms of osteoporosis result as a consequence of diseases associated with low bone mass and increased risk of fractures, such as neuromuscular disorders, chronic or endocrine diseases, and inborn errors of metabolism. Moreover, the treatment of some of these diseases may be associated to osteoporosis since several medications such as glucocorticoids, anticoagulants or anticonvulsant drugs can be negatively related to bone metabolism (Bianchi, 2007; Campos et al., 2003). On the other hand, conditions that result in pubertal retardation in adolescents such as anorexia nervosa or amenorrhea induced by

exercise, can also be highlighted as causes of osteoporosis in this stage of life.

Although osteoporosis is not common among adolescents, adolescence is a key factor on the development of this disease in the adult age. It has been reported that, probably, the most important factor in the primary prevention of osteoporosis is the attainment of an optimal

**1. Introduction** 

pediatric disease".

Isabel Seiquer, Marta Mesías and M. Pilar Navarro *Consejo Superior de Investigaciones Científicas (CSIC)* 

## **Osteoporosis, Nutrition and Adolescence**

Isabel Seiquer, Marta Mesías and M. Pilar Navarro *Consejo Superior de Investigaciones Científicas (CSIC)* 

*Spain* 

### **1. Introduction**

Osteoporosis is a worldwide health problem characterized by low bone mineral density and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures. Skeletal bone is maintained by the continuous process of bone remodeling by osteoclasts, cells that break down bone, and osteoblasts, cells that rebuild bone. An imbalance between bone resorption and accrual derives to overall bone loss, which in time leads to osteoporosis (Schettler & Gustafson, 2004). After the third decade of life, the bone mass naturally declines approximately 1-2% per year in women, and 0.3-1% per year in men, leading to losses of 30-50% of their initial bone mass in women and 20-30% in men during their lifetime (Riggs & Melton, 1986). As a consequence, both men and women may develop osteoporosis, maybe the most common chronic disability of postmenopausal women. However, osteoporosis should not be considered solely as adult disease, since bone health must be a lifelong concern, with special focus on the adolescent years (Schettler & Gustafson, 2004). In this sense, Kreipe (1992) suggested that "senile osteoporosis is a pediatric disease".

Osteoporosis in adolescence may be a primary or secondary consequence of diseases or disorders genetic but, in addition, it may be induced by erroneous lifestyle habits, including poor dietary habits, insufficient exposure to sunlight and low physical activities (Campos et al., 2003). The primary forms of osteoporosis in adolescents are relatively rare, and some of them are familiar or genetically determined. In this group may be included the osteogenesis imperfecta, a form of osteoporosis because of bone fragility which is characterized by weak bones that fracture easily, and the idiopathic juvenile osteoporosis, a rare disease associated with a negative calcium balance and characterized by repeated fractures (Bianchi, 2007). The secondary forms of osteoporosis result as a consequence of diseases associated with low bone mass and increased risk of fractures, such as neuromuscular disorders, chronic or endocrine diseases, and inborn errors of metabolism. Moreover, the treatment of some of these diseases may be associated to osteoporosis since several medications such as glucocorticoids, anticoagulants or anticonvulsant drugs can be negatively related to bone metabolism (Bianchi, 2007; Campos et al., 2003). On the other hand, conditions that result in pubertal retardation in adolescents such as anorexia nervosa or amenorrhea induced by exercise, can also be highlighted as causes of osteoporosis in this stage of life.

Although osteoporosis is not common among adolescents, adolescence is a key factor on the development of this disease in the adult age. It has been reported that, probably, the most important factor in the primary prevention of osteoporosis is the attainment of an optimal

Osteoporosis, Nutrition and Adolescence 413

important constituent of bone and, therefore, promoting calcium metabolism is a positive factor to enhance bone mineralization. The hormonal changes associated with puberty begin 2–3 years before this period, when an acceleration of growth is observed. The maturation of the hypothalamo-pituitary gonadal axis includes the gonadotropin-releasing hormone (GnRH). At a preprogrammed time in a child's life, there is an increase in the amplitude of GnRH pulses which triggers a cascade of events including increases in the amplitude of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) pulses, followed by a marked elevation in gonadal sex steroidal output, which in turn increases the production of growth hormone (GH) in the hypophysis and of insulin-like growth factor-1 (IGF-1) in different tissues (Mauras et al., 1996). Moreover, sex steroids can act centrally by regulating GH secretion and peripherally modulating GH responsiveness (Figure 1). Higher levels of GH and of sexual steroids during the prepubertal period have a positive influence on bone mineral density and the accumulation of calcium in the skeleton (Krabbe et al., 1979). The effects of GH on bone turnover may be partly mediated by locally produced IGF-1, which is a beneficial factor on skeletal development and bone formation. IGF-1 serum levels increase and reach a maximum during puberty, at 14.5 years in girls and 15.5 years in boys (Juul et al., 1994). This factor seems to be a major regulator of bone growth during childhood and adolescence.

Fig. 1. Hormonal changes during adolescence which are determinants of calcium absorption and bone formation. GnRH: Gonadotropin-relasing hormone. FSH: Folliclestimulating hormone. LH: Luteinizing hormone. GH: Growth hormone. IGF-1: insulin-like growth factor-1. \*\*\* : Pulses. —: Hormonal changes. - - - : Effects on calcium absorption and bone

formation. Modified from Mesias et al. (2011).

peak bone mass during adolescence (Ott, 1990) and, therefore, any factor adversely impacting on bone acquisition during childhood or adolescence can potentially have longstanding detrimental effects on bone health predisposing to osteoporosis (Saggese et al., 2001). Several interconnected factors influence bone mass accumulation during growth, including genetic, hormonal, nutritional and lifestyle factors. Hereditary factors are responsible for around 80% of final peak bone mass, although there are clear suggestions that exogenous factors influence the acquisition of up to 20-25% of bone mass, so that the attainment of 100% of peak bone mass potential may be achieved only by their modulation. According to Ferrari et al. (2000), nutritional and genetic factors may interact to influence bone modeling, affecting bone mineral density (BMD), bone size and architecture, and mineral homeostasis during the years of peak bone mass acquisition. Therefore, together with another lifestyle factors, nutrition during adolescence has an important role in prevention of osteoporosis, and diets consumed during this stage of life should be balanced and equilibrated in order to meet the adolescent's requirements, especially those related to bone health.

### **2. Bone physiology during adolescence**

Adolescence is characterized by an accelerated growth rate associated with rapid muscular, skeletal, and sexual development. During this period 15-25% of the adult size is acquired, approximately 45-50% of total adult skeletal mass is completed and up to 95% of total bone development is completed prior to the age of 18 (Bailey et al., 2000; Henry et al., 2004). Bones are growing in length and width, cortical thickness is increasing, and there is a dramatic increase in bone mass as well as a significant increase in bone density. Bone mineral content during adolescence is more a function of pubertal stage than a function of chronological age (Rico et al., 1993). Before puberty, no substantial gender difference has been reported in bone mass when adjusted for age, nutrition and physical activity. This absence of sex differences in bone mass is maintained until the onset of pubertal maturation, since the gender difference in bone mass is expressed during this period. Bone mineral content accretion accelerates in girls, reflecting the earlier onset of puberty in them, whereas boys have a greater increase in bone mineral content during puberty, resulting in greater values of skeletal maturity (Faulkner et al., 1996). Then, by the age of 10 the mean height-gain velocity is 6 cm/year in girls and increases to an average peak of 9 cm/year by the age of 12. Peak height-gain velocity for boys starts at the age of 12 years (5 cm/year) and reaches a maximum by the age of 14 years (10 cm/year). Mean height gain velocity is close to zero at age 15 in girls, and at age 17 in boys (Matkovic et al., 2004).

Bone is composed by cells (osteoblasts and osteoclasts), minerals (mainly calcium and phosphorus) and organic matrix (collagen and other proteins). Osteoblasts synthesize and mineralize the matrix proteins with hydroxyapatite crystals, whereas osteoclasts promote bone resorption, thus maintaining constant tissue remodeling (Van der sluis & Muinck Keizer-Schrama, 2001). During adolescence two phenomena are produced simultaneously, the synthesis of new bone from growth cartilage due to the process of endochondral ossification, and the modelling-remodelling of previously synthesized bone. The process of bone formation and resorption in the body is continuous, but in adolescents the rate of formation predominates over that of resorption. During puberty, several physiological and endocrine factors have a main role in the accumulation of bone mass. Some of these factors have an important influence on calcium absorption and retention; calcium is the most

peak bone mass during adolescence (Ott, 1990) and, therefore, any factor adversely impacting on bone acquisition during childhood or adolescence can potentially have longstanding detrimental effects on bone health predisposing to osteoporosis (Saggese et al., 2001). Several interconnected factors influence bone mass accumulation during growth, including genetic, hormonal, nutritional and lifestyle factors. Hereditary factors are responsible for around 80% of final peak bone mass, although there are clear suggestions that exogenous factors influence the acquisition of up to 20-25% of bone mass, so that the attainment of 100% of peak bone mass potential may be achieved only by their modulation. According to Ferrari et al. (2000), nutritional and genetic factors may interact to influence bone modeling, affecting bone mineral density (BMD), bone size and architecture, and mineral homeostasis during the years of peak bone mass acquisition. Therefore, together with another lifestyle factors, nutrition during adolescence has an important role in prevention of osteoporosis, and diets consumed during this stage of life should be balanced and equilibrated in order to meet the adolescent's requirements, especially those related to

Adolescence is characterized by an accelerated growth rate associated with rapid muscular, skeletal, and sexual development. During this period 15-25% of the adult size is acquired, approximately 45-50% of total adult skeletal mass is completed and up to 95% of total bone development is completed prior to the age of 18 (Bailey et al., 2000; Henry et al., 2004). Bones are growing in length and width, cortical thickness is increasing, and there is a dramatic increase in bone mass as well as a significant increase in bone density. Bone mineral content during adolescence is more a function of pubertal stage than a function of chronological age (Rico et al., 1993). Before puberty, no substantial gender difference has been reported in bone mass when adjusted for age, nutrition and physical activity. This absence of sex differences in bone mass is maintained until the onset of pubertal maturation, since the gender difference in bone mass is expressed during this period. Bone mineral content accretion accelerates in girls, reflecting the earlier onset of puberty in them, whereas boys have a greater increase in bone mineral content during puberty, resulting in greater values of skeletal maturity (Faulkner et al., 1996). Then, by the age of 10 the mean height-gain velocity is 6 cm/year in girls and increases to an average peak of 9 cm/year by the age of 12. Peak height-gain velocity for boys starts at the age of 12 years (5 cm/year) and reaches a maximum by the age of 14 years (10 cm/year). Mean height gain velocity is close to zero at

Bone is composed by cells (osteoblasts and osteoclasts), minerals (mainly calcium and phosphorus) and organic matrix (collagen and other proteins). Osteoblasts synthesize and mineralize the matrix proteins with hydroxyapatite crystals, whereas osteoclasts promote bone resorption, thus maintaining constant tissue remodeling (Van der sluis & Muinck Keizer-Schrama, 2001). During adolescence two phenomena are produced simultaneously, the synthesis of new bone from growth cartilage due to the process of endochondral ossification, and the modelling-remodelling of previously synthesized bone. The process of bone formation and resorption in the body is continuous, but in adolescents the rate of formation predominates over that of resorption. During puberty, several physiological and endocrine factors have a main role in the accumulation of bone mass. Some of these factors have an important influence on calcium absorption and retention; calcium is the most

bone health.

**2. Bone physiology during adolescence** 

age 15 in girls, and at age 17 in boys (Matkovic et al., 2004).

important constituent of bone and, therefore, promoting calcium metabolism is a positive factor to enhance bone mineralization. The hormonal changes associated with puberty begin 2–3 years before this period, when an acceleration of growth is observed. The maturation of the hypothalamo-pituitary gonadal axis includes the gonadotropin-releasing hormone (GnRH). At a preprogrammed time in a child's life, there is an increase in the amplitude of GnRH pulses which triggers a cascade of events including increases in the amplitude of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) pulses, followed by a marked elevation in gonadal sex steroidal output, which in turn increases the production of growth hormone (GH) in the hypophysis and of insulin-like growth factor-1 (IGF-1) in different tissues (Mauras et al., 1996). Moreover, sex steroids can act centrally by regulating GH secretion and peripherally modulating GH responsiveness (Figure 1). Higher levels of GH and of sexual steroids during the prepubertal period have a positive influence on bone mineral density and the accumulation of calcium in the skeleton (Krabbe et al., 1979). The effects of GH on bone turnover may be partly mediated by locally produced IGF-1, which is a beneficial factor on skeletal development and bone formation. IGF-1 serum levels increase and reach a maximum during puberty, at 14.5 years in girls and 15.5 years in boys (Juul et al., 1994). This factor seems to be a major regulator of bone growth during childhood and adolescence.

Fig. 1. Hormonal changes during adolescence which are determinants of calcium absorption and bone formation. GnRH: Gonadotropin-relasing hormone. FSH: Folliclestimulating hormone. LH: Luteinizing hormone. GH: Growth hormone. IGF-1: insulin-like growth factor-1. \*\*\* : Pulses. —: Hormonal changes. - - - : Effects on calcium absorption and bone formation. Modified from Mesias et al. (2011).

Osteoporosis, Nutrition and Adolescence 415

presumably in response to the high requirements for calcium during this critical phase of

During adolescence several nutritional factors play a major role in the bone mass gain process and, therefore, some of the nutrients and food components consumed as part of the diet can potentially impact bone accrual during this stage of life. In addition, several

Dietary factors that may affect bone metabolism include minerals such as calcium, phosphorus and magnesium and a variety of nutrients cofactors such as vitamins D, C and K, and other minerals such as copper, zinc and manganese. In addition, a positive energy balance from macronutrients is important during growth for synthesis of bone. On the other hand, protein comprises most of the nonmineral composition of bone, and an adequate protein intake is essential for bone matrix synthesis (Saggese et al., 2001). Therefore, diet must contribute sufficient and appropriate nutrients to allow, together with healthy lifestyle

Calcium is the most abundant mineral in the organism and contributes approximately 1-2% to the adult human body weight. About 99% of body calcium is deposited in bone and teeth and, hence, its main function is structural, being essential for optimal growth and development. A dynamic balance exists between calcium in the extracellular medium and that found in bone, and about 500 mg of this mineral enter and depart daily from the bones (Pérez Llamas et al., 2010). The bone acts as a reservoir of calcium to maintain extracellular homeostasis and transfers the mineral if its concentration in blood falls below normal values (9.0-10.2 mg/dl), especially in situations of chronic calcium deficiency resulting from continual inadequate intake or poor intestinal absorption. Therefore, mineral deficiency leads to inadequate mineralization of bone matrix, resulting in rickets in children and adolescents and, along with other risk factors, contributing to possible osteoporosis in

Calcium requirements vary throughout life; greater needs are shown during periods of intense growth such as childhood and adolescence, during pregnancy and lactation, and also later in life. Among adolescents, a calcium increase is needed as a result of the intensive bone and muscular development. Therefore, adequate calcium intake during growing is essential to reach the optimum peak bone mass, which, as it has been above mentioned, protects against osteoporosis in the adult age (Story & Stang, 2005). Although peak bone mass has a large genetic component, there is evidence that it can be enhanced by increasing calcium consumption. Several studies in children and adolescents have shown that bone mass and bone density increase with calcium dietary supplements, and therefore, providing adequate calcium intake during the formative years is one approach to optimizing peak

Given the high proportion of body calcium present in bone and the importance of this as the major calcium reservoir, the development and maintenance of bone are the major determinants of calcium needs. Therefore, adolescents must consume diets that are balanced and adjusted to their requirements in order to meet calcium recommendations and to obtain the energy and nutrients that promote mineral utilization. Several studies have

habits, achieve the maximum genetic potential for bone mass development.

**3. Nutritional factors affecting bone development** 

nutritional disorders may be associated with osteoporosis.

skeletal development.

**3.1 Calcium** 

adulthood (Mesías et al., 2011).

bone mass (Cromer & Harel, 2000).

Many of these hormones have an influence on calcium absorption: GH enhances intestinal calcium absorption, increasing 1,25-dihydroxyvitamin D production by stimulating renal 1 *α*-hydroxylase and supports phosphate retention by increasing the renal threshold for phosphate excretion (Bouillon, 1991). The final effect of these actions is the increase of the calcium-phosphate product in the extracellular fluids, which represents a main mechanism for bone matrix mineralization. It is known that GH deficiency may decrease bone turnover, and the balance between bone formation and bone resorption might be uncontrolled. In this sense, it has been demonstrated that children with GH deficiency have reduced bone turnover and bone mass accumulation (Saggese et al., 1995). Several studies have showed that adequate doses and duration of GH replacement therapy are able to increase bone turnover and to achieve bone mineral density values within the normal range (Saggese et al., 1996), suggesting that GH has a fundamental role in the acquisition of peak of bone mass. Moreover, GH, together with IGF-1 stimulates sex steroids secretion (Bouillon, 1991). Both estrogens and androgens influence phospho-calcium metabolism regulating calcium fluxes and bone calcium deposition, increasing calcium absorption and retention (Mauras, 1999). The route by which many of these hormones augment during puberty favoring calcium absorption and bone mass accumulation is across 1,25-dihydroxyvitamin D, the principal enhancer of this mineral absorption at any stage of life but especially in the pediatric period. Nevertheless, although vitamin D is necessary for calcium absorption, on the contrary to the situation found with adults, no relation seems to exist between serum levels of 25-hydroxyvitamin D and calcium absorption in adolescents who are not deficient in this vitamin. This may be because they can adapt to low levels of this vitamin, by increasing calcium absorption independently of the vitamin or, as diverse authors indicate, because during puberty the efficacy of conversion of 25-hydroxyvitamin D to 1,25 dihydroxyvitamin D increases to meet the needs for skeletal growth (Abrams et al., 2005). With the secretion of sex hormones during puberty, bone growth accelerates and bone mass accumulation increases. In females, the accretion rate increases about 4-fold before menarche, although bone mass changes little or even decreases thereafter. In males, bone mass accretion increases approximately 6-fold during puberty with a slower but still marked accretion at many skeletal sites thereafter. In addition, there are gender differences in the porosity of bone between adolescent boys and girls that may reflect greater bone remodelling in boys at this time. As a result of these differences, males have a larger bone size and greater thickness after puberty than females, but there is little difference in volumetric density (Prentice et al., 2006). Estrogens are an important determinant of bone mineral density in girls during puberty; this is confirmed by diverse studies in which girls with an early or regular menarche had higher bone mineral density, while a late menarche or amenorrhea in ballet ballerinas or in patients with anorexia nervosa were related to a limited density and even to fractures (Bachrach et al., 1991; Young et al., 1994). Estrogens can decrease the rate of bone turnover, and inhibit the osteoclastic resorption of bone by affecting bone cell differentiation and function. They also affect the parathyroid hormone (PTH) and, as mentioned previously, vitamin D metabolism. Androgens may also be important determinants of bone density, although studies carried out with animals have shown that estrogens play a more important role than androgens in skeletal mineralization (Frank, 1995). Another factor related to mineral density is serum calcitriol (1,25 dihydroxyvitaminD). It is demonstrated (Ilich et al., 1997) that calcitriol levels can be positively associated with changes in total bone mineral density during pubertal growth, presumably in response to the high requirements for calcium during this critical phase of skeletal development.

### **3. Nutritional factors affecting bone development**

During adolescence several nutritional factors play a major role in the bone mass gain process and, therefore, some of the nutrients and food components consumed as part of the diet can potentially impact bone accrual during this stage of life. In addition, several nutritional disorders may be associated with osteoporosis.

Dietary factors that may affect bone metabolism include minerals such as calcium, phosphorus and magnesium and a variety of nutrients cofactors such as vitamins D, C and K, and other minerals such as copper, zinc and manganese. In addition, a positive energy balance from macronutrients is important during growth for synthesis of bone. On the other hand, protein comprises most of the nonmineral composition of bone, and an adequate protein intake is essential for bone matrix synthesis (Saggese et al., 2001). Therefore, diet must contribute sufficient and appropriate nutrients to allow, together with healthy lifestyle habits, achieve the maximum genetic potential for bone mass development.

#### **3.1 Calcium**

414 Osteoporosis

Many of these hormones have an influence on calcium absorption: GH enhances intestinal calcium absorption, increasing 1,25-dihydroxyvitamin D production by stimulating renal 1 *α*-hydroxylase and supports phosphate retention by increasing the renal threshold for phosphate excretion (Bouillon, 1991). The final effect of these actions is the increase of the calcium-phosphate product in the extracellular fluids, which represents a main mechanism for bone matrix mineralization. It is known that GH deficiency may decrease bone turnover, and the balance between bone formation and bone resorption might be uncontrolled. In this sense, it has been demonstrated that children with GH deficiency have reduced bone turnover and bone mass accumulation (Saggese et al., 1995). Several studies have showed that adequate doses and duration of GH replacement therapy are able to increase bone turnover and to achieve bone mineral density values within the normal range (Saggese et al., 1996), suggesting that GH has a fundamental role in the acquisition of peak of bone mass. Moreover, GH, together with IGF-1 stimulates sex steroids secretion (Bouillon, 1991). Both estrogens and androgens influence phospho-calcium metabolism regulating calcium fluxes and bone calcium deposition, increasing calcium absorption and retention (Mauras, 1999). The route by which many of these hormones augment during puberty favoring calcium absorption and bone mass accumulation is across 1,25-dihydroxyvitamin D, the principal enhancer of this mineral absorption at any stage of life but especially in the pediatric period. Nevertheless, although vitamin D is necessary for calcium absorption, on the contrary to the situation found with adults, no relation seems to exist between serum levels of 25-hydroxyvitamin D and calcium absorption in adolescents who are not deficient in this vitamin. This may be because they can adapt to low levels of this vitamin, by increasing calcium absorption independently of the vitamin or, as diverse authors indicate, because during puberty the efficacy of conversion of 25-hydroxyvitamin D to 1,25 dihydroxyvitamin D increases to meet the needs for skeletal growth (Abrams et al., 2005). With the secretion of sex hormones during puberty, bone growth accelerates and bone mass accumulation increases. In females, the accretion rate increases about 4-fold before menarche, although bone mass changes little or even decreases thereafter. In males, bone mass accretion increases approximately 6-fold during puberty with a slower but still marked accretion at many skeletal sites thereafter. In addition, there are gender differences in the porosity of bone between adolescent boys and girls that may reflect greater bone remodelling in boys at this time. As a result of these differences, males have a larger bone size and greater thickness after puberty than females, but there is little difference in volumetric density (Prentice et al., 2006). Estrogens are an important determinant of bone mineral density in girls during puberty; this is confirmed by diverse studies in which girls with an early or regular menarche had higher bone mineral density, while a late menarche or amenorrhea in ballet ballerinas or in patients with anorexia nervosa were related to a limited density and even to fractures (Bachrach et al., 1991; Young et al., 1994). Estrogens can decrease the rate of bone turnover, and inhibit the osteoclastic resorption of bone by affecting bone cell differentiation and function. They also affect the parathyroid hormone (PTH) and, as mentioned previously, vitamin D metabolism. Androgens may also be important determinants of bone density, although studies carried out with animals have shown that estrogens play a more important role than androgens in skeletal mineralization (Frank, 1995). Another factor related to mineral density is serum calcitriol (1,25 dihydroxyvitaminD). It is demonstrated (Ilich et al., 1997) that calcitriol levels can be positively associated with changes in total bone mineral density during pubertal growth,

Calcium is the most abundant mineral in the organism and contributes approximately 1-2% to the adult human body weight. About 99% of body calcium is deposited in bone and teeth and, hence, its main function is structural, being essential for optimal growth and development. A dynamic balance exists between calcium in the extracellular medium and that found in bone, and about 500 mg of this mineral enter and depart daily from the bones (Pérez Llamas et al., 2010). The bone acts as a reservoir of calcium to maintain extracellular homeostasis and transfers the mineral if its concentration in blood falls below normal values (9.0-10.2 mg/dl), especially in situations of chronic calcium deficiency resulting from continual inadequate intake or poor intestinal absorption. Therefore, mineral deficiency leads to inadequate mineralization of bone matrix, resulting in rickets in children and adolescents and, along with other risk factors, contributing to possible osteoporosis in adulthood (Mesías et al., 2011).

Calcium requirements vary throughout life; greater needs are shown during periods of intense growth such as childhood and adolescence, during pregnancy and lactation, and also later in life. Among adolescents, a calcium increase is needed as a result of the intensive bone and muscular development. Therefore, adequate calcium intake during growing is essential to reach the optimum peak bone mass, which, as it has been above mentioned, protects against osteoporosis in the adult age (Story & Stang, 2005). Although peak bone mass has a large genetic component, there is evidence that it can be enhanced by increasing calcium consumption. Several studies in children and adolescents have shown that bone mass and bone density increase with calcium dietary supplements, and therefore, providing adequate calcium intake during the formative years is one approach to optimizing peak bone mass (Cromer & Harel, 2000).

Given the high proportion of body calcium present in bone and the importance of this as the major calcium reservoir, the development and maintenance of bone are the major determinants of calcium needs. Therefore, adolescents must consume diets that are balanced and adjusted to their requirements in order to meet calcium recommendations and to obtain the energy and nutrients that promote mineral utilization. Several studies have

Osteoporosis, Nutrition and Adolescence 417

and most cereals and seeds, oxalates in spinach or walnuts, and tannins in tea, can form insoluble complexes with calcium, thereby reducing its absorption. However, Guéguen and Pointillart (2000) show that these factors only seem to significantly affect calcium balance if the overall diet is unbalanced. Milk and dairy products are considered good sources of this mineral due to their high calcium content and bioavailability (proportion of calcium retained from intake). Around 40% of the calcium from these products may be absorbed due to the particular physico-chemical form of the element and the presence of absorption promoters such as lactose and caseinphosphopeptides. The latter, moreover, can limit the inhibitory effect of other compounds (Guéguen and Pointillart, 2000). Milk nutrients may promote bone mineralization because, in addition of being a major source of calcium, milk provides phosphates, magnesium, proteins, and as yet unidentified nutrients likely to favor bone health (Esterle et al., 2009). Vitamin D is also an essential factor for intestinal calcium absorption and plays a central role in maintaining calcium homeostasis and skeletal integrity. Adequate levels of this vitamin are obtained by suitable intake and sufficient exposure to sunlight, which is the major source of vitamin D in the organism (Bener et al., 2008). On the other hand, certain lipids may favor calcium bioavailability; it has been shown that a high ratio of unsaturated to saturated fatty acids has beneficial effects on calcium absorption (Haag et al., 2003). Fish may be a good source of calcium because on the one hand its protein is as positive as casein in promoting calcium absorption (García-Arias et al., 1994), and on the other hand because omega-3 fatty acid might promote calcium transport (Haag et al., 2003). It should be noted that the positive effect of fish fat in calcium utilization is promoted when it is consumed together with olive oil (Pérez-Granados et al., 2000), as it occurs when fried fish are consumed. Olive oil may be another contributor to enhanced calcium utilization, assays have shown that oleuropein, an olive oil phenolic compound, reduces bone loss (Puel et al., 2004). Studies in humans (Van den Heuvel et al., 1999) and experiments in rats (López et al., 2000) have revealed a positive effect on apparent calcium absorption after consumption of oligofructose. This compound may also diminish the negative effects of phytic acids. A diet rich in cereals, fruits, and vegetables can increase the presence of these prebiotic products in the digestive system, helping to improve calcium

absorption in this physiological stage when demands for the mineral are high.

Dietary calcium intake and urinary excretion of calcium seem to be also important determinants of mineral retention in the body. Although in adults urinary calcium may reflect the intake, in adolescents levels of calcium in urine represent obligatory renal losses that are independent of the consumption. Therefore, it can be supposed that only an unavoidable amount of calcium is lost because its use at this stage of life is a matter of priority for the organism. During childhood, urinary calcium excretion doubles, from ~40 mg/day in young children to ~80 mg/day just before puberty. However, during the peak of maximum growth, this value decreases, especially among males. Calcium excretion rises to reach the values of adulthood (100-250 mg/day) by the end of adolescence (Manz et al., 1999; Peacock, 1991). This increase in urinary calcium excretion in late adolescence probably reflects the decreasing needs of the skeleton for calcium (Peacock, 1991). In addition to the physiological status, certain dietary components may affect urinary losses of calcium. Some dietary factors affecting urine losses have a major influence on calcium balance and may even become more important than those influencing the intestinal availability of calcium. Thus, excessive protein intake, particularly animal protein, generally leads to an increase of the calcium lost in urine (Ginty, 2003), although it seems unclear whether protein intake has a negative effect on calcium balance and bone mineralization in children and adolescents.

demonstrated the importance of considering both food groups and the overall diet in assessing their impact on bone health, which may partially explain the relationship between nutrient intake and bone mineral acquisition in children and adolescents (Heaney, 2004; Seiquer et al., 2008). Milk and dairy products contribute around 70% of total dietary calcium and thus, they are by far the main source of calcium in Western diets (Guéguen & Pointillart, 2000). Addition of these products to the adolescent's diet is the best strategy to meet calcium recommendations and to achieve optimal bone mineralization (Cadogan et al., 1997). Dairy products contribute from 42% of the total calcium consumed by British adolescents (Moynihan et al., 1996) to 70% by Australian (Department of Community Services, 1989), Spanish (Seiquer et al., 2006), or American adolescents (Fiorito et al., 2006). Dietary calcium supplements improves bone mineral accretion by 1-5% among adolescents consuming less than 1000 mg Ca/day, and by up to 10% when supplemental calcium is provided by dairy products (Kerstetter & Insogna, 1995). In this sense, Lyriris et al. (1997) found a correlation between the consumption of dairy products by young adult humans and bone density. Moreover, low milk intake during childhood and adolescence is associated with a greater incidence of fracture among older women (Kalkwarf et al., 2003). Cereals may also constitute an important calcium source, whereas meat, eggs, fish and legumes are minority calcium sources in the diet of adolescents (Seiquer et al., 2008). In addition, drinking water, including mineral water, may provide 6–7% of daily calcium intake (Guéguen & Pointillart, 2000). On the other hand, nutrients found in abundance in fruit and vegetables may be protective for bone health (Jones et al., 2001), as discussed below.

To achieve the maximum peak bone mass during adolescence, it is mandatory a positive calcium balance, i.e., the calcium body retention calculated as intake minus losses (Anderson & Garner, 1996). Usually the calcium balance increase in parallel to the intake, which suggests that the intake of this mineral may limit growth. Dietary calcium during this stage has a direct relationship with bone mineralization and low intake during puberty may limit it (Cadogan et al., 1997; Matkovic et al., 2004). Thus, if calcium intake is below 500 mg/day in childhood, more than 50% of ingested calcium must be retained in order to obtain adequate mineral accretion (Mølgaard et al., 1999). Balance studies carried out in adolescents support that calcium retention is associated with calcium intake, but at intakes up to 1300 mg/day a plateau is reached (Jackman et al., 1997). Therefore, calcium is a threshold nutrient, i.e., at suboptimal intake the body's ability to store calcium as bone tissue is limited by the intake of the mineral, but increasing calcium intake above the body's requirements does not result in further increases of stores (Mesías et al. 2011). At calcium intakes producing optimal bone mass, increasing calcium intake will not result in more bone (Flynn, 2003).

Intestinal calcium absorption varies with age and adapts to different physiological situations, so that when needs are high, mineral absorption becomes more efficient. Puberty is associated with a high rate of dietary calcium absorption, not only in absolute values but in fractional absorption rates or digestibility, in order to satisfy the increased calcium requirements for the intensive adolescent growth (Abrams & Stuff, 1994). To enable an increase in mineral absorption, adolescents have a low rate of calcium fecal excretion. Besides the amount of calcium in the diet, food ingredients are also a critical factor in determining the available calcium for bone development and maintenance. There is therefore a need to identify food components and/or functional food ingredients that optimize calcium absorption and bioavailability. Some components of the diet have been suggested as enhancers or inhibitors of calcium absorption. Thus, phytates found in bran

demonstrated the importance of considering both food groups and the overall diet in assessing their impact on bone health, which may partially explain the relationship between nutrient intake and bone mineral acquisition in children and adolescents (Heaney, 2004; Seiquer et al., 2008). Milk and dairy products contribute around 70% of total dietary calcium and thus, they are by far the main source of calcium in Western diets (Guéguen & Pointillart, 2000). Addition of these products to the adolescent's diet is the best strategy to meet calcium recommendations and to achieve optimal bone mineralization (Cadogan et al., 1997). Dairy products contribute from 42% of the total calcium consumed by British adolescents (Moynihan et al., 1996) to 70% by Australian (Department of Community Services, 1989), Spanish (Seiquer et al., 2006), or American adolescents (Fiorito et al., 2006). Dietary calcium supplements improves bone mineral accretion by 1-5% among adolescents consuming less than 1000 mg Ca/day, and by up to 10% when supplemental calcium is provided by dairy products (Kerstetter & Insogna, 1995). In this sense, Lyriris et al. (1997) found a correlation between the consumption of dairy products by young adult humans and bone density. Moreover, low milk intake during childhood and adolescence is associated with a greater incidence of fracture among older women (Kalkwarf et al., 2003). Cereals may also constitute an important calcium source, whereas meat, eggs, fish and legumes are minority calcium sources in the diet of adolescents (Seiquer et al., 2008). In addition, drinking water, including mineral water, may provide 6–7% of daily calcium intake (Guéguen & Pointillart, 2000). On the other hand, nutrients found in abundance in fruit and

vegetables may be protective for bone health (Jones et al., 2001), as discussed below.

(Flynn, 2003).

To achieve the maximum peak bone mass during adolescence, it is mandatory a positive calcium balance, i.e., the calcium body retention calculated as intake minus losses (Anderson & Garner, 1996). Usually the calcium balance increase in parallel to the intake, which suggests that the intake of this mineral may limit growth. Dietary calcium during this stage has a direct relationship with bone mineralization and low intake during puberty may limit it (Cadogan et al., 1997; Matkovic et al., 2004). Thus, if calcium intake is below 500 mg/day in childhood, more than 50% of ingested calcium must be retained in order to obtain adequate mineral accretion (Mølgaard et al., 1999). Balance studies carried out in adolescents support that calcium retention is associated with calcium intake, but at intakes up to 1300 mg/day a plateau is reached (Jackman et al., 1997). Therefore, calcium is a threshold nutrient, i.e., at suboptimal intake the body's ability to store calcium as bone tissue is limited by the intake of the mineral, but increasing calcium intake above the body's requirements does not result in further increases of stores (Mesías et al. 2011). At calcium intakes producing optimal bone mass, increasing calcium intake will not result in more bone

Intestinal calcium absorption varies with age and adapts to different physiological situations, so that when needs are high, mineral absorption becomes more efficient. Puberty is associated with a high rate of dietary calcium absorption, not only in absolute values but in fractional absorption rates or digestibility, in order to satisfy the increased calcium requirements for the intensive adolescent growth (Abrams & Stuff, 1994). To enable an increase in mineral absorption, adolescents have a low rate of calcium fecal excretion. Besides the amount of calcium in the diet, food ingredients are also a critical factor in determining the available calcium for bone development and maintenance. There is therefore a need to identify food components and/or functional food ingredients that optimize calcium absorption and bioavailability. Some components of the diet have been suggested as enhancers or inhibitors of calcium absorption. Thus, phytates found in bran and most cereals and seeds, oxalates in spinach or walnuts, and tannins in tea, can form insoluble complexes with calcium, thereby reducing its absorption. However, Guéguen and Pointillart (2000) show that these factors only seem to significantly affect calcium balance if the overall diet is unbalanced. Milk and dairy products are considered good sources of this mineral due to their high calcium content and bioavailability (proportion of calcium retained from intake). Around 40% of the calcium from these products may be absorbed due to the particular physico-chemical form of the element and the presence of absorption promoters such as lactose and caseinphosphopeptides. The latter, moreover, can limit the inhibitory effect of other compounds (Guéguen and Pointillart, 2000). Milk nutrients may promote bone mineralization because, in addition of being a major source of calcium, milk provides phosphates, magnesium, proteins, and as yet unidentified nutrients likely to favor bone health (Esterle et al., 2009). Vitamin D is also an essential factor for intestinal calcium absorption and plays a central role in maintaining calcium homeostasis and skeletal integrity. Adequate levels of this vitamin are obtained by suitable intake and sufficient exposure to sunlight, which is the major source of vitamin D in the organism (Bener et al., 2008). On the other hand, certain lipids may favor calcium bioavailability; it has been shown that a high ratio of unsaturated to saturated fatty acids has beneficial effects on calcium absorption (Haag et al., 2003). Fish may be a good source of calcium because on the one hand its protein is as positive as casein in promoting calcium absorption (García-Arias et al., 1994), and on the other hand because omega-3 fatty acid might promote calcium transport (Haag et al., 2003). It should be noted that the positive effect of fish fat in calcium utilization is promoted when it is consumed together with olive oil (Pérez-Granados et al., 2000), as it occurs when fried fish are consumed. Olive oil may be another contributor to enhanced calcium utilization, assays have shown that oleuropein, an olive oil phenolic compound, reduces bone loss (Puel et al., 2004). Studies in humans (Van den Heuvel et al., 1999) and experiments in rats (López et al., 2000) have revealed a positive effect on apparent calcium absorption after consumption of oligofructose. This compound may also diminish the negative effects of phytic acids. A diet rich in cereals, fruits, and vegetables can increase the presence of these prebiotic products in the digestive system, helping to improve calcium absorption in this physiological stage when demands for the mineral are high.

Dietary calcium intake and urinary excretion of calcium seem to be also important determinants of mineral retention in the body. Although in adults urinary calcium may reflect the intake, in adolescents levels of calcium in urine represent obligatory renal losses that are independent of the consumption. Therefore, it can be supposed that only an unavoidable amount of calcium is lost because its use at this stage of life is a matter of priority for the organism. During childhood, urinary calcium excretion doubles, from ~40 mg/day in young children to ~80 mg/day just before puberty. However, during the peak of maximum growth, this value decreases, especially among males. Calcium excretion rises to reach the values of adulthood (100-250 mg/day) by the end of adolescence (Manz et al., 1999; Peacock, 1991). This increase in urinary calcium excretion in late adolescence probably reflects the decreasing needs of the skeleton for calcium (Peacock, 1991). In addition to the physiological status, certain dietary components may affect urinary losses of calcium. Some dietary factors affecting urine losses have a major influence on calcium balance and may even become more important than those influencing the intestinal availability of calcium. Thus, excessive protein intake, particularly animal protein, generally leads to an increase of the calcium lost in urine (Ginty, 2003), although it seems unclear whether protein intake has a negative effect on calcium balance and bone mineralization in children and adolescents.

Osteoporosis, Nutrition and Adolescence 419

is likely to be 5-10 mg/day (Andon et al., 1996) and may increase during the pubertal growth spurt in order to support the more rapid rate of bone formation during this period

The bioavailability of magnesium may be affected by several dietary factors such as phosphorus, calcium, sodium or protein. It is known that high phosphate diets can decrease intestinal magnesium absorption due to the ability of phosphate to bind magnesium (Reinhold et al., 1991), whereas high sodium and calcium intake may result in increased renal magnesium excretion (Kesteloot & Joossens, 1990). In addition, dietary protein may also influence magnesium utilization; magnesium balance is negative when protein intake is less than 30 g/day, due to a high mineral excretion in urine and feces (Hunt & Schofield, 1969) whereas higher protein intakes, around 94 g/day, also may increase renal magnesium excretion (Mahalko et al., 1983), since the acid load increases urinary magnesium excretion

In addition to calcium, dietary protein represents a nutrient essential for the synthesis of bone matrix. Protein is a major constituent of bone, so adequate protein intake is critical to maintaining bone health. Several studies have demonstrate that a selective deficiency in dietary proteins, without any associated insufficiency in other macronutrients such as total energy, calcium and vitamin D, causes a rapid and marked alteration in bone mass, microarchitecture and strength (Bonjour, 2005). It is known that proteins can stimulate intestinal calcium absorption and enhance IGF-I. Preclinical studies in adult animals have documented that an isocaloric low protein diet reduces IGF-1, induces negative bone balance with both decreased formation and increased resorption, thereby leading to a

However, the effects of dietary protein intake on bone health are controversial, since it also has been documented that higher protein diets increase urinary calcium, being therefore a risk factor for osteoporosis. Protein intake increases acid production and renal acid excretion due to the releasing of protons during the oxidation of sulfur-containing amino acids such as methionine, cysteine, and cystine. This metabolic acid load might cause the dissolution of bone mineral, which would originate an increased calciuria, resulting in an accelerated loss of bone mineral mass and, thereby, increasing the risk of osteoporotic fracture at long term. The higher content of sulfur-containing amino acids in animal proteins compared with vegetable proteins would lead to increased urinary excretion of calcium and, therefore, to exacerbation of age-related bone loss. Therefore, vegetal proteins might be bone protective whereas animal proteins would be harmful for the acquisition and the maintenance of the bone mineral mass (Sellmeyer et al., 2001). However, the harmful effect of excessive animal protein in skeleton formation seems to be only significant when calcium intake is inadequate

Although adequate calcium intake during childhood and adolescence is mandatory, a high percentage of American and European adolescents fail to meet the recommendations of this

decline in bone strength (Ammann et al., 2000; Bourrin et al., 2000).

**4. Dietary habits of adolescents related to bone health** 

(Abrams et al., 1997).

(Wong et al., 1986).

**3.4 Protein** 

(Heaney, 1998).

mineral (Table 1).

**4.1 Intake of bone-forming nutrients** 

Independent factors can be related to urinary mineral excretion, but total urinary excretion is determined by the metabolic effect of the overall diet. Nutritional intervention studies have shown that a high intake of fruits and vegetables decreases urinary calcium in adults and adolescents (Tylavsky et al., 2004). In turn, fruits and vegetables provide organic salts of potassium and magnesium that have a buffering effect and consequently decrease urinary calcium. This effect has been demonstrated in adults (Whiting et al., 1997) and in adolescents (Jones et al., 2001). On the contrary, low phosphorus and high sodium and caffeine intake are associated with increased urinary calcium (Kiel et al., 1990; Brunette et al., 1992; Weisinger & Bellorin-Font, 1998). With an adequate diet, calcium bioavailability is favored, reaching values around 36.5% for boys and 29.6% for girls, or even higher when diets provide suitable amounts of the mineral (Bailey et al., 2000; Seiquer et al., 2008). Thus, as mentioned above, the dietary habits of adolescents are an important factor to meet calcium requirements and, consequently, needs for pubertal growth.

#### **3.2 Phosphorus**

Together with calcium, phosphorus is essential during adolescence to support the rapid rate of bone accretion that takes place in the adolescent growth spurt. Almost 85% of the body's phosphorus is located in bone as calcium phosphate salt in the form of hydroxyapatite, with a Ca:P molar ratio approximating 1.7:1 and, therefore, this mineral must be present in adequate amounts in the diet to mineralize and maintain the skeleton. Adequate supplies of both minerals are crucial to maximize bone mineral accrual during growth, considered the best strategy to prevent age-related osteoporotic fractures later in life (Weaver, 2000). However, in spite of dietary phosphorus has an important and positive role to play in the development of peak bone mass, it has been suggested that both high and low phosphorus intakes may seriously alter calcium metabolism. On the one hand, excessive amounts of this element may be harmful to bone health and it should be taken into account the low calcium to phosphorus ratio. There is some evidence that increased phosphorus intake depresses ionised calcium leading to an increase in PHT and, hence, a rise in the rate of bone resorption (Calvo et al., 1988). On the other hand, it has been reported that low phosphorus intake is associated with increased urinary calcium (Weisinger & Bellorin-Font, 1998). Other studies have failed to show a deleterious long-term effect of different phosphorus intakes on calcium balance (Heaney & Recker, 1982).

#### **3.3 Magnesium**

Total body magnesium content is approximately 25 g, 60-65% of which is found in bone. Part of this magnesium is in equilibrium in an exchangeable way with the extracellular magnesium, and may serve as a reservoir for maintaining a normal extracellular magnesium concentration; so that at reduced plasma concentration, magnesium can be rapidly released from the bone surface and at increased plasma concentrations magnesium remains bound to the surface of bone (Elin, 1994). However, experimental evidences that dietary magnesium influences the development of peak bone mass are scarce.

Magnesium plays a major role in bone and mineral homeostasis and can also directly affect bone cell function as well as influence hydroxyapatite crystal formation and growth. This element is required for matrix and mineral metabolism in the bone through its indispensable role in metabolism of ATP and as a cofactor for over 300 enzymes (Sojka, 1995). Although the requirement for magnesium retention during childhood and adolescence is uncertain, it is likely to be 5-10 mg/day (Andon et al., 1996) and may increase during the pubertal growth spurt in order to support the more rapid rate of bone formation during this period (Abrams et al., 1997).

The bioavailability of magnesium may be affected by several dietary factors such as phosphorus, calcium, sodium or protein. It is known that high phosphate diets can decrease intestinal magnesium absorption due to the ability of phosphate to bind magnesium (Reinhold et al., 1991), whereas high sodium and calcium intake may result in increased renal magnesium excretion (Kesteloot & Joossens, 1990). In addition, dietary protein may also influence magnesium utilization; magnesium balance is negative when protein intake is less than 30 g/day, due to a high mineral excretion in urine and feces (Hunt & Schofield, 1969) whereas higher protein intakes, around 94 g/day, also may increase renal magnesium excretion (Mahalko et al., 1983), since the acid load increases urinary magnesium excretion (Wong et al., 1986).

#### **3.4 Protein**

418 Osteoporosis

Independent factors can be related to urinary mineral excretion, but total urinary excretion is determined by the metabolic effect of the overall diet. Nutritional intervention studies have shown that a high intake of fruits and vegetables decreases urinary calcium in adults and adolescents (Tylavsky et al., 2004). In turn, fruits and vegetables provide organic salts of potassium and magnesium that have a buffering effect and consequently decrease urinary calcium. This effect has been demonstrated in adults (Whiting et al., 1997) and in adolescents (Jones et al., 2001). On the contrary, low phosphorus and high sodium and caffeine intake are associated with increased urinary calcium (Kiel et al., 1990; Brunette et al., 1992; Weisinger & Bellorin-Font, 1998). With an adequate diet, calcium bioavailability is favored, reaching values around 36.5% for boys and 29.6% for girls, or even higher when diets provide suitable amounts of the mineral (Bailey et al., 2000; Seiquer et al., 2008). Thus, as mentioned above, the dietary habits of adolescents are an important factor to meet

Together with calcium, phosphorus is essential during adolescence to support the rapid rate of bone accretion that takes place in the adolescent growth spurt. Almost 85% of the body's phosphorus is located in bone as calcium phosphate salt in the form of hydroxyapatite, with a Ca:P molar ratio approximating 1.7:1 and, therefore, this mineral must be present in adequate amounts in the diet to mineralize and maintain the skeleton. Adequate supplies of both minerals are crucial to maximize bone mineral accrual during growth, considered the best strategy to prevent age-related osteoporotic fractures later in life (Weaver, 2000). However, in spite of dietary phosphorus has an important and positive role to play in the development of peak bone mass, it has been suggested that both high and low phosphorus intakes may seriously alter calcium metabolism. On the one hand, excessive amounts of this element may be harmful to bone health and it should be taken into account the low calcium to phosphorus ratio. There is some evidence that increased phosphorus intake depresses ionised calcium leading to an increase in PHT and, hence, a rise in the rate of bone resorption (Calvo et al., 1988). On the other hand, it has been reported that low phosphorus intake is associated with increased urinary calcium (Weisinger & Bellorin-Font, 1998). Other studies have failed to show a deleterious long-term effect of different phosphorus intakes on

Total body magnesium content is approximately 25 g, 60-65% of which is found in bone. Part of this magnesium is in equilibrium in an exchangeable way with the extracellular magnesium, and may serve as a reservoir for maintaining a normal extracellular magnesium concentration; so that at reduced plasma concentration, magnesium can be rapidly released from the bone surface and at increased plasma concentrations magnesium remains bound to the surface of bone (Elin, 1994). However, experimental evidences that dietary magnesium

Magnesium plays a major role in bone and mineral homeostasis and can also directly affect bone cell function as well as influence hydroxyapatite crystal formation and growth. This element is required for matrix and mineral metabolism in the bone through its indispensable role in metabolism of ATP and as a cofactor for over 300 enzymes (Sojka, 1995). Although the requirement for magnesium retention during childhood and adolescence is uncertain, it

calcium requirements and, consequently, needs for pubertal growth.

**3.2 Phosphorus** 

**3.3 Magnesium** 

calcium balance (Heaney & Recker, 1982).

influences the development of peak bone mass are scarce.

In addition to calcium, dietary protein represents a nutrient essential for the synthesis of bone matrix. Protein is a major constituent of bone, so adequate protein intake is critical to maintaining bone health. Several studies have demonstrate that a selective deficiency in dietary proteins, without any associated insufficiency in other macronutrients such as total energy, calcium and vitamin D, causes a rapid and marked alteration in bone mass, microarchitecture and strength (Bonjour, 2005). It is known that proteins can stimulate intestinal calcium absorption and enhance IGF-I. Preclinical studies in adult animals have documented that an isocaloric low protein diet reduces IGF-1, induces negative bone balance with both decreased formation and increased resorption, thereby leading to a decline in bone strength (Ammann et al., 2000; Bourrin et al., 2000).

However, the effects of dietary protein intake on bone health are controversial, since it also has been documented that higher protein diets increase urinary calcium, being therefore a risk factor for osteoporosis. Protein intake increases acid production and renal acid excretion due to the releasing of protons during the oxidation of sulfur-containing amino acids such as methionine, cysteine, and cystine. This metabolic acid load might cause the dissolution of bone mineral, which would originate an increased calciuria, resulting in an accelerated loss of bone mineral mass and, thereby, increasing the risk of osteoporotic fracture at long term. The higher content of sulfur-containing amino acids in animal proteins compared with vegetable proteins would lead to increased urinary excretion of calcium and, therefore, to exacerbation of age-related bone loss. Therefore, vegetal proteins might be bone protective whereas animal proteins would be harmful for the acquisition and the maintenance of the bone mineral mass (Sellmeyer et al., 2001). However, the harmful effect of excessive animal protein in skeleton formation seems to be only significant when calcium intake is inadequate (Heaney, 1998).

#### **4. Dietary habits of adolescents related to bone health**

#### **4.1 Intake of bone-forming nutrients**

Although adequate calcium intake during childhood and adolescence is mandatory, a high percentage of American and European adolescents fail to meet the recommendations of this mineral (Table 1).

Osteoporosis, Nutrition and Adolescence 421

intake, therefore, should be taken into account due to its negative association with calcium

Regarding magnesium intake, many adolescents usually do not reach mineral recommendations (Table 1), but, moreover, dietary factors can affect metabolism and excretion of this mineral, as mentioned. Abrams et al. (1997) reported that among boys and girls aged 9-14 years consuming RDA magnesium intakes, a significant number of them were in negative magnesium balance. This negative balance appeared to be related primarily to urinary excretion of magnesium, probably affected by dietary factors, which

On the other hand, as it is usual among population of Western countries, the protein intake among adolescents is above the recommendations, with special contribution of animal proteins (García-Closas et al., 2006). High protein intake may be related to increased urinary calcium and magnesium excretion but, moreover, the low consumption of fruits and vegetables among adolescents decreases the buffering effect above-mentioned, increasing the negative effects of protein on mineral utilization and, therefore, on bone health. Several authors have shown the link between fruits and vegetables and peak bone mass acquisition in boys and girls (Tylavsky et al., 2004). Whiting et al. (2004) confirm that girls consuming adequate amounts of this food group show a greater bone mineral trajectory than those consuming fewer than 5 servings/day. In the same way, subjects with an intake of 10 servings per day of fruits and vegetables presented a higher total body bone mineral content than did those consuming 1 serving/day (Vatanparast et al., 2005). Moreover, fruit and vegetables provide vitamin K, which is an essential cofactor for osteoblastic activity (Feskanich et al., 1999) and natural antioxidants like phytestrogens, which seem to play a role in bone metabolism. Phytestrogens, like estrogens, stimulate human osteoblasts and modulate osteoclast activity, thus preventing bone resorption (Chiechi & Micheli, 2005). Therefore, a diminution of fruits and vegetable consumption, frequently observed in

It is well known that the dietary habits of adolescents have changed in recent decades and that there is a tendency to a higher consumption of soft drinks, snacks, bakery products, and fast foods, which, particularly, has increased from 2% of total energy in the late 1970s to 10% of total energy in the mid-1990s (Guthrie et al., 2002; Libuda et al., 2008). As it has been mentioned, the consumption of these kinds of foods may be associated to lower intake of fruits and dairy products and greater intake of phosphorus due to high phosphoruscontaining additives, which implies negative effects on calcium utilization. Together with phosphate salts, processed foods are also rich in sodium salts-containing additives (He et al., 2008) which, certainly, increases sodium intake. It is known that average sodium intakes in children and adolescents well exceed nutritional needs, overcoming even 3.5 g/day (Falkner & Michel, 1997). Since the elevated consumption of sodium also damages bone by increasing the urinary calcium excretion and decreasing calcium absorption (Brunette et al., 1992),

The Maillard reaction, also termed nonenzymatic browning reaction, is usually developed in processed and fast foods, since it commonly occurs during the thermal processing of foods rich in proteins and sugars or fats, producing colored compounds that contribute to the aroma, color, and flavor of cooked foods. Controlled browning is therefore pursued through

metabolism and, in addition, with intestinal magnesium absorption.

adolescents, avoid the protector effect of these types of foods on bone.

reducing sodium intake should be seriously considered among adolescents.

**4.2 Intake of Maillard reaction products** 

might affect to mineral homeostasis and bone formation.


References: 1Institute of Medicine (1997); 2Institute of Medicine (2005); 3Lambert et al. (2004); 4Elmadfa et al. (2005); 5Rockett et al. (2001); 6Ervin et al. (2004).

Table 1. Recommendations and intakes of calcium, phosphorus, magnesium and protein among adolescents.

According to Grunbaum et al. (2004), only 11% of female and 23% of male American adolescents drink three or more glasses of milk daily, and only 19% of girls and 52% of boys meet calcium recommendations (Damore et al., 2007). Among Spanish population, 13–14% of boys and 29–40% of girls have inadequate calcium intakes (Serra Majem et al., 2006). In conclusion, calcium content in the adolescents diet frequently fails to meet the body's needs during the growth spurt (Rocket et al., 2001; Lambert et al., 2004; Elmadfa et al., 2005), which, as it has been mentioned before, might have a deleterious effect on the acquisition of the peak bone mass and, therefore, an important repercussion on osteoporosis in adult age.

In recent years the contribution of milk to total beverage intake has significantly decreased among boys and girls because milk has been replaced by carbonated beverages (Vatanparast et al., 2006). Since 1965, milk consumption has decreased by 74%, and consumption of noncitrus juices and carbonated beverages has increased by 118% (Schettler & Gustafson, 2004). Therefore, soft drinks negatively affect bone mineralization because they are associated with lower milk consumption. But, moreover, a further negative effect concerns their phosphorus and caffeine content; the phosphoric acid content of soft drinks may limit calcium absorption and contribute to bone loss increasing bone resorption and fracture risk (Wyshak & Frisch, 1994; Wyshak, 2000), whereas caffeine has been associated with reduced bone mineral density and increased fracture risk (Kiel et al., 1990). Both effects have been demonstrated in children who frequently consume cola drinks (Heaney et al., 2000). However, several studies have reported that the negative impact of soft drink on bone mass is observed in adolescent girls but not in boys (Whiting et al., 2001; McGartland et al., 2003), which implies that bone accrual mechanisms in adolescent girls have more vulnerable conditions.

As it can be observed in Table 1, a certain proportion of American and European adolescents also fail to meet phosphorus recommendations. However, the overall phosphorus intake has increased during the last years as a consequence of the changing dietary habits of adolescents, on the one hand, the greater carbonated beverages consumption and, on the other hand, the increased intake of processed and fast foods, very frequently consumed among this age group. Manufactured and fast foods have a high content of phosphoruscontaining additives, used to preserve moisture or color, to emulsify ingredients, enhance flavor, and to stabilize foods. According to Coates et al. (2005), these additives are the most rapidly growing source of dietary phosphorus over the last two decades and may contribute to one-third of overall phosphorus intake in the general population. The high phosphorus

 DRIs1-2 Europeans2-3 Americans4-5 Calcium 1300 mg/day 596-1400 mg/day 793-1081 mg/day Phosphorus 1250 mg/day 949-1848 mg/day 1093-1533 mg/day Magnesium 240-410 mg/day 185-360 mg/day 216-284 mg/day Protein 34-52 g/day 53-127 g/day 78 g/day

References: 1Institute of Medicine (1997); 2Institute of Medicine (2005); 3Lambert et al. (2004); 4Elmadfa et

According to Grunbaum et al. (2004), only 11% of female and 23% of male American adolescents drink three or more glasses of milk daily, and only 19% of girls and 52% of boys meet calcium recommendations (Damore et al., 2007). Among Spanish population, 13–14% of boys and 29–40% of girls have inadequate calcium intakes (Serra Majem et al., 2006). In conclusion, calcium content in the adolescents diet frequently fails to meet the body's needs during the growth spurt (Rocket et al., 2001; Lambert et al., 2004; Elmadfa et al., 2005), which, as it has been mentioned before, might have a deleterious effect on the acquisition of the peak bone mass and, therefore, an important repercussion on osteoporosis in adult age. In recent years the contribution of milk to total beverage intake has significantly decreased among boys and girls because milk has been replaced by carbonated beverages (Vatanparast et al., 2006). Since 1965, milk consumption has decreased by 74%, and consumption of noncitrus juices and carbonated beverages has increased by 118% (Schettler & Gustafson, 2004). Therefore, soft drinks negatively affect bone mineralization because they are associated with lower milk consumption. But, moreover, a further negative effect concerns their phosphorus and caffeine content; the phosphoric acid content of soft drinks may limit calcium absorption and contribute to bone loss increasing bone resorption and fracture risk (Wyshak & Frisch, 1994; Wyshak, 2000), whereas caffeine has been associated with reduced bone mineral density and increased fracture risk (Kiel et al., 1990). Both effects have been demonstrated in children who frequently consume cola drinks (Heaney et al., 2000). However, several studies have reported that the negative impact of soft drink on bone mass is observed in adolescent girls but not in boys (Whiting et al., 2001; McGartland et al., 2003), which implies that bone accrual mechanisms in adolescent girls have more vulnerable

As it can be observed in Table 1, a certain proportion of American and European adolescents also fail to meet phosphorus recommendations. However, the overall phosphorus intake has increased during the last years as a consequence of the changing dietary habits of adolescents, on the one hand, the greater carbonated beverages consumption and, on the other hand, the increased intake of processed and fast foods, very frequently consumed among this age group. Manufactured and fast foods have a high content of phosphoruscontaining additives, used to preserve moisture or color, to emulsify ingredients, enhance flavor, and to stabilize foods. According to Coates et al. (2005), these additives are the most rapidly growing source of dietary phosphorus over the last two decades and may contribute to one-third of overall phosphorus intake in the general population. The high phosphorus

Table 1. Recommendations and intakes of calcium, phosphorus, magnesium and protein

Recommendations Intakes

al. (2005); 5Rockett et al. (2001); 6Ervin et al. (2004).

among adolescents.

conditions.

intake, therefore, should be taken into account due to its negative association with calcium metabolism and, in addition, with intestinal magnesium absorption.

Regarding magnesium intake, many adolescents usually do not reach mineral recommendations (Table 1), but, moreover, dietary factors can affect metabolism and excretion of this mineral, as mentioned. Abrams et al. (1997) reported that among boys and girls aged 9-14 years consuming RDA magnesium intakes, a significant number of them were in negative magnesium balance. This negative balance appeared to be related primarily to urinary excretion of magnesium, probably affected by dietary factors, which might affect to mineral homeostasis and bone formation.

On the other hand, as it is usual among population of Western countries, the protein intake among adolescents is above the recommendations, with special contribution of animal proteins (García-Closas et al., 2006). High protein intake may be related to increased urinary calcium and magnesium excretion but, moreover, the low consumption of fruits and vegetables among adolescents decreases the buffering effect above-mentioned, increasing the negative effects of protein on mineral utilization and, therefore, on bone health. Several authors have shown the link between fruits and vegetables and peak bone mass acquisition in boys and girls (Tylavsky et al., 2004). Whiting et al. (2004) confirm that girls consuming adequate amounts of this food group show a greater bone mineral trajectory than those consuming fewer than 5 servings/day. In the same way, subjects with an intake of 10 servings per day of fruits and vegetables presented a higher total body bone mineral content than did those consuming 1 serving/day (Vatanparast et al., 2005). Moreover, fruit and vegetables provide vitamin K, which is an essential cofactor for osteoblastic activity (Feskanich et al., 1999) and natural antioxidants like phytestrogens, which seem to play a role in bone metabolism. Phytestrogens, like estrogens, stimulate human osteoblasts and modulate osteoclast activity, thus preventing bone resorption (Chiechi & Micheli, 2005). Therefore, a diminution of fruits and vegetable consumption, frequently observed in adolescents, avoid the protector effect of these types of foods on bone.

It is well known that the dietary habits of adolescents have changed in recent decades and that there is a tendency to a higher consumption of soft drinks, snacks, bakery products, and fast foods, which, particularly, has increased from 2% of total energy in the late 1970s to 10% of total energy in the mid-1990s (Guthrie et al., 2002; Libuda et al., 2008). As it has been mentioned, the consumption of these kinds of foods may be associated to lower intake of fruits and dairy products and greater intake of phosphorus due to high phosphoruscontaining additives, which implies negative effects on calcium utilization. Together with phosphate salts, processed foods are also rich in sodium salts-containing additives (He et al., 2008) which, certainly, increases sodium intake. It is known that average sodium intakes in children and adolescents well exceed nutritional needs, overcoming even 3.5 g/day (Falkner & Michel, 1997). Since the elevated consumption of sodium also damages bone by increasing the urinary calcium excretion and decreasing calcium absorption (Brunette et al., 1992), reducing sodium intake should be seriously considered among adolescents.

#### **4.2 Intake of Maillard reaction products**

The Maillard reaction, also termed nonenzymatic browning reaction, is usually developed in processed and fast foods, since it commonly occurs during the thermal processing of foods rich in proteins and sugars or fats, producing colored compounds that contribute to the aroma, color, and flavor of cooked foods. Controlled browning is therefore pursued through

Osteoporosis, Nutrition and Adolescence 423

an increasing proportion of total energy intake is obtained from fast food and snacks, as mentioned. In these conditions, the effects observed in our studies could be aggravated. In view of the current dietary habits of adolescents, and the well-established relationship between protein and mineral deficiency with bone formation during the growth spurt, and, consequently, with osteoporosis in the adult period, it seems of special interest to take into

The Mediterranean diet has been proposed as one of the healthiest dietary models and its health benefits have been demonstrated in a large number of studies. Moreover, the Mediterranean diet incorporates practically all the factors that may positively influence bone health. However, current dietary patterns are considerably far from the characteristics of the Mediterranean diet, particularly among adolescents due to the increased habit of eating

This diet is characterized by moderate levels of animal protein, abundant fresh fruits and vegetables, cereals and fish, and little saturated fat. Olive oil is used as the main dietary fat. Our research group has also studied the effects of a varied diet based on Mediterranean patterns on the utilization and availability of nutrients essential for bone formation, such as protein and minerals, among adolescents. A summary of the results obtained in our studies, comparing with those obtained when the subjects are under their own diets, is shown in

Factor Absorption Retention Digestibility Bioavailability References Calcium ↑↑ ↑↑ ↑ ↑↑ Seiquer et al., 2008 Phosphorus ↑ ↑↑ = ↑↑ unpublished data Protein = ↑↑ = ↑↑ unpublished data Table 3. Effects of a varied diet based on Mediterranean patterns on protein and mineral availability in adolescents. =: non effect; ↑↑: effect statistically significant; ↑: effect non

It has been shown that dietary calcium utilization during adolescence may be greatly improved by a diet based on the Mediterranean patterns (Seiquer et al., 2008). Compared with the consumption of their habitual diets, adolescents significantly increased the absorption and retention of the dietary calcium, and, as a consequence, calcium utilization efficiency was significantly improved when subjects consumed the Mediterranean diet. In a similar way, after this same diet consumption, adolescents significantly increased phosphorus and protein retention and bioavailability (unpublished data). Therefore, a diet with sufficient calcium, phosphorus and protein and based on the Mediterranean diet patterns is advantageous for bone formation during periods of intense growth, such as the adolescence, when factors affecting bone health will be determinants for the development of

Together with eating behaviors, weight-bearing physical activity is a modifiable pattern that could be of potential importance in ensuring that the maximum genetic potential for bone

account the possible long-term effects of dietary MRP on bone health.

away from home and the higher consumption of snacks and fast foods.

**4.3 The Mediterranean diet** 

Table 3.

significant statistically.

osteoporosis later in life.

**4.4 Lifestyle: Physical activity and others** 

many food technologic and domestic processes such as roasting, baking, frying and even reheating, aimed at promoting consumer acceptance (Ames, 1998). Thus, the Maillard reaction products (MRP) are widely consumed as a part of the human diet, especially among adolescents, according to their dietary habits and the high content of snacks and fast foods in their diets (Delgado-Andrade et al., 2007). In addition to their sensory properties, MRP is associated with certain positive biological effects, such as antioxidant activity (Seiquer et al., 2008), but at the same time with negative actions, including degradation of nutritional protein quality (Alkanhal et al., 2001) and modifications in vitamins (O'Brien and Morrissey, 1989) or mineral availability (Navarro, 2003).

Our research group has realized several studies with the objective of comparing the effects of diets with different MRP contents on the utilization of dietary protein and on mineral availability in adolescents. In a 2-period crossover trial, a group of healthy male adolescents aged 11-14 years consumed two types of diets, both balanced and varied and with the same nutrient composition, but with different content in MRP. The first one was a MRP-poor diet, free, as far as possible, of foods in which the Maillard reaction develops during cooking practices or foods that naturally contain these products whereas the second one was a MRPrich diet, high, as far as possible, in processed foods with an evident development of browning. The utilization of the different nutrients by the subjects under consumption of the different diets was measured. The effects of the high consumption of MRP on nutrient concerning bone formation are summarized in Table 2.


Table 2. Effects of a MRP-rich diet on protein and mineral availability compared with a MRP-poor diet in adolescents. =: non effect; ↓↓: effect statistically significant; ↓: effect non significant statistically.

Absorption and digestibility of nitrogen were significantly lower when subjects consumed the MRP-rich diet than the MRP-poor diet, whereas negative effects on the protein balance did not reach statistical significance. It was deduced that the consumption of a diet rich in browning products negatively affects protein digestibility (Seiquer et al., 2006). Regarding minerals, it is known that MRP may behave as anionic polymers that chelate metal cations, affecting mineral solubility at intestinal conditions and mineral availability (Navarro, 2003). In our assays we observed that high MRP intake has no apparent effects on dietary calcium bioavailability in adolescent, although possible metabolic changes cannot be discounted, as a lower deoxypyridinoline urinary excretion was observed with MRP-rich diet consumption, which may be related to decreased bone turnover at this age (Mesías et al., 2009). On the contrary, this diet had clear negative effects on dietary phosphorus absorption, tending to decrease the phosphorus balance (Delgado-Andrade et al., 2011). In a similar way, MRP-rich diet did not affect zinc but negatively affected copper bioavailability (unpublished data). It should be borne in mind that the food habits of adolescents are changing toward monotonous and unbalanced diets with a considerable MRP content, and

many food technologic and domestic processes such as roasting, baking, frying and even reheating, aimed at promoting consumer acceptance (Ames, 1998). Thus, the Maillard reaction products (MRP) are widely consumed as a part of the human diet, especially among adolescents, according to their dietary habits and the high content of snacks and fast foods in their diets (Delgado-Andrade et al., 2007). In addition to their sensory properties, MRP is associated with certain positive biological effects, such as antioxidant activity (Seiquer et al., 2008), but at the same time with negative actions, including degradation of nutritional protein quality (Alkanhal et al., 2001) and modifications in vitamins (O'Brien and Morrissey,

Our research group has realized several studies with the objective of comparing the effects of diets with different MRP contents on the utilization of dietary protein and on mineral availability in adolescents. In a 2-period crossover trial, a group of healthy male adolescents aged 11-14 years consumed two types of diets, both balanced and varied and with the same nutrient composition, but with different content in MRP. The first one was a MRP-poor diet, free, as far as possible, of foods in which the Maillard reaction develops during cooking practices or foods that naturally contain these products whereas the second one was a MRPrich diet, high, as far as possible, in processed foods with an evident development of browning. The utilization of the different nutrients by the subjects under consumption of the different diets was measured. The effects of the high consumption of MRP on nutrient

Factor Absorption Retention Digestibility Bioavailability References Calcium = = = = Mesías et al., 2009 Phosphorus ↓↓ <sup>↓</sup> ↓↓ <sup>↓</sup> Delgado-Andrade

Protein ↓↓ ↓ ↓↓ ↓ Seiquer et al., 2006 Table 2. Effects of a MRP-rich diet on protein and mineral availability compared with a MRP-poor diet in adolescents. =: non effect; ↓↓: effect statistically significant; ↓: effect non

Absorption and digestibility of nitrogen were significantly lower when subjects consumed the MRP-rich diet than the MRP-poor diet, whereas negative effects on the protein balance did not reach statistical significance. It was deduced that the consumption of a diet rich in browning products negatively affects protein digestibility (Seiquer et al., 2006). Regarding minerals, it is known that MRP may behave as anionic polymers that chelate metal cations, affecting mineral solubility at intestinal conditions and mineral availability (Navarro, 2003). In our assays we observed that high MRP intake has no apparent effects on dietary calcium bioavailability in adolescent, although possible metabolic changes cannot be discounted, as a lower deoxypyridinoline urinary excretion was observed with MRP-rich diet consumption, which may be related to decreased bone turnover at this age (Mesías et al., 2009). On the contrary, this diet had clear negative effects on dietary phosphorus absorption, tending to decrease the phosphorus balance (Delgado-Andrade et al., 2011). In a similar way, MRP-rich diet did not affect zinc but negatively affected copper bioavailability (unpublished data). It should be borne in mind that the food habits of adolescents are changing toward monotonous and unbalanced diets with a considerable MRP content, and

et al., 2011

1989) or mineral availability (Navarro, 2003).

concerning bone formation are summarized in Table 2.

significant statistically.

an increasing proportion of total energy intake is obtained from fast food and snacks, as mentioned. In these conditions, the effects observed in our studies could be aggravated. In view of the current dietary habits of adolescents, and the well-established relationship between protein and mineral deficiency with bone formation during the growth spurt, and, consequently, with osteoporosis in the adult period, it seems of special interest to take into account the possible long-term effects of dietary MRP on bone health.

### **4.3 The Mediterranean diet**

The Mediterranean diet has been proposed as one of the healthiest dietary models and its health benefits have been demonstrated in a large number of studies. Moreover, the Mediterranean diet incorporates practically all the factors that may positively influence bone health. However, current dietary patterns are considerably far from the characteristics of the Mediterranean diet, particularly among adolescents due to the increased habit of eating away from home and the higher consumption of snacks and fast foods.

This diet is characterized by moderate levels of animal protein, abundant fresh fruits and vegetables, cereals and fish, and little saturated fat. Olive oil is used as the main dietary fat.

Our research group has also studied the effects of a varied diet based on Mediterranean patterns on the utilization and availability of nutrients essential for bone formation, such as protein and minerals, among adolescents. A summary of the results obtained in our studies, comparing with those obtained when the subjects are under their own diets, is shown in Table 3.


Table 3. Effects of a varied diet based on Mediterranean patterns on protein and mineral availability in adolescents. =: non effect; ↑↑: effect statistically significant; ↑: effect non significant statistically.

It has been shown that dietary calcium utilization during adolescence may be greatly improved by a diet based on the Mediterranean patterns (Seiquer et al., 2008). Compared with the consumption of their habitual diets, adolescents significantly increased the absorption and retention of the dietary calcium, and, as a consequence, calcium utilization efficiency was significantly improved when subjects consumed the Mediterranean diet. In a similar way, after this same diet consumption, adolescents significantly increased phosphorus and protein retention and bioavailability (unpublished data). Therefore, a diet with sufficient calcium, phosphorus and protein and based on the Mediterranean diet patterns is advantageous for bone formation during periods of intense growth, such as the adolescence, when factors affecting bone health will be determinants for the development of osteoporosis later in life.

### **4.4 Lifestyle: Physical activity and others**

Together with eating behaviors, weight-bearing physical activity is a modifiable pattern that could be of potential importance in ensuring that the maximum genetic potential for bone

Osteoporosis, Nutrition and Adolescence 425

prevention of osteoporosis due, on the one hand, to the special dietary habits of adolescents, and on the other hand, to the great development and acquisition of the skeletal mass during this stage of life. Not only meeting adequate intakes of minerals and protein is required during adolescence, but, moreover, the composition of the whole diet will be determinant for consecution of the maximum genetic potential for growth and bone development. Diet, therefore, must contribute sufficient and appropriate nutrients to allow, together with healthy lifestyle habits including physical activity, the maximum bone mass development genetically programmed, which will be the best strategy in the prevention of osteoporosis. Due to the progressive incidence of osteoporosis in Western countries, intervention policies for this important and vulnerable sector of the population should be aimed to promote the consumption of adjusted and balanced diets among adolescents, since the adequate utilization of nutrients, together with exercise, will benefit their present and future health.

Abrams, S.A. & Stuff J.E. (1994). Calcium metabolism in girls: Current dietary intakes lead to

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**6. References** 

mass is achieved (Matkovic et al., 1990). This kind of activity could be defined as physical activity in which gravity exerts force on bones or any activity done standing up (e.g., walking or jumping), not including activities that involve only resistance or that are done sitting down (e.g., bicycling or swimming). In general, studies support the view that moderate weightbearing activity has a more positive effect on bone mass than do non-weight-bearing activities, which impose minimal physical strain on bone (Cromer & Harel, 2000). Several studies have shown that both exercise and calcium interventions have an overall beneficial impact on bone acquisition during childhood and adolescence (Stear et al., 2003). According to Anderson (2001), physical activities during the critical growing years make important contributions to the accrual of bone mass, perhaps independently of calcium intake. In this way, Nickols-Richardson et al. (1999) reported that a relatively low calcium intake may be compensated by regular physical activities in the accrual of peak bone mass.

The current lifestyle habits of many adolescents, based mainly in inadequate dietary intake and insufficient physical activity, have resulted in an increased level of overweight and obesity particularly in Western countries. Overweight among children has been related with an increased incidence of fractures (Greer & Krebs, 2006), which is probably explained by the fact that calcium intake is negatively correlated with body fat percentage and body mass index during childhood (Carruth and Skinner, 2001; Skinner et al., 2003). The inverse relationship between calcium intake and fatty tissue gain has been recently confirmed by Lederer et al. (2009) in male adolescents. It has been shown that overweight children have a lower bone mass and bone area relative to their body weight than do children with a healthy body weight, which may predispose them to fractures (Goulding et al., 2000). Trends in diet and exercise coupled with an increasingly aging population indicate that the incidence of osteoporosis will triple by the year of 2040 (Schettler & Gustafson, 2004), with the result that both diet and physical activity are considered to be important and complementary factors to prevent this disease.

Other fact that should be taken into account among adolescents in order to prevent osteoporosis is tobacco and alcohol consumption. It has been reported that the prevalence of concurrent alcohol and tobacco use among European and American adolescents comes to 20- 25% (Anthony and Echeagaray-Wagner, 2000; Schmid et al., 2007). Clinical findings indicate that there is an inverse relationship between bone mineral density and smoking, due to its negative effect on calcium absorption and estrogen metabolism (Bailey et al., 2000; Valimaki et al., 1994). Moreover, heavy alcohol consumption hinders calcium absorption and damages bone cells (Bennet, 1995). On the other hand anorexia nervosa, a dangerous disease in adolescent girls at the time of the initial peak bone mass formation, is known to be associated with low bone mass content, even in short duration cases, effects that may persist even after recovery (Misra et al., 2004; Winston et al., 2008). It has been reported that adult women with anorexia nervosa initiated during adolescence have lower bone mass than those with adult onset anorexia nervosa (Biller et al., 1989). This disease includes alterations of the GH-IGF-1 axis and, moreover, both hypogonadism and the cortisol excess associated to it may contribute to the development of osteopenia and osteoporosis (Misra et al., 2005a; 2005b).

#### **5. Conclusion**

Prevention of osteoporosis in adulthood begins in childhood. Therefore, in the fight against osteoporosis, modifiable factors such as dietary and lifestyle patterns should be taken into account from the beginning of life. Adolescence is a phase of particular interest for the prevention of osteoporosis due, on the one hand, to the special dietary habits of adolescents, and on the other hand, to the great development and acquisition of the skeletal mass during this stage of life. Not only meeting adequate intakes of minerals and protein is required during adolescence, but, moreover, the composition of the whole diet will be determinant for consecution of the maximum genetic potential for growth and bone development. Diet, therefore, must contribute sufficient and appropriate nutrients to allow, together with healthy lifestyle habits including physical activity, the maximum bone mass development genetically programmed, which will be the best strategy in the prevention of osteoporosis. Due to the progressive incidence of osteoporosis in Western countries, intervention policies for this important and vulnerable sector of the population should be aimed to promote the consumption of adjusted and balanced diets among adolescents, since the adequate utilization of nutrients, together with exercise, will benefit their present and future health.

### **6. References**

424 Osteoporosis

mass is achieved (Matkovic et al., 1990). This kind of activity could be defined as physical activity in which gravity exerts force on bones or any activity done standing up (e.g., walking or jumping), not including activities that involve only resistance or that are done sitting down (e.g., bicycling or swimming). In general, studies support the view that moderate weightbearing activity has a more positive effect on bone mass than do non-weight-bearing activities, which impose minimal physical strain on bone (Cromer & Harel, 2000). Several studies have shown that both exercise and calcium interventions have an overall beneficial impact on bone acquisition during childhood and adolescence (Stear et al., 2003). According to Anderson (2001), physical activities during the critical growing years make important contributions to the accrual of bone mass, perhaps independently of calcium intake. In this way, Nickols-Richardson et al. (1999) reported that a relatively low calcium intake may be compensated by

The current lifestyle habits of many adolescents, based mainly in inadequate dietary intake and insufficient physical activity, have resulted in an increased level of overweight and obesity particularly in Western countries. Overweight among children has been related with an increased incidence of fractures (Greer & Krebs, 2006), which is probably explained by the fact that calcium intake is negatively correlated with body fat percentage and body mass index during childhood (Carruth and Skinner, 2001; Skinner et al., 2003). The inverse relationship between calcium intake and fatty tissue gain has been recently confirmed by Lederer et al. (2009) in male adolescents. It has been shown that overweight children have a lower bone mass and bone area relative to their body weight than do children with a healthy body weight, which may predispose them to fractures (Goulding et al., 2000). Trends in diet and exercise coupled with an increasingly aging population indicate that the incidence of osteoporosis will triple by the year of 2040 (Schettler & Gustafson, 2004), with the result that both diet and physical activity are considered to be important and complementary factors to

Other fact that should be taken into account among adolescents in order to prevent osteoporosis is tobacco and alcohol consumption. It has been reported that the prevalence of concurrent alcohol and tobacco use among European and American adolescents comes to 20- 25% (Anthony and Echeagaray-Wagner, 2000; Schmid et al., 2007). Clinical findings indicate that there is an inverse relationship between bone mineral density and smoking, due to its negative effect on calcium absorption and estrogen metabolism (Bailey et al., 2000; Valimaki et al., 1994). Moreover, heavy alcohol consumption hinders calcium absorption and damages bone cells (Bennet, 1995). On the other hand anorexia nervosa, a dangerous disease in adolescent girls at the time of the initial peak bone mass formation, is known to be associated with low bone mass content, even in short duration cases, effects that may persist even after recovery (Misra et al., 2004; Winston et al., 2008). It has been reported that adult women with anorexia nervosa initiated during adolescence have lower bone mass than those with adult onset anorexia nervosa (Biller et al., 1989). This disease includes alterations of the GH-IGF-1 axis and, moreover, both hypogonadism and the cortisol excess associated to it may contribute

Prevention of osteoporosis in adulthood begins in childhood. Therefore, in the fight against osteoporosis, modifiable factors such as dietary and lifestyle patterns should be taken into account from the beginning of life. Adolescence is a phase of particular interest for the

to the development of osteopenia and osteoporosis (Misra et al., 2005a; 2005b).

regular physical activities in the accrual of peak bone mass.

prevent this disease.

**5. Conclusion** 


Osteoporosis, Nutrition and Adolescence 427

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**22** 

 *Greece* 

Yannis Dionyssiotis

**Rehabilitation in Osteoporosis** 

*University of Athens, Laboratory for Research of the Musculoskeletal System* 

Osteoporosis is a metabolic bone disease usually occurring with increasing age and is defined as a skeletal disorder characterized by reduced bone mineral density and strength. Osteoporosis is characterized as the "silent disease" because is painless until the first occurrence of a fracture and thus remain unnoticed. The first symptom of osteoporosis is the bone fracture with a preference of distal radius or proximal humerus fracture, vertebral collapse and femoral neck fractures beyond the 50th, 60th and 70-75th year respectively (Pfeifer et al., 2005). This phase of the disease is characterized by acute pain. Moreover, vertebral fractures cause acute musculoskeletal pain in the back in the acute phase of the fracture and chronic pain resulting from the associated skeletal deformity, joint incongruity, and tension on muscles and tendons, leading to disability. In generally osteoporosis represents one of the main causes of back pain in postmenopausal women because of common clinical or subclinical vertebral fractures causing back pain. On the other hand, in the same population, no osteoporotic vertebral deformities are seen as often as osteoporotic ones, and back pain was found to be mostly due to degenerative disorders of the spine in

Osteoporosis is a disease that predominantly affects postmenopausal women and older people although in individual cases could concern people in younger age i.e. in the juvenile form, mainly men with idiopathic osteoporosis, pregnancy-associated osteoporosis, the form of secondary osteoporosis in young steroid-treated patients with chronic inflammatory diseases etc. The goals of rehabilitation are changing depending on the stage of disease. In the acute phase of a vertebral body collapse the therapy is to the relief pain by a limited period of bed rest, local and systemic analgesia, bracing, physical therapy, education with proper exercises and instructions according to daily living activities in order to mobilise the patient with safety. Rehabilitation after surgical stabilization of a hip fracture is crucial in order to optimize post-injury mobility and the functional recovery of the patient, restore prefracture function and avoid long-term institutionalization. Most evidence-based guidelines suggesting possible treatments and rehabilitation pathways for hip fracture patients, agree that it would be best if they underwent multidisciplinary rehabilitation (Dionyssiotis et al., 2008a). In prevention and management of osteoporosis modern rehabilitation medicine should not only focus on bone ignoring muscular strength and balance. These elements are directly related to the disease offering protection against predisposing a person to an increased risk of falls and fall-related fracture. An extensive research in the area of pharmacological

**1. Introduction** 

women above 60 years (Dionyssiotis, 2010b).

*Physical and Social Rehabilitation Center Amyntæo* 


## **Rehabilitation in Osteoporosis**

### Yannis Dionyssiotis

*Physical and Social Rehabilitation Center Amyntæo University of Athens, Laboratory for Research of the Musculoskeletal System Greece* 

#### **1. Introduction**

434 Osteoporosis

Van der sluis, I.M. & Muinck Keizer-Schrama, S.M.P.F. (2001). Osteoporosis in childhood:

*Metabolism*, Vol.14, No.7, (July-August 2004), pp. 817-832, ISSN 0334-018X. Vatanparast, H.; Baxter-Jones, A.; Faulkner, R.A.; Bailey, D.A. & Whiting, S.J. (2005).

Weaver, C.M. (2000). The growing years and prevention of osteoporosis in later life.

Weisinger, J.R. & Bellorin-Font, E. (1998). Magnesium and phosphorus. *Lancet,* Vol.352,

Whiting, S.J.; Anderson, D.J. & Weeks, S.J. (1997). Calciuric effects of protein and potassium

Whiting, S.J.; Healey, A.; Psiuk, S.; Mirwald, R.; Kowalski, K and Bailey, D.A. (2001).

Whiting, S.J.; Vatanparast, H.; Baxter-Jones, A.; Faulkner, R.A.; Mirwald, R. & Bailey, D.A.

Wyshak, G. & Frisch, R.E. (1994). Carbonated beverages, dietary calcium, the dietary

*Adolescent Health,* Vol.15, No.3, (May 1994), pp. 210–215, ISSN 1054-139X. Wyshak, G. (2000). Teenage Girls, Carbonated Beverage Consumption, and Bone Fractures.

Young, N.; Formica, C.; Szumukler, G. & Seeman, E. (1994). Bone density at weight-bearing

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ISSN 1072-4710.

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bone density in children in health and disease. *Journal of Pediatric Endocrinology and* 

Possitive effects of vegetable and fruit consumption and calcium intake on bone mineral accrual in boys during growth from childhood to adolescence: The University of Saskatchewan Pediatric Bone Mineral Accrual Study. *American Journal of Clinical Nutrition,* Vol.82, No.3, (September 2005), pp. 700–706, ISSN 0002-9165. Vatanparast, H.; Lo, E.; Henrt, C.J. & Whiting, S.J. (2006). A negative trend in calcium was

accompanied by a substitution of milk by noncarbonated soft drinks in Canadian female students. *Nutrition Research,* Vol.26, No.7, (July 2006), pp. 325–329, ISSN

*Proceeding of the Nutrition Society,* Vol.59, No.2, (February 2007), pp. 303–306, ISSN

bicarbonate but not of sodium chloride or phosphate can be detected acutely in adult women and men. *American Journal of Clinical Nutrition,* Vol.65, No.5, (May

Relationship between carbonated and other low nutrient dense beverages and bone mineral content of adolescents. *Nutrition Research*, Vol.21, No.8, (August 2001), pp.

(2004). Factors that affect bone mineral accrual in the adolescent growth spurt. *Journal of Nutrition, Vol.*134, No.3, (March 2004), pp. 699-700, ISSN 0022-3166. Winston, A.P.; Alwazeer, A.E. & Bankart, M.J. (2008). Screening for osteoporosis in anorexia

nervosa: prevalence and predictors of reduced bone mineral density. *Internatioal Journal of Eating Disorders*, Vol.41, No.3, (April 2008), pp. 284-287, ISSN 1098-108X. Wong, N.L.; Quamme, G.A. & Dirks, J.H. (1986). Effects of acid-base disturbances on renal

handling of magnesium in the dog. *Clinical Science*, Vol.70, No.3, (March 1986), pp.

calcium/phosphorus ratio, and bone fractures in girls and boys. *Journal of* 

*Archives of Pediatrics and Adolescent Medicine*, Vol.154, No.6, (June 2000), pp. 610-613,

and nonweight-bearing sites in ballet dancers: the effects of exercise, hypogonadism and body weight. *Journal of Clinical Endocrinology and Metabolism,*  Osteoporosis is a metabolic bone disease usually occurring with increasing age and is defined as a skeletal disorder characterized by reduced bone mineral density and strength. Osteoporosis is characterized as the "silent disease" because is painless until the first occurrence of a fracture and thus remain unnoticed. The first symptom of osteoporosis is the bone fracture with a preference of distal radius or proximal humerus fracture, vertebral collapse and femoral neck fractures beyond the 50th, 60th and 70-75th year respectively (Pfeifer et al., 2005). This phase of the disease is characterized by acute pain. Moreover, vertebral fractures cause acute musculoskeletal pain in the back in the acute phase of the fracture and chronic pain resulting from the associated skeletal deformity, joint incongruity, and tension on muscles and tendons, leading to disability. In generally osteoporosis represents one of the main causes of back pain in postmenopausal women because of common clinical or subclinical vertebral fractures causing back pain. On the other hand, in the same population, no osteoporotic vertebral deformities are seen as often as osteoporotic ones, and back pain was found to be mostly due to degenerative disorders of the spine in women above 60 years (Dionyssiotis, 2010b).

Osteoporosis is a disease that predominantly affects postmenopausal women and older people although in individual cases could concern people in younger age i.e. in the juvenile form, mainly men with idiopathic osteoporosis, pregnancy-associated osteoporosis, the form of secondary osteoporosis in young steroid-treated patients with chronic inflammatory diseases etc. The goals of rehabilitation are changing depending on the stage of disease. In the acute phase of a vertebral body collapse the therapy is to the relief pain by a limited period of bed rest, local and systemic analgesia, bracing, physical therapy, education with proper exercises and instructions according to daily living activities in order to mobilise the patient with safety. Rehabilitation after surgical stabilization of a hip fracture is crucial in order to optimize post-injury mobility and the functional recovery of the patient, restore prefracture function and avoid long-term institutionalization. Most evidence-based guidelines suggesting possible treatments and rehabilitation pathways for hip fracture patients, agree that it would be best if they underwent multidisciplinary rehabilitation (Dionyssiotis et al., 2008a). In prevention and management of osteoporosis modern rehabilitation medicine should not only focus on bone ignoring muscular strength and balance. These elements are directly

related to the disease offering protection against predisposing a person to an increased risk of falls and fall-related fracture. An extensive research in the area of pharmacological

Rehabilitation in Osteoporosis 437

(Figure 1) (van der Meulen, 1993). This increases the diameter of the bone and therefore provides greater resistance to the loads. This adaptive process allows the bone to resist in compression, tension and shear forces, but also to be light enough for efficient and

Fig. 1. An increase in bone dimensions during development and the gradual age-related endosteal resorption, periosteal apposition and cortical thinning. The increase in bone strength because of the increase in diameter replaces the loss of density (adapted, modified

According to Wolff's law bone will optimize its structure, to withstand the functional burden and to ensure the metabolic efficiency of movement (Wolff, 1892). The loading of the skeleton is described as a strain that produces the modified response of bone to loading. It has been suggested that the osteocyte reacts-perceives the strain and transmits signals to osteoblasts to build bone. The magnitude of strain can be defined as the amount of relative change in length of the bone under mechanical loading (Beck et al., 2001). Mechanical stimulation generated by exercising has at least two opposite effects on bone. The bone as a material is weakened by repeated strains, causing minor damages on bone structure; on the other side, stress strain which exceeds a certain threshold leads to generation and thereby adjusts the strength of the bone load usually applied (Wolff, 1870). This is a feedback cycle,

The mechanostat theory describes a system in which a minimum effective strain (MES) is essential for maintaining bone (Frost, 1987b). In the overload zone of the system (2000–3000 micro strain) bone is stimulated and new bone is added in response to mechanical requirement. This leads to increased bone strength. Finally, in the pathological overload zone (>4000 micro strain), a minor damage of bone is present and bone mineral is added as part of the repair process. A sufficient number of studies suggest the ability of estrogen to alter the set point of bone strain in responses to mechanical loading as the result of indirect effect of oestrogen' receptors number (Lanyon & Skerry, 2001; Lee & Lanyon, 2004). The decrease in sensitivity of oestrogen receptors as a result of oestrogen deficiency may reduce the response of bone to mechanical loading (Cheng et al., 2002; Jessop et al., 1995). Strain of about 1.000 micro strain increases bone formation, in the presence but not in the absence of oestrogen. Loading forces in the skeleton are caused by gravity (weight bearing), muscles

Physical activity targeting muscles and balance is the cornerstone of each rehabilitation program for osteoporosis and fracture prevention. Although, in postmenopausal individuals, results of physical activity studies on the positive association of physical activity with bone status are conflicting (Burger et al., 1998; Nguyen et al., 1998). However, it is clear that physical activity is vital in adults (Kelley, 1998; Beitz & Doren, 2004) because it reduces the rate of bone loss during the peri-menopausal period, and decelerates bone loss

economical movement (Wolff,1870).

and translated with permission from Dionyssiotis, 2008b).

which is usually called as the mechanostat (Frost, 1987a).

and other external factors.

**3.2 Targeted exercise for osteoporosis** 

associated with aging (Asikainen et al., 2004).

treatment is ongoing. Pharmacologic treatment increases bone strength, but has no effect in muscle strengthening or balance. Moreover beyond drugs there are other interventions often overlooked: supplementation with calcium, exercise programs, orthoses, vitamin D, and fall prevention.

### **2. Calcium, vitamin D and vitamin D analogues**

All of the studies on the effectiveness of anti-osteoporotic drugs required the taking of calcium and vitamin D and recent findings reveal a decreased effectiveness of therapy in individuals with low levels of vitamin D during the therapy (Nieves et al., 1998; Koster et al., 1996; Adami et al., 2009). Trials reporting bone-mineral density, calcium and calcium in combination with vitamin D were associated with a reduced bone loss at the hip and in the spine. A positive treatment effect on bone-mineral density was evident in most studies (Tang et al., 2007). In opposition to findings on the use of calcium and vitamin D together, studies which researched the relative role calcium or vitamin D separately, produced conflicting results. Moreover, calcium and vitamin D or vitamin D by itself increase muscular strength and decrease the number of falls Bischoff-Ferrari, et al., 2006; Bischoff et al., 2003).

Pooled data comparing vitamin D alone with placebo or no treatment showed no statistically significant effect on vertebral fracture or deformity. Vitamin D (including 25 hydroxy vitamin D) with calcium was no more effective than calcium alone on vertebral fracture. Evidence has shown that vitamin D alone was less effective than calcium for the prevention of vertebral fracture or deformity. There was no evidence of a statistically significant preventive effect on clinical vertebral fractures from the administration of vitamin D and calcium and vitamin D plus calcium versus placebo or no treatment. In participants with osteoporosis no statistically significant effect of alfacalcidol (1-alphahydroxy vitamin D3) compared with vitamin D and calcium on people with new vertebral deformities was found. Calcitriol (1,25 dihydroxy vitamin D3) and additional supplementation with calcitriol in people with osteoporosis already taking calcium had no statistically significant effect on new vertebral deformity. No statistically significant effect on the number of people developing new vertebral deformities receiving calcitriol plus vitamin D and calcium versus vitamin D and calcium was found. Overall, there was no statistically significant effect on the incidence of vertebral deformities with calcitriol versus calcium. When calcitriol was compared with vitamin D in people with pre-existing osteoporosis no statistically significant effect was seen for vertebral deformities (Avenell et al., 2009).

### **3. Exercise in osteoporosis**

#### **3.1 Biomechanics and mechanobiology of bone**

One useful introduction to understanding the response of bone in physical activity is to understand bone's morphology and mechanical properties (Dionyssiotis, 2008b). Bone is a unique material, within the functional structure of the skeleton, which is strong enough to withstand the demands of intense physical activity and external forces exerted, adjusted to changes in those requirements, and light in weight to allow efficient movement and energy saving. The mechanical capacity of bone is a function of internal properties of material (mass, density, stiffness, strength) and geometrical characteristics (size, shape, thickness of cortical cross-sectional area and architecture of trabeculae). The peripheral bone adapts to mechanical loading through endosteal resorption and periosteal apposition of bone tissue

treatment is ongoing. Pharmacologic treatment increases bone strength, but has no effect in muscle strengthening or balance. Moreover beyond drugs there are other interventions often overlooked: supplementation with calcium, exercise programs, orthoses, vitamin D, and fall

All of the studies on the effectiveness of anti-osteoporotic drugs required the taking of calcium and vitamin D and recent findings reveal a decreased effectiveness of therapy in individuals with low levels of vitamin D during the therapy (Nieves et al., 1998; Koster et al., 1996; Adami et al., 2009). Trials reporting bone-mineral density, calcium and calcium in combination with vitamin D were associated with a reduced bone loss at the hip and in the spine. A positive treatment effect on bone-mineral density was evident in most studies (Tang et al., 2007). In opposition to findings on the use of calcium and vitamin D together, studies which researched the relative role calcium or vitamin D separately, produced conflicting results. Moreover, calcium and vitamin D or vitamin D by itself increase muscular strength and decrease the

Pooled data comparing vitamin D alone with placebo or no treatment showed no statistically significant effect on vertebral fracture or deformity. Vitamin D (including 25 hydroxy vitamin D) with calcium was no more effective than calcium alone on vertebral fracture. Evidence has shown that vitamin D alone was less effective than calcium for the prevention of vertebral fracture or deformity. There was no evidence of a statistically significant preventive effect on clinical vertebral fractures from the administration of vitamin D and calcium and vitamin D plus calcium versus placebo or no treatment. In participants with osteoporosis no statistically significant effect of alfacalcidol (1-alphahydroxy vitamin D3) compared with vitamin D and calcium on people with new vertebral deformities was found. Calcitriol (1,25 dihydroxy vitamin D3) and additional supplementation with calcitriol in people with osteoporosis already taking calcium had no statistically significant effect on new vertebral deformity. No statistically significant effect on the number of people developing new vertebral deformities receiving calcitriol plus vitamin D and calcium versus vitamin D and calcium was found. Overall, there was no statistically significant effect on the incidence of vertebral deformities with calcitriol versus calcium. When calcitriol was compared with vitamin D in people with pre-existing osteoporosis no

statistically significant effect was seen for vertebral deformities (Avenell et al., 2009).

One useful introduction to understanding the response of bone in physical activity is to understand bone's morphology and mechanical properties (Dionyssiotis, 2008b). Bone is a unique material, within the functional structure of the skeleton, which is strong enough to withstand the demands of intense physical activity and external forces exerted, adjusted to changes in those requirements, and light in weight to allow efficient movement and energy saving. The mechanical capacity of bone is a function of internal properties of material (mass, density, stiffness, strength) and geometrical characteristics (size, shape, thickness of cortical cross-sectional area and architecture of trabeculae). The peripheral bone adapts to mechanical loading through endosteal resorption and periosteal apposition of bone tissue

**2. Calcium, vitamin D and vitamin D analogues** 

number of falls Bischoff-Ferrari, et al., 2006; Bischoff et al., 2003).

**3. Exercise in osteoporosis** 

**3.1 Biomechanics and mechanobiology of bone** 

prevention.

(Figure 1) (van der Meulen, 1993). This increases the diameter of the bone and therefore provides greater resistance to the loads. This adaptive process allows the bone to resist in compression, tension and shear forces, but also to be light enough for efficient and economical movement (Wolff,1870).

Fig. 1. An increase in bone dimensions during development and the gradual age-related endosteal resorption, periosteal apposition and cortical thinning. The increase in bone strength because of the increase in diameter replaces the loss of density (adapted, modified and translated with permission from Dionyssiotis, 2008b).

According to Wolff's law bone will optimize its structure, to withstand the functional burden and to ensure the metabolic efficiency of movement (Wolff, 1892). The loading of the skeleton is described as a strain that produces the modified response of bone to loading. It has been suggested that the osteocyte reacts-perceives the strain and transmits signals to osteoblasts to build bone. The magnitude of strain can be defined as the amount of relative change in length of the bone under mechanical loading (Beck et al., 2001). Mechanical stimulation generated by exercising has at least two opposite effects on bone. The bone as a material is weakened by repeated strains, causing minor damages on bone structure; on the other side, stress strain which exceeds a certain threshold leads to generation and thereby adjusts the strength of the bone load usually applied (Wolff, 1870). This is a feedback cycle, which is usually called as the mechanostat (Frost, 1987a).

The mechanostat theory describes a system in which a minimum effective strain (MES) is essential for maintaining bone (Frost, 1987b). In the overload zone of the system (2000–3000 micro strain) bone is stimulated and new bone is added in response to mechanical requirement. This leads to increased bone strength. Finally, in the pathological overload zone (>4000 micro strain), a minor damage of bone is present and bone mineral is added as part of the repair process. A sufficient number of studies suggest the ability of estrogen to alter the set point of bone strain in responses to mechanical loading as the result of indirect effect of oestrogen' receptors number (Lanyon & Skerry, 2001; Lee & Lanyon, 2004). The decrease in sensitivity of oestrogen receptors as a result of oestrogen deficiency may reduce the response of bone to mechanical loading (Cheng et al., 2002; Jessop et al., 1995). Strain of about 1.000 micro strain increases bone formation, in the presence but not in the absence of oestrogen. Loading forces in the skeleton are caused by gravity (weight bearing), muscles and other external factors.

### **3.2 Targeted exercise for osteoporosis**

Physical activity targeting muscles and balance is the cornerstone of each rehabilitation program for osteoporosis and fracture prevention. Although, in postmenopausal individuals, results of physical activity studies on the positive association of physical activity with bone status are conflicting (Burger et al., 1998; Nguyen et al., 1998). However, it is clear that physical activity is vital in adults (Kelley, 1998; Beitz & Doren, 2004) because it reduces the rate of bone loss during the peri-menopausal period, and decelerates bone loss associated with aging (Asikainen et al., 2004).

Rehabilitation in Osteoporosis 439

Duration

8-10 repetitions

2 sets

2-3 times weekly

20-30 minutes

Table 1. Muscle strengthening exercises in osteoporosis; the table summarises the following characteristics of this type of exercise: how we can do them, which are the targets, the intensity, frequency and duration of the program, when to expect the results and the

Fig. 2. *(1 to 6) Back muscles:* This group of muscles is usually underestimated in exercise programs, but it requires special attention. The subject should begin warm up in the prone position with the hands flat on the ground and the elbows facing outwards and hold for one minute (photo 1), then raise the head keeping this position for five seconds (photo 2), then return to the starting position. The exercise needs to be repeated five times. The simplest style is photo 3: from the prone position to raise only the hands, with the elbows bent at 90 degrees, whereas it becomes more difficult when the arms are placed at the side of the body and the head is gently raised (photos 4, 5). The exercise needs 15 repetitions 6 times per day (3 in the morning – 3 in the evening). As strength increases it is possible to do more difficult exercises; from a kneeling position, extend one arm and raise the opposite leg. This exercise

should be repeated ten times every day. (Dionyssiotis Y., 2010 c).

Time to target Contradictions

Subjects with kyphosis should avoid bending and turning the spine and perform the exercises seated

6 months for bone mineral density changes

Target Intensity Frequency

Increasing strength, stimulate bone to increase bone density (targets are mostly hip muscles, back muscles, biceps, triceps)

contradictions (Dionyssiotis Y. , 2010 c).

Type Muscle strengthening

Using body weight, free weights, elastic bands, sophisticated equipment in the gym etc.

In the design of an exercise program to increase bone mass we need to take in mind the following five principles (Drinkwater, 1994) 1. Specificity: The program must be designed to load specific bones or body regions, 2. Overload: To induce stimulation for increasing bone density according to mechanostat theory exercise must overload the bone, 3. Reversibility: In adults, any gains in bone density during an exercise program will be lost if the program stops. However, in children and adolescents the benefits achieved by increased mechanical loading during exercise program remain even if the exercise program stops, 4. Initial Values: The response of bone to increased loading is greater when bone mass is below average. Patients with bone mass below normal will experience greater gains in bone density with exercise programmes, compared with people who have a good bone density, 5. Diminishing Returns: The greatest gains in bone density will be seen early in an exercise program. After the initial increase, the benefits continue but at a slower pace. We added the 6th principle of Variety which is a component of success in all exercise programs. We need to enrich the programs with various exercises and not perform the same exercises, at the same duration and interval. By changing the way of bone and muscle stimulation we challenge them in new way shifting the loading stress causing new results (Dionyssiotis, 2008b).

To summarize the principles: Not all types of physical activities that provide bone loading to the skeleton produce bone mass benefits. Some activities (i.e. a progressive jogging program) charge and stimulate adaptation of the cardiovascular system, but do not stimulate an adaptive bone response that would increase bone density (Khan et al., 2001). The bone has a lazy zone! Each exercise that stimulates the metabolism in the body (i.e. exercise for the cardiovascular system etc.), is not able to stimulate the adaptation of bone to increase bone density. The load on a bone during the exercise should be substantially greater than the load experiencing of the bone during activities of daily living. There is definitely a threshold load which must be reached to generate gains in bone mass. Moreover, loading of the bone should be done in such a way that mimics the physical loads (Skerry, 1997).

There are also activities that provide bone loading at one site of the body, but not at other sites. The osteogenic effects of exercise should be specific to the anatomical sites where the mechanical strain occurs (Lohman et al., 1995). The most common types of physical activities (e.g., gardening, swimming) use many muscles but do not involve targeted bone loading, and therefore do not produce loads heavy enough to exceed the load threshold on bones achieved by usual daily activities (Beck & Snow, 2003; Madalozzo & Snow, 2000). The duration of the physical activity is also important; up to 2 hours per week is considered to positively affect bone mass maintenance (Snow-Harter & Marcus, 1991). Muscle strengthening, weight bearing combined with flexibility, posture control, balance, coordination and training in daily living activities to improve functional capabilities of the subjects should be part of a rehabilitation program in osteoporosis. The following subchapters explain basic exercises of each category (except balance and coordination exercises which will be analyzed in the subchapter of falls prevention) in detail.

#### **3.2.1 Muscle strengthening exercises**

In osteoporosis we do not recommend muscle strengthening in generally. Programs are focused on specific regions of the skeleton where fractures are most commonly expected, namely the spine, the hip and the wrist. For this reason in all ages, but particularly in postmenopausal women, exercise programs focusing on muscles in these regions (Table 1) including exercises for the back muscles, the hip and the hand (with weights or pulleys) but also for the thighs because research has shown that the quadriceps is an important muscle for balance and falls prevention.

In the design of an exercise program to increase bone mass we need to take in mind the following five principles (Drinkwater, 1994) 1. Specificity: The program must be designed to load specific bones or body regions, 2. Overload: To induce stimulation for increasing bone density according to mechanostat theory exercise must overload the bone, 3. Reversibility: In adults, any gains in bone density during an exercise program will be lost if the program stops. However, in children and adolescents the benefits achieved by increased mechanical loading during exercise program remain even if the exercise program stops, 4. Initial Values: The response of bone to increased loading is greater when bone mass is below average. Patients with bone mass below normal will experience greater gains in bone density with exercise programmes, compared with people who have a good bone density, 5. Diminishing Returns: The greatest gains in bone density will be seen early in an exercise program. After the initial increase, the benefits continue but at a slower pace. We added the 6th principle of Variety which is a component of success in all exercise programs. We need to enrich the programs with various exercises and not perform the same exercises, at the same duration and interval. By changing the way of bone and muscle stimulation we challenge them in

new way shifting the loading stress causing new results (Dionyssiotis, 2008b).

be done in such a way that mimics the physical loads (Skerry, 1997).

To summarize the principles: Not all types of physical activities that provide bone loading to the skeleton produce bone mass benefits. Some activities (i.e. a progressive jogging program) charge and stimulate adaptation of the cardiovascular system, but do not stimulate an adaptive bone response that would increase bone density (Khan et al., 2001). The bone has a lazy zone! Each exercise that stimulates the metabolism in the body (i.e. exercise for the cardiovascular system etc.), is not able to stimulate the adaptation of bone to increase bone density. The load on a bone during the exercise should be substantially greater than the load experiencing of the bone during activities of daily living. There is definitely a threshold load which must be reached to generate gains in bone mass. Moreover, loading of the bone should

There are also activities that provide bone loading at one site of the body, but not at other sites. The osteogenic effects of exercise should be specific to the anatomical sites where the mechanical strain occurs (Lohman et al., 1995). The most common types of physical activities (e.g., gardening, swimming) use many muscles but do not involve targeted bone loading, and therefore do not produce loads heavy enough to exceed the load threshold on bones achieved by usual daily activities (Beck & Snow, 2003; Madalozzo & Snow, 2000). The duration of the physical activity is also important; up to 2 hours per week is considered to positively affect bone mass maintenance (Snow-Harter & Marcus, 1991). Muscle strengthening, weight bearing combined with flexibility, posture control, balance, coordination and training in daily living activities to improve functional capabilities of the subjects should be part of a rehabilitation program in osteoporosis. The following subchapters explain basic exercises of each category (except balance and coordination

exercises which will be analyzed in the subchapter of falls prevention) in detail.

In osteoporosis we do not recommend muscle strengthening in generally. Programs are focused on specific regions of the skeleton where fractures are most commonly expected, namely the spine, the hip and the wrist. For this reason in all ages, but particularly in postmenopausal women, exercise programs focusing on muscles in these regions (Table 1) including exercises for the back muscles, the hip and the hand (with weights or pulleys) but also for the thighs because research has shown that the quadriceps is an important muscle

**3.2.1 Muscle strengthening exercises** 

for balance and falls prevention.


Table 1. Muscle strengthening exercises in osteoporosis; the table summarises the following characteristics of this type of exercise: how we can do them, which are the targets, the intensity, frequency and duration of the program, when to expect the results and the contradictions (Dionyssiotis Y. , 2010 c).

Fig. 2. *(1 to 6) Back muscles:* This group of muscles is usually underestimated in exercise programs, but it requires special attention. The subject should begin warm up in the prone position with the hands flat on the ground and the elbows facing outwards and hold for one minute (photo 1), then raise the head keeping this position for five seconds (photo 2), then return to the starting position. The exercise needs to be repeated five times. The simplest style is photo 3: from the prone position to raise only the hands, with the elbows bent at 90 degrees, whereas it becomes more difficult when the arms are placed at the side of the body and the head is gently raised (photos 4, 5). The exercise needs 15 repetitions 6 times per day (3 in the morning – 3 in the evening). As strength increases it is possible to do more difficult exercises; from a kneeling position, extend one arm and raise the opposite leg. This exercise should be repeated ten times every day. (Dionyssiotis Y., 2010 c).

Rehabilitation in Osteoporosis 441

Fig. 4. *Abdominal muscles strengthening*: The subject should begin warm up in the supine position, bringing the chin to the chest for five to ten repetitions (photos 1, 2). The safest exercise for abdominal muscle strengthening includes performing from the supine position with the back flat on the ground, the legs raised and the knees bent at ninety degrees (photo 3). The knees are then extended while lowering the legs with movement coming from the hip joint (photos 4, 5, 6). The spine must be flat on the ground while this exercise is performed. If it is not possible to perform the total movement of this exercise, it should be performed in the half of range as shown in photograph 4. If this exercise causes pain, the subject should alter it as follows: with the legs bent and the sole of the foot on the ground, bend one leg to the abdominals then lower the leg to the ground and the same movement with the other leg (photos 7, 8, 9). Another option is to raise the head with the arms

extended to touch the knees (photo 10), (Dionyssiotis Y., 2010 c).

Fig. 3. *Resistance against a wall (such as push-ups)*: The subject stands opposite a wall and place the hands against the wall with the palms flat on the wall. The feet are spread 15 cm apart. In the next step the subject presses against the wall with the elbows bent and then returns to the initial position. This exercise needs 20 repetitions 3 times per day (Dionyssiotis Y., 2010 c).

Fig. 3. *Resistance against a wall (such as push-ups)*: The subject stands opposite a wall and place the hands against the wall with the palms flat on the wall. The feet are spread 15 cm apart. In the next step the subject presses against the wall with the elbows bent and then returns to the initial position. This exercise needs 20 repetitions 3 times per day (Dionyssiotis Y., 2010 c).

Fig. 4. *Abdominal muscles strengthening*: The subject should begin warm up in the supine position, bringing the chin to the chest for five to ten repetitions (photos 1, 2). The safest exercise for abdominal muscle strengthening includes performing from the supine position with the back flat on the ground, the legs raised and the knees bent at ninety degrees (photo 3). The knees are then extended while lowering the legs with movement coming from the hip joint (photos 4, 5, 6). The spine must be flat on the ground while this exercise is performed. If it is not possible to perform the total movement of this exercise, it should be performed in the half of range as shown in photograph 4. If this exercise causes pain, the subject should alter it as follows: with the legs bent and the sole of the foot on the ground, bend one leg to the abdominals then lower the leg to the ground and the same movement with the other leg (photos 7, 8, 9). Another option is to raise the head with the arms extended to touch the knees (photo 10), (Dionyssiotis Y., 2010 c).

Rehabilitation in Osteoporosis 443

Fig. 6. *Quadriceps:* The subject sits upright in a chair with the back as straight as possible, the knees bent and the feet flat on the ground (a chair with armrest is recommended), grips the chair firmly and extends one knee at a time keeping it extended for 4 seconds. This exercise is particularly indicated for elderly people and after hip surgery. The exercise can be done with pulleys and with special equipment in the gym. Each leg needs fifteen repetitions

Fig. 7. *Exercises with dumbbells for the arms:* Exercises for strengthening the biceps and triceps can be done from a standing or seated position. From a standing position the subject flexes the knees slightly, and using medium weights performs three sets of 10 repetitions with each arm (photos 1, 2, 3). Weights can be replaced with pulleys for lower resistance

Subjects need to perform the exercise as above with the same number of repetitions remembering to maintain the correct posture while exercising. For additional safety, exercises should be performed in a seated position by patients with severe osteoporosis.

Weight bearing exercises are exercises during which the weight of the body passes through the bones. Examples of these types of exercises are walking, jogging, dancing, gardening, tennis, football, basketball and trampoline etc. There is a variety of this type of exercise to suit every age group. The impact to the bone during this exercise should be higher than that during normal everyday activities. Many women believe that housework and the level of

(Dionyssiotis Y., 2010 c).

(Dionyssiotis Y., 2010 c).

**3.2.2 Weight bearing exercises** 

Fig. 5. *Extensor and abductor muscles of the hips:* The subject places the hand on a fixed spot for safety (i.e: chair photo 1) and lift one leg backwards in order to exercise the gluteus maximus muscle extensor muscle (photo 2). Then the movement is repeated with the other leg. From the same position lifts one leg to the side, in order to strengthen the gluteus medius muscle abductor muscle (photo 3); then the other leg follows. For each leg three sets of 15 repetitions are needed. Both exercises can be done with pulleys (at home or at the gym), lying sideways on the ground and also with specific equipment at the gym under the guidance of a qualified instructor (see photos 5-9). Keeping good technique during this exercise is very important and four sets of fifteen repetitions are necessary (Dionyssiotis Y., 2010 c).

Fig. 5. *Extensor and abductor muscles of the hips:* The subject places the hand on a fixed spot for safety (i.e: chair photo 1) and lift one leg backwards in order to exercise the gluteus maximus muscle extensor muscle (photo 2). Then the movement is repeated with the other leg. From the same position lifts one leg to the side, in order to strengthen the gluteus medius muscle abductor muscle (photo 3); then the other leg follows. For each leg three sets of 15 repetitions are needed. Both exercises can be done with pulleys (at home or at the gym), lying sideways on the ground and also with specific equipment at the gym under the guidance of a qualified instructor (see photos 5-9). Keeping good technique during this exercise is very important and four sets of fifteen repetitions are necessary

(Dionyssiotis Y., 2010 c).

Fig. 6. *Quadriceps:* The subject sits upright in a chair with the back as straight as possible, the knees bent and the feet flat on the ground (a chair with armrest is recommended), grips the chair firmly and extends one knee at a time keeping it extended for 4 seconds. This exercise is particularly indicated for elderly people and after hip surgery. The exercise can be done with pulleys and with special equipment in the gym. Each leg needs fifteen repetitions (Dionyssiotis Y., 2010 c).

Fig. 7. *Exercises with dumbbells for the arms:* Exercises for strengthening the biceps and triceps can be done from a standing or seated position. From a standing position the subject flexes the knees slightly, and using medium weights performs three sets of 10 repetitions with each arm (photos 1, 2, 3). Weights can be replaced with pulleys for lower resistance (Dionyssiotis Y., 2010 c).

Subjects need to perform the exercise as above with the same number of repetitions remembering to maintain the correct posture while exercising. For additional safety, exercises should be performed in a seated position by patients with severe osteoporosis.

### **3.2.2 Weight bearing exercises**

Weight bearing exercises are exercises during which the weight of the body passes through the bones. Examples of these types of exercises are walking, jogging, dancing, gardening, tennis, football, basketball and trampoline etc. There is a variety of this type of exercise to suit every age group. The impact to the bone during this exercise should be higher than that during normal everyday activities. Many women believe that housework and the level of

Rehabilitation in Osteoporosis 445

Fig. 9. *Dancing* as exercise is safe and social which in turn makes this an attractive activity. Jumps and aerobic weight bearing exercises during dancing or gymnastics are related to increasing and maintaining bone density. Traditional Greek dances include movement like jumps, sideways steps and squatting which have a weight bearing effect on the hip and

The aim of these exercises is to: Eliminate the bent-over position (hunchback), which increases the pressure on the front part of the vertebrae and to improve stability. Exercises can be done in the sitting or standing position with eyes open or closed. The optimal is to be performed in front of a mirror and next to a wall. The reason why the exercises are performed in front of a mirror is that the trainees can see their reflection and can correct the possible mistakes in their posture, with the guidance of the experts (visual biofeedback). The

 Fig. 10. *Exercises in patients with osteoporosis for correction of posture: Decompression of the spine*: the exercise starts lying on the ground with the knees bent, the feet flat on the ground, the elbow bent and the palms facing upwards and this position is kept for five minutes. This exercise decompresses the spine and relieves back pain. *Shoulder press:* beginning from the same position, the shoulders are pressed to the ground holding for three seconds, and then the subject relaxes himself and repeats three times. This exercise strengthens the muscles of the upper back. *Leg press:* beginning with the position of exercise 1) above, the subjects extends one leg with foot pointing upwards, presses the full length of the leg into the ground, concentrates for 2-3 seconds and relaxes himself. The same steps are performed with the other leg (4 repetitions with each leg). This exercise helps with posture and

strengthens the extensor muscles of the thigh (Dionyssiotis Y., 2010 c).

spine (Dionyssiotis Y., 2010 c).

wall assists the safe performance of the exercises.

**3.2.3 Postural exercises** 

activity it involves constitutes a good level of exercise. However, this is not correct as in order for exercises to be effective they need to be performed with specific technique and systematically.


Table 2. Weight bearing exercises; the table summarises the following characteristics of this type of exercise: how we can do them, which are the targets, the intensity, frequency and duration of the program, when to expect the results and the contradictions (Dionyssiotis Y., 2010 c)

Fig. 8. *Walking:* Dynamic walking is the best option for prevention of osteoporosis. Simple walking is not enough; it should be in an open environment without obstacles, not around the house or workplace. Dynamic walking differs from regular walking and to achieve maximum benefit to the skeleton a special technique is required. Brisk walking (dynamic walking) does not require any special equipment except for a good pair of training shoes. Moreover it has the advantage of low risk of injury. Walking should begin at a normal pace, progressively increasing after five minutes to a medium and then to a fast pace for twenty minutes. The pace must be sufficient to allow normal speech but not so fast that the person is out of breath. The level of intensity however should be sufficient for the person to sweat. In order to move the feet faster it is necessary to move the hands faster. Arms should move in the opposite direction to the feet. During the movement of the hands, the subject need to flex the elbows and keep the arms close to the body. Attention should be paid to change of pace, using bigger steps and the feet should be kept in a forward facing direction and not sideway. This kind of walking should be done as often as possible (Dionyssiotis Y., 2010 c).

activity it involves constitutes a good level of exercise. However, this is not correct as in order for exercises to be effective they need to be performed with specific technique and

> Intensity requency Duration

40-70% max. Power 3-5 times/ week 20-30 min

Table 2. Weight bearing exercises; the table summarises the following characteristics of this type of exercise: how we can do them, which are the targets, the intensity, frequency and duration of the program, when to expect the results and the contradictions (Dionyssiotis Y.,

Fig. 8. *Walking:* Dynamic walking is the best option for prevention of osteoporosis. Simple walking is not enough; it should be in an open environment without obstacles, not around the house or workplace. Dynamic walking differs from regular walking and to achieve maximum benefit to the skeleton a special technique is required. Brisk walking (dynamic walking) does not require any special equipment except for a good pair of training shoes. Moreover it has the advantage of low risk of injury. Walking should begin at a normal pace, progressively increasing after five minutes to a medium and then to a fast pace for twenty minutes. The pace must be sufficient to allow normal speech but not so fast that the person is out of breath. The level of intensity however should be sufficient for the person to sweat. In order to move the feet faster it is necessary to move the hands faster. Arms should move in the opposite direction to the feet. During the movement of the hands, the subject need to flex the elbows and keep the arms close to the body. Attention should be paid to change of pace, using bigger steps and the feet should be kept in a forward facing direction and not sideway. This kind of walking should be done as often as possible (Dionyssiotis Y., 2010 c).

Time to target Contradictions

Bending and turning in patients with osteopenia

9-12 months to improve BMD

systematically.

Type

Walking, jogging, dancing, gardening, tennis, basketball etc.

2010 c)

Weight bearing Target

Maintenance of bone mass Improvement in physical function

Fig. 9. *Dancing* as exercise is safe and social which in turn makes this an attractive activity. Jumps and aerobic weight bearing exercises during dancing or gymnastics are related to increasing and maintaining bone density. Traditional Greek dances include movement like jumps, sideways steps and squatting which have a weight bearing effect on the hip and spine (Dionyssiotis Y., 2010 c).

### **3.2.3 Postural exercises**

The aim of these exercises is to: Eliminate the bent-over position (hunchback), which increases the pressure on the front part of the vertebrae and to improve stability. Exercises can be done in the sitting or standing position with eyes open or closed. The optimal is to be performed in front of a mirror and next to a wall. The reason why the exercises are performed in front of a mirror is that the trainees can see their reflection and can correct the possible mistakes in their posture, with the guidance of the experts (visual biofeedback). The wall assists the safe performance of the exercises.

Fig. 10. *Exercises in patients with osteoporosis for correction of posture: Decompression of the spine*: the exercise starts lying on the ground with the knees bent, the feet flat on the ground, the elbow bent and the palms facing upwards and this position is kept for five minutes. This exercise decompresses the spine and relieves back pain. *Shoulder press:* beginning from the same position, the shoulders are pressed to the ground holding for three seconds, and then the subject relaxes himself and repeats three times. This exercise strengthens the muscles of the upper back. *Leg press:* beginning with the position of exercise 1) above, the subjects extends one leg with foot pointing upwards, presses the full length of the leg into the ground, concentrates for 2-3 seconds and relaxes himself. The same steps are performed with the other leg (4 repetitions with each leg). This exercise helps with posture and strengthens the extensor muscles of the thigh (Dionyssiotis Y., 2010 c).

Rehabilitation in Osteoporosis 447

Fig. 13. *Stretching muscles of the lumbar spine:* The subject is kneeling on the floor with knees slightly apart (photo 1), raises the arms high towards the ceiling and carefully bends forwards, until the palms touch the floor (photo 2, 3), keeping this position for several

**3.2.5 Exercises to improve functional ability – Osteoporosis and daily living activities**  The program of exercises becomes more efficient if combined with the use of proper body

Fig. 14. *Lifting, carrying and placing weights; the correct and wrong way to lift and place objects:*  The correct way for the osteoporotic patient to lift an object is to bend the knees, the hips and the ankles so that the object is at waist level. Bringing the object towards him with both hands and returning to the upright position using the strength of both feet. The spine should be straight during this movement, keeping the head and chest upright and the abdominal muscles tight. An osteoporotic patient is not allowed to lift more than 5-10 kg. The subject stands next to the object keeping the back straight bending the knees and lifting the weight using the strength of the feet and not that of the back, avoiding turning or rotating during the weight lift. The weight must be kept at the level of the waist. When transferring a heavy object, it is preferable to push rather than to pull it and while carrying a weight to separate it evenly on both sides of the body. The abdominal muscles should be flexed, so that the back

seconds and repeats 5 times (Dionyssiotis Y., 2010c).

mechanics and posture in everyday activities.

is in the correct position (Dionyssiotis Y., 2010 c).

### **3.2.4 Flexibility exercises**

During aging the body becomes more rigid which results in movement difficulties leading to falls and increasing risk of fracture. For this reason it is necessary to perform exercises to maintain flexibility. The exercises in this category help to maintain the elasticity and the length of the muscle, the range of movement of the joints, improve posture and reduce pain (mostly back pain etc).

Fig. 11*. Stretching the pectoralis major (stretching of the chest):* From the standing or sitting position (for greater safety), with the arms bent at the elbows and to the side of the torso, the subject moves the elbows backwards (photo 1). The arms can also be raised in front of the chest with the elbows bent up to the height of the shoulders (photo 2) and then spreads open the arms stretching them out (photo 3). The exercise should be performed daily with 10 repetitions, 3 times (Dionyssiotis Y., 2010 c).

Fig. 12. *Stretching the upper torso:* In this exercise the subject stands or sits on a comfortable chair, the fingers are placed behind ears, palms facing forwards and elbows pointing outwards (photo 1). Stretching the chest by pushing the elbows backwards (without pressing the head) is followed holding this position for 4 seconds and then bringing the elbows together, in front of the face, in order to stretch the muscles of the upper back (photo 2). Exercise is repeated 5-10 times (Dionyssiotis Y., 2010 c).

During aging the body becomes more rigid which results in movement difficulties leading to falls and increasing risk of fracture. For this reason it is necessary to perform exercises to maintain flexibility. The exercises in this category help to maintain the elasticity and the length of the muscle, the range of movement of the joints, improve posture and reduce pain

Fig. 11*. Stretching the pectoralis major (stretching of the chest):* From the standing or sitting position (for greater safety), with the arms bent at the elbows and to the side of the torso, the subject moves the elbows backwards (photo 1). The arms can also be raised in front of the chest with the elbows bent up to the height of the shoulders (photo 2) and then spreads open the arms stretching them out (photo 3). The exercise should be performed daily with

Fig. 12. *Stretching the upper torso:* In this exercise the subject stands or sits on a comfortable chair, the fingers are placed behind ears, palms facing forwards and elbows pointing outwards (photo 1). Stretching the chest by pushing the elbows backwards (without pressing the head) is followed holding this position for 4 seconds and then bringing the elbows together, in front of the face, in order to stretch the muscles of the upper back (photo

10 repetitions, 3 times (Dionyssiotis Y., 2010 c).

2). Exercise is repeated 5-10 times (Dionyssiotis Y., 2010 c).

**3.2.4 Flexibility exercises** 

(mostly back pain etc).

Fig. 13. *Stretching muscles of the lumbar spine:* The subject is kneeling on the floor with knees slightly apart (photo 1), raises the arms high towards the ceiling and carefully bends forwards, until the palms touch the floor (photo 2, 3), keeping this position for several seconds and repeats 5 times (Dionyssiotis Y., 2010c).

### **3.2.5 Exercises to improve functional ability – Osteoporosis and daily living activities**  The program of exercises becomes more efficient if combined with the use of proper body mechanics and posture in everyday activities.

Fig. 14. *Lifting, carrying and placing weights; the correct and wrong way to lift and place objects:*  The correct way for the osteoporotic patient to lift an object is to bend the knees, the hips and the ankles so that the object is at waist level. Bringing the object towards him with both hands and returning to the upright position using the strength of both feet. The spine should be straight during this movement, keeping the head and chest upright and the abdominal muscles tight. An osteoporotic patient is not allowed to lift more than 5-10 kg. The subject stands next to the object keeping the back straight bending the knees and lifting the weight using the strength of the feet and not that of the back, avoiding turning or rotating during the weight lift. The weight must be kept at the level of the waist. When transferring a heavy object, it is preferable to push rather than to pull it and while carrying a weight to separate it evenly on both sides of the body. The abdominal muscles should be flexed, so that the back is in the correct position (Dionyssiotis Y., 2010 c).

Rehabilitation in Osteoporosis 449

The credibility of this theory has been demonstrated in sheep, where one arm vibration caused a 34% increase in volumetric trabecular bone mineral density of the femur (Rubin et al., 2002). Moreover through this type of vibration trabecular bone density of the tibia in children with cerebral palsy was increased, whereas bone loss was expected without treatment (Ward et al., 2004). A recent study demonstrated benefits in postmenopausal women: an increase of 2.2% and 1.7% in bone density of the hip and spine respectively (Rubin et al., 2004). The second theory supports the concept of the important action of the muscles; vibrations make bones stronger through powerful muscular contractions (Rauch & Schoenau, 2001; Rittweger et al., 2000; Schiessl et al., 1998). In postmenopausal women, bone density increased by 1% after 6 months when vibration of static and dynamic knee-extensor exercises on a vibration platform (35-40 Hz, 2.28-5.09g) was performed which also increased muscle strength (Verschueren et al., 2004). However, these increases were also evident in the comparison group of women who performed traditional resistance exercises. A study performed on immobilized young men (Berlin bed rest study) concluded that a combination of vibration and resistance exercises prevent bone loss due to immobilization (Rittweger & Felsenberg, 2004). A systematic review and meta-analysis found significant but small improvements in BMD in postmenopausal women and children and adolescents, but not in

Fig. 16. Galileo vibration platform (Novotec Medical GmbH, Pforzheim, Germany, with

The effect of aerobic exercise on bone density has been studied by review papers which report a decrease in bone loss at the spine and wrist but not at the hip (Bonaiuti et al., 2002; Martyn-St James & Carroll, 2008; Martyn-St James & Carroll, 2006). In meta-analysis studies which reviewed the effects of walking on bone density showed that walking has a small effect on sustaining bone density at the spine in postmenopausal women, however it has a significant positive effect on the femoral neck and concludes that other types of exercises which provide larger "targeted" weight bearing forces are needed to maintain bone density in this group (Martyn-St James & Carroll, 2006). In a review of 35 RCT's it was shown that in premenopausal women and in postmenopausal women intense exercise probably had a

young adults (Slatkovska et al., 2010).

permission).

**3.3 Exercise and bone density** 

Fig. 15. *The correct way for the osteoporotic patient to get up from chair:* The head and the chest must be in the upright position, the body must be bent forward using the hip joint and the base of the spine must be slightly bent with the help of abdominal muscle contraction. Standing up is achieved using the leg muscles. The subject should sit at the edge of the chair with feet slightly behind the knees, pushing forward by placing the weight on toes of the feet while getting up. If necessary the arm rests can be helpful in getting up from the chair. With this way subject is getting up keeping the back and the neck straight (Dionyssiotis Y., 2010 c).

#### **3.2.6 Whole body vibration as antiosteoporotic intervention**

Vibration platforms are used in rehabilitation of osteoporosis, based on the concept that non-invasive, short-duration, mechanical stimulation could have an impact on osteoporosis risk. The mechanical loading of bone can be done with application of non-physiological factors, such as vibrations that combine dynamic loads and high intensity loading on the skeleton (Dionyssiotis, 2008b). The implementation should be shortly and has specific indications, contraindications and adverse reactions. These machines cause whole-body vibration. The vibration is a mechanical stimulation of the whole body; the person is standing on the vibration platform trying to keep his head and body straight and upright. All the muscles that keep the body in this position are forced to react to the oscillating movements provided by the device. The duration of this exercise depends on the type of machine in order to have measurable results and benefits.

According to the mechanostat theory bones need great forces for their development. The mechanical loading of bone can be done either with usual exercise activities as those reported in subchapter 3.2 or by applying non-physiological factors, such as body vibration. With platforms goal is achieved safely, without injury and quickly. Mechanical loads are applied in a dynamic way with a high intensity defined by its frequency (hertz) and magnitude, where magnitude is expressed as vertical acceleration (g; 1g=9.8 m/s2 acceleration due to gravity) or vertical displacement (millimeters). In the scientific world there is a debate about how exercise with vibrations develops bones. One theory holds that low vibration intensity but high frequency can cause osteogenic response by direct action on bone (Rubin et al., 2001). They support the following concept: because of small strains caused by this mechanism, there are benefits to bone without the risk of causing mechanical damage.

Fig. 15. *The correct way for the osteoporotic patient to get up from chair:* The head and the chest must be in the upright position, the body must be bent forward using the hip joint and the base of the spine must be slightly bent with the help of abdominal muscle contraction. Standing up is achieved using the leg muscles. The subject should sit at the edge of the chair with feet slightly behind the knees, pushing forward by placing the weight on toes of the feet while getting up. If necessary the arm rests can be helpful in getting up from the chair. With this way subject is getting up keeping the back and the neck straight (Dionyssiotis Y.,

Vibration platforms are used in rehabilitation of osteoporosis, based on the concept that non-invasive, short-duration, mechanical stimulation could have an impact on osteoporosis risk. The mechanical loading of bone can be done with application of non-physiological factors, such as vibrations that combine dynamic loads and high intensity loading on the skeleton (Dionyssiotis, 2008b). The implementation should be shortly and has specific indications, contraindications and adverse reactions. These machines cause whole-body vibration. The vibration is a mechanical stimulation of the whole body; the person is standing on the vibration platform trying to keep his head and body straight and upright. All the muscles that keep the body in this position are forced to react to the oscillating movements provided by the device. The duration of this exercise depends on the type of

According to the mechanostat theory bones need great forces for their development. The mechanical loading of bone can be done either with usual exercise activities as those reported in subchapter 3.2 or by applying non-physiological factors, such as body vibration. With platforms goal is achieved safely, without injury and quickly. Mechanical loads are applied in a dynamic way with a high intensity defined by its frequency (hertz) and magnitude, where magnitude is expressed as vertical acceleration (g; 1g=9.8 m/s2 acceleration due to gravity) or vertical displacement (millimeters). In the scientific world there is a debate about how exercise with vibrations develops bones. One theory holds that low vibration intensity but high frequency can cause osteogenic response by direct action on bone (Rubin et al., 2001). They support the following concept: because of small strains caused by this mechanism, there are benefits to bone without the risk of causing mechanical

**3.2.6 Whole body vibration as antiosteoporotic intervention** 

machine in order to have measurable results and benefits.

2010 c).

damage.

The credibility of this theory has been demonstrated in sheep, where one arm vibration caused a 34% increase in volumetric trabecular bone mineral density of the femur (Rubin et al., 2002). Moreover through this type of vibration trabecular bone density of the tibia in children with cerebral palsy was increased, whereas bone loss was expected without treatment (Ward et al., 2004). A recent study demonstrated benefits in postmenopausal women: an increase of 2.2% and 1.7% in bone density of the hip and spine respectively (Rubin et al., 2004). The second theory supports the concept of the important action of the muscles; vibrations make bones stronger through powerful muscular contractions (Rauch & Schoenau, 2001; Rittweger et al., 2000; Schiessl et al., 1998). In postmenopausal women, bone density increased by 1% after 6 months when vibration of static and dynamic knee-extensor exercises on a vibration platform (35-40 Hz, 2.28-5.09g) was performed which also increased muscle strength (Verschueren et al., 2004). However, these increases were also evident in the comparison group of women who performed traditional resistance exercises. A study performed on immobilized young men (Berlin bed rest study) concluded that a combination of vibration and resistance exercises prevent bone loss due to immobilization (Rittweger & Felsenberg, 2004). A systematic review and meta-analysis found significant but small improvements in BMD in postmenopausal women and children and adolescents, but not in young adults (Slatkovska et al., 2010).

Fig. 16. Galileo vibration platform (Novotec Medical GmbH, Pforzheim, Germany, with permission).

#### **3.3 Exercise and bone density**

The effect of aerobic exercise on bone density has been studied by review papers which report a decrease in bone loss at the spine and wrist but not at the hip (Bonaiuti et al., 2002; Martyn-St James & Carroll, 2008; Martyn-St James & Carroll, 2006). In meta-analysis studies which reviewed the effects of walking on bone density showed that walking has a small effect on sustaining bone density at the spine in postmenopausal women, however it has a significant positive effect on the femoral neck and concludes that other types of exercises which provide larger "targeted" weight bearing forces are needed to maintain bone density in this group (Martyn-St James & Carroll, 2006). In a review of 35 RCT's it was shown that in premenopausal women and in postmenopausal women intense exercise probably had a

Rehabilitation in Osteoporosis 451

the lumbar spine and femoral neck, while exercise is effective in increasing the mechanical

On the other hand the combined and separate effects of exercise training and bisphosphonate (etidronate) therapy on bone mineral in postmenopausal women were investigated in forty-eight postmenopausal women randomly assigned to groups that took intermittent cyclical etidronate; performed strength training (3 d/week) and received matched placebo; combined strength training with etidronate; or took placebo and served as non-exercising controls. Bone mineral was assessed by dual-energy X-ray absorptiometry before and after 12 months of intervention changes in bone mineral density (BMD) of the lumbar spine were greater in the subjects given etidronate compared with placebo, while exercise had no effect. No effect of etidronate or exercise on the proximal femur and there was no interaction between exercise and etidronate at any bone site was found (Chilibeck et

Traditionally, spinal orthoses have been used in the management of thoracolumbar injuries treated with or without surgical stabilization. The vast majority of orthoses, however, are used in patients with low back pain (Perry, 1970). These orthoses, however, have never been tested under standardized conditions. Especially, no prospective, randomized, and controlled clinical trials are available to document efficacy according to the criteria of evidence-based medicine. Moreover, there is a lack of specific studies comparing various types of braces and orthoses. This is also the case for osteoporosis, in which approximately one-fourth of women above 50 years of age have one or more vertebral fractures (Melton,

Even though, it is widely accepted that spinal orthoses whether made of cloth, metal, or plastic, or whether rigid or flexible, relieve pain and promote the healing process by stabilizing the spine i.e. reducing the load applied on the anterior column and vertebral body by restraining any attempt of forward flexion. The most broadly used types of spinal orthoses use a three-point pressure system (Dionyssiotis et al., 2008; Mazanec et al., 2003): a) the TLSO type (Knight-Taylor, Jewett, CASH or Cruciform Anterior Sternal Hyperextension brace, Boston); that provides support to the thoracolumbosacral spine by making it adopt an anatomically correct position. The CASH or Jewett brace has been favoured for patients with acute vertebral fractures. The goal of these braces is to provide forces to encourage hyperextension. However, a drawback to these orthoses is the limited compliance because of their rigid configuration, b) the PTS (Posture Training Support) type, or the newer postural training support vest with weights (PTSW), two orthoses made of a softer material, gained popularity because of their improved comfort and increased compliance. The postural training support is worn over the shoulders similar to a mini-backpack and has a pocket into which small weights (total 1.75 lb) weights are added. The postural training support vest with weights is similar except that it is fashioned as a vest, with a Velcro attachment that fastens around the abdomen (Sinaki & Lynn, 2002), c) Spinomed and Spinomed active based on biofeedback theory (Pfeifer et al., 2004; Pfeifer et al., 2011); Spinomed consists of an abdominal pad, splint along the spine, back pad, and a system of belts with Velcro. The back orthosis consists of a back pad, which is workable as a cold material, and a system of belts with Velcro. This allows adjustments for individual sizes by an orthopedic technician. The orthosis weighs 450 g and is worn like a back pad and d) Osteomed, which is based upon

properties of bone at some of the most loaded bone sites (Uusi-Rasi et al., 2003).

al., 2002).

1993).

**4. Modern orthoses in osteoporosis** 

positive effect on the femoral neck and in spinal lumbar bone density, where less intensive exercise also helped (Kerr et al., 1996). In one meta-analysis study it was found that systematic high intensity resistance training is required for the maintenance of spinal lumbar bone density in postmenopausal women; however weight bearing exercise is necessary to help bone density of the hip beyond any other therapeutic intervention (Kelley, 1998).

In a three year period during the EFOPS study (Erlangen Fitness Osteoporosis Study), which included a exercise protocol with a combined strengthening program, jumping and high intensity resistance training in early onset postmenopausal women, sustained the bone density in the spine, the hip and in the heel, however not in the forearm. A well planned study which compared muscle strengthening exercises with weights and with resistance exercises with repetitions showed that the weight used was more important than the number of repetitions in postmenopausal bone (Engelke et al., 2006). A similar analysis in men revealed similar results (Kelley et al., 2000). With respect to bone quality a review study which used peripheral quantitative computed tomography (pQCT) revealed that exercise possibly increased bone mass and geometry in postmenopausal women, changes which theoretically increase bone resistance. Specifically, the effects of exercise are moderate, area specific and act primarily on cortical rather than trabecular bone (Hamilton et al., 2010).

#### **3.4 Combined exercise with calcium, bisphosphonates**

A decreased rate of bone loss in postmenopausal women undergoing exercise and taking calcium supplements is reported in comparison with exercisers only suggesting that calcium deficiency reduces the efficacy of loading to improve bone mass (Prince et al., 2006). In another study included 1890 pre- and postmenopausal women measured by quantitative ultrasound (QUS) at the heel and assessed with validated questionnaire according to physical activity and daily calcium consumption (greater than or less than 800 mg/day) was found that systematically active premenopausal and postmenopausal women had significantly higher values of QUS parameters than their sedentary and moderately active counterparts. Moreover a statistically significant difference in QUS T-score between sedentary premenopausal women and those who exercise systematically was found suggesting that vigorous physical activity is a regulator of bone status during premenopausal years (Dionyssiotis et al, 2010a).

In a randomized, double-blind, placebo-controlled trial the primary endpoint was the 12 month change in bone mass and geometry of the effects of weight-bearing jumping exercise conducted in an average 1.6 ± 0.9 (mean ± SD) times a week and oral alendronate, alone or in combination, measured with dual-energy X-ray absorptiometry and peripheral computed tomography at several axial and limb sites. A total of 164 healthy, sedentary, early postmenopausal women were randomly assigned to one of four experimental groups:(1) 5 mg of alendronate daily plus progressive jumping exercise, (2) 5 mg alendronate, (3) placebo plus progressive jumping exercise, or (4) placebo. Alendronate daily was effective in increasing bone mass at the lumbar spine and femoral neck but did not affect other bone sites. Exercise alone had no effect on bone mass at the lumbar spine or femoral neck; it had neither an additive nor an interactive effect with alendronate at these bone sites. However, at the distal tibia the mean increase in the section modulus (a bone strength parameter) and in the ratio of cortical bone to total bone area were statistically significant in the exercise group compared to the non exercise group, indicating exercise-induced thickening of the bone cortex. The authors concluded that alendronate is effective in increasing bone mass at

positive effect on the femoral neck and in spinal lumbar bone density, where less intensive exercise also helped (Kerr et al., 1996). In one meta-analysis study it was found that systematic high intensity resistance training is required for the maintenance of spinal lumbar bone density in postmenopausal women; however weight bearing exercise is necessary to help bone

In a three year period during the EFOPS study (Erlangen Fitness Osteoporosis Study), which included a exercise protocol with a combined strengthening program, jumping and high intensity resistance training in early onset postmenopausal women, sustained the bone density in the spine, the hip and in the heel, however not in the forearm. A well planned study which compared muscle strengthening exercises with weights and with resistance exercises with repetitions showed that the weight used was more important than the number of repetitions in postmenopausal bone (Engelke et al., 2006). A similar analysis in men revealed similar results (Kelley et al., 2000). With respect to bone quality a review study which used peripheral quantitative computed tomography (pQCT) revealed that exercise possibly increased bone mass and geometry in postmenopausal women, changes which theoretically increase bone resistance. Specifically, the effects of exercise are moderate, area specific and act primarily on cortical rather than trabecular bone (Hamilton et al., 2010).

A decreased rate of bone loss in postmenopausal women undergoing exercise and taking calcium supplements is reported in comparison with exercisers only suggesting that calcium deficiency reduces the efficacy of loading to improve bone mass (Prince et al., 2006). In another study included 1890 pre- and postmenopausal women measured by quantitative ultrasound (QUS) at the heel and assessed with validated questionnaire according to physical activity and daily calcium consumption (greater than or less than 800 mg/day) was found that systematically active premenopausal and postmenopausal women had significantly higher values of QUS parameters than their sedentary and moderately active counterparts. Moreover a statistically significant difference in QUS T-score between sedentary premenopausal women and those who exercise systematically was found suggesting that vigorous physical activity is a regulator of bone status during

In a randomized, double-blind, placebo-controlled trial the primary endpoint was the 12 month change in bone mass and geometry of the effects of weight-bearing jumping exercise conducted in an average 1.6 ± 0.9 (mean ± SD) times a week and oral alendronate, alone or in combination, measured with dual-energy X-ray absorptiometry and peripheral computed tomography at several axial and limb sites. A total of 164 healthy, sedentary, early postmenopausal women were randomly assigned to one of four experimental groups:(1) 5 mg of alendronate daily plus progressive jumping exercise, (2) 5 mg alendronate, (3) placebo plus progressive jumping exercise, or (4) placebo. Alendronate daily was effective in increasing bone mass at the lumbar spine and femoral neck but did not affect other bone sites. Exercise alone had no effect on bone mass at the lumbar spine or femoral neck; it had neither an additive nor an interactive effect with alendronate at these bone sites. However, at the distal tibia the mean increase in the section modulus (a bone strength parameter) and in the ratio of cortical bone to total bone area were statistically significant in the exercise group compared to the non exercise group, indicating exercise-induced thickening of the bone cortex. The authors concluded that alendronate is effective in increasing bone mass at

density of the hip beyond any other therapeutic intervention (Kelley, 1998).

**3.4 Combined exercise with calcium, bisphosphonates** 

premenopausal years (Dionyssiotis et al, 2010a).

the lumbar spine and femoral neck, while exercise is effective in increasing the mechanical properties of bone at some of the most loaded bone sites (Uusi-Rasi et al., 2003).

On the other hand the combined and separate effects of exercise training and bisphosphonate (etidronate) therapy on bone mineral in postmenopausal women were investigated in forty-eight postmenopausal women randomly assigned to groups that took intermittent cyclical etidronate; performed strength training (3 d/week) and received matched placebo; combined strength training with etidronate; or took placebo and served as non-exercising controls. Bone mineral was assessed by dual-energy X-ray absorptiometry before and after 12 months of intervention changes in bone mineral density (BMD) of the lumbar spine were greater in the subjects given etidronate compared with placebo, while exercise had no effect. No effect of etidronate or exercise on the proximal femur and there was no interaction between exercise and etidronate at any bone site was found (Chilibeck et al., 2002).

### **4. Modern orthoses in osteoporosis**

Traditionally, spinal orthoses have been used in the management of thoracolumbar injuries treated with or without surgical stabilization. The vast majority of orthoses, however, are used in patients with low back pain (Perry, 1970). These orthoses, however, have never been tested under standardized conditions. Especially, no prospective, randomized, and controlled clinical trials are available to document efficacy according to the criteria of evidence-based medicine. Moreover, there is a lack of specific studies comparing various types of braces and orthoses. This is also the case for osteoporosis, in which approximately one-fourth of women above 50 years of age have one or more vertebral fractures (Melton, 1993).

Even though, it is widely accepted that spinal orthoses whether made of cloth, metal, or plastic, or whether rigid or flexible, relieve pain and promote the healing process by stabilizing the spine i.e. reducing the load applied on the anterior column and vertebral body by restraining any attempt of forward flexion. The most broadly used types of spinal orthoses use a three-point pressure system (Dionyssiotis et al., 2008; Mazanec et al., 2003): a) the TLSO type (Knight-Taylor, Jewett, CASH or Cruciform Anterior Sternal Hyperextension brace, Boston); that provides support to the thoracolumbosacral spine by making it adopt an anatomically correct position. The CASH or Jewett brace has been favoured for patients with acute vertebral fractures. The goal of these braces is to provide forces to encourage hyperextension. However, a drawback to these orthoses is the limited compliance because of their rigid configuration, b) the PTS (Posture Training Support) type, or the newer postural training support vest with weights (PTSW), two orthoses made of a softer material, gained popularity because of their improved comfort and increased compliance. The postural training support is worn over the shoulders similar to a mini-backpack and has a pocket into which small weights (total 1.75 lb) weights are added. The postural training support vest with weights is similar except that it is fashioned as a vest, with a Velcro attachment that fastens around the abdomen (Sinaki & Lynn, 2002), c) Spinomed and Spinomed active based on biofeedback theory (Pfeifer et al., 2004; Pfeifer et al., 2011); Spinomed consists of an abdominal pad, splint along the spine, back pad, and a system of belts with Velcro. The back orthosis consists of a back pad, which is workable as a cold material, and a system of belts with Velcro. This allows adjustments for individual sizes by an orthopedic technician. The orthosis weighs 450 g and is worn like a back pad and d) Osteomed, which is based upon

Rehabilitation in Osteoporosis 453

Fig. 19. Schematic presentation of differences in the values of personal isometric force: Force (F)/Weight (W) in abdominals and extensors muscles (F/W abdominals and F/W extensors, respectively, after 6 months wearing Spinomed orthosis (F: force in Newton, W: weight in Kg), measured with ISO-RACK device (Digimax, ΜechaTronic, Hamm, Germany). Figure

According to the results obtained from Osteomed studies, the orthosis brings an active erection of the spine of 60% on average of the deliberate maximum possible active erection. The wearing of the orthosis leads to an improvement of posture and statics (Vogt et al., 2005), a straightening of the spine of on average 46% of the conscious maximum achievable straightening (Vogt et al., 2008) and a statistically significant and clinically relevant reduction in chronic back pain by approximately 25% in female patients with osteoporosis

Fig. 20. a) Front view of the Osteomed osteoporosis orthosis (Osteomed, Thaemert Ltd, Germany), b) Dorsal view of the Osteomed osteoporosis orthosis (for demonstration

chamber pads, d) View of the placebo device (adapted from Fink et al., 2006, with

purposes the air chamber pads are shown on the outside), c) View of the orthosis without air

adapted from Dionyssiotis et al., 2010b (with permission).

worn it in a period of 2.5 months (Fink et al., 2007).

permission).

the gate control theory of pain (Vogt et al., 2008); the external appearance of the orthosis Osteomed resembles an item of clothing characterised by a constructively functional cut with Velcro tabs exerting pressure in the lumbosacral region as well as air chamber pads fixed in the paravertebral and lumbosacral areas which are filled with air to between 2/3 and ¾ of their maximum capacity (Vogt et al., 2008).

Fig. 17. Front, back and lateral view of the Spinomed (unpublished images of Dionyssiotis et al.)

Fig. 18. Front, back and lateral view of the Spinomed active orthosis for men and women (Medi-Bayreuth, Bayreuth, Germany, with permission).

In a controlled pilot study with a 4-week observation period the strength of the back extensors was reduced to below the initial value in 40% of female patients wearing a stable orthotic device pointed out that orthotic devices impose a risk of reduction in muscular strength (Kaplan et al., 1996). On the contrary, recently published results of women with established osteoporosis and/or an angle of kyphosis more than 55 degrees wearing Spinomed for at least 2 hours/day for 6 months showing significantly decreased back pain (p=0.001) (evaluation was performed using visual analogue scale at the beginning and 6 months follow up of the examination) and increased personal isometric trunk muscle strength (figure 19) (Dionyssiotis et al., 2010b). Moreover in another Spinomed study subjects separated in two groups, the control and orthosis group, who switched after 6 months. Wearing the orthosis resulted in a 73% increase in back extensor strength, a 58% increase in abdominal flexor strength, most likely because of increased muscular activity while wearing the orthosis, a 11% decrease in angle of kyphosis, a 25% decrease in body sway, a 7% increase in vital capacity, a 38% decrease in average pain, a 15% increase in wellbeing, and a 27% decrease in limitations of daily living (Pfeifer et al., 2004).

the gate control theory of pain (Vogt et al., 2008); the external appearance of the orthosis Osteomed resembles an item of clothing characterised by a constructively functional cut with Velcro tabs exerting pressure in the lumbosacral region as well as air chamber pads fixed in the paravertebral and lumbosacral areas which are filled with air to between 2/3

Fig. 17. Front, back and lateral view of the Spinomed (unpublished images of Dionyssiotis et

Fig. 18. Front, back and lateral view of the Spinomed active orthosis for men and women

being, and a 27% decrease in limitations of daily living (Pfeifer et al., 2004).

In a controlled pilot study with a 4-week observation period the strength of the back extensors was reduced to below the initial value in 40% of female patients wearing a stable orthotic device pointed out that orthotic devices impose a risk of reduction in muscular strength (Kaplan et al., 1996). On the contrary, recently published results of women with established osteoporosis and/or an angle of kyphosis more than 55 degrees wearing Spinomed for at least 2 hours/day for 6 months showing significantly decreased back pain (p=0.001) (evaluation was performed using visual analogue scale at the beginning and 6 months follow up of the examination) and increased personal isometric trunk muscle strength (figure 19) (Dionyssiotis et al., 2010b). Moreover in another Spinomed study subjects separated in two groups, the control and orthosis group, who switched after 6 months. Wearing the orthosis resulted in a 73% increase in back extensor strength, a 58% increase in abdominal flexor strength, most likely because of increased muscular activity while wearing the orthosis, a 11% decrease in angle of kyphosis, a 25% decrease in body sway, a 7% increase in vital capacity, a 38% decrease in average pain, a 15% increase in well-

and ¾ of their maximum capacity (Vogt et al., 2008).

(Medi-Bayreuth, Bayreuth, Germany, with permission).

al.)

Fig. 19. Schematic presentation of differences in the values of personal isometric force: Force (F)/Weight (W) in abdominals and extensors muscles (F/W abdominals and F/W extensors, respectively, after 6 months wearing Spinomed orthosis (F: force in Newton, W: weight in Kg), measured with ISO-RACK device (Digimax, ΜechaTronic, Hamm, Germany). Figure adapted from Dionyssiotis et al., 2010b (with permission).

According to the results obtained from Osteomed studies, the orthosis brings an active erection of the spine of 60% on average of the deliberate maximum possible active erection. The wearing of the orthosis leads to an improvement of posture and statics (Vogt et al., 2005), a straightening of the spine of on average 46% of the conscious maximum achievable straightening (Vogt et al., 2008) and a statistically significant and clinically relevant reduction in chronic back pain by approximately 25% in female patients with osteoporosis worn it in a period of 2.5 months (Fink et al., 2007).

Fig. 20. a) Front view of the Osteomed osteoporosis orthosis (Osteomed, Thaemert Ltd, Germany), b) Dorsal view of the Osteomed osteoporosis orthosis (for demonstration purposes the air chamber pads are shown on the outside), c) View of the orthosis without air chamber pads, d) View of the placebo device (adapted from Fink et al., 2006, with permission).

Rehabilitation in Osteoporosis 455

Fig. 21. Heel to toe exercise and balance standing on one foot: walking heel to toe beside a wall or rail for a short time. In alternative standing at the side of a chair (for safety) and leaning on the chair with one hand, whereas at the same time the opposite leg is raised with the knee bent as shown in the picture. Subjects perform the exercise, first with open and then with closed eyes and continue by changing side and leg of support. Ten repetitions for

These exercises help the cooperation of muscle and nerves in order to avoid falls and fractures and should be done routinely every day for at least 5 minutes. This category includes exercises such as marching, walking around a chair and throwing and catching a

Fig. 22. Marching (photo 1) and walking around a chair (photos 2 and 3). Marching is an excellent exercise for coordination. Training consists of the simultaneous movement of one arm and the opposite leg in turn. During the execution of the exercise, the head must look forward; the arms must be slightly bent on the elbows and must reach up to the height of the shoulders. Placing a chair in a room, to make it able to walk around it on all sides, walking clockwise and then counter clockwise, as fast as they can, (should stop before

each leg are necessary (Dionyssiotis Y., 2010 c).

getting dizzy) and repeat for 5 times (Dionyssiotis Y., 2010 c).

**5.1.2 Coordination exercises** 

ball.

Strengthening the back muscles not only maintains bone density in the spine but also reduces the risk of vertebral fractures. Ten years after a 2-year back exercise program in women fractures, both wedging and vertebral compression fractures, were significantly less (only 11% in the exercise group as compared to 30% in the control group) several years after the exercises were discontinued (Sinaki et al., 2002).

### **5. Prevention of falls and fall related fractures**

An important issue in rehabilitation medicine is the prevention of falls and fall related fractures. Falls is a serious problem facing elderly persons. Falling results in increased mortality, morbidity, reduced functioning and premature nursing home admissions. Falls generally result from an interaction of multiple and diverse risk factors and situations, many of which can be corrected (Dionyssiotis et al., 2008a).

Falls can also result in deterioration of physical functioning and quality of life due to injury or due to fear of falling; 16% of fallers reported that they limited their usual activity because of fear of falling and one third of fallers reduced their participation in social activities (Nevitt et al., 1991). Fear of falling is reported by one in four older people in the community and can lead to distress and reduced quality of life, increased medication use and activity restriction, further decline in physical functioning, greater falling risk and admission to institutional care (Yardley et al., 2005). It is necessary to assess possible intrinsic and extrinsic risk factors for falls, as well as the exposure to individual's risk (Todd & Skelton, 2004).

Identifying risk factors is as important as appreciating the interaction and probable synergism between multiple risk factors because the percentage of persons falling increased from 27% for those with no or one risk factor to 78% for those with four or more risk factors (Tinetti et al., 1988). Important potentially modifiable risk factors for community-dwelling older adults are: mental status and psychotropic drugs, multiple drugs, environmental hazards, vision, lower extremity impairments, balance, gait status and for institution-dwelling older adults: mental status, depression, urinary incontinence, hypotension, hearing, balance, gait, lower extremity impairments, low activity level (exercise less than once a week), psychotropic drugs, cardiac drugs, analgesics and use of a mechanical restraint; non-modifiable risk factors (i.e. hemiplegia, blindness) also exist (Moreland et al., 2003).

Interventions to prevent falls may be planned to reduce a single internal or external risk factor of falling or be broadly focused to reduce multiple risk factors simultaneously (Sjösten et al., 2007). Single evidence based interventions include exercise, reassessment of medications and environmental modification (American Geriatrics Society [AGS], British Geriatrics Society [BGS], and American Academy of Orthopaedic Surgeons [AAOS], 2001; Tinetti, 2003). Although exercise has many proven benefits, the optimal type, duration and intensity of exercise for falls prevention remain unclear. Older people who have had recurrent falls should be offered long-term exercise and balance training (Dionyssiotis et al., 2008a).

#### **5.1 Exercise for falls prevention**

#### **5.1.1 Balance exercises**

Without good balance, there is always the danger of fracture. This type of exercise is the most important in falls prevention. Simple exercises for balance are walking heel to toe beside a wall or rail and balancing on one foot. The purpose of the exercises is the development of synchronized movements, resulting in balanced sitting and standing positions (Dionyssiotis, 2010c).

Strengthening the back muscles not only maintains bone density in the spine but also reduces the risk of vertebral fractures. Ten years after a 2-year back exercise program in women fractures, both wedging and vertebral compression fractures, were significantly less (only 11% in the exercise group as compared to 30% in the control group) several years after

An important issue in rehabilitation medicine is the prevention of falls and fall related fractures. Falls is a serious problem facing elderly persons. Falling results in increased mortality, morbidity, reduced functioning and premature nursing home admissions. Falls generally result from an interaction of multiple and diverse risk factors and situations, many

Falls can also result in deterioration of physical functioning and quality of life due to injury or due to fear of falling; 16% of fallers reported that they limited their usual activity because of fear of falling and one third of fallers reduced their participation in social activities (Nevitt et al., 1991). Fear of falling is reported by one in four older people in the community and can lead to distress and reduced quality of life, increased medication use and activity restriction, further decline in physical functioning, greater falling risk and admission to institutional care (Yardley et al., 2005). It is necessary to assess possible intrinsic and extrinsic risk factors for falls, as well

Identifying risk factors is as important as appreciating the interaction and probable synergism between multiple risk factors because the percentage of persons falling increased from 27% for those with no or one risk factor to 78% for those with four or more risk factors (Tinetti et al., 1988). Important potentially modifiable risk factors for community-dwelling older adults are: mental status and psychotropic drugs, multiple drugs, environmental hazards, vision, lower extremity impairments, balance, gait status and for institution-dwelling older adults: mental status, depression, urinary incontinence, hypotension, hearing, balance, gait, lower extremity impairments, low activity level (exercise less than once a week), psychotropic drugs, cardiac drugs, analgesics and use of a mechanical restraint; non-modifiable risk factors (i.e.

Interventions to prevent falls may be planned to reduce a single internal or external risk factor of falling or be broadly focused to reduce multiple risk factors simultaneously (Sjösten et al., 2007). Single evidence based interventions include exercise, reassessment of medications and environmental modification (American Geriatrics Society [AGS], British Geriatrics Society [BGS], and American Academy of Orthopaedic Surgeons [AAOS], 2001; Tinetti, 2003). Although exercise has many proven benefits, the optimal type, duration and intensity of exercise for falls prevention remain unclear. Older people who have had recurrent falls should

Without good balance, there is always the danger of fracture. This type of exercise is the most important in falls prevention. Simple exercises for balance are walking heel to toe beside a wall or rail and balancing on one foot. The purpose of the exercises is the development of synchronized movements, resulting in balanced sitting and standing

be offered long-term exercise and balance training (Dionyssiotis et al., 2008a).

the exercises were discontinued (Sinaki et al., 2002).

**5. Prevention of falls and fall related fractures** 

of which can be corrected (Dionyssiotis et al., 2008a).

as the exposure to individual's risk (Todd & Skelton, 2004).

hemiplegia, blindness) also exist (Moreland et al., 2003).

**5.1 Exercise for falls prevention** 

positions (Dionyssiotis, 2010c).

**5.1.1 Balance exercises** 

Fig. 21. Heel to toe exercise and balance standing on one foot: walking heel to toe beside a wall or rail for a short time. In alternative standing at the side of a chair (for safety) and leaning on the chair with one hand, whereas at the same time the opposite leg is raised with the knee bent as shown in the picture. Subjects perform the exercise, first with open and then with closed eyes and continue by changing side and leg of support. Ten repetitions for each leg are necessary (Dionyssiotis Y., 2010 c).

### **5.1.2 Coordination exercises**

These exercises help the cooperation of muscle and nerves in order to avoid falls and fractures and should be done routinely every day for at least 5 minutes. This category includes exercises such as marching, walking around a chair and throwing and catching a ball.

Fig. 22. Marching (photo 1) and walking around a chair (photos 2 and 3). Marching is an excellent exercise for coordination. Training consists of the simultaneous movement of one arm and the opposite leg in turn. During the execution of the exercise, the head must look forward; the arms must be slightly bent on the elbows and must reach up to the height of the shoulders. Placing a chair in a room, to make it able to walk around it on all sides, walking clockwise and then counter clockwise, as fast as they can, (should stop before getting dizzy) and repeat for 5 times (Dionyssiotis Y., 2010 c).

Rehabilitation in Osteoporosis 457

more by Tai Chi than by other types of exercise (Graafmans et al., 1996). Although Tai Chi is probably the exercise programme we would least recommend to people who have previously suffered fractures because they show a level of frailty that means they could not fully participate in Tai Chi unless it was adapted so much it was no longer dynamic balance training (Skelton D, personal communication). From the most training studies after hip fracture it seems that combined training with task-specific and functionally based exercises may be a sensible way of retraining leg strength, balance and gait ability in elderly people after a hip fracture. The training thus may include a variety of gait exercises, step exercises, stair climbing, and rising from and sitting down on a chair (Sherrington et al., 2004; Hauer et

A review about the effectiveness of interventions to prevent falls in older adults concluded that exercise programs help prevent falls with no differences between types of exercise (Chang et al., 2004).The results from the FICSIT trials (Frailty and Injuries: Cooperative Studies of Intervention Techniques) suggest that interventions that addressed strength alone did not reduce falls. On the other side balance training may be more effective in lowering

Others concluded that exercise programmes must be regular and sustainable to be effective but more trials are required to determine the exercise type, frequency, duration, and intensity that are most effective in lowering falls risk in different groups of older people (Gardner et al., 2000). However, as ageing is related with reduced physical functioning, exercise prescription for falls prevention, beyond balance and strength training, may include exercises to increase the functional capabilities in all elderly. The suggested guidelines especially for the Greek population are low intensity balance exercises (tandem walking and standing on one's foot) combined with coordination exercises. Individuals who are frail, severely kyphotic or suffer from pain or poor balance may benefit from water exercise (hydrotherapy). People are also advised to undergo strengthening exercises of the quadriceps, hip abductors/extensors, back extensors and the arm muscles (Dionyssiotis et

Frequent fallers should have their medications reviewed. Studies have indicated that the use of medication is a potential cause for falls (Hartikainen et al., 2007). Central nervous system drugs, especially psychotropics warrant particular attention, since there is very strong evidence that use of these medications is linked to the occurrence of falls. Reducing the total number of medications to four or fewer, if feasible, has also been demonstrated to reduce the risk of falling (AGS, BGS, AAOS, 2001; Tinetti, 2003). Environmental hazards could be a cause of falls (Lord et al., 2007). In reducing environmental hazards, falls prevention programs may need to provide and install safety devices particularly in the homes (Wyman et al., 2007). Studies have shown that when older patients at increased risk of falls are discharged from the hospital, a facilitated environmental home assessment should be

There is emerging clinical evidence that alfacalcidol, a prodrug of D-hormone, improves muscle function (Runge & Schacht, 2005). In community dwelling elderly women and men with a total calcium intake of more than 500 mg daily and normal vitamin D serum levels 1 μg alfacalcidol daily reduced significantly the number of falls (-54%) and fallers (-55%) (Dukas et al., 2004). Other authors reported that cholecalciferol-calcium supplementation

al., 2002; Lindelφf et al., 2002).

al., 2008a)

**5.1.4 Clinical trials and multifactorial intervention** 

considered (AGS, BGS, AAOS, 2001; Tinetti, 2003).

falls risk than the other exercise components (Lord et al., 2007).

Fig. 23. Exercise balls. Throwing and catching a ball is a very good exercise for coordination. The exercise is performed for security, from the sitting position and the ball thrown at a low height (photos 4 and 5). After enough practice at the previous exercise and while still in the sitting position, the ball can be thrown to and from another person sitting opposite (photos 6 and 7), (Dionyssiotis Y., 2010 c).


Table 3. Balance and coordination exercises are important for falls prevention; the table summarises the following characteristics of this type of exercise: how we can do them, which are the targets, the intensity, frequency and duration of the program and when to expect the results (Dionyssiotis Y., 2010 c).

### **5.1.3 Tai Chi**

Tai Chi is a promising type of balance exercise, although it requires further evaluation before it can be recommended as the preferred method for balance training (AGS, BGS, AAOS, 2001). Tai Chi which consists of slow, rhythmic movements emphasizing on the trunk rotation, weight shifting, coordination, and a gradual narrowing of the lower extremities position is thought to be an excellent choice of exercise for the elderly.There is experimental evidence from both cross-sectional and longitudinal studies that Tai Chi exercise has beneficial effects on balance control and that the postural stability is improved

Fig. 23. Exercise balls. Throwing and catching a ball is a very good exercise for coordination. The exercise is performed for security, from the sitting position and the ball thrown at a low height (photos 4 and 5). After enough practice at the previous exercise and while still in the sitting position, the ball can be thrown to and from another person sitting opposite (photos 6

> Improving coordinated movements resulting an improve in balance in seated and standing position

Table 3. Balance and coordination exercises are important for falls prevention; the table summarises the following characteristics of this type of exercise: how we can do them, which are the targets, the intensity, frequency and duration of the program and when to

Tai Chi is a promising type of balance exercise, although it requires further evaluation before it can be recommended as the preferred method for balance training (AGS, BGS, AAOS, 2001). Tai Chi which consists of slow, rhythmic movements emphasizing on the trunk rotation, weight shifting, coordination, and a gradual narrowing of the lower extremities position is thought to be an excellent choice of exercise for the elderly.There is experimental evidence from both cross-sectional and longitudinal studies that Tai Chi exercise has beneficial effects on balance control and that the postural stability is improved

Target Intensity

Frequency Duration

medium intensity 5-7 times/week 5-10 min

Time to target

2-4 weeks

and 7), (Dionyssiotis Y., 2010 c).

Type Balance & Coordination

Execution in parallel bars or next to a wall or a chair, because it has to be safe, in order to avoid falls

**5.1.3 Tai Chi** 

expect the results (Dionyssiotis Y., 2010 c).

more by Tai Chi than by other types of exercise (Graafmans et al., 1996). Although Tai Chi is probably the exercise programme we would least recommend to people who have previously suffered fractures because they show a level of frailty that means they could not fully participate in Tai Chi unless it was adapted so much it was no longer dynamic balance training (Skelton D, personal communication). From the most training studies after hip fracture it seems that combined training with task-specific and functionally based exercises may be a sensible way of retraining leg strength, balance and gait ability in elderly people after a hip fracture. The training thus may include a variety of gait exercises, step exercises, stair climbing, and rising from and sitting down on a chair (Sherrington et al., 2004; Hauer et al., 2002; Lindelφf et al., 2002).

### **5.1.4 Clinical trials and multifactorial intervention**

A review about the effectiveness of interventions to prevent falls in older adults concluded that exercise programs help prevent falls with no differences between types of exercise (Chang et al., 2004).The results from the FICSIT trials (Frailty and Injuries: Cooperative Studies of Intervention Techniques) suggest that interventions that addressed strength alone did not reduce falls. On the other side balance training may be more effective in lowering falls risk than the other exercise components (Lord et al., 2007).

Others concluded that exercise programmes must be regular and sustainable to be effective but more trials are required to determine the exercise type, frequency, duration, and intensity that are most effective in lowering falls risk in different groups of older people (Gardner et al., 2000). However, as ageing is related with reduced physical functioning, exercise prescription for falls prevention, beyond balance and strength training, may include exercises to increase the functional capabilities in all elderly. The suggested guidelines especially for the Greek population are low intensity balance exercises (tandem walking and standing on one's foot) combined with coordination exercises. Individuals who are frail, severely kyphotic or suffer from pain or poor balance may benefit from water exercise (hydrotherapy). People are also advised to undergo strengthening exercises of the quadriceps, hip abductors/extensors, back extensors and the arm muscles (Dionyssiotis et al., 2008a)

Frequent fallers should have their medications reviewed. Studies have indicated that the use of medication is a potential cause for falls (Hartikainen et al., 2007). Central nervous system drugs, especially psychotropics warrant particular attention, since there is very strong evidence that use of these medications is linked to the occurrence of falls. Reducing the total number of medications to four or fewer, if feasible, has also been demonstrated to reduce the risk of falling (AGS, BGS, AAOS, 2001; Tinetti, 2003). Environmental hazards could be a cause of falls (Lord et al., 2007). In reducing environmental hazards, falls prevention programs may need to provide and install safety devices particularly in the homes (Wyman et al., 2007). Studies have shown that when older patients at increased risk of falls are discharged from the hospital, a facilitated environmental home assessment should be considered (AGS, BGS, AAOS, 2001; Tinetti, 2003).

There is emerging clinical evidence that alfacalcidol, a prodrug of D-hormone, improves muscle function (Runge & Schacht, 2005). In community dwelling elderly women and men with a total calcium intake of more than 500 mg daily and normal vitamin D serum levels 1 μg alfacalcidol daily reduced significantly the number of falls (-54%) and fallers (-55%) (Dukas et al., 2004). Other authors reported that cholecalciferol-calcium supplementation

Rehabilitation in Osteoporosis 459

This includes several old favourite exercises which are now considered outdated, namely straight-leg toe touches and sit ups (or crunches) for strengthening the abdominal muscles (Bassey, 2001). The latter are associated with a dramatically increased rate of vertebral fracture in osteoporotic women (89% compared to 16% of those who did extension exercises) (Sinaki & Mikkelsen, 1984). As the acute fracture pain subsides, a walking program can begin with gentle strengthening exercises focusing on spinal extensor muscles (Bonner et al., 2003). A carefully supervised rehabilitation program should be started after 3 to 4 months, to strengthen the spinal extensor and abdominal muscles more aggressively (a detailed

Physical therapy after a Colles' fracture consists of muscle strengthening, motion range recovery, wound healing and scar adhesion. Early reduction of oedema is of primary importance in determining hand functions. Elevation of the hand above the heart's level and an active range of motion exercises are instructed to facilitate the pumping action of hand muscles to decrease swelling. Physical modalities and exercise programs consisting of passive and active range of motion; transverse scar massages, progressive resistive exercise, focusing on strengthening both extrinsic and intrinsic muscle groups of the hand are necessary (Morey & Watson, 1986; Dionyssiotis et al., 2008a). Physical therapy is followed

I would like to thank Prof. of Orthopedics George P. Lyritis (University of Athens), for trusting and supporting me during the years 2004-2007 in the Laboratory for Research of the Musculoskeletal System in Athens. Many thanks to Christoforidou Z., Spyrou S., Nixon A., and Spyropoulos Y., Verveniotis D. (graduates of the Faculty of Physical Education and Sport Science of Komotini and Athens, respectively), who became the main models during

Adami, S., Giannini, S., Bianchi, G., Sinigaglia, L., Di Munno, O., Fiore, C. E., Minisola, S.,

Asikainen T.M., Kukkonen-Harjula K., & Miilunpalo S. (2004). Exercise for health for early

Avenell A., Gillespie W.J., Gillespie L.D., & O'Connell D. 2009. Vitamin D and vitamin D

Bassey EJ. (2001). Exercise for prevention of osteoporotic fracture. *Age Ageing*. Vol. 30, No

Beck BR., & Snow CM. (2003). Bone health across the lifespan-exercising our options. *Exerc* 

osteoporosis. *Osteoporos Int.* Vol 20, No 2, pp. 239-244.

Rossini, M. (2009). Vitamin D status and response to treatment in post-menopausal

postmenopausal women: a systematic review of randomised controlled trials.

analogues for preventing fractures associated with involutional and postmenopausal osteoporosis. *Cochrane Database Syst Rev.* Vol. 15, No Apr

rehabilitation program is published in Dionyssiotis et al., 2008a).

by occupational therapy for 3 weeks (Christensen et al., 2001).

the photo shooting of the exercises for osteoporosis.

*Sports Med*. Vol. 34, pp. 753-778.

*Sport Sci Rev.* Vol. 31, pp. 117-122.

(2):CD000227.

(Suppl.4), pp. 29-31.

**7. Acknowledgments** 

**8. References** 

reduces falls by 46% to 65% in community-dwelling older women, but has a neutral effect on falls in men (Bischoff-Ferrari et al., 2006). Prevention may be even more effective when multiple risk factors of falls are taken into account. Most multifactorial fall prevention programmes have been successful in reducing the incidence of falls and risk factors of falling, especially when prevention has been individually tailored and targeted to populations at high risk of falling (Moreland et al., 2003).

Multifactorial interventions should include: a) among community-dwelling older persons (i.e. those living in their own homes), gait training and advice on the appropriate use of assistive devices, review and modification of medication, especially psychotropic medication, exercise programs, with balance training as one of the components, treatment of postural hypotension, modification of environmental hazards and treatment of cardiovascular disorders, b) among older persons in long-term care and assisted living settings staff education programs, gait training and advice on the appropriate use of assistive devices and review and modification of medications, especially psychotropic medications (AGS, BGS, AAOS, 2001; Tinetti, 2003).

### **6. Rehabilitation of common osteoporotic fractures**

Successful operative treatment of hip fracture victims is necessary for the optimization of post-injury mobility and the functional recovery of the patient (Koval, 2005). Two evidencebased clinical practice guidelines suggesting possible treatments and rehabilitation pathways for hip fracture patients, agree that it would be best if they underwent multidisciplinary rehabilitation (Scottish Intercollegiate Guidelines Network [SIGN], 2002; Chilov et al., 2003). Multidisciplinary rehabilitation can be defined as the combined and coordinated use of medical, social, educational and vocational measures for training or retraining the individual to the highest possible level of function (Cameron, 2005).

Hip fracture patients should start breathing exercises so that pulmonary secretions are drained, thus reducing the risk of atelectasies and other complications deriving from the pulmonary system. "Pump like" energetic exercises (ankle pumps) and dorsal/plantar flexion of the foot, knee joint flexion, exercises for the hip and thigh, abduction exercises for the gluteal muscles and exercises for the quadriceps are important. Exercises of the upper extremities and trunk must also be part of the rehabilitation program, so that the patient can move in bed, stand up from a chair and later on be able to mobilize himself by using crutches or a stick. Abdominal and dorsal muscles should also be exercised isometrically and then energetically, in order to minimize the risk of low back pain during weight-bearing exercises (a detailed rehabilitation program is published in Dionyssiotis et al., 2008a).

After a vertebral fracture a program of physical therapy is necessary and helps prevent deformity by strengthening anti-gravity muscles and promoting postural retraining. Breathing exercises promote thoracic expansion and improve the heavily degraded pulmonary function found in patients with spinal osteoporotic fractures (Pfeifer et al., 2004). Instruction on the proper way of lifting things, as well as how to appropriately use a walker or a cane, could be beneficial and thus is strongly recommended. Patients with fractures could perform low-intensity exercise and gentle strengthening programs (e.g., Tai Chi and hydrotherapy) and are strongly recommended to avoid high impact exercise or movements, so that they avoid suffering new vertebral fractures (Tosi et al., 2004). Forward bending of the spine or flexion exercises, especially in combination with twisting, should be avoided.

reduces falls by 46% to 65% in community-dwelling older women, but has a neutral effect on falls in men (Bischoff-Ferrari et al., 2006). Prevention may be even more effective when multiple risk factors of falls are taken into account. Most multifactorial fall prevention programmes have been successful in reducing the incidence of falls and risk factors of falling, especially when prevention has been individually tailored and targeted to

Multifactorial interventions should include: a) among community-dwelling older persons (i.e. those living in their own homes), gait training and advice on the appropriate use of assistive devices, review and modification of medication, especially psychotropic medication, exercise programs, with balance training as one of the components, treatment of postural hypotension, modification of environmental hazards and treatment of cardiovascular disorders, b) among older persons in long-term care and assisted living settings staff education programs, gait training and advice on the appropriate use of assistive devices and review and modification of medications, especially psychotropic

Successful operative treatment of hip fracture victims is necessary for the optimization of post-injury mobility and the functional recovery of the patient (Koval, 2005). Two evidencebased clinical practice guidelines suggesting possible treatments and rehabilitation pathways for hip fracture patients, agree that it would be best if they underwent multidisciplinary rehabilitation (Scottish Intercollegiate Guidelines Network [SIGN], 2002; Chilov et al., 2003). Multidisciplinary rehabilitation can be defined as the combined and coordinated use of medical, social, educational and vocational measures for training or

Hip fracture patients should start breathing exercises so that pulmonary secretions are drained, thus reducing the risk of atelectasies and other complications deriving from the pulmonary system. "Pump like" energetic exercises (ankle pumps) and dorsal/plantar flexion of the foot, knee joint flexion, exercises for the hip and thigh, abduction exercises for the gluteal muscles and exercises for the quadriceps are important. Exercises of the upper extremities and trunk must also be part of the rehabilitation program, so that the patient can move in bed, stand up from a chair and later on be able to mobilize himself by using crutches or a stick. Abdominal and dorsal muscles should also be exercised isometrically and then energetically, in order to minimize the risk of low back pain during weight-bearing

retraining the individual to the highest possible level of function (Cameron, 2005).

exercises (a detailed rehabilitation program is published in Dionyssiotis et al., 2008a).

After a vertebral fracture a program of physical therapy is necessary and helps prevent deformity by strengthening anti-gravity muscles and promoting postural retraining. Breathing exercises promote thoracic expansion and improve the heavily degraded pulmonary function found in patients with spinal osteoporotic fractures (Pfeifer et al., 2004). Instruction on the proper way of lifting things, as well as how to appropriately use a walker or a cane, could be beneficial and thus is strongly recommended. Patients with fractures could perform low-intensity exercise and gentle strengthening programs (e.g., Tai Chi and hydrotherapy) and are strongly recommended to avoid high impact exercise or movements, so that they avoid suffering new vertebral fractures (Tosi et al., 2004). Forward bending of the spine or flexion exercises, especially in combination with twisting, should be avoided.

populations at high risk of falling (Moreland et al., 2003).

medications (AGS, BGS, AAOS, 2001; Tinetti, 2003).

**6. Rehabilitation of common osteoporotic fractures** 

This includes several old favourite exercises which are now considered outdated, namely straight-leg toe touches and sit ups (or crunches) for strengthening the abdominal muscles (Bassey, 2001). The latter are associated with a dramatically increased rate of vertebral fracture in osteoporotic women (89% compared to 16% of those who did extension exercises) (Sinaki & Mikkelsen, 1984). As the acute fracture pain subsides, a walking program can begin with gentle strengthening exercises focusing on spinal extensor muscles (Bonner et al., 2003). A carefully supervised rehabilitation program should be started after 3 to 4 months, to strengthen the spinal extensor and abdominal muscles more aggressively (a detailed rehabilitation program is published in Dionyssiotis et al., 2008a).

Physical therapy after a Colles' fracture consists of muscle strengthening, motion range recovery, wound healing and scar adhesion. Early reduction of oedema is of primary importance in determining hand functions. Elevation of the hand above the heart's level and an active range of motion exercises are instructed to facilitate the pumping action of hand muscles to decrease swelling. Physical modalities and exercise programs consisting of passive and active range of motion; transverse scar massages, progressive resistive exercise, focusing on strengthening both extrinsic and intrinsic muscle groups of the hand are necessary (Morey & Watson, 1986; Dionyssiotis et al., 2008a). Physical therapy is followed by occupational therapy for 3 weeks (Christensen et al., 2001).

### **7. Acknowledgments**

I would like to thank Prof. of Orthopedics George P. Lyritis (University of Athens), for trusting and supporting me during the years 2004-2007 in the Laboratory for Research of the Musculoskeletal System in Athens. Many thanks to Christoforidou Z., Spyrou S., Nixon A., and Spyropoulos Y., Verveniotis D. (graduates of the Faculty of Physical Education and Sport Science of Komotini and Athens, respectively), who became the main models during the photo shooting of the exercises for osteoporosis.

### **8. References**


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**1. Introduction** 

Szejnfeld et al., 2007).

remade every 10 years (Manolagas, 2000).

by the osteoblasts (Manolagas, 2000).

*Universidade Federal de São Paulo, Brasil Universidade Federal do Amazonas, Brasil*

promoted by the osteoblasts (Position Statement, 2002).

\*Joelma Magalhães, Stella Peccin, Rebeca Teixeira, Kelson Silva,

Tiago Teixeira, Jander Souza and Virgínia Trevisani

**23** 

*Brasil* 

**Physical Exercise for** 

*Universidade Federal de São Paulo, Universidade Federal do Amazonas,* 

Lucas Teixeira et al.\*

**Prevention of Falls and Fractures** 

Osteoporosis is a metabolic bone disease that specially affects postmenopausal women resulting in devastating effects associated to the high social-economic impact in the population in general. The World Health Organization defines osteoporosis as a skeletal disorder characterized by a reduction in bone mass with alterations in the microarchitecture of the bone tissue leading to a decrease in bone resistance and increased susceptibility to fractures (World Health Organization, 1994; Bennell et al., 2000; Gali, 2001;

Bone is a highly metabolic active tissue that maintains its remodeling throughout life (Hunter & Sambrook, 2000). On the other side, bone mineral density is a result of a dynamic process of bone formation and resorption called remodeling. Resorption causes the tissue deterioration, while its deposition is responsible for the reconstruction and strengthening of the deteriorated tissue. This process occurs through life in cycles of four to six months (Bemben et al., 2000). The bone wear out in daily life demands a process of permanent remodeling. This remodeling process renews in a year about 10% of the skeleton, that is, all bone tissue is

The global rate of bone resorption is regulated by the osteoclastic differentiation through the regulation of fundamental functional proteins, which specific role is to control its migration and resorption (Bruzzaniti & Baron, 2006). Osteoblasts are the cells responsible for the bone formation through the synthesis and mineralization of the skeleton and formation of osteoids (Bodine & Komm, 2006). Because the osteoids are not able to reproduce when they are damaged they go through a process of apoptosis, releasing osteoclast-forming inductors which will phagocyte them. This is the first stage for its replacement that will be performed

In a regular remodeling process, there is a balance between the enzymatic production of osteoclasts and the production of a primary matrix of collagen and fixation of calcium


## **Physical Exercise for Prevention of Falls and Fractures**

Lucas Teixeira et al.\* *Universidade Federal de São Paulo, Universidade Federal do Amazonas, Brasil* 

### **1. Introduction**

466 Osteoporosis

Wyman J.F., Croghan C.F., Nachreiner N.M., Gross C.R., Stock H.H., Talley K., & Monigold

Yardley L., Beyer N., Hauer K., Kempen G., Piot-Ziegler C., & Todd C. (2005). Development

*Geriatr Soc.*, Vol. 55, No 10, pp. 1548-1556.

Vol 34, No 6, pp. 614-619.

M. (2007). Effectiveness of education and individualized counseling in reducing environmental hazards in the homes of community-dwelling older women. *J Am* 

and initial validation of the Falls Efficacy Scale-International (FES-I). *Age Ageing.,* 

Osteoporosis is a metabolic bone disease that specially affects postmenopausal women resulting in devastating effects associated to the high social-economic impact in the population in general. The World Health Organization defines osteoporosis as a skeletal disorder characterized by a reduction in bone mass with alterations in the microarchitecture of the bone tissue leading to a decrease in bone resistance and increased susceptibility to fractures (World Health Organization, 1994; Bennell et al., 2000; Gali, 2001; Szejnfeld et al., 2007).

Bone is a highly metabolic active tissue that maintains its remodeling throughout life (Hunter & Sambrook, 2000). On the other side, bone mineral density is a result of a dynamic process of bone formation and resorption called remodeling. Resorption causes the tissue deterioration, while its deposition is responsible for the reconstruction and strengthening of the deteriorated tissue. This process occurs through life in cycles of four to six months (Bemben et al., 2000).

The bone wear out in daily life demands a process of permanent remodeling. This remodeling process renews in a year about 10% of the skeleton, that is, all bone tissue is remade every 10 years (Manolagas, 2000).

The global rate of bone resorption is regulated by the osteoclastic differentiation through the regulation of fundamental functional proteins, which specific role is to control its migration and resorption (Bruzzaniti & Baron, 2006). Osteoblasts are the cells responsible for the bone formation through the synthesis and mineralization of the skeleton and formation of osteoids (Bodine & Komm, 2006). Because the osteoids are not able to reproduce when they are damaged they go through a process of apoptosis, releasing osteoclast-forming inductors which will phagocyte them. This is the first stage for its replacement that will be performed by the osteoblasts (Manolagas, 2000).

In a regular remodeling process, there is a balance between the enzymatic production of osteoclasts and the production of a primary matrix of collagen and fixation of calcium promoted by the osteoblasts (Position Statement, 2002).

<sup>\*</sup>Joelma Magalhães, Stella Peccin, Rebeca Teixeira, Kelson Silva,

Tiago Teixeira, Jander Souza and Virgínia Trevisani

*Universidade Federal de São Paulo, Brasil* 

*Universidade Federal do Amazonas, Brasil*

Physical Exercise for Prevention of Falls and Fractures 469

It is believed that about 25% of menopausal women in the USA will exhibit some kind of fracture as a consequence of osteoporosis. The most severe fractures are the fractures of femur and they are associated with higher medical expenses than all other osteoporotic fractures together (Moreira & Xaxier, 2001). The incidence of these fractures has doubled in the last 25 years and it is estimated that six million people in the world will suffer fracture of the proximal femur in 2050. Fractures resulted from the decrease of bone mineral loss are considered an orthopedic epidemic leading to an increase in costs for several countries and

There have been a significant number of evidences showing that the decrease in bone quality, from generation to generation, is caused by a change in life style, having as a main determinant the lack of physical activity. This evidence varies with the biology of the basic bone. However, epidemiological studies indicate that physical activity is the most important

Almost all hip fractures (more than 90%) occur as a result of a fall and these fractures are related not only to the decreased bone mass, but also to other factors such as reduction of balance, muscle strength and power in the lower extremities (American College of Sports Medicine [ACSM], 1995; Parkkari et al. 1999). Therefore, aging and alterations in balance and muscle strength, as well as sensorial changes, predispose patients with osteoporosis to a

The aaging process is associated to several anatomic and physiological changes which are

The visual system with aging tends to decrease the visual acuity and visual field, also decreasing the speed in adjusting to dark and increase in the *threshold* for *luminosity* (Sloane

When the somatosensorial system gets old, it show a loss of proprioceptive fibers related to *kinesthetic* sensitivity. Histological studies have shown the decrease in the number of Pacini,

The main structural and electrophysiological changes in the vestibular system due to aging are: after the age of 40 years, microscopic synaptic changes in the vestibular nerve, increase in the degeneration of the vestibular receptors mainly in the ampullary crest of semicircular

consequently representing a big social and economic problem (Ramalho et al., 2001).

factor to maintain bone mass and prevent fractures (Mosekilde, 1995).

directly related to musculoskeletal frailty and falls (Walsh et al., 2006).

Merkel and Meissner corpuscles in the (Sloane et al., 1989).

Fig. 1. A femoral neck fracture of the hip.

higher risk of having fractures due to falls.

**2. Physiology of aging and falls** 

et al., 1989).

Human beings reach their bone mass peak around age 30 years being strongly affected by genetic, representing 60-80% of the bone mass peak showed by an individual (Ramalho & Castro, 1999).

In the adult, 90% of bone mass is resting, while 10% is in constant activity to revitalize the bone tissue. Neoformation occurs only after the resorption of a damaged bone. In a year, 25% of the trabecular bone and 1% of cortical bone are remodeled by a still unknown mechanism. During growth, the balance of this renewal is positive. In the adulthood, it is even and after age 40 it starts being negative. During the age where this balance is negative, the portion destroyed is not completely remodeled and around 1% of the bone mass is lost annually (Carvalho, 2006).

The decrease in bone mineral density (BMD) with age is considered as a physiological osteopeny, being a universal phenomenon that affects all races and cultures; nonpathological by itself in most of the individuals, but it is the background to development of osteoporosis and consequently, a higher risk of fractures (Ramalho & Castro, 1999). The sequence of this negative renewal throughout the years is responsible for the primary osteoporosis (Carvalho, 2006).

During the age-related bone loss, there is an unbalance in bone remodeling, with an increase of bone resorption compared to formation. In the stage of accelerated postmenopausal bone loss, there is a high rate of bone remodeling, with an increase in the number of osteoclasts that forms a very deep resorption cavity leading to a trabecular perforation. In the slow process of bone loss, osteoclasts build a bone resorption cavity with a normal depth, however the osteoclasts fail in replacing the new bone in a proper way (Yoshinari & Bonfá, 2000).

The incidence of osteoporotic fractures (Figure 1) is strictly related to the individual bone mass that depends on the speed of loss throughout life as well as the amount of bone tissue in the end of puberty and beginning of adulthood. The great variation in bone mass peak is explained not only by hereditary factors but also by gender, race, eating habits, several hormone influence, body composition of lean mass and body fat, intercurrent diseases, chronic use of medications and physical activity (Brandão & Vieira, 1999).

Like any other chronic disease, the ethiology of osteoporosis is multifactorial. Genetic factors contribute approximately with 46% to 62% of bone mineral density (BMD) whereas other causes include lifestyle, diet and physical exercise (Neto et al., 2002).

Osteoporosis is considered a "silent disease" until a fracture occurs. Approximately 1.5 million fractures per year are attributable to this disease. Only in the USA, these fractures result in 500.000 hospitalizations, 800.000 emergency room visits, 2.6 million physician visits. The treatment cost is high. In 2002, 12 billion dollars to 18 billion dollars were spent (Gass & Huges, 2006). In 1998, cost management of osteoporosis fractures in the UK recorded *942 million pounds* per year (Szejnfeld et al., 2007). Because it is considered a "silent" disease, it may progress for decades before being diagnosed. *Osteoporosis* has become one of the major public health problems. Nowadays, the impact of osteoporosis is compared to the impact caused by most important health problems, such as cardiovascular diseases and cancer (Froes et al., 2002).

It exposes the fallers to a high risk of fractures (Johnell et al., 2005; Siris et al., 2006). The first hip fracture is associated to 2.5-fold increased risk of subsequent fracture (Cólon-Emeric et al., 2003) with a high level of morbidity and mortality (Cathleen et al., 2006).

Human beings reach their bone mass peak around age 30 years being strongly affected by genetic, representing 60-80% of the bone mass peak showed by an individual (Ramalho &

In the adult, 90% of bone mass is resting, while 10% is in constant activity to revitalize the bone tissue. Neoformation occurs only after the resorption of a damaged bone. In a year, 25% of the trabecular bone and 1% of cortical bone are remodeled by a still unknown mechanism. During growth, the balance of this renewal is positive. In the adulthood, it is even and after age 40 it starts being negative. During the age where this balance is negative, the portion destroyed is not completely remodeled and around 1% of the bone mass is lost

The decrease in bone mineral density (BMD) with age is considered as a physiological osteopeny, being a universal phenomenon that affects all races and cultures; nonpathological by itself in most of the individuals, but it is the background to development of osteoporosis and consequently, a higher risk of fractures (Ramalho & Castro, 1999). The sequence of this negative renewal throughout the years is responsible for the primary

During the age-related bone loss, there is an unbalance in bone remodeling, with an increase of bone resorption compared to formation. In the stage of accelerated postmenopausal bone loss, there is a high rate of bone remodeling, with an increase in the number of osteoclasts that forms a very deep resorption cavity leading to a trabecular perforation. In the slow process of bone loss, osteoclasts build a bone resorption cavity with a normal depth, however the osteoclasts fail in replacing the new bone in a proper way (Yoshinari & Bonfá,

The incidence of osteoporotic fractures (Figure 1) is strictly related to the individual bone mass that depends on the speed of loss throughout life as well as the amount of bone tissue in the end of puberty and beginning of adulthood. The great variation in bone mass peak is explained not only by hereditary factors but also by gender, race, eating habits, several hormone influence, body composition of lean mass and body fat, intercurrent diseases,

Like any other chronic disease, the ethiology of osteoporosis is multifactorial. Genetic factors contribute approximately with 46% to 62% of bone mineral density (BMD) whereas other

Osteoporosis is considered a "silent disease" until a fracture occurs. Approximately 1.5 million fractures per year are attributable to this disease. Only in the USA, these fractures result in 500.000 hospitalizations, 800.000 emergency room visits, 2.6 million physician visits. The treatment cost is high. In 2002, 12 billion dollars to 18 billion dollars were spent (Gass & Huges, 2006). In 1998, cost management of osteoporosis fractures in the UK recorded *942 million pounds* per year (Szejnfeld et al., 2007). Because it is considered a "silent" disease, it may progress for decades before being diagnosed. *Osteoporosis* has become one of the major public health problems. Nowadays, the impact of osteoporosis is compared to the impact caused by most important health problems, such as

It exposes the fallers to a high risk of fractures (Johnell et al., 2005; Siris et al., 2006). The first hip fracture is associated to 2.5-fold increased risk of subsequent fracture (Cólon-Emeric et

al., 2003) with a high level of morbidity and mortality (Cathleen et al., 2006).

chronic use of medications and physical activity (Brandão & Vieira, 1999).

causes include lifestyle, diet and physical exercise (Neto et al., 2002).

cardiovascular diseases and cancer (Froes et al., 2002).

Castro, 1999).

2000).

annually (Carvalho, 2006).

osteoporosis (Carvalho, 2006).

Fig. 1. A femoral neck fracture of the hip.

It is believed that about 25% of menopausal women in the USA will exhibit some kind of fracture as a consequence of osteoporosis. The most severe fractures are the fractures of femur and they are associated with higher medical expenses than all other osteoporotic fractures together (Moreira & Xaxier, 2001). The incidence of these fractures has doubled in the last 25 years and it is estimated that six million people in the world will suffer fracture of the proximal femur in 2050. Fractures resulted from the decrease of bone mineral loss are considered an orthopedic epidemic leading to an increase in costs for several countries and consequently representing a big social and economic problem (Ramalho et al., 2001).

There have been a significant number of evidences showing that the decrease in bone quality, from generation to generation, is caused by a change in life style, having as a main determinant the lack of physical activity. This evidence varies with the biology of the basic bone. However, epidemiological studies indicate that physical activity is the most important factor to maintain bone mass and prevent fractures (Mosekilde, 1995).

Almost all hip fractures (more than 90%) occur as a result of a fall and these fractures are related not only to the decreased bone mass, but also to other factors such as reduction of balance, muscle strength and power in the lower extremities (American College of Sports Medicine [ACSM], 1995; Parkkari et al. 1999). Therefore, aging and alterations in balance and muscle strength, as well as sensorial changes, predispose patients with osteoporosis to a higher risk of having fractures due to falls.

### **2. Physiology of aging and falls**

The aaging process is associated to several anatomic and physiological changes which are directly related to musculoskeletal frailty and falls (Walsh et al., 2006).

The visual system with aging tends to decrease the visual acuity and visual field, also decreasing the speed in adjusting to dark and increase in the *threshold* for *luminosity* (Sloane et al., 1989).

When the somatosensorial system gets old, it show a loss of proprioceptive fibers related to *kinesthetic* sensitivity. Histological studies have shown the decrease in the number of Pacini, Merkel and Meissner corpuscles in the (Sloane et al., 1989).

The main structural and electrophysiological changes in the vestibular system due to aging are: after the age of 40 years, microscopic synaptic changes in the vestibular nerve, increase in the degeneration of the vestibular receptors mainly in the ampullary crest of semicircular

Physical Exercise for Prevention of Falls and Fractures 471

Other physiological factors also contribute for the development of sarcopenia in advanced age, such as the decreased production of anabolic hormones, which jeopardizes the musculoskeletal capacity to incorporate aminoacids and to perform the protein synthesis. An increase in the release of catabolic agents also increases the muscle wear in seniors causing a decreased supply of glycolytic enzymes and smaller supply of ATP (Deschenes et al., 2004). Studies have shown that the muscle mass starts to decrease in approximately 1% a year after the fourth decade of life. Most of the times, sarcopenia is marked by the stability of weight, due to the changes related to age in the body composition. However, several groups have reported the prevalence of sarcopenia, but these findings need to be further researched since they use different techniques to measure the lean mass and also use populations of different references. The prevalence of osteopenia and osteoporosis were estimated as 42% and 17%, respectively in women over 50 years old, where caucasian women showed the greatest number of cases of low bone density. Since the proportion of elderly older than 65 years in the population might increase, the incidence of sarcopenia and osteopenia might also increase. In women, menopause has been associated to a reduction in lean mass (LM) and bone mineral density (BMD). Several researches have demonstrated a positive relationship between LM and BMD and females with osteoporosis have been shown to have a significantly lower appendicular skeletal muscle mass compared to control groups. Based on the theory that the muscle mass is an indicator of BMD, one might speculate that sarcopenia is a risk factor for the development of oestopenia and that it is more prevalent in osteopenic

Studies conducted by Walsh et al., 2006, revealed that 12.5% of postmenopausal women were osteopenic and that 25% of those postmenopausal osteopenic women and 50% of postmenopausal women with osteoporosis have sarcopenia. Therefore, they might present a higher risk of fractures compared to osteopenic women and osteoporotic women with a

Possible neural mechanisms that evidence this decrease in power associated to aging include the undefined changes in the CNS, a delay in the conduction velocity of motor nerve fibers and a delayed transmission in the neuromuscular junction or all three (Krueger et al., 2001). Similarly, a decrease in the number or the relative cross-sectional area of type II fibers, alterations in the sarcoplasmic reticulum and metabolism of calcium within the fibers, changes in the composition of isoforms of myosin in different fibers, functional and enzymatic properties of the myosin, an increase in the non contractile tissue, generating a greater resistance or combination of factors, might be responsible for the decreased power

The reduced capillary density and blood flow, impairment of glucose transport and lower mitochondrial density, decreased activity of oxidative enzymes and reduced rate of phosphocreatinine repletion contribute to the decrease in muscle endurance verified in

The loss of power might cause more damage to the elderly than the loss of maximum muscle strength since the development of explosive force is an important mechanism to prevent falls and to perform heavy duties such as velocity in rising from a chair and walking

A fall can be defined as a sudden, unintentional change in position causing an individual to

Almost all hip fractures occur as a result of a fall. These fractures are related not only to a decreased bone mass but also to factors such as a reduction in balance, strength and muscle

land at a lower level in relation to his initial position (Feder et al., 2000).

individuals (Walsh et al., 2006).

relatively normal skeletal muscle index.

in the elderly (Hunter et al., 2004; Krueger et al., 2001).

people with advanced age (Krueger et al., 2001)

(Krueger et al., 2001; Hunter et al., 2004).

canals and saccule at the age of 50 years, preceding the decrease in the proportion of cells in the Scarpa ganglion. After the age of 60, there is an increase in friction among the fibers of the vestibular nerve, selective loss of density in the myelin fibers leading to a decrease in conduction velocity of the electrical stimuli in the vestibular nerve, decrease of the nystagmic response to caloric and rotational tests in elderly people, decrease in the ptokinetic nystagmus amplitude and pursue eye movements, mainly for the visual stimulus with high speed (Vicini et al., 1989).

Qualitative and quantitative changes in the ciliated cells are observed as well cystic degenerations, fusion of cilia and lipofuscin inclusion in the cell (Isuji et al., 2000).

The loss of ciliated cells is relevant and in general occurs in five sensorial structures of the vestibular system (three semicircular canals, saccule and utricle) in elderly patients, being greater in the crista of semicircular canals than at the saccular and utricular maculae (Isuji et al., 2000).

In the elderly, the vestibulo-ocular reflex (VOR) shows a bigger capacity of compensation than the vestibular-spinal reflex (VSR) aggravating the difficult in maintaining the stability in posture stability (Enrietto et al., 1999; Norré et al., 1987). Another factor that has an influence on the postural instability in the elderly is the alteration in the neuromuscular system.

Studies have shown that the muscle strength reaches its peak around the age of 30 years and it is satisfactory preserved up to the age of 50 years (Deschenes, 2004). However, a decrease in strength is observed around the age of 50 and 60 years, with a faster decrease after the age of 60 years (Krueger et al., 2001). The muscle mass decrease around 50% between 20 and 90 years of age and the number of fibers in the elderly is approximately 20% smaller than in the adults (Rossi & Sadler, 2002).

When measured after the 50s, the progression rate related to a reduction in strength is around 8 to 15% by decade and men, as well as women, show the same pattern of strength decrease during aging (Deschenes, 2004; Krueger et al., 2001). However, longitudinal investigations have shown a greater increase in the strength reduction in seniors than the results found in transversal studies (Deschenes, 2004).

Additional complications in muscle function associated to severe or chronic diseases, hospitalizations after trauma or surgery and lack of activity might accelerate the muscular strength decrease (Krueger et al., 2001). Age-associated decrease of muscle strength mainly results in a substantial reduction in muscle mass that follows the aging process, generating a great loss of muscle mass and an increase in the subcutaneous and intramuscular fat, denominated "sarcopenia" (Wilmore & Costill, 1999; Deschenes, 2004; Hunter et al., 2004; Krueger et al., 2001).

According to Deschenes, 2004, the decrease in the number of muscle fibers is the main cause of sarcopenia, although fiber atrophy is also involved.

A decline in strength of around 30% is observed in people with ages ranging from 50 to 70 years. These changes in the muscle structure are more common in women than in men, in the lower limbs than in the upper limbs and most of this decrease is caused by a selective atrophy in type IIB muscle fibers (American College of Sports Medicine, 1998).

However, it is believed that the aging process is responsible for the loss of α motoneurons; therefore, elderly individuals would show smaller amounts of motor units. This is explained by the degeneration of neural elements, re-organization of the other components, variation in the ratio of different types of motor units and alterations in the propriety of each motor unit.

canals and saccule at the age of 50 years, preceding the decrease in the proportion of cells in the Scarpa ganglion. After the age of 60, there is an increase in friction among the fibers of the vestibular nerve, selective loss of density in the myelin fibers leading to a decrease in conduction velocity of the electrical stimuli in the vestibular nerve, decrease of the nystagmic response to caloric and rotational tests in elderly people, decrease in the ptokinetic nystagmus amplitude and pursue eye movements, mainly for the visual stimulus

Qualitative and quantitative changes in the ciliated cells are observed as well cystic

The loss of ciliated cells is relevant and in general occurs in five sensorial structures of the vestibular system (three semicircular canals, saccule and utricle) in elderly patients, being greater in the crista of semicircular canals than at the saccular and utricular maculae (Isuji et

In the elderly, the vestibulo-ocular reflex (VOR) shows a bigger capacity of compensation than the vestibular-spinal reflex (VSR) aggravating the difficult in maintaining the stability in posture stability (Enrietto et al., 1999; Norré et al., 1987). Another factor that has an influence on the postural instability in the elderly is the alteration in the neuromuscular

Studies have shown that the muscle strength reaches its peak around the age of 30 years and it is satisfactory preserved up to the age of 50 years (Deschenes, 2004). However, a decrease in strength is observed around the age of 50 and 60 years, with a faster decrease after the age of 60 years (Krueger et al., 2001). The muscle mass decrease around 50% between 20 and 90 years of age and the number of fibers in the elderly is approximately 20% smaller than in the

When measured after the 50s, the progression rate related to a reduction in strength is around 8 to 15% by decade and men, as well as women, show the same pattern of strength decrease during aging (Deschenes, 2004; Krueger et al., 2001). However, longitudinal investigations have shown a greater increase in the strength reduction in seniors than the

Additional complications in muscle function associated to severe or chronic diseases, hospitalizations after trauma or surgery and lack of activity might accelerate the muscular strength decrease (Krueger et al., 2001). Age-associated decrease of muscle strength mainly results in a substantial reduction in muscle mass that follows the aging process, generating a great loss of muscle mass and an increase in the subcutaneous and intramuscular fat, denominated "sarcopenia" (Wilmore & Costill, 1999; Deschenes, 2004; Hunter et al., 2004;

According to Deschenes, 2004, the decrease in the number of muscle fibers is the main cause

A decline in strength of around 30% is observed in people with ages ranging from 50 to 70 years. These changes in the muscle structure are more common in women than in men, in the lower limbs than in the upper limbs and most of this decrease is caused by a selective

However, it is believed that the aging process is responsible for the loss of α motoneurons; therefore, elderly individuals would show smaller amounts of motor units. This is explained by the degeneration of neural elements, re-organization of the other components, variation in the ratio of different types of motor units and alterations in the propriety of each motor unit.

atrophy in type IIB muscle fibers (American College of Sports Medicine, 1998).

degenerations, fusion of cilia and lipofuscin inclusion in the cell (Isuji et al., 2000).

with high speed (Vicini et al., 1989).

adults (Rossi & Sadler, 2002).

Krueger et al., 2001).

results found in transversal studies (Deschenes, 2004).

of sarcopenia, although fiber atrophy is also involved.

al., 2000).

system.

Other physiological factors also contribute for the development of sarcopenia in advanced age, such as the decreased production of anabolic hormones, which jeopardizes the musculoskeletal capacity to incorporate aminoacids and to perform the protein synthesis. An increase in the release of catabolic agents also increases the muscle wear in seniors causing a decreased supply of glycolytic enzymes and smaller supply of ATP (Deschenes et al., 2004).

Studies have shown that the muscle mass starts to decrease in approximately 1% a year after the fourth decade of life. Most of the times, sarcopenia is marked by the stability of weight, due to the changes related to age in the body composition. However, several groups have reported the prevalence of sarcopenia, but these findings need to be further researched since they use different techniques to measure the lean mass and also use populations of different references. The prevalence of osteopenia and osteoporosis were estimated as 42% and 17%, respectively in women over 50 years old, where caucasian women showed the greatest number of cases of low bone density. Since the proportion of elderly older than 65 years in the population might increase, the incidence of sarcopenia and osteopenia might also increase. In women, menopause has been associated to a reduction in lean mass (LM) and bone mineral density (BMD). Several researches have demonstrated a positive relationship between LM and BMD and females with osteoporosis have been shown to have a significantly lower appendicular skeletal muscle mass compared to control groups. Based on the theory that the muscle mass is an indicator of BMD, one might speculate that sarcopenia is a risk factor for the development of oestopenia and that it is more prevalent in osteopenic individuals (Walsh et al., 2006).

Studies conducted by Walsh et al., 2006, revealed that 12.5% of postmenopausal women were osteopenic and that 25% of those postmenopausal osteopenic women and 50% of postmenopausal women with osteoporosis have sarcopenia. Therefore, they might present a higher risk of fractures compared to osteopenic women and osteoporotic women with a relatively normal skeletal muscle index.

Possible neural mechanisms that evidence this decrease in power associated to aging include the undefined changes in the CNS, a delay in the conduction velocity of motor nerve fibers and a delayed transmission in the neuromuscular junction or all three (Krueger et al., 2001). Similarly, a decrease in the number or the relative cross-sectional area of type II fibers, alterations in the sarcoplasmic reticulum and metabolism of calcium within the fibers, changes in the composition of isoforms of myosin in different fibers, functional and enzymatic properties of the myosin, an increase in the non contractile tissue, generating a greater resistance or combination of factors, might be responsible for the decreased power in the elderly (Hunter et al., 2004; Krueger et al., 2001).

The reduced capillary density and blood flow, impairment of glucose transport and lower mitochondrial density, decreased activity of oxidative enzymes and reduced rate of phosphocreatinine repletion contribute to the decrease in muscle endurance verified in people with advanced age (Krueger et al., 2001)

The loss of power might cause more damage to the elderly than the loss of maximum muscle strength since the development of explosive force is an important mechanism to prevent falls and to perform heavy duties such as velocity in rising from a chair and walking (Krueger et al., 2001; Hunter et al., 2004).

A fall can be defined as a sudden, unintentional change in position causing an individual to land at a lower level in relation to his initial position (Feder et al., 2000).

Almost all hip fractures occur as a result of a fall. These fractures are related not only to a decreased bone mass but also to factors such as a reduction in balance, strength and muscle

Physical Exercise for Prevention of Falls and Fractures 473

furniture, small objects, wires), lack of rails in halls and bathrooms, extremely low or high shelves, inadequate shoes and clothes, poorly maintained streets with holes or irregularities

Intensity, duration, frequency and progression of the training are arguable, therefore future studies with better designs are required to evaluate these variables. Below are the exercise

In general, the counter-indications are similar to the ones for a young adult. However, the need of a stress ECG is contradictory and it should be considered for patients with cardiac

The exercises might have as a purpose to improve the functional limitations that seniors might have (pain, reduced movement range or muscle weakness). As soon as the limitations are improved, a program of general conditioning should be implemented to improve health

Training sessions should include three stages: warm-up, which involves low impact exercises to gain joint range of motion, training period (the effort itself), that involves muscle strengthening and/or aerobic exercises and the final stage that consists of stretching (cool

Stretching should be performed during the warm up and in the last phase. A great joint range of motion (ROM) increases the muscle, reduces the risk of lesion and increases the cartilage nutrition. Painful joints should not be stretched excessively to a point that will result in more pain; all movements should be made in order to get the maximum pain-free ROM. The use of heat before stretching reduces pain and increases the range. At least three sessions of stretching might be performed a week. In the beginning, three to five repetitions and a gradual increase up to 10 repetitions is the ideal. The muscle should be stretched

Muscle strengthening should be acquired with weights or elastic bands which will give endurance to the movement. The training protocols should include the following principles:






should include few repetitions;

prescriptions for the elderly based on some consensus found in the literature:

and inappropriate orthosis.

**3. Exercise prescription** 

**3.1 Pre-participation** 

risk factors.

down).

**3.3 Stretching** 

during 10 to 30 seconds.

**3.4 Muscle strengthening** 

**3.2 How to start** 

and functional capacity of the elderly.

power in the lower extremities (American College of Sports Medicine, 1995; Nyberg et al., 1996).

The pathogenesis of fall is multifactorial (Nevitt et al., 1989; Tinetti et al., 1989). According to the Brazilian Society of Geriatric and Gerontology, 2008, the causes for falling might be divided in intrinsic and extrinsic and they are the following:

### **2.1 Intrinsic risk factors**


#### **2.2 Extrinsic risk factors**

The participation of environmental risk factors might reach, according to studies, up to 50% of the falls in elderly that live in the community. These factors include poor lighting, slippery surfaces, loose or folded rugs, high or narrow stairs, obstacles in the way (low furniture, small objects, wires), lack of rails in halls and bathrooms, extremely low or high shelves, inadequate shoes and clothes, poorly maintained streets with holes or irregularities and inappropriate orthosis.

### **3. Exercise prescription**

472 Osteoporosis

power in the lower extremities (American College of Sports Medicine, 1995; Nyberg et al.,

The pathogenesis of fall is multifactorial (Nevitt et al., 1989; Tinetti et al., 1989). According to the Brazilian Society of Geriatric and Gerontology, 2008, the causes for falling might be

Previous history of falls – One or more falls in the previous year increase the risk of new

 Age – The prevalence of falls increases with age, however a review has shown that from 11 studies, only four found a positive association between aging and future falls; Females – In older women, the rate of women who fall is greater than in men and

 Medications – Medications such as psychotropic drugs, cardiac medications like diuretics, antiarrhythmic, vasodilators and cardiac glycoside and polipharmacy

 Clinical condition – Diseases such as systemic arterial hypertension, diabetes mellitus and neurological or osteoarticular diseases affecting muscle strength, balance and gait are common risk factors. Orthostatic hypotension might be systematically researched due to its high prevalence. Severe diseases or unbalanced chronic conditions that affect

 Gait and balance disorders – They might be caused by aging itself, predisposing to falls when there is a decrease in force and endurance below the minimum threshold to

Lack of physical exercise – The lack of physical exercise might cause an important

 Psychological state – The fear of falling again after a fall is correlated to the worse performance of gait and new episodes of fall, which might restrict physical and social

Nutritional deficiency – It is related to the gait disorder, loss of muscle strength and

Visual impairment – Changes in acuity and visual field, as well as cataracts, glaucoma

 Orthopedic disease – Diseases such as cervical spondilosis that might provoke dizziness, unbalance and feet problems, such as callus, deformities, ulcers and pain

Functional state – the risk of falling is progressively increased according to the

The participation of environmental risk factors might reach, according to studies, up to 50% of the falls in elderly that live in the community. These factors include poor lighting, slippery surfaces, loose or folded rugs, high or narrow stairs, obstacles in the way (low

Cognitive impairment – Even a small deficit might increase the risk of fall;

and macular degeneration are correlated to the increased risk of fall;

(simultaneous use of four or more medications) are predisposing factors;

divided in intrinsic and extrinsic and they are the following:

1996).

**2.1 Intrinsic risk factors** 

falls in the subsequent year;

shows a greatest risk of fractures;

the brain perfusion might also trigger a fall;

perform independent daily life activities;

activities. Depression is also correlated to falls;

when walking also contribute to the genesis of fall;

individual degree of dependence;

musculoskeletal disorder;

osteoporosis;

**2.2 Extrinsic risk factors** 

Intensity, duration, frequency and progression of the training are arguable, therefore future studies with better designs are required to evaluate these variables. Below are the exercise prescriptions for the elderly based on some consensus found in the literature:

### **3.1 Pre-participation**

In general, the counter-indications are similar to the ones for a young adult. However, the need of a stress ECG is contradictory and it should be considered for patients with cardiac risk factors.

### **3.2 How to start**

The exercises might have as a purpose to improve the functional limitations that seniors might have (pain, reduced movement range or muscle weakness). As soon as the limitations are improved, a program of general conditioning should be implemented to improve health and functional capacity of the elderly.

Training sessions should include three stages: warm-up, which involves low impact exercises to gain joint range of motion, training period (the effort itself), that involves muscle strengthening and/or aerobic exercises and the final stage that consists of stretching (cool down).

### **3.3 Stretching**

Stretching should be performed during the warm up and in the last phase. A great joint range of motion (ROM) increases the muscle, reduces the risk of lesion and increases the cartilage nutrition. Painful joints should not be stretched excessively to a point that will result in more pain; all movements should be made in order to get the maximum pain-free ROM. The use of heat before stretching reduces pain and increases the range. At least three sessions of stretching might be performed a week. In the beginning, three to five repetitions and a gradual increase up to 10 repetitions is the ideal. The muscle should be stretched during 10 to 30 seconds.

### **3.4 Muscle strengthening**

Muscle strengthening should be acquired with weights or elastic bands which will give endurance to the movement. The training protocols should include the following principles:


Physical Exercise for Prevention of Falls and Fractures 475

is processed, having an influence on reflex responses and voluntary motor control. Proprioception contributes to postural control, joint stability and several conscious

It is extremely important to understand that proprioception is only limited to the acquisition of the mechanical stimulus and its transduction in neural stimuli, not having any influence

Proprioception is part of a system denominated somatosensorial system. This includes all mechanical information provided by the mechanoreceptors. The feeling of pain is provided by the nociceptors and the thermal information provided by thermoreceptors (Guyton &

All propriocetive information are originated at the muscular and tendon receptors called muscular fusion and Golgi tendon organ and receptors located in ligaments, articular

Four elements should be focused to reestablish the sensorimotor deficits: proprioception, stabilization, reactive neuromuscular control and functional motor patterns (Lephart &

The proprioceptive mechanism comprises both conscious and unconscious pathways. Therefore, the prescribed exercises need to include conscious exercises to stimulate the cognition as well as sudden and unexpected alterations of joint position that initiate reflex muscle contraction. These exercises should involve balance in an unstable surface while the individual perform functional activities. The purpose of the dynamic stabilization training is

Exercises to stimulate proprioception and dynamic stabilization should be performed in closed-chain activities and with small movements, since the compression stimulates the articular receptors and the changes in the curve length-tension stimulate the muscle receptors. Limbs repositioning exercises should also be performed to stimulate the sense of

The improvement of dynamic stiffness is another important aspect. It is suggested that muscle receptors increase its sensitivity through the increase of dynamic stiffness (Adler et al., 2008).

Fig. 2. Balance control: Sensory and motor system. Credit: http://resourcesonbalance.com

to improve the co-activation between the antagonist muscles (Hurd et al., 2006)

joint position and neuromuscular control (Lephart & Henry, 1995).

on the CNS processing and its motor response (Lephart & Fu, 2000).

capsule, meniscus and cutaneous tissues (Guyton & Hall, 2006).

sensations (Lephart & Fu, 2000).

Hall, 2006).

Henry, 1995).


### **4. Physical exercise to prevent falls**

Prevention in individuals older than 60 years has an important role in avoiding adverse consequences resulting from falls (Weatherall, 2004).

The work to prevent fractures related to osteoporosis should focus the prevention or increase of material and structural properties of the bone, the prevention of falls and improvement of total mass of lean tissue (American College of Sports Medicine, 1995). The American College of Sports Medicine recommends that:


#### **4.1 Exercises for postural control**

Postural control is a result of the combination of several types of sensorial information, such as visual, vestibular and somatosensorial information, and passive and active properties of the nervous system and skeletomuscle system that composes the human postural control system (Figure 2), (Shumway-Cook et al., 2000).

The postural control system use three functions that are required to maintain balance: support, stabilization and balance. The body should contract the adequate muscles to sustain the body against gravity; the articular segments should be stabilized and the body should be stabilized in the body's support base (Rothwell, 1994).

Currently, proprioception is defined as a set of afferent information provided by joints, muscles, tendons and other tissues that reaches the Central Nervous System (CNS) where it


after the inflammation is over, it should be increased from 5 to 10 times a day. - Isotonic exercises should include from 8 to 10 exercises involving the major muscle groups (four exercises for the upper limbs and from four to six for the lower limbs). At first, patients should use weights with 40% of the individual's maximal load, increasing up to 80%. Generally, a series of four to six repetitions should be made, avoiding the muscle fatigue. At first, the frequency should be at most twice a week but in case of individuals with advanced age or significant fragility the exercises should be made only

once a week. Between the sessions, there might be at least one full day of rest.

Prevention in individuals older than 60 years has an important role in avoiding adverse

The work to prevent fractures related to osteoporosis should focus the prevention or increase of material and structural properties of the bone, the prevention of falls and improvement of total mass of lean tissue (American College of Sports Medicine, 1995).

1. physical activity of transporting weight is essential to the normal development and maintenance of a health skeleton. Activities that focus the increase of muscle strength

2. a sedentary woman might progressively increase her bone mass by becoming active, but the primary benefit of increasing the activity is to prevent a future bone reduction

4. the optimal program for an older woman might include activities that improve the strength, flexibility and coordination which might indirectly, but effectively decrease the incidence of osteoporotic fractures by reducing the probability of falls. Therefore, the treatment of osteoporosis should aim the prevention of falls and fractures and

Postural control is a result of the combination of several types of sensorial information, such as visual, vestibular and somatosensorial information, and passive and active properties of the nervous system and skeletomuscle system that composes the human postural control

The postural control system use three functions that are required to maintain balance: support, stabilization and balance. The body should contract the adequate muscles to sustain the body against gravity; the articular segments should be stabilized and the body

Currently, proprioception is defined as a set of afferent information provided by joints, muscles, tendons and other tissues that reaches the Central Nervous System (CNS) where it

might also be beneficial, particularly for bones that do not support weight;

3. exercise should not be recommended as a replacement to medications treatment;

**4. Physical exercise to prevent falls** 

consequences resulting from falls (Weatherall, 2004).

that resulting from the lack of activity;

system (Figure 2), (Shumway-Cook et al., 2000).

**4.1 Exercises for postural control** 

The American College of Sports Medicine recommends that:

preservation or improvement of bone mineral density.

should be stabilized in the body's support base (Rothwell, 1994).

is processed, having an influence on reflex responses and voluntary motor control. Proprioception contributes to postural control, joint stability and several conscious sensations (Lephart & Fu, 2000).

It is extremely important to understand that proprioception is only limited to the acquisition of the mechanical stimulus and its transduction in neural stimuli, not having any influence on the CNS processing and its motor response (Lephart & Fu, 2000).

Proprioception is part of a system denominated somatosensorial system. This includes all mechanical information provided by the mechanoreceptors. The feeling of pain is provided by the nociceptors and the thermal information provided by thermoreceptors (Guyton & Hall, 2006).

All propriocetive information are originated at the muscular and tendon receptors called muscular fusion and Golgi tendon organ and receptors located in ligaments, articular capsule, meniscus and cutaneous tissues (Guyton & Hall, 2006).

Four elements should be focused to reestablish the sensorimotor deficits: proprioception, stabilization, reactive neuromuscular control and functional motor patterns (Lephart & Henry, 1995).

The proprioceptive mechanism comprises both conscious and unconscious pathways. Therefore, the prescribed exercises need to include conscious exercises to stimulate the cognition as well as sudden and unexpected alterations of joint position that initiate reflex muscle contraction. These exercises should involve balance in an unstable surface while the individual perform functional activities. The purpose of the dynamic stabilization training is to improve the co-activation between the antagonist muscles (Hurd et al., 2006)

Exercises to stimulate proprioception and dynamic stabilization should be performed in closed-chain activities and with small movements, since the compression stimulates the articular receptors and the changes in the curve length-tension stimulate the muscle receptors. Limbs repositioning exercises should also be performed to stimulate the sense of joint position and neuromuscular control (Lephart & Henry, 1995).

The improvement of dynamic stiffness is another important aspect. It is suggested that muscle receptors increase its sensitivity through the increase of dynamic stiffness (Adler et al., 2008).

Fig. 2. Balance control: Sensory and motor system. Credit: http://resourcesonbalance.com

(Table 1).

Balance exercises (balance board, mini-trampoline. Dyna disc)

Table 1. Examples of exercises

falls (Pfeifer et al., 2004).

(Lange et al., 2005).

et al., 1996).

Physical Exercise for Prevention of Falls and Fractures 477

with eyes open and/or closed; change in floor for a more unstable surface such as a trampoline and balance board; exercises with dissociation of waist and use of a stick

Mat exercises Go up/down: 1 to 3 mats 10 rep / 3 series

Exercises on the stairs Variation in speed 10 rep / 3 series

Evidences have shown that specific exercises might reduce the risk factors for falls and number of falls in older people (Lord & Clark, 1996; Robertson et al., 2001-1, 2001-2; Hartard

In 2006, Carvalho stated that the main goal of the osteoporosis treatment is to prevent fractures and as 90% of the fractures resulted from falls, the fundamental part of fracture treatment is to prevent them. This prevention represents a great area of interest in

Because of the strong interaction between osteoporosis and falls, the selection of participants in protocols for the prevention of fractures should be based on factors related to bones and

The German Society of Sport Medicine and the American College of Sport Medicine also recommend that the ideal program for women with osteoporosis should include activities that improve strength, flexibility and coordination that might indirectly and more effectively decrease the incidence of osteoporotic fractures by the reduction in the probability of falls

Data combined from three studies conducted by Gillespie et al., 2006, with a total of 556 women aged 80 years or older, who underwent to the same progressive muscular strengthening program, balance training and gait training indicate that this intervention decreased the number of individuals that fell during a year, having also reduced the number of injurious falls. Although the studies had methodological limitations, there is a determined consistency as for the decrease of falls in multiple interventions exercises (Gillespie et al., 2009). As for the physical exercise, we only know that it improves balance without a direct association with the decrease in the number of falls (Howe Tracey et al., 2009) and that

Stability exercises Unipodal or bipodal support

Anteroposterior and latero-lateral gait With or without obstacle and

Exercises with sticks With or without arm

researches on older people's health (Weatherall, 2004).

**Options of Exercises Evolution of Exercises Time or # of** 

Eyes open or closed

/ stable or unstable 10 rep / 30s

/ open or close base 10 rep / 30s

Variation in speed 10 rep (3 m)

movements 10 rep / 3 series

**repetitions** 

Exercises that involve eccentric training, like going down the stairs and landing after jumps, are the most efficient to increase anticipatory and reactive muscular stiffness (Bastian et al., 2006).

The reactive neuromuscular control is reached through exercises that create unexpected situations, such as perturbations in unstable surfaces in unipodal support and during gait. Apparently, this kind of training improves the preparatory and reactive muscle activation (Swanik et al., 2002).

The training protocol might include:


Fig. 3. Example of a circuit training

Examples of exercises: ten repetitions with one-minute intervals for antero-posterior and latero-lateral gait; gait with obstacles (20 cm high); gait over mattress; going up and down the stairs; change in direction according to the sound stimulus; balance exercises lasting 30 seconds and with one-minute interval for unipodal and bipodal support on the floor

Exercises that involve eccentric training, like going down the stairs and landing after jumps, are the most efficient to increase anticipatory and reactive muscular stiffness (Bastian et al.,

The reactive neuromuscular control is reached through exercises that create unexpected situations, such as perturbations in unstable surfaces in unipodal support and during gait. Apparently, this kind of training improves the preparatory and reactive muscle activation

1. 5 – 10 minutes of warm-up, with stretching movements for upper and lower limbs, 03 repetitions for each movement being kept for 30 seconds, with 30-second intervals among the series. After stretching, movements of fast gait as previous warm-up were

Examples of exercises: ten repetitions with one-minute intervals for antero-posterior and latero-lateral gait; gait with obstacles (20 cm high); gait over mattress; going up and down the stairs; change in direction according to the sound stimulus; balance exercises lasting 30 seconds and with one-minute interval for unipodal and bipodal support on the floor

performed and in the end of the session, slow gait movements and stretching. 2. Proprioceptive exercises followed an evolution sequence based on the use of stable surfaces to unstable, walking straight forward progressing to changes in direction, from gait with no obstacles to gait with obstacles, alteration in the support base (from open to closed), exercises with eyes open to closed eyes, always respecting the functional capacity of each patient and progressively increasing the difficulty of each exercise. To aid the training, cones, balance boards, sticks, mats and trampolines were used. According to the patient's evolution, the exercises were combined creating the circuits

2006).

(Swanik et al., 2002).

(Figure 3).

Fig. 3. Example of a circuit training

The training protocol might include:

**Options of Exercises Evolution of Exercises Time or # of repetitions**  Balance exercises (balance board, mini-trampoline. Dyna disc) Eyes open or closed / stable or unstable 10 rep / 30s Stability exercises Unipodal or bipodal support / open or close base 10 rep / 30s Anteroposterior and latero-lateral gait With or without obstacle and Variation in speed 10 rep (3 m) Mat exercises Go up/down: 1 to 3 mats 10 rep / 3 series Exercises on the stairs Variation in speed 10 rep / 3 series Exercises with sticks With or without arm

with eyes open and/or closed; change in floor for a more unstable surface such as a trampoline and balance board; exercises with dissociation of waist and use of a stick (Table 1).

Table 1. Examples of exercises

Evidences have shown that specific exercises might reduce the risk factors for falls and number of falls in older people (Lord & Clark, 1996; Robertson et al., 2001-1, 2001-2; Hartard et al., 1996).

movements 10 rep / 3 series

In 2006, Carvalho stated that the main goal of the osteoporosis treatment is to prevent fractures and as 90% of the fractures resulted from falls, the fundamental part of fracture treatment is to prevent them. This prevention represents a great area of interest in researches on older people's health (Weatherall, 2004).

Because of the strong interaction between osteoporosis and falls, the selection of participants in protocols for the prevention of fractures should be based on factors related to bones and falls (Pfeifer et al., 2004).

The German Society of Sport Medicine and the American College of Sport Medicine also recommend that the ideal program for women with osteoporosis should include activities that improve strength, flexibility and coordination that might indirectly and more effectively decrease the incidence of osteoporotic fractures by the reduction in the probability of falls (Lange et al., 2005).

Data combined from three studies conducted by Gillespie et al., 2006, with a total of 556 women aged 80 years or older, who underwent to the same progressive muscular strengthening program, balance training and gait training indicate that this intervention decreased the number of individuals that fell during a year, having also reduced the number of injurious falls. Although the studies had methodological limitations, there is a determined consistency as for the decrease of falls in multiple interventions exercises (Gillespie et al., 2009). As for the physical exercise, we only know that it improves balance without a direct association with the decrease in the number of falls (Howe Tracey et al., 2009) and that

Physical Exercise for Prevention of Falls and Fractures 479

In another randomized clinical trial, physiotherapy-directed exercise in 30 patients with osteoporosis significantly improved static balance measured by functional reach and

These two studies indicate that the exercises programs improved the profile of fall risk but showed limitations because of the small number of samples and short time of the

Hartard et al., 1996, studied the effects of muscle strength training in 16 postmenopausal women with osteopenia, where fifteen belonged to the control group. Although they used a small group, a proper load protocol for 6 months, twice a week at 70% 1RM was applied demonstrating a considerable increase in muscle strength ranging from 44 to 76%, with

Kemmler et ak., 2002, evaluated the dynamic force (1RM tests) in 137 postmenopausal women with osteopenia divided in two groups and observed a significant increase of 43% in the leg press in the intervention group training at 70% of 1-RM for fourteen months. Carter et al., 2001, in a program that trains instructors to work with the community selected 93 postmenopausal women with osteoporosis who were randomized and underwent physical exercises of balance and muscle strength for twenty weeks. No improvement in the quality of life was found, which might be explained by the high quality of life at baseline. Researchers observed an improvement of 6.3% in the dynamic balance and an increase of

On the other hand, Teixeira et al., 2010, showed a significant improvement in the quality of life evaluated by SF-36, where the values (regarding the physical aspects as well as mental aspects) were considerably superior than the controls and values at baseline. These results might be related to the systemic physiologic benefits provided by training, resulting in a better skill to perform daily life activities. We also related these results to the psychological effects of training, socialization with other patients and low initial levels

Madureira et al., 2006, conducted a randomized clinical trial that included 66 postmenopausal women with osteoporosis assigned to two groups. One of the groups underwent a 12-month of balance training once a week combined with oriented training at home showing significant results concerning balance, mobility and decrease in the number

Swanenburg et al., 2007, studied 24 women (65 years old or older) with osteoporosis or osteopeny who underwent three months of strength, balance and coordination training. After twelve months, they observed a reduction in the risk of fall (Berg Scale) and increase in the muscle strength of lower limbs. They also found a decrease in the number of falls in the intervention group (89%), showing a significant number although it was a pilot study. As for the reduction of the risk of fall, although it shows an average of 40% (Barnett et al., 2003; Teixeira et al., 2010) it still is not well evidenced, which might be explained by the use

Several studies have shown to be effective in increasing the strength, improving the balance and functional capacity and decreasing the risk of falls (Table 2). Only the researches carried out by Madureira et al., 2006, Swanenburg et al., 2007 and Teixeira et al., 2010, directly associate these results and the number of falls demonstrating how effective these

increased quadriceps dynamic strength (Mitchell et al., 1998).

results similar to the ones found in the present investigation.

of different populations and mainly the interventions used.

interventions.

12.8% in the muscular strength.

of quality of life.

interventions were.

of falls.

although the decline in muscle strength is a risk factor for falls, the muscle strength training could not be associated to the reduced number of falls (Sherrington et al., 2008; Gillespie, et al., 2009).

Few studies take into consideration the importance of the proprioceptive training as a fundamental and unseparable part of a muscular strengthening program. Mechanoreceptors located in the joints, tendons, muscles and neighbor tissue provide information to the Nervous System about the position and articular movements and about the forces generated in the muscles (Hurley, 2003; Van der Esch et al., 2007).

The knee proprioception is essential for the modulation and accurate activation of the muscle contraction, once the functional skill and muscular balance are strongly affected by the proprioceptive inaccuracy and muscle weakness (Van der Esch et al., 2007). Studies including patients with knee ligament lesions show that the proprioceptive training promotes additional sensorial information that contributes to the improvement in postural control (Bonfin et al., 2008). This relationship becomes even more important when the muscle strengthening program aims to improve the functional balance and prevention of falls.

The significant results found in the present research might be explained by the concern in following the ACSM recommendations when prescribing exercises, respecting the basic concepts of prescription exercises.

Additionally, one should take into consideration that the skill to develop muscle strength decreases with aging (Hakkinen et al., 1998) explaining the importance of the gradual progression (Adams et al., 1999). With sedentary elderly people, a period of adaptation and low working load for two weeks should be applied for further implementation of a loading progression protocol (American College of Sports Medicine, 2002).

Teixeira et al., 2010, after eighteen weeks of training, observed an average increase of 87.5% in the maximal dynamic muscle strength in the quadriceps (1-RM) in volunteers in the intervention group, which is similar to the results found by Humphries et al., 2000, showing an increase from 20 to 200% in the dynamic muscle strength of the quadriceps depending on the figures in baseline and time of training. This increased knee extension strength is significantly important since the knee extension strength is an independent risk factor for falls and fractures caused by osteoporosis (Nguyen et al., 1993). The increase in strength results from neural alterations and muscle adaptations (Resende et al., 2008).

The combination of muscle strength and proprioceptive training was fundamental for a research that included postmenopausal women with osteoporosis conducted by Teixeira et al., 2010. The authors found an increase in mobility and functional capacity that might be related to a 36% decrease in time for performing the timed up & go test. We could observe that the shorter the time spent to perform the test, the better the balance (Resende et al., 2008). In this research, Teixeira et al., 2010, observed an improvement in balance evaluated by the Berg Balance Scale, where although there were small numerical changes, it was consistent, agreeing with the outcomes found by Madureira et al., 2006.

Bemben et al., 2000, compared the effects of high and low-intensity training in 25 postmenopausal women (41 to 60 years old) using a high repetition (40% 1-RM, 16 repetitions) and high load (80 % 1-RM, 8 repetitions) protocols for six months showing increases from 30 to 40%, respectively in the dynamic strength in quadriceps.

In a randomized controlled trial of 10 weeks of strength, balance and stretching training in 53 postmenopausal women with osteoporosis, Malmros et al., 1998, showed that strength and muscle mass and also the static balance improved significantly.

although the decline in muscle strength is a risk factor for falls, the muscle strength training could not be associated to the reduced number of falls (Sherrington et al., 2008; Gillespie, et

Few studies take into consideration the importance of the proprioceptive training as a fundamental and unseparable part of a muscular strengthening program. Mechanoreceptors located in the joints, tendons, muscles and neighbor tissue provide information to the Nervous System about the position and articular movements and about the forces generated

The knee proprioception is essential for the modulation and accurate activation of the muscle contraction, once the functional skill and muscular balance are strongly affected by the proprioceptive inaccuracy and muscle weakness (Van der Esch et al., 2007). Studies including patients with knee ligament lesions show that the proprioceptive training promotes additional sensorial information that contributes to the improvement in postural control (Bonfin et al., 2008). This relationship becomes even more important when the muscle strengthening

The significant results found in the present research might be explained by the concern in following the ACSM recommendations when prescribing exercises, respecting the basic

Additionally, one should take into consideration that the skill to develop muscle strength decreases with aging (Hakkinen et al., 1998) explaining the importance of the gradual progression (Adams et al., 1999). With sedentary elderly people, a period of adaptation and low working load for two weeks should be applied for further implementation of a loading

Teixeira et al., 2010, after eighteen weeks of training, observed an average increase of 87.5% in the maximal dynamic muscle strength in the quadriceps (1-RM) in volunteers in the intervention group, which is similar to the results found by Humphries et al., 2000, showing an increase from 20 to 200% in the dynamic muscle strength of the quadriceps depending on the figures in baseline and time of training. This increased knee extension strength is significantly important since the knee extension strength is an independent risk factor for falls and fractures caused by osteoporosis (Nguyen et al., 1993). The increase in strength

The combination of muscle strength and proprioceptive training was fundamental for a research that included postmenopausal women with osteoporosis conducted by Teixeira et al., 2010. The authors found an increase in mobility and functional capacity that might be related to a 36% decrease in time for performing the timed up & go test. We could observe that the shorter the time spent to perform the test, the better the balance (Resende et al., 2008). In this research, Teixeira et al., 2010, observed an improvement in balance evaluated by the Berg Balance Scale, where although there were small numerical changes, it was

Bemben et al., 2000, compared the effects of high and low-intensity training in 25 postmenopausal women (41 to 60 years old) using a high repetition (40% 1-RM, 16 repetitions) and high load (80 % 1-RM, 8 repetitions) protocols for six months showing

In a randomized controlled trial of 10 weeks of strength, balance and stretching training in 53 postmenopausal women with osteoporosis, Malmros et al., 1998, showed that strength

in the muscles (Hurley, 2003; Van der Esch et al., 2007).

concepts of prescription exercises.

program aims to improve the functional balance and prevention of falls.

progression protocol (American College of Sports Medicine, 2002).

results from neural alterations and muscle adaptations (Resende et al., 2008).

consistent, agreeing with the outcomes found by Madureira et al., 2006.

and muscle mass and also the static balance improved significantly.

increases from 30 to 40%, respectively in the dynamic strength in quadriceps.

al., 2009).

In another randomized clinical trial, physiotherapy-directed exercise in 30 patients with osteoporosis significantly improved static balance measured by functional reach and increased quadriceps dynamic strength (Mitchell et al., 1998).

These two studies indicate that the exercises programs improved the profile of fall risk but showed limitations because of the small number of samples and short time of the interventions.

Hartard et al., 1996, studied the effects of muscle strength training in 16 postmenopausal women with osteopenia, where fifteen belonged to the control group. Although they used a small group, a proper load protocol for 6 months, twice a week at 70% 1RM was applied demonstrating a considerable increase in muscle strength ranging from 44 to 76%, with results similar to the ones found in the present investigation.

Kemmler et ak., 2002, evaluated the dynamic force (1RM tests) in 137 postmenopausal women with osteopenia divided in two groups and observed a significant increase of 43% in the leg press in the intervention group training at 70% of 1-RM for fourteen months.

Carter et al., 2001, in a program that trains instructors to work with the community selected 93 postmenopausal women with osteoporosis who were randomized and underwent physical exercises of balance and muscle strength for twenty weeks. No improvement in the quality of life was found, which might be explained by the high quality of life at baseline. Researchers observed an improvement of 6.3% in the dynamic balance and an increase of 12.8% in the muscular strength.

On the other hand, Teixeira et al., 2010, showed a significant improvement in the quality of life evaluated by SF-36, where the values (regarding the physical aspects as well as mental aspects) were considerably superior than the controls and values at baseline. These results might be related to the systemic physiologic benefits provided by training, resulting in a better skill to perform daily life activities. We also related these results to the psychological effects of training, socialization with other patients and low initial levels of quality of life.

Madureira et al., 2006, conducted a randomized clinical trial that included 66 postmenopausal women with osteoporosis assigned to two groups. One of the groups underwent a 12-month of balance training once a week combined with oriented training at home showing significant results concerning balance, mobility and decrease in the number of falls.

Swanenburg et al., 2007, studied 24 women (65 years old or older) with osteoporosis or osteopeny who underwent three months of strength, balance and coordination training. After twelve months, they observed a reduction in the risk of fall (Berg Scale) and increase in the muscle strength of lower limbs. They also found a decrease in the number of falls in the intervention group (89%), showing a significant number although it was a pilot study.

As for the reduction of the risk of fall, although it shows an average of 40% (Barnett et al., 2003; Teixeira et al., 2010) it still is not well evidenced, which might be explained by the use of different populations and mainly the interventions used.

Several studies have shown to be effective in increasing the strength, improving the balance and functional capacity and decreasing the risk of falls (Table 2). Only the researches carried out by Madureira et al., 2006, Swanenburg et al., 2007 and Teixeira et al., 2010, directly associate these results and the number of falls demonstrating how effective these interventions were.

Physical Exercise for Prevention of Falls and Fractures 481

Although factors as genetic, hormonal homeostasis and nutrition may be affect the bone mineral density, the level of physical activity seems to have an important influence on this variable. The physiological mechanism that explains the osteogenic action of physical activity is not clearly understood. The moment the bone is compressed; negative charges in

the place compressed are generated and positive charges in other areas (Figure 4).

Fig. 4. a) The application of force to a slightly bent bone produces a greater compressive force on the inside curvatures. Compressive force producers weak electrical currents which stimulate osteoblast; b) Over time, bone is deposited in the inside curvature and removed from outside curvature; c) The final results is a bone matched to the compressive force to

Minimal amounts of electric current stimulate the osteoblasts (bone-forming cells) in the negative extremity that is being compressed, increasing the bone formation in this area

Another aspect that should be taken into consideration when ideally prescribing the strengthening training in order to stimulate the bone formation is the type of muscle contraction used. In studies comparing the eccentric and concentric strength training with the same relative load, the first showed to be more effective increasing the BMD (Hawkins et

The mechanism to increase the bone mineral density (BMD) through the strength training depends on the magnitude of bone deformation caused during this activity. In fact, higherintensity training related to maximum load is generally associated to greater stimuli for the increase of BMD compared to low-intensity training (Kerr et al., 2001; Vincent & Braith, 2002). Besides that, the use of higher-intensity training implies in more immediate responses

which it is exposed. Credit: Copyright, Person Education, Benjamin Cumings.

al., 1999; Hortobágvi et al., 1996; Aagaard et al., 2000).

(Bankoff et al., 1998).

in the BMD.

**5. Muscle strength training and the use of vibration platform** 



**Muscle Strength Training** 

Ninety-eight (98) communitydwelling osteopenic women aged 41-78 years

One hundred sedentary postmenopausal women with osteoporosis, ages ranging from 55 to

Sample consisted of 33 women with osteoporosis

75,

At the completion of the trial, the intervention group showed markedly significant better performances in balance (unilateral and bilateral stance sway measures, lateral reach, timed up and go and step test) (p < 0.05) with strong positive training effects reflecting improvements of between 10% to 71%. Similarly, there were gains in strength of the hip muscles (abductors, adductors, and external rotators), quadriceps and trunk extensors with training effects between 9% and 23%.

The authors found out that the program promoted a significant difference among the groups for SF-36 in the eight sub-scales (p <or= 0.0018), Timed Up & Go Test (p < 0.0001), 1-RM test (p < 0.0001), Berg Balance Scale (p < 0.0001) and also a decrease in the number of falls in the intervention group compared to control (IRR = 0.263, 95% CI 0.10-0.68, p = 0.0064).

When compared with the control group, individuals in the intervention group significantly improved the center of pressure velocity (P = 0.02) in the modified clinical test of sensory interaction for balance test, center of pressure velocity (P < 0.01), and directional control (P < 0.01) in limits of stability test, isometric force during ankle dorsiflexion (P = 0.01), knee extension (P < 0.01), and knee

flexion (P < 0.01).

**Author Period Method, intensity and volume Sample Results** 

In this study, subjects were randomised via computergenerated random numbers lists into either a control (receiving no intervention), or exercise group (two one-hour exercise sessions per week for 20 weeks with a trained physiotherapist).

The authors performed a study and randomized the sample into two groups: the intervention group comprised of 50 patients who underwent a 18-week of progressive load training for the quadriceps muscle (50% up to 80% of 1-RM-one maximum repetition) and proprioception training associated to a drug treatment of osteoporosis and the control group that included 50 patients who only underwent a drug treatment of osteoporosis. The muscular strength, balance, functional mobility, and quality of life were evaluated in the beginning and end of the research. The number of falls was evaluated 24 weeks post-

treatment.

dynamometry.

Table 2. Studies that used different methods of muscle strength training

The authors randomized the sample into two groups: intervention group, in which exercises for balance and improvement of muscular strength of the inferior members were performed for 8 wks (n = 17, age 72.8 +/- 3.6 yrs); control group, which was women not practicing exercises (n = 16, age 74.4 +/- 3.7 yrs). At baseline and after 8 wks of treatment, postural control was assessed using a force plate (Balance Master, Neurocom), and muscular strength during ankle dorsiflexion, knee extension, and flexion was assessed by

Hourigan, et al., 2008

Teixeira, et al., 2010

Burk, et al., 2010

8 weeks

20 weeks

18 weeks

### **5. Muscle strength training and the use of vibration platform**

Although factors as genetic, hormonal homeostasis and nutrition may be affect the bone mineral density, the level of physical activity seems to have an important influence on this variable. The physiological mechanism that explains the osteogenic action of physical activity is not clearly understood. The moment the bone is compressed; negative charges in the place compressed are generated and positive charges in other areas (Figure 4).

Fig. 4. a) The application of force to a slightly bent bone produces a greater compressive force on the inside curvatures. Compressive force producers weak electrical currents which stimulate osteoblast; b) Over time, bone is deposited in the inside curvature and removed from outside curvature; c) The final results is a bone matched to the compressive force to which it is exposed. Credit: Copyright, Person Education, Benjamin Cumings.

Minimal amounts of electric current stimulate the osteoblasts (bone-forming cells) in the negative extremity that is being compressed, increasing the bone formation in this area (Bankoff et al., 1998).

Another aspect that should be taken into consideration when ideally prescribing the strengthening training in order to stimulate the bone formation is the type of muscle contraction used. In studies comparing the eccentric and concentric strength training with the same relative load, the first showed to be more effective increasing the BMD (Hawkins et al., 1999; Hortobágvi et al., 1996; Aagaard et al., 2000).

The mechanism to increase the bone mineral density (BMD) through the strength training depends on the magnitude of bone deformation caused during this activity. In fact, higherintensity training related to maximum load is generally associated to greater stimuli for the increase of BMD compared to low-intensity training (Kerr et al., 2001; Vincent & Braith, 2002). Besides that, the use of higher-intensity training implies in more immediate responses in the BMD.

Physical Exercise for Prevention of Falls and Fractures 483

Fig. 5. Three different types of whole body vibration technology, including oscillating, linear and tri-planar platforms. Credit Larry Leggh. PhD and Jonathan Scherer MHK. J Active

In a research conducted by Rubin et al., 2001, in adult rats, they found out that a combination of low magnitude and high frequency vibration significantly increased the

Studies (Torniven et al., 2003) in animals have shown that the vibrations might be an effective and safe way to improve mass competence and bone mechanic, providing a great

High frequency (28Hz), very-low-magnitude vibration exercise has recently been reported to increase bone mass in experimental animals and in humans (Russo et al., 2003). Therefore, in order to obtain bone reinforcement, the frequency and amplitude of vibration should not exceed specified levels for the treatment. Furthermore, low-frequency vibration does not stimulate the bone sufficiently to cause significant remodeling (Aleyaasin & Harrigan, 2008). Fractures are among the commonest and most expensive health problems in the elderly population, therefore the physical exercise is considered an effective and frequently recommended strategy. However, hard bone stress induced by the vigorous activity of weight bearing might increase the risk of lesions (Gusi et al., 2006; Gilsanz et al., 2006). Although evidence is overwhelming that physical exercise positively affects muscle strength at all ages, compliance of older persons with traditional exercise programs is low, and only a small percentage of older persons exercise regularly (Russo et al., 2003). According to Liu et al., 2011, osteoporosis and its associated fractures are common complications of aging and that the purpose of most therapeutical strategies is to prevent and/or treat bone loss focused on nonpharmacological approaches. Therefore, aerobic exercise and/or whole-body vibration (WBV) might have beneficial effect on bone mass and provide an alternative approach to

increase or maintain bone mineral density and reduce the risk of fracture (Table 3).

and concluded there was no effect on the bones of young and healthy adults.

However, the mechanism through which the vibrations influence the bone tissue is still obscure. There is a lack of understanding the physiological mechanisms involved in the adaptive responses or the most appropriate vibration parameters to be used in order to maximize gains (Santin-Medeiros & Garatachea, 2010; Cardinale & Rittweger, 2006). The high-frequency postural displacements induced by the alternating movements of the platform produce reex muscle contractions aimed at stabilizing posture. Thus, vibration can be viewed as a special form of muscle training that may particularly affect muscle power. It has been proposed that the force applied to bone during muscle contraction has a pivotal role in the homeostatic and adaptive regulation of bone strength (Russo et al., 2003). However, researchers (Torniven et al., 2003) carried out a study with the vibration platform

anabolic activity of bone, bone density and specifically bone formation.

Aging. Nov/Dec 200

potential to prevent osteoporosis.

Therefore, it can be concluded that in order to have a strength training providing beneficial effects over bone density, it is important to follow and respect some basic principles of physical training, such as proper overload, volume and intensity. On the other side, this training modality is the one that allows the greatest control of these variables.

#### **5.1 Vibration platform**

Vibration platform is a new type of exercise involving the application of a vibratory stimulus to the entire body as opposed to local stimulation of specific muscle groups (Merriman & Jackson, 2009) and has been increasingly tested for the ability to prevent bone fractures and osteoporosis in frail people (Gusi et al., 2006). It has become increasingly popular over the last several year as a form of physical training (Merriman & Jackson, 2009), since it is a non-pharmacological treatment alternative for osteoporosis (Cardinale & Wakeling, 2005). The platform can increase bone strength and bone mass (Sehmisch et al., 2009) since the vibration provides a low level of mechanical load stimulating, therefore the bone remodeling (Hannan et al., 2004). This can be explained by the combined effect on the neuromuscular and neuroendocrine systems (Cardinale & Wakeling, 2005). Vibrational physical exercise causes reflecting muscle contractions like tonic vibration reflex. This type of intervention leads to a high intensive stimulation of proprioceptors called muscle spindles which result in alteration in parameters of activity and development of human physiological functions (Piatin et al., 2009).

The vibrating devices currently marketed show two types of vibrating plates: a) the whole plate oscillates up and down; b) vertical displacements on the left and right side of a fulcrum, increasing the lateral accelerations (Gusi et al., 2006), (Figure 5). The units provide a vibration by using either a rotational or vertical stimulus, that is, the platform rotates about an anterior-posterior axis so that the positioning of feet further apart results in increased amplitude of movement and applies force asynchronously to the left and right foot, similar to standing near the middle of a 'teeter-totter. Vibration units that provide a vertical stimulus have a platform that translates vertically and symmetrically causing simultaneous movement of the lower extremities in the same direction. In addition to the duration of the vibration stimulus, there are several treatment parameters that are important to consider. These include frequency (Hz), amplitude (mm), duration and vibration magnitude (g), which is a gravitational acceleration imposed on the body. However, some studies have used frequencies ranging from 25-50 Hz, amplitudes from 2- 10 mm, and total durations of 30 sec — 10 minutes. Currently, there is no consensus regarding the correct parameters needed to achieve a specific physiological response (Merriman & Jackson, 2009). However, some researchers have used frequencies ranging from 15-35 Hz to obtain a maximum transmissibility of the mechanical stimulus produced by the vibratory plate. Some recent studies have included in their protocols 15/10-Hz frequencies to allow a smooth adjustment in individuals considered frail, like the elderly (Gusi et al., 2006).

The effects of this vibration have been studied extensively in occupational medicine, mainly in industrial settings. It has been shown that when the body undergoes chronically to whole body vibrations spinal degeneration is likely to be one of the deleterious outcomes. Symptom of low back pain has been shown to be the leading major cause of industrial disability in the population under the age of 45 years (Cardinale & Pope, 2003).

Therefore, it can be concluded that in order to have a strength training providing beneficial effects over bone density, it is important to follow and respect some basic principles of physical training, such as proper overload, volume and intensity. On the other side, this

Vibration platform is a new type of exercise involving the application of a vibratory stimulus to the entire body as opposed to local stimulation of specific muscle groups (Merriman & Jackson, 2009) and has been increasingly tested for the ability to prevent bone fractures and osteoporosis in frail people (Gusi et al., 2006). It has become increasingly popular over the last several year as a form of physical training (Merriman & Jackson, 2009), since it is a non-pharmacological treatment alternative for osteoporosis (Cardinale & Wakeling, 2005). The platform can increase bone strength and bone mass (Sehmisch et al., 2009) since the vibration provides a low level of mechanical load stimulating, therefore the bone remodeling (Hannan et al., 2004). This can be explained by the combined effect on the neuromuscular and neuroendocrine systems (Cardinale & Wakeling, 2005). Vibrational physical exercise causes reflecting muscle contractions like tonic vibration reflex. This type of intervention leads to a high intensive stimulation of proprioceptors called muscle spindles which result in alteration in parameters of activity and development of human

The vibrating devices currently marketed show two types of vibrating plates: a) the whole plate oscillates up and down; b) vertical displacements on the left and right side of a fulcrum, increasing the lateral accelerations (Gusi et al., 2006), (Figure 5). The units provide a vibration by using either a rotational or vertical stimulus, that is, the platform rotates about an anterior-posterior axis so that the positioning of feet further apart results in increased amplitude of movement and applies force asynchronously to the left and right foot, similar to standing near the middle of a 'teeter-totter. Vibration units that provide a vertical stimulus have a platform that translates vertically and symmetrically causing simultaneous movement of the lower extremities in the same direction. In addition to the duration of the vibration stimulus, there are several treatment parameters that are important to consider. These include frequency (Hz), amplitude (mm), duration and vibration magnitude (g), which is a gravitational acceleration imposed on the body. However, some studies have used frequencies ranging from 25-50 Hz, amplitudes from 2- 10 mm, and total durations of 30 sec — 10 minutes. Currently, there is no consensus regarding the correct parameters needed to achieve a specific physiological response (Merriman & Jackson, 2009). However, some researchers have used frequencies ranging from 15-35 Hz to obtain a maximum transmissibility of the mechanical stimulus produced by the vibratory plate. Some recent studies have included in their protocols 15/10-Hz frequencies to allow a smooth adjustment in individuals considered frail, like the elderly

The effects of this vibration have been studied extensively in occupational medicine, mainly in industrial settings. It has been shown that when the body undergoes chronically to whole body vibrations spinal degeneration is likely to be one of the deleterious outcomes. Symptom of low back pain has been shown to be the leading major cause of industrial

disability in the population under the age of 45 years (Cardinale & Pope, 2003).

training modality is the one that allows the greatest control of these variables.

**5.1 Vibration platform** 

(Gusi et al., 2006).

physiological functions (Piatin et al., 2009).

Fig. 5. Three different types of whole body vibration technology, including oscillating, linear and tri-planar platforms. Credit Larry Leggh. PhD and Jonathan Scherer MHK. J Active Aging. Nov/Dec 200

In a research conducted by Rubin et al., 2001, in adult rats, they found out that a combination of low magnitude and high frequency vibration significantly increased the anabolic activity of bone, bone density and specifically bone formation.

Studies (Torniven et al., 2003) in animals have shown that the vibrations might be an effective and safe way to improve mass competence and bone mechanic, providing a great potential to prevent osteoporosis.

High frequency (28Hz), very-low-magnitude vibration exercise has recently been reported to increase bone mass in experimental animals and in humans (Russo et al., 2003). Therefore, in order to obtain bone reinforcement, the frequency and amplitude of vibration should not exceed specified levels for the treatment. Furthermore, low-frequency vibration does not stimulate the bone sufficiently to cause significant remodeling (Aleyaasin & Harrigan, 2008). Fractures are among the commonest and most expensive health problems in the elderly population, therefore the physical exercise is considered an effective and frequently recommended strategy. However, hard bone stress induced by the vigorous activity of weight bearing might increase the risk of lesions (Gusi et al., 2006; Gilsanz et al., 2006).

Although evidence is overwhelming that physical exercise positively affects muscle strength at all ages, compliance of older persons with traditional exercise programs is low, and only a small percentage of older persons exercise regularly (Russo et al., 2003). According to Liu et al., 2011, osteoporosis and its associated fractures are common complications of aging and that the purpose of most therapeutical strategies is to prevent and/or treat bone loss focused on nonpharmacological approaches. Therefore, aerobic exercise and/or whole-body vibration (WBV) might have beneficial effect on bone mass and provide an alternative approach to increase or maintain bone mineral density and reduce the risk of fracture (Table 3).

However, the mechanism through which the vibrations influence the bone tissue is still obscure. There is a lack of understanding the physiological mechanisms involved in the adaptive responses or the most appropriate vibration parameters to be used in order to maximize gains (Santin-Medeiros & Garatachea, 2010; Cardinale & Rittweger, 2006). The high-frequency postural displacements induced by the alternating movements of the platform produce reex muscle contractions aimed at stabilizing posture. Thus, vibration can be viewed as a special form of muscle training that may particularly affect muscle power. It has been proposed that the force applied to bone during muscle contraction has a pivotal role in the homeostatic and adaptive regulation of bone strength (Russo et al., 2003). However, researchers (Torniven et al., 2003) carried out a study with the vibration platform and concluded there was no effect on the bones of young and healthy adults.

Physical Exercise for Prevention of Falls and Fractures 485

In a systematic review (Merriman & Jackson, 2009) conducted about the vibration platform to understand the effects on bone density, muscle performance, balance, and functional mobility in older adults concluded that most of the studies is methodologically weak and should be interpreted with caution. The study protocols use widely variable parameters which make the study interpretation difficult. The effects of this long term vibration ( >1 year) still need to be studied. Some but not all of the studies in this review reported that individuals exposed to those vibrations showed similar improvements in muscle performance, balance, and functional mobility as compared to traditional exercise programs and that the vibration platform does not provide any additional benefit. Bone studies consistently showed that WBV improved bone density in the hip and tibia but not in the lumbar spine. Additional studies are needed to determine safe and effective parameters for

However, the treatment has to follow specific safety guidelines to prevent vibration exercise-related injuries, such as limiting the exposure to vibration to a maximum of 10

Due to a great controversy in studies on its effects and parameters, more studies in humans with specific clinical recommendations and protocols are necessary for the vibration training

Physical activity is an essential factor in bone health. The benefits of exercise have been demonstrated throughout the life cycle. Exercise can positively affect peak bone mass in children and adolescents; has been shown to help maintain or even modestly increase bone density in adulthood and; can assist in minimizing age related bone mass peak loss in older adults. Physical exercises that cause mechanical stress are the most recommended to increase or keep bone mass. However, the prevention of falls seems to be the most important factor in decreasing the risk of fractures in women with osteoporosis and in

The authors would like to thank Universidade Federal de São Paulo and Universidade Federal do Amazonas for all the support given when developing this project and also

Aagaard, P.; Simonsen, EB.; Andersen, JL.; Magnusson, SP; Halkjaer-kristensen, J. & Dyhre-

Adler, SS.; Beckers, D. & Buck M. (2008). *PNF in practice: an illustrated guide*. 3rd ed. Berlin:

poulsen, P. (2000). Neural inhibition during maximal eccentric and concentric quadriceps contraction: effects of resistance training*. J Appl Physiol*. 89:2249-57. Adams, KL.; Barnard, KL.; Swank, AM.; Mann, E. & Kushnick, MR. (1999). Denny M.

Combined high-intensity strength and aerobic training in diverse phase 11 cardiac

WBV training in older adults.

**6. Conclusion** 

**7. Acknowledgments** 

Springer.

**8. References** 

(Gusi et al, 2006; Torniven et al., 2003).

minutes and maintaining a good posture of the participant.

elderly people, since more than 90% of hip fractures results from falls.

translator Cybeles Lehner for her great contribution to this chapter.

rehabilitation patient. *J Cardiopulm Rehabil*. 19:209-215.


Table 3. Studies that used whole body vibration (WBV)

In a systematic review (Merriman & Jackson, 2009) conducted about the vibration platform to understand the effects on bone density, muscle performance, balance, and functional mobility in older adults concluded that most of the studies is methodologically weak and should be interpreted with caution. The study protocols use widely variable parameters which make the study interpretation difficult. The effects of this long term vibration ( >1 year) still need to be studied. Some but not all of the studies in this review reported that individuals exposed to those vibrations showed similar improvements in muscle performance, balance, and functional mobility as compared to traditional exercise programs and that the vibration platform does not provide any additional benefit. Bone studies consistently showed that WBV improved bone density in the hip and tibia but not in the lumbar spine. Additional studies are needed to determine safe and effective parameters for WBV training in older adults.

However, the treatment has to follow specific safety guidelines to prevent vibration exercise-related injuries, such as limiting the exposure to vibration to a maximum of 10 minutes and maintaining a good posture of the participant.

Due to a great controversy in studies on its effects and parameters, more studies in humans with specific clinical recommendations and protocols are necessary for the vibration training (Gusi et al, 2006; Torniven et al., 2003).

### **6. Conclusion**

484 Osteoporosis

**Whole-body vibration**

Seventy volunteers (age, 58-74 years) were randomly assigned to a whole body vibration training group (WBV, n = 25), a resistance training group (RES, n = 22) or a control group (CON, n = 23)

Eight RCTs in postmenopausal women (five RCTs), young adults (one RCT), and children and adolescents (two RCTs) were included. The regimens were heterogeneous, study durations were relatively short, and available data was mostly perprotocol.

The authors found out that vibration training improved isometric and dynamic muscle strength (+15% and + 16%, respectively; p < 0.01) and also significantly increased BMD of the hip (+0.93%, p < 0.05). No changes in hip BMD were observed in women participating in resistance training or age-matched controls (- 0.60% and -0.62%, respectively; not significant). Serum markers of bone turnover did not change in any of the groups.

In postmenopausal women, WBV was found to significantly increase hip aBMD (0.015 g cm(- 2); 95% confidence interval (CI), 0.008-0.022; n = 131) versus controls, but not spine aBMD (n = 181) or tibia trabecular vBMD (n = 29). In young adults, WBV did not increase spine or hip bone mineral content, or tibia trabecular vBMD (n = 53). In children and adolescents, WBV significantly increased spine (6.2 mg cm(-3); 95% CI, 2.5-10.0; n = 65) and tibia (14.2 mg cm(- 3); 95% CI, 5.2-23.2; n = 17) trabecular vBMD.

Author Period of time Method, intensity and volume Sample Results

The authors performed this randomized controlled trial to assess the musculoskeletal effects of high-frequency loading by means of whole body vibration (WBV) in postmenopausal women.

The authors performed a systematic review and metaanalysis where eligible RCTs included randomized or quasirandomized trials, with follow-up of ≥ 6 months, examining WBV effects on BMD in ambulatory

individuals without secondary causes of osteoporosis. The weighted mean differences between WBV and control groups in absolute pre-post change in spine and hip aBMD, and in spine and tibia trabecular volumetric BMD (vBMD) were calculated.

Verschueren, et al., 2004

Slatkovska, et al., 2010

The WBV group and the RES group trained three times weekly for 24 weeks

Follow-up of ≥ 6 months

Table 3. Studies that used whole body vibration (WBV)

Physical activity is an essential factor in bone health. The benefits of exercise have been demonstrated throughout the life cycle. Exercise can positively affect peak bone mass in children and adolescents; has been shown to help maintain or even modestly increase bone density in adulthood and; can assist in minimizing age related bone mass peak loss in older adults. Physical exercises that cause mechanical stress are the most recommended to increase or keep bone mass. However, the prevention of falls seems to be the most important factor in decreasing the risk of fractures in women with osteoporosis and in elderly people, since more than 90% of hip fractures results from falls.

### **7. Acknowledgments**

The authors would like to thank Universidade Federal de São Paulo and Universidade Federal do Amazonas for all the support given when developing this project and also translator Cybeles Lehner for her great contribution to this chapter.

### **8. References**


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**24** 

**The Effect of Exercise on Bone** 

*1Faculty of Physical Culture, Palacký University Olomouc,* 

*2Faculty of Medicine, University of Ostrava,* 

*3Mediekos Labor Zlín, Czech Republic* 

**Mineral Density, Bone Markers and** 

M. Janura1, Z. Krhutová2, Z. Svoboda1 and P. Novosad3

**Postural Stability in Subjects with Osteoporosis** 

Osteoporosis, as one of the major causes of disability, morbidity and mortality in older people, is currently considered as a global socioeconomic problem that is increasing in

The diagnosis of osteoporosis is based on the measurement of bone mineral density (BMD), which accounts for 70% of the bone strength, and is, therefore, a good indicator of an impending risk of fracture (Wilkins & Birge, 2005). According to World Health Organization, BMD values are divided into three groups: normal BMD (T-score up to -1.0 standard deviation (SD)), osteopenia (T-score between -1.0 and -2.4 SD), osteoporosis (T-score -2.5 SD and below). Wilkins and Birge (2005) presented these factors as contributing to reduced BMD: nonmodifiable – advanced age, female sex, white/asian race, family history of osteoporosis, family history of hip fracture, lactose intolerance, metabolic disorders affecting the skeleton, certain malignancies (myeloma, lymphoma), and modifiable – smoking, low calcium intake, low vitamin D intake/sunlight exposure, sedentary lifestyle, low body weight, stress/depression, surgical or drug induced

The risk of fracture is considered as age-related. There are two main reasons: age-related decrease in bone mineral density of the proximal femur and the age-related increase in falls

Intervention strategies for osteoporosis are based on a combination of pharmacological

When determining the effect of movement (overcoming gravitational force) on the quality of bone tissue, three basic mechanisms are applied: activation of osteoblasts, storing Ca+2 ions

which is associated with worsening balance (Dontas & Yiannakopoulos, 2007).

agents, nutrition and a suitable physical activity (Melendez-Ortega, 2007).

severity and frequency (Dontas & Yiannakopoulos, 2007).

**1.1.1 Factors affecting osteoporosis incidence** 

hypogonadism, and glucocorticoid therapy.

**1.1.2 Effect of physical activity on BMD** 

**1. Introduction 1.1 Osteoporosis** 

World Health Organization (WHO) Working Group. (1994). Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. *World Health Organ Tech Rep Ser.* 843, Geneva: WHO.

Yoshinari, NH. & Bonfá, ESD. (2000). *Reumatologia para o clínico*. Roca, 1ª Ed.149-1.

## **The Effect of Exercise on Bone Mineral Density, Bone Markers and Postural Stability in Subjects with Osteoporosis**

M. Janura1, Z. Krhutová2, Z. Svoboda1 and P. Novosad3 *1Faculty of Physical Culture, Palacký University Olomouc, 2Faculty of Medicine, University of Ostrava, 3Mediekos Labor Zlín, Czech Republic* 

### **1. Introduction**

492 Osteoporosis

World Health Organization (WHO) Working Group. (1994). Assessment of fracture risk and

Yoshinari, NH. & Bonfá, ESD. (2000). *Reumatologia para o clínico*. Roca, 1ª Ed.149-1.

*Tech Rep Ser.* 843, Geneva: WHO.

its application to screening for postmenopausal osteoporosis. *World Health Organ* 

### **1.1 Osteoporosis**

Osteoporosis, as one of the major causes of disability, morbidity and mortality in older people, is currently considered as a global socioeconomic problem that is increasing in severity and frequency (Dontas & Yiannakopoulos, 2007).

### **1.1.1 Factors affecting osteoporosis incidence**

The diagnosis of osteoporosis is based on the measurement of bone mineral density (BMD), which accounts for 70% of the bone strength, and is, therefore, a good indicator of an impending risk of fracture (Wilkins & Birge, 2005). According to World Health Organization, BMD values are divided into three groups: normal BMD (T-score up to -1.0 standard deviation (SD)), osteopenia (T-score between -1.0 and -2.4 SD), osteoporosis (T-score -2.5 SD and below). Wilkins and Birge (2005) presented these factors as contributing to reduced BMD: nonmodifiable – advanced age, female sex, white/asian race, family history of osteoporosis, family history of hip fracture, lactose intolerance, metabolic disorders affecting the skeleton, certain malignancies (myeloma, lymphoma), and modifiable – smoking, low calcium intake, low vitamin D intake/sunlight exposure, sedentary lifestyle, low body weight, stress/depression, surgical or drug induced hypogonadism, and glucocorticoid therapy.

The risk of fracture is considered as age-related. There are two main reasons: age-related decrease in bone mineral density of the proximal femur and the age-related increase in falls which is associated with worsening balance (Dontas & Yiannakopoulos, 2007).

### **1.1.2 Effect of physical activity on BMD**

Intervention strategies for osteoporosis are based on a combination of pharmacological agents, nutrition and a suitable physical activity (Melendez-Ortega, 2007).

When determining the effect of movement (overcoming gravitational force) on the quality of bone tissue, three basic mechanisms are applied: activation of osteoblasts, storing Ca+2 ions

The Effect of Exercise on Bone Mineral Density, Bone

• biomechanical constraints, • stability limits/verticality,

• postural responses, • sensory orientation, • and stability in gait.

*Posturography* 

• anticipatory postural adjustments,

• reaction to tripping of a force platform, • solution when using a dual task, • testing the stability limits,

• targeted modification of sensory inputs, • and testing a stand in varying conditions.

*Measurement accuracy and reliability* 

obtain reliable measurements.

**1.3 Fall risks** 

minimum of 0 points (no performance) (Berg et al., 1989).

between balance deficits. This test encompasses six areas:

Markers and Postural Stability in Subjects with Osteoporosis 495

An often used instrument for balance evaluation is "The Berg Balance Test". This test consists of 14 functional subtests with a maximum of 4 points (normal performance) and a

Horak et al. (2009) created "The balance evaluation systems test (BESTest)" to differentiate

Instrumental measurement of balance can be performed by posturography, which, by means of force platforms, analyses the centre of pressure (COP) movement on various types of stands. The basic measured parameters are the area of confidence ellipse, the length of COP trajectory,

In recent years, the focus of attention has been especially on the character of a task being handled and on data analysis. When looking to predict falls, stability evaluation in

A review of the test–retest reliability of the centre of pressure measurements in the bipedal static condition was presented by Ruhe et al. (2010). They mentioned that the reliability of the traditional COP parameters can be acceptable; however, it depends primarily on factors such as the number of trial recordings and the duration rather than the selection of particular COP parameters. They also recommend that care should be taken to assess the

Le Clair and Riach (1996) demonstrated that the test duration affects the measurement of postural sway, with 10 s being the least reliable. They also reported that COP, force, and velocity measurements are reliable in retest situations and that only one trial is necessary to

On the contrary, the results of the theory analysis (Doyle et al., 2007) suggest that COP

One of the biggest problems in people with osteoporosis is an increase in the risk of fall. Patients with osteoporosis do not have a good level of stability and have less muscular strength. This makes the risk of fall a lot higher than in individuals without this illness (Park et al., 2008). Regular balance, strength training and diet supplementation with vitamin D

subject's physical status and anthropometric properties prior to the measurements.

measurements reached acceptable levels of reliability with at least five 60 s trials.

and calcium are important in falls prevention (Kannus et al., 2005).

sway of COP and its velocity in the antero-posterior and medio-lateral direction.

quasistatic and dynamic situations is better. The basic tasks here are:

on the bone surface, and increase in the bone substance required for ossification (Němcová & Korsa, 2008).

The results of studies focused on the effect of physical activity on changes in the quality of bone tissue vary. Englund et al. (2005) present the direct effect of weight-bearing training programme on improvement in BMD. Kemmler et al. (2004), Kerry (2003), Uusi-Rasi et al. (2003) and others didn't find the effect of exercise on BMD in postmenopausal women. The results, which were presented in the study of Bloomfield (2005), indicate that exercise may minimize or even stop the bones losing weight in postmenopausal women. However, it does not substitute pharmacological agents nor does it ensure increase in BMD.

### **1.2 Balance**

The human body in standing can be described as a naturally unstable system. The complexity and instability of this system is given by a large number of mobile segments (Véle, 1996) and also by the fact that in standing, 2/3 of body mass is at 2/3 of the individual's height above ground (Winter, 1995).

### **1.2.1 Factors influencing balance**

Besides low bone mineral density, also poor stability contributes to increased risk of fractures associated with a fall (Winters & Snow, 2000).

The basic factors affecting balance include the quality of sensory inputs (vestibular, eyes, tactile, proprioreception …), neural control (central nervous system) and the effectors (muscles, bones …).

Poulain and Giraudet (2008) proved the existence of greater visual sensitivity in posture control from 44 years of age. They also showed that the measurement of the role of vision in posture control among subjects aged 44–60 years strongly depends on the task performed.

The effect of ageing and vision on limb load asymmetry during a quiet stance was observed by Blaszczyk et al. (2000). Their observations may indicate that increased limb load asymmetry in the elderly is a consequence of many kinds of compensatory changes in postural stability control.

Some studies have shown that postural stability is also affected by anthropometric parameters. Chiari et al. (2002) suggested that some anthropometric measurements and standardization or tracing foot position could be considered. The study by Hue et al. (2007) shows that increase in body weight correlates with higher balance instability.

The effect of local fatigue was observed by Caron (2004). The main result of this study was that local fatigue of the lower limbs produced similar effects on postural control and postural stability in the standing with a more pronounced increase in neuromuscular activity with the eyes open as compared to eyes closed.

Hlavačková et al. (2009) suggested that elderly people with some limb deficiencies (transfemoral amputees) were able to integrate augmented visual biofeedback through the use of mirror-reflected body image to improve their stance control during quiet standing.

### **1.2.2 Balance evaluation**

#### *Clinical assessment of balance*

The main purpose of the clinical balance assessment is to identify whether or not a balance problem exists and whether treatment is needed (Horak, 1997).

An often used instrument for balance evaluation is "The Berg Balance Test". This test consists of 14 functional subtests with a maximum of 4 points (normal performance) and a minimum of 0 points (no performance) (Berg et al., 1989).

Horak et al. (2009) created "The balance evaluation systems test (BESTest)" to differentiate between balance deficits. This test encompasses six areas:


### *Posturography*

494 Osteoporosis

on the bone surface, and increase in the bone substance required for ossification (Němcová

The results of studies focused on the effect of physical activity on changes in the quality of bone tissue vary. Englund et al. (2005) present the direct effect of weight-bearing training programme on improvement in BMD. Kemmler et al. (2004), Kerry (2003), Uusi-Rasi et al. (2003) and others didn't find the effect of exercise on BMD in postmenopausal women. The results, which were presented in the study of Bloomfield (2005), indicate that exercise may minimize or even stop the bones losing weight in postmenopausal women. However, it does

The human body in standing can be described as a naturally unstable system. The complexity and instability of this system is given by a large number of mobile segments (Véle, 1996) and also by the fact that in standing, 2/3 of body mass is at 2/3 of the

Besides low bone mineral density, also poor stability contributes to increased risk of

The basic factors affecting balance include the quality of sensory inputs (vestibular, eyes, tactile, proprioreception …), neural control (central nervous system) and the effectors

Poulain and Giraudet (2008) proved the existence of greater visual sensitivity in posture control from 44 years of age. They also showed that the measurement of the role of vision in posture control among subjects aged 44–60 years strongly depends on the task performed. The effect of ageing and vision on limb load asymmetry during a quiet stance was observed by Blaszczyk et al. (2000). Their observations may indicate that increased limb load asymmetry in the elderly is a consequence of many kinds of compensatory changes in

Some studies have shown that postural stability is also affected by anthropometric parameters. Chiari et al. (2002) suggested that some anthropometric measurements and standardization or tracing foot position could be considered. The study by Hue et al. (2007)

The effect of local fatigue was observed by Caron (2004). The main result of this study was that local fatigue of the lower limbs produced similar effects on postural control and postural stability in the standing with a more pronounced increase in neuromuscular

Hlavačková et al. (2009) suggested that elderly people with some limb deficiencies (transfemoral amputees) were able to integrate augmented visual biofeedback through the use of mirror-reflected body image to improve their stance control during quiet standing.

The main purpose of the clinical balance assessment is to identify whether or not a balance

shows that increase in body weight correlates with higher balance instability.

not substitute pharmacological agents nor does it ensure increase in BMD.

individual's height above ground (Winter, 1995).

fractures associated with a fall (Winters & Snow, 2000).

activity with the eyes open as compared to eyes closed.

problem exists and whether treatment is needed (Horak, 1997).

**1.2.1 Factors influencing balance** 

& Korsa, 2008).

**1.2 Balance** 

(muscles, bones …).

postural stability control.

**1.2.2 Balance evaluation**  *Clinical assessment of balance*  Instrumental measurement of balance can be performed by posturography, which, by means of force platforms, analyses the centre of pressure (COP) movement on various types of stands. The basic measured parameters are the area of confidence ellipse, the length of COP trajectory, sway of COP and its velocity in the antero-posterior and medio-lateral direction.

In recent years, the focus of attention has been especially on the character of a task being handled and on data analysis. When looking to predict falls, stability evaluation in quasistatic and dynamic situations is better. The basic tasks here are:


### *Measurement accuracy and reliability*

A review of the test–retest reliability of the centre of pressure measurements in the bipedal static condition was presented by Ruhe et al. (2010). They mentioned that the reliability of the traditional COP parameters can be acceptable; however, it depends primarily on factors such as the number of trial recordings and the duration rather than the selection of particular COP parameters. They also recommend that care should be taken to assess the subject's physical status and anthropometric properties prior to the measurements.

Le Clair and Riach (1996) demonstrated that the test duration affects the measurement of postural sway, with 10 s being the least reliable. They also reported that COP, force, and velocity measurements are reliable in retest situations and that only one trial is necessary to obtain reliable measurements.

On the contrary, the results of the theory analysis (Doyle et al., 2007) suggest that COP measurements reached acceptable levels of reliability with at least five 60 s trials.

### **1.3 Fall risks**

One of the biggest problems in people with osteoporosis is an increase in the risk of fall. Patients with osteoporosis do not have a good level of stability and have less muscular strength. This makes the risk of fall a lot higher than in individuals without this illness (Park et al., 2008). Regular balance, strength training and diet supplementation with vitamin D and calcium are important in falls prevention (Kannus et al., 2005).

The Effect of Exercise on Bone Mineral Density, Bone

physical activity with resultant reduction in the fall risk profile.

and dynamic balance after 10 weeks of exercise intervention.

intervention programme.

**2. Aim** 

observed in the intervention group.

**3. Material and methods** 

**3.1 Characteristics of the group** 

specific exercise programme for postural stability.

pharmacological therapy), 6 sub-groups were formed:

controlled intake of vitamin D3 0.25 μg).

Markers and Postural Stability in Subjects with Osteoporosis 497

The effect of three types of exercises (resistance training, agility training, and general stretching) on risks of fall and the physical activity level of women with low BMD was observed by Liu-Ambrose et al. (2005). They found significant decrease in the fall risk after a 6-month regimen. Even twelve months after intervention the risks of fall remained significantly lower than before exercising. It is very interesting to note that after all three types of exercise programmes, the benefits remained sustainable for at least 12 months. Thus, these 6-month exercise interventions appeared to act as a catalyst for increasing

Exercising leads, above all, to improvement in the medio-lateral direction and individuals are then able to control movement at the hip joints within a greater range and with better results (Nagy et al., 2007). Twiss et al. (2009) found improvements in balance after carrying out yearly exercises focused on the development of muscular strength and weight training. The number of falls in those exercising dropped, though insignificantly. Improvement in balance and quality of life after five weeks of exercising was recorded by Alp et al. (2007). Multifactor preventive and individually-focused balance programmes may reduce the risk of falls in individuals by 25 to 30% (Dargent-Molina, 2004). Whereas Carter et al. (2001) recorded insignificant differences between the observed group and control group in static

Swanenburg et al. (2007) observed the effect of a three-month exercise programme that included training for muscular strength, coordination, balance, and endurance when accompanied with nutritional (protein) supplements. They mentioned that the combination of calcium/vitamin D and exercise/protein intervention programme significantly reduced the risk of fall and in addition, these effects lasted for up to 9 months after the end of the

Madureira et al. (2007) compared groups with and without the balance training programme. The percentage of patients in the intervention group whose static balance improved in two sensory conditions (eyes closed, unstable surface; and eyes open, visual conflict, unstable surface) was statistically significant when compared to the control group. Also, significant difference in the functional mobility as well as reduction in the number of falls/patient were

The aim of this study was to assess the effect of exercise on bone mineral density and bone markers in postmenopausal women with osteoporosis and to determine the effect of a

The tested group included 163 women, patients of the Osteology centre in Zlín, who were randomly divided into groups to perform an exercising programme (n=90) and control (non-exercising) group (n=73). Through a combination of two factors (exercise, specific

1. NEX/NS (n=23, age 57.8±6.05 years): non-exercising group with nonspecific pharmacological therapy (i.e. daily controlled intake of Ca 1000–1500 mg, daily

Reduction of the risk of fall requires identification of the individual with risk of fall and identification of the modifiable risk factors (Wilkins & Birge, 2005).

#### *Causes of falls*

Four major categories of the causes of falls were defined by Lach et al. (1991):


Extrinsic factors pertain to environmental hazards such as loose carpeting, stairs, and poor footwear or lighting. Intrinsic factors are conditions that relate directly to a specific person such as dizziness, use of medication, osteoporosis, and arthritis (Hale et al., 1992).

A comprehensive prospective study concerning the risks associated with falls in older men was performed by Chan et al. (2007). They found that leg extension power, grip strength, and activity level are significant determinants in assessing the risk of fall. The authors also reported increased activity being associated with higher risk of fall; household activities were associated with the risk whereas leisure activities were not.

#### *Measuring falls*

Hauer et al. (2006) presented a systematic review of the definitions and methods of measuring falls in randomised controlled fall prevention trials. Studies focused on assessing the risk of fall have brought forward many issues, one of them being an inconclusive definition of the term "fall" itself. Additionally, the method used in the studies to report falls remains problematic and highly inconsistent. For future research, they recommend a comprehensive and non-exclusive definition of a fall.

#### *Evaluation of the risks of fall*

In order to determine the risk of fall, it is important to firstly render an evaluation of the act. Brauer et al. (2000) presented a prospective study of laboratory and clinical measurements of postural stability to predict fallers in community dwellers. They found out that not all older adults with reduced or compromised balance ability reported a fall over a 6-month period. Therefore, they emphasized the importance of the multifactor nature of falls.

Lord et al. (2003) described the use of a physiological profile approach to falls risk assessment and prevention. This evaluation involves a series of simple tests of vision, peripheral sensation, muscle force, reaction time, and postural sway.

#### *The effect of physical activity on balance and risk of falls*

Hourigan et al. (2008) found an increase in strength of the hip joint muscles and trunk extensors by 9-23% as well as significant improvement in balance after 20 weeks of exercise. Wendlová (2008) states an increase in muscular strength, improved possibility of reacting to loss of balance and reduced risk of fall as a result of exercising. Vaillant et al. (2006) supplemented exercising for balance development with cognitive tasks. While exercising resulted in improved balance, the use of cognitive tasks brought no further changes.

Karinkanta et al. (2007) analysed four groups with different intervention (resistance training, balance-jumping training, combination of both trainings, and no training) criteria and concluded that training prevented functional decline in home-dwelling elderly women.

For osteoporosis patients, weight-bearing activities, balance exercise and strengthening exercises to reduce fall and fracture risk are recommended (De Kam et al., 2009).

The effect of three types of exercises (resistance training, agility training, and general stretching) on risks of fall and the physical activity level of women with low BMD was observed by Liu-Ambrose et al. (2005). They found significant decrease in the fall risk after a 6-month regimen. Even twelve months after intervention the risks of fall remained significantly lower than before exercising. It is very interesting to note that after all three types of exercise programmes, the benefits remained sustainable for at least 12 months. Thus, these 6-month exercise interventions appeared to act as a catalyst for increasing physical activity with resultant reduction in the fall risk profile.

Exercising leads, above all, to improvement in the medio-lateral direction and individuals are then able to control movement at the hip joints within a greater range and with better results (Nagy et al., 2007). Twiss et al. (2009) found improvements in balance after carrying out yearly exercises focused on the development of muscular strength and weight training. The number of falls in those exercising dropped, though insignificantly. Improvement in balance and quality of life after five weeks of exercising was recorded by Alp et al. (2007).

Multifactor preventive and individually-focused balance programmes may reduce the risk of falls in individuals by 25 to 30% (Dargent-Molina, 2004). Whereas Carter et al. (2001) recorded insignificant differences between the observed group and control group in static and dynamic balance after 10 weeks of exercise intervention.

Swanenburg et al. (2007) observed the effect of a three-month exercise programme that included training for muscular strength, coordination, balance, and endurance when accompanied with nutritional (protein) supplements. They mentioned that the combination of calcium/vitamin D and exercise/protein intervention programme significantly reduced the risk of fall and in addition, these effects lasted for up to 9 months after the end of the intervention programme.

Madureira et al. (2007) compared groups with and without the balance training programme. The percentage of patients in the intervention group whose static balance improved in two sensory conditions (eyes closed, unstable surface; and eyes open, visual conflict, unstable surface) was statistically significant when compared to the control group. Also, significant difference in the functional mobility as well as reduction in the number of falls/patient were observed in the intervention group.

### **2. Aim**

496 Osteoporosis

Reduction of the risk of fall requires identification of the individual with risk of fall and

Extrinsic factors pertain to environmental hazards such as loose carpeting, stairs, and poor footwear or lighting. Intrinsic factors are conditions that relate directly to a specific person

A comprehensive prospective study concerning the risks associated with falls in older men was performed by Chan et al. (2007). They found that leg extension power, grip strength, and activity level are significant determinants in assessing the risk of fall. The authors also reported increased activity being associated with higher risk of fall; household activities

Hauer et al. (2006) presented a systematic review of the definitions and methods of measuring falls in randomised controlled fall prevention trials. Studies focused on assessing the risk of fall have brought forward many issues, one of them being an inconclusive definition of the term "fall" itself. Additionally, the method used in the studies to report falls remains problematic and highly inconsistent. For future research, they recommend a

In order to determine the risk of fall, it is important to firstly render an evaluation of the act. Brauer et al. (2000) presented a prospective study of laboratory and clinical measurements of postural stability to predict fallers in community dwellers. They found out that not all older adults with reduced or compromised balance ability reported a fall over a 6-month period.

Lord et al. (2003) described the use of a physiological profile approach to falls risk assessment and prevention. This evaluation involves a series of simple tests of vision,

Hourigan et al. (2008) found an increase in strength of the hip joint muscles and trunk extensors by 9-23% as well as significant improvement in balance after 20 weeks of exercise. Wendlová (2008) states an increase in muscular strength, improved possibility of reacting to loss of balance and reduced risk of fall as a result of exercising. Vaillant et al. (2006) supplemented exercising for balance development with cognitive tasks. While exercising

Karinkanta et al. (2007) analysed four groups with different intervention (resistance training, balance-jumping training, combination of both trainings, and no training) criteria and concluded that training prevented functional decline in home-dwelling elderly women. For osteoporosis patients, weight-bearing activities, balance exercise and strengthening

resulted in improved balance, the use of cognitive tasks brought no further changes.

exercises to reduce fall and fracture risk are recommended (De Kam et al., 2009).

Therefore, they emphasized the importance of the multifactor nature of falls.

peripheral sensation, muscle force, reaction time, and postural sway.

identification of the modifiable risk factors (Wilkins & Birge, 2005).

were associated with the risk whereas leisure activities were not.

comprehensive and non-exclusive definition of a fall.

*The effect of physical activity on balance and risk of falls* 

Four major categories of the causes of falls were defined by Lach et al. (1991):

such as dizziness, use of medication, osteoporosis, and arthritis (Hale et al., 1992).

*Causes of falls* 

*Measuring falls* 

• falls related to extrinsic factors, • falls related to intrinsic factors, • falls from a non-bipedal stance,

• and unclassified falls.

*Evaluation of the risks of fall* 

The aim of this study was to assess the effect of exercise on bone mineral density and bone markers in postmenopausal women with osteoporosis and to determine the effect of a specific exercise programme for postural stability.

### **3. Material and methods**

### **3.1 Characteristics of the group**

The tested group included 163 women, patients of the Osteology centre in Zlín, who were randomly divided into groups to perform an exercising programme (n=90) and control (non-exercising) group (n=73). Through a combination of two factors (exercise, specific pharmacological therapy), 6 sub-groups were formed:

1. NEX/NS (n=23, age 57.8±6.05 years): non-exercising group with nonspecific pharmacological therapy (i.e. daily controlled intake of Ca 1000–1500 mg, daily controlled intake of vitamin D3 0.25 μg).

The Effect of Exercise on Bone Mineral Density, Bone

Clinical Diagnostics, Rochester, NY, USA) analyser.

anterior superior iliac spines).

**3.4 Statistical data processing** 

**4.1 Bone mineral density, bone markers** 

**4. Results** 

p<0.05.

EX/BP (7.6%).

*BMD L1-L4 (Fig. 1)* 

*BMD femoral neck (Fig. 2)* 

Markers and Postural Stability in Subjects with Osteoporosis 499

Saluggia, Italy). The biochemical parameters were evaluated using VITROS 250 (Ortho-

For all patient groups, the baseline values of bone density (BMD L1-L4, BMD femoral neck) and bone markers (Ca, P, creatinine, ALP, ALP isoenzyme, osteocalcin, crosslaps) were measured at the beginning of research. For ascertaining the bone marker values, measurement was repeated after 3 weeks and 3 months. The last measurement in the range

In the second phase of the research, all measured women repeatedly completed the six basic types of stands (eyes open, eyes closed, head extension, standing on foam, tandem stand twice), whereas each such stand was of 30 s duration. The feet position during such stand (with the exception of tandem stand) was set at pelvic width (the distance between the

Two Kistler piezoelectric platforms, type 9286AA (Kistler Instrumente AG, Winterthur, Switzerland) were used for evaluating postural stability. The changes in the load on the lower limbs during standing as well as changes to the centre of pressure (COP) displacement (postural sway of COP and its velocity in antero-posterior and in medio-

The measured data was processed by the Statistica 8.0 (StatSoft, Inc., Tulsa, OK, USA) programme. In order to compare the impact of exercise on BMD and bone markers, one-way ANOVA with Fisher's post-hoc test were used. The comparison of differences between the exercising and control groups upon evaluating postural stability was performed by means

The basic statistical characteristics of the measured parameters for non-exercising groups as

During the monitored period, statistically significant increase in BMD L1-L4 value occurred in all measured groups with the exception of EX/SERM. A higher increase in BMD L1-L4 occurred in persons who did not undergo the targeted exercise intervention. The highest increase was recorded in NEX/BP and NEX/SERM. The difference in values between the groups with same medication is not statistically significant at baseline and after 1 year with

Increase in the value of BMD femoral neck occurred in all measured groups with the exception of EX/NS. The extent of changes is comparable in the exercising as well as in the non-exercising patients. This increase is statistically significant in NEX/BP, EX/BP and NEX/SERM. Between groups with the same medication, there is a statistically significant difference at baseline and after 1 year measurements for NEX/BP (7.1%) and

of t-test for independent groups. Any p-value less than 0.05 was deemed significant.

well as groups undergoing the intervention programme are stated in Tables 1 and 2.

of baseline measurement was performed after 1 year of starting the research.

lateral directions) were determined by the software Bioware, version 3.2.6.104.


#### **3.2 Exercise**

Exercise intervention was divided into three parts:


In the further phase of the research, we evaluated the effect of long-term exercise on postural stability. The observed group consisted of 43 women, which were divided into a group with long-term exercise programme (n=29, age 64.6±4.52 years) and the control group (n=14, age 65.5±4.98 years). Sample size was influenced by agreement of subjects with follow-up to research and limitations of workplace for application of the special exercise. The group went through controlled exercise intervention of low intensity for 50 minutes per week for a period of one year. The exercise unit was focused on maintaining and improving the quality of sensorimotor functions and postural strategies and was also completed by an hour daily home exercises. The progression of exercise consisted in repetition of a selected exercise pattern and in the change of position, i.e. transition from a lower to a higher position. The aim of the exercise in such easier and more demanding positions was to adjust and improve the quality of the respiratory mechanics, postural pattern and motor functions. Exercising in the vertical position was stipulated for adaptation to various types of stands, exercising balance strategies, and enabled an increased self-confidence for motion in space.

#### **3.3 Measurement process, technical equipment, measured parameters**

The bone mineral density was measured by the LUNAR-DPX device (GE Healthcare, Madison, WI, USA) and bone markers were determined by ETI-MAX 3000 (Diasorin S.p.A., Saluggia, Italy). The biochemical parameters were evaluated using VITROS 250 (Ortho-Clinical Diagnostics, Rochester, NY, USA) analyser.

For all patient groups, the baseline values of bone density (BMD L1-L4, BMD femoral neck) and bone markers (Ca, P, creatinine, ALP, ALP isoenzyme, osteocalcin, crosslaps) were measured at the beginning of research. For ascertaining the bone marker values, measurement was repeated after 3 weeks and 3 months. The last measurement in the range of baseline measurement was performed after 1 year of starting the research.

In the second phase of the research, all measured women repeatedly completed the six basic types of stands (eyes open, eyes closed, head extension, standing on foam, tandem stand twice), whereas each such stand was of 30 s duration. The feet position during such stand (with the exception of tandem stand) was set at pelvic width (the distance between the anterior superior iliac spines).

Two Kistler piezoelectric platforms, type 9286AA (Kistler Instrumente AG, Winterthur, Switzerland) were used for evaluating postural stability. The changes in the load on the lower limbs during standing as well as changes to the centre of pressure (COP) displacement (postural sway of COP and its velocity in antero-posterior and in mediolateral directions) were determined by the software Bioware, version 3.2.6.104.

### **3.4 Statistical data processing**

The measured data was processed by the Statistica 8.0 (StatSoft, Inc., Tulsa, OK, USA) programme. In order to compare the impact of exercise on BMD and bone markers, one-way ANOVA with Fisher's post-hoc test were used. The comparison of differences between the exercising and control groups upon evaluating postural stability was performed by means of t-test for independent groups. Any p-value less than 0.05 was deemed significant.

### **4. Results**

498 Osteoporosis

2. EX/NS (n=32, age 59.0±7.11 years): exercising group with nonspecific pharmacological therapy (i.e. daily controlled intake of Ca 1000–1500 mg, daily controlled intake of

3. NEX/BP (n=27, age 62.9±7.06 years): non-exercising group with specific pharmacological therapy, suppressing bone resorption (bisphosphonates – Fosamax,

4. EX/BP (n=35, age 59.7±7.56 years): exercising group with specific pharmacological therapy, suppressing bone resorption (bisphosphonates – Fosamax, controlled intake of

5. NEX/SERM (n=23, age 61.1±6.90 years): non-exercising group with specific pharmacological therapy (selective estrogen receptor modulators – Evista, controlled

6. EX/SERM (n=23, age 59.0±6.53 years): exercising group with specific pharmacological therapy (selective estrogen receptor modulators – Evista, controlled intake of Ca,

1. Three-week institutionalised exercise intervention in a rehabilitation centre focused on changing posture, adjustment of joint mobility, adjustment of muscle imbalance, coordination and postural correction, relaxing of shortened muscle groups and soft tissues, activation of muscles in the area of axis system, deep stabilization system and extremities, breathing exercises and coordination training, training for activity of daily

2. Three-month controlled group exercise programme focused on motivating and educating patients towards active approach; once a week of low intensity and of 50 min duration. 3. Daily exercise programme at home lasting 30 minutes, supplemented with walking of

In the further phase of the research, we evaluated the effect of long-term exercise on postural stability. The observed group consisted of 43 women, which were divided into a group with long-term exercise programme (n=29, age 64.6±4.52 years) and the control group (n=14, age 65.5±4.98 years). Sample size was influenced by agreement of subjects with follow-up to research and limitations of workplace for application of the special exercise. The group went through controlled exercise intervention of low intensity for 50 minutes per week for a period of one year. The exercise unit was focused on maintaining and improving the quality of sensorimotor functions and postural strategies and was also completed by an hour daily home exercises. The progression of exercise consisted in repetition of a selected exercise pattern and in the change of position, i.e. transition from a lower to a higher position. The aim of the exercise in such easier and more demanding positions was to adjust and improve the quality of the respiratory mechanics, postural pattern and motor functions. Exercising in the vertical position was stipulated for adaptation to various types of stands, exercising balance strategies, and enabled an increased self-confidence for motion in space.

**3.3 Measurement process, technical equipment, measured parameters** 

The bone mineral density was measured by the LUNAR-DPX device (GE Healthcare, Madison, WI, USA) and bone markers were determined by ETI-MAX 3000 (Diasorin S.p.A.,

controlled intake of Ca, administration of vitamin D3).

vitamin D3 0.25 μg).

Ca, administration of vitamin D3).

administration of vitamin D3).

living and training for walking.

minimum 60 min duration.

**3.2 Exercise** 

intake of Ca, administration of vitamin D3).

Exercise intervention was divided into three parts:

### **4.1 Bone mineral density, bone markers**

The basic statistical characteristics of the measured parameters for non-exercising groups as well as groups undergoing the intervention programme are stated in Tables 1 and 2.

### *BMD L1-L4 (Fig. 1)*

During the monitored period, statistically significant increase in BMD L1-L4 value occurred in all measured groups with the exception of EX/SERM. A higher increase in BMD L1-L4 occurred in persons who did not undergo the targeted exercise intervention. The highest increase was recorded in NEX/BP and NEX/SERM. The difference in values between the groups with same medication is not statistically significant at baseline and after 1 year with p<0.05.

### *BMD femoral neck (Fig. 2)*

Increase in the value of BMD femoral neck occurred in all measured groups with the exception of EX/NS. The extent of changes is comparable in the exercising as well as in the non-exercising patients. This increase is statistically significant in NEX/BP, EX/BP and NEX/SERM. Between groups with the same medication, there is a statistically significant difference at baseline and after 1 year measurements for NEX/BP (7.1%) and EX/BP (7.6%).

The Effect of Exercise on Bone Mineral Density, Bone

Weight (kg)

(g/cm2)

Calcium (mmol/l)

Phosphorus (mmol/l)

Creatinine (µmol/l)

ALP isoenzyme (µkat/l)

(\* p<0.05, \*\* p<0.01)

exercise intervention (Mean ± SD)

Osteocalcin (ng/ml)

Crosslaps (ng/ml)

ALP (µkat/l)

BMD L1-L4 (g/cm2)

BMD femoral neck

Markers and Postural Stability in Subjects with Osteoporosis 501

Age at baseline 59.0±7.11 62.9±7.06 61.1±6.90 Height (cm) 161.2±6.48 159.4±6.02 158.3±7.17

EX/NS (n=32) EX/BP (n=35) EX/SERM (n=23)

baseline 73.0±13.49 65.4±8.55 68.2±10.84 1 year 72.6±13.36 66.0±8.50 68.4±11.01

baseline 1.00±0.079 0.92±0.114 0.91±0.147 1 year 1.02±0.086 0.96±0.110 0.93±0.151

baseline 0.94±0.093 0.85±0.123 0.85±0.148 1 year 0.94±0.091 0.86±0.129 0.86±0.140

baseline 2.40±0.109 2.37±0.101 2.42±0.180 1 year 2.38±0.093 2.41±0.158 2.34±0.112

baseline 1.02±0.162 1.02±0.129 1.05±0.130 1 year 1.06±0.167 1.05±0.115 1.06±0.171

baseline 80.0±12.46 81.7±9.13 79.4±9.60 1 year 81.4±16.61 81.4±12.08 79.2±11.90

baseline 1.15±0.437 1.09±0.320 1.10±0.309 1 year 1.13±0.490 1.01±0.265 1.19±0.461

baseline 0.54±0.005 0.53±0.007 0.54±0.006 1 year 0.52±0.043 0.53±0.008 0.53±0.010

baseline 14.7±10.55 17.6±17.72 18.0±10.44 1 year 16.9±15.00 11.5±5.41 18.7±8.79

baseline 0.33±0.168 0.33±0.199 0.39±0.223 1 year 0.38±0.198 0.27±0.170 0.45±0.187

Table 2. Characteristics of measured parameters for the groups performing the targeted

Fig. 2. Changes between the baseline and after 1 year measurements – BMD femoral neck


Table 1. Characteristics of measured parameters for the non-exercising groups (Mean ± SD)

Fig. 1. Changes between the baseline and after 1 year measurements – BMD L1-L4 (\* p<0.05, \*\* p<0.01)

Age at baseline 57.8±6.05 59.7±7.56 59.0±6.53 Height (cm) 162.1±6.09 158.7±5.74 158.2±5.05

Weight (kg)

(g/cm2)

Calcium (mmol/l)

Phosphorus (mmol/l)

Creatinine (µmol/l)

ALP isoenzyme (µkat/l)

Osteocalcin (ng/ml)

Crosslaps (ng/ml)

\*\* p<0.01)

ALP (µkat/l)

BMD L1-L4 (g/cm2)

BMD femoral neck

NEX/NS (n=23) NEX/BP (n=27) NEX/SERM (n=23)

baseline 72.2±8.67 64.9±9.00 65.2±10.05 1 year 73.6±8.68 66.1±8.65 65.2±9.37

baseline 0.99±0.089 0.92±0.110 0.93±0.089 1 year 1.03±0.107 0.97±0.110 0.98±0.102

baseline 0.93±0.115 0.91±0.115 0.87±0.082 1 year 0.94±0.109 0.93±0.111 0.88±0.080

baseline 2.36±0.112 2.42±0.167 2.39±0.060 1 year 2.38±0.113 2.41±0.133 2.48±0.154

baseline 1.11±0.164 1.12±0.232 1.11±0.205 1 year 1.06±0.162 1.08±0.166 1.07±0.151

baseline 81.2±10.21 83.2±10.06 78.4±11.16 1 year 79.0±12.78 79.0±9.09 75.3±16.08

baseline 1.09±0.409 1.28±0.481 1.17±0.383 1 year 1.03±0.317 1.03±0.358 1.01±0.263

baseline 0.54±0.008 0.53±0.011 0.54±0.006 1 year 0.54±0.007 0.53±0.042 0.53±0.029

baseline 25.0±19.20 30.0±26.51 21.3±12.72 1 year 19.0±10.88 20.1±30.77 13.8±6.18

baseline 0.46±0.246 0.63±0.449 0.45±0.209 1 year 0.37±0.190 0.42±0.652 0.31±0.167

Table 1. Characteristics of measured parameters for the non-exercising groups (Mean ± SD)

Fig. 1. Changes between the baseline and after 1 year measurements – BMD L1-L4 (\* p<0.05,


Table 2. Characteristics of measured parameters for the groups performing the targeted exercise intervention (Mean ± SD)

Fig. 2. Changes between the baseline and after 1 year measurements – BMD femoral neck (\* p<0.05, \*\* p<0.01)

The Effect of Exercise on Bone Mineral Density, Bone

*Osteocalcin (Fig. 4)* 

*Crosslaps* 

Markers and Postural Stability in Subjects with Osteoporosis 503

In groups with the same medication, the value at baseline is higher in patients, who did not undergo exercise intervention. No significant difference was recorded at measurement after 1 year. Throughout the monitored period, a significant reduction in this parameter occurred

in NEX/NS, NEX/BP and NEX/SERM. A similar result was also valid for EX/BP.

Fig. 4. Changes of osteocalcin in the course of the monitored period (\* p<0.05, \*\* p<0.01)

significant for NEX/BP (p<0.05) and NEX/SERM (p<0.01).

for the resulting velocity of COP when standing on foam (Fig. 5).

**4.2 Postural stability evaluation** 

exercising patients.

At baseline, the parameter was significantly higher in patients who did not undergo exercise intervention in comparison to the group of exercising patients. This difference was not recorded at measurement after 1 year. The decrease in value for the monitored period is

No differences in weight-bearing distribution between the left and right lower extremity were found in any measured group or individual type of stand. Differences vary between 0.09 and 0.56% in the group of exercising and between 0.13 and 1.68% in the group of non-

Amongst both groups, we found no significant differences in COP sway in any directions measured for individual types of stand. In the group of non-exercising patients, faster change in COP position in the medio-lateral direction (p<0.05) occurs when standing with eyes closed, and such changes are reflected in higher resulting velocity of COP movement (p<0.05). A similar result applies to the velocity of COP in the antero-posterior direction, and

### *Calcium*

Differences between baseline and after 1 year measurements are statistically insignificant, when compared for the exercising and non-exercising patients, with the exception of NEX/SERM. In this group, there was an increase in Ca during the entire period of monitoring; differences are also significant in the measurements after 3 weeks or 3 months in comparison with the values measured after 1 year.

### *Phosphorus*

When comparing groups with the same medication, the value measured at baseline was significantly lower in groups of patients that were starting exercise intervention. Such difference was not found in any other measurements.

### *Creatinine*

In NEX/BP and NEX/SERM, statistically significant decrease (p<0.05) in the value of this parameter occurred after 1 year. Throughout the entire period, no significant differences were found in groups undergoing targeted intervention.

### *ALP (Fig. 3)*

In NEX/BP and EX/BP decrease in ALP value occurred during the monitored period. Differences between baseline and after 1 year measurements are significant (NEX/BP, p<0.01). A similar result is also valid for NEX/SERM where the parameter had a declining tendency throughout the entire monitored period.

### *ALP isoenzyme*

With the exception of EX/NS, differences in the values between individual measurements in all other groups were not statistically significant at level p<0.05.

### *Osteocalcin (Fig. 4)*

502 Osteoporosis

Differences between baseline and after 1 year measurements are statistically insignificant, when compared for the exercising and non-exercising patients, with the exception of NEX/SERM. In this group, there was an increase in Ca during the entire period of monitoring; differences are also significant in the measurements after 3 weeks or 3 months

When comparing groups with the same medication, the value measured at baseline was significantly lower in groups of patients that were starting exercise intervention. Such

In NEX/BP and NEX/SERM, statistically significant decrease (p<0.05) in the value of this parameter occurred after 1 year. Throughout the entire period, no significant differences

In NEX/BP and EX/BP decrease in ALP value occurred during the monitored period. Differences between baseline and after 1 year measurements are significant (NEX/BP, p<0.01). A similar result is also valid for NEX/SERM where the parameter had a declining

Fig. 3. Changes of the ALP in the course of the monitored period (\* p<0.05, \*\* p<0.01)

all other groups were not statistically significant at level p<0.05.

With the exception of EX/NS, differences in the values between individual measurements in

in comparison with the values measured after 1 year.

difference was not found in any other measurements.

were found in groups undergoing targeted intervention.

tendency throughout the entire monitored period.

*Calcium* 

*Phosphorus* 

*Creatinine* 

*ALP (Fig. 3)* 

*ALP isoenzyme* 

In groups with the same medication, the value at baseline is higher in patients, who did not undergo exercise intervention. No significant difference was recorded at measurement after 1 year. Throughout the monitored period, a significant reduction in this parameter occurred in NEX/NS, NEX/BP and NEX/SERM. A similar result was also valid for EX/BP.

Fig. 4. Changes of osteocalcin in the course of the monitored period (\* p<0.05, \*\* p<0.01)

#### *Crosslaps*

At baseline, the parameter was significantly higher in patients who did not undergo exercise intervention in comparison to the group of exercising patients. This difference was not recorded at measurement after 1 year. The decrease in value for the monitored period is significant for NEX/BP (p<0.05) and NEX/SERM (p<0.01).

### **4.2 Postural stability evaluation**

No differences in weight-bearing distribution between the left and right lower extremity were found in any measured group or individual type of stand. Differences vary between 0.09 and 0.56% in the group of exercising and between 0.13 and 1.68% in the group of nonexercising patients.

Amongst both groups, we found no significant differences in COP sway in any directions measured for individual types of stand. In the group of non-exercising patients, faster change in COP position in the medio-lateral direction (p<0.05) occurs when standing with eyes closed, and such changes are reflected in higher resulting velocity of COP movement (p<0.05). A similar result applies to the velocity of COP in the antero-posterior direction, and for the resulting velocity of COP when standing on foam (Fig. 5).

The Effect of Exercise on Bone Mineral Density, Bone

resistance training, regardless of intensity and frequency.

strength exercise group was significantly lower.

lumbar spine.

Markers and Postural Stability in Subjects with Osteoporosis 505

The results of Angin and Erden (2009) demonstrate positive influence of the exercise program in increasing BMD and quality of life. The efficacy of a 5-year exercise program on the BMD and balance was investigated by Walker et al. (2000). For the post-menopausal women with osteoporosis who participated in the program it was possible to stabilize the BMD of the lumbar site, and to reduce fractures. Lange et al. (2007) presented that physical activity has a decelerating effect on the bone loss rate in postmenopausal women, independent of hormone replacement therapy. A significant increase in BMD and decrease in bone markers was found by Ďurišová and Zvarka (2004) in both exercise and control group. Authors state that regular exercise should become an important component of the comprehensive management of osteoporosis. Bergström et al. (2008) indicated a positive effect of physical training on hip BMD. No significant effect of exercise was found in the

The effect of exercise on BMD can be influenced by its type, intensity and frequency. Kerr et al. (1996) examined the effect of a 1-year progressive resistance training program (strength and endurance group) on bone mass. They state that postmenopausal bone mass can be significantly increased by strength exercise with high-load low repetitions. For an endurance regimen this change was not established. On the contrary, Bemben and Bemben (2011) found positive BMD responses for the hip and spine (not for the total body) for all types of

The effect of exercise over a period of 3 years on stopping or decelerating of bone loss during the early postmenopausal years was assessed by Engelke et al. (2006). The application of the high-intensity exercise program succeeded to maintain bone mineral density at the spine, hip and calcaneus, but not at the forearm. Chow et al. (1987) evaluated the effect of 1-year aerobic and strength exercise programmes on bone mass. They found that both exercise groups showed a significant improvement in measured parameters. The effect of a 2-year exercise intervention and calcium supplementation (600 mg) on BMD was assessed by Kerr et al. (2001). Three groups of patients (strength, fitness, no exercise control) participated at this study. There was no difference between the groups at the forearm, lumbar spine, or whole body sites. The significant effect of the strength program was found at the hip (intertrochanter hip site). Judge et al. (2005) tested the effect of the resistance home-based training on the femoral BMD in long-term users of hormone therapy. The exercise decreased bone turnover and increased femur BMD. Korpelainen et al. (2006) didn't found the effect of long-term impact exercise on BMD at the radius and hip, while there was a positive effect on bone mineral content at the trochanter. High-impact loading exercise in osteopenic postmenopausal women was assessed by Chien et al. (2000) and Vainionpää et al. (2005). A 24-week program had a positive effect on the deceleration of the decline in BMD (Chien et al., 2000). Vainionpää et al. (2005) suggested that this type of exercise may be an efficient way to prevent osteoporosis. Martyn-St James and Carroll (2009) assessed the effects of mixed exercise programmes on postmenopausal bone loss at the hip and spine. The exercise programmes combining jogging with other low-impact loading activity and programmes mixing impact activity with high-magnitude exercise could be effective in reducing bone loss at the hip and spine. The effects of slow (strength) and fast (power) resistance exercises on various osteodensitometric parameters were compared by Von Stengel et al. (2005) and Von Stengel et al. (2007). The changes in BMD after 1 year of training were not significant for the power exercise group, whereas the BMD value in

Fig. 5. The COP velocity in different types of stands for exercising and non-exercising patients (vX – COP velocity in medio-lateral direction, vY – COP velocity in antero-posterior direction, v – resultant COP velocity, \* p<0.05, \*\* p<0.01)

With the exception of standard deviation for COP movement in the antero-posterior direction at stand with eyes open and stand on foam in the group of exercising patients, we found no significant differences (p<0.05). The exclusion of visual control or head extension thereby did not reflect in the change(s) of the measured parameters.

### **5. Discussion**

### **5.1 Exercise, medication and bone mineral density**

In order to maintain desirable optimal amount of BMD, it is required to keep an optimal level of tension relating to functional load given by physical activity (Melendez-Ortega, 2007). Mechanic load, induced in the course of exercise, is essential for adaptation of bone architecture in the place of the load (Vainionpää et al., 2005). That is the reason why movement is a significant element in prevention and treatment of osteoporosis.

### **5.1.1 Effect of exercise on postmenopausal bone**

From the results of our study follows that BMD was increased in all participants who were involved in the exercise intervention. The changes are, however, not significantly higher in comparison with the non-exercising groups. For bone density of the colli femoris (BMD femoral neck), the increase was smaller than in the area of lumbar spine (BMD L1-L4) for all types of medications.

Opinions of authors concerning the effect of exercise on the quality of bone tissue vary. The effect of exercise on regional BMD in postmenopausal women was evaluated by Kelley (1998). Across all designs and categories, treatment effect changes in bone density ranged from -17.10 to 17.30%. Meta-analytic review of included studies suggests that exercise may slow the rate of bone loss in this group of patients.

Fig. 5. The COP velocity in different types of stands for exercising and non-exercising patients (vX – COP velocity in medio-lateral direction, vY – COP velocity in antero-posterior

With the exception of standard deviation for COP movement in the antero-posterior direction at stand with eyes open and stand on foam in the group of exercising patients, we found no significant differences (p<0.05). The exclusion of visual control or head extension

In order to maintain desirable optimal amount of BMD, it is required to keep an optimal level of tension relating to functional load given by physical activity (Melendez-Ortega, 2007). Mechanic load, induced in the course of exercise, is essential for adaptation of bone architecture in the place of the load (Vainionpää et al., 2005). That is the reason why

From the results of our study follows that BMD was increased in all participants who were involved in the exercise intervention. The changes are, however, not significantly higher in comparison with the non-exercising groups. For bone density of the colli femoris (BMD femoral neck), the increase was smaller than in the area of lumbar spine (BMD L1-L4) for all

Opinions of authors concerning the effect of exercise on the quality of bone tissue vary. The effect of exercise on regional BMD in postmenopausal women was evaluated by Kelley (1998). Across all designs and categories, treatment effect changes in bone density ranged from -17.10 to 17.30%. Meta-analytic review of included studies suggests that exercise may

movement is a significant element in prevention and treatment of osteoporosis.

direction, v – resultant COP velocity, \* p<0.05, \*\* p<0.01)

**5.1 Exercise, medication and bone mineral density** 

**5.1.1 Effect of exercise on postmenopausal bone** 

slow the rate of bone loss in this group of patients.

**5. Discussion** 

types of medications.

thereby did not reflect in the change(s) of the measured parameters.

The results of Angin and Erden (2009) demonstrate positive influence of the exercise program in increasing BMD and quality of life. The efficacy of a 5-year exercise program on the BMD and balance was investigated by Walker et al. (2000). For the post-menopausal women with osteoporosis who participated in the program it was possible to stabilize the BMD of the lumbar site, and to reduce fractures. Lange et al. (2007) presented that physical activity has a decelerating effect on the bone loss rate in postmenopausal women, independent of hormone replacement therapy. A significant increase in BMD and decrease in bone markers was found by Ďurišová and Zvarka (2004) in both exercise and control group. Authors state that regular exercise should become an important component of the comprehensive management of osteoporosis. Bergström et al. (2008) indicated a positive effect of physical training on hip BMD. No significant effect of exercise was found in the lumbar spine.

The effect of exercise on BMD can be influenced by its type, intensity and frequency. Kerr et al. (1996) examined the effect of a 1-year progressive resistance training program (strength and endurance group) on bone mass. They state that postmenopausal bone mass can be significantly increased by strength exercise with high-load low repetitions. For an endurance regimen this change was not established. On the contrary, Bemben and Bemben (2011) found positive BMD responses for the hip and spine (not for the total body) for all types of resistance training, regardless of intensity and frequency.

The effect of exercise over a period of 3 years on stopping or decelerating of bone loss during the early postmenopausal years was assessed by Engelke et al. (2006). The application of the high-intensity exercise program succeeded to maintain bone mineral density at the spine, hip and calcaneus, but not at the forearm. Chow et al. (1987) evaluated the effect of 1-year aerobic and strength exercise programmes on bone mass. They found that both exercise groups showed a significant improvement in measured parameters. The effect of a 2-year exercise intervention and calcium supplementation (600 mg) on BMD was assessed by Kerr et al. (2001). Three groups of patients (strength, fitness, no exercise control) participated at this study. There was no difference between the groups at the forearm, lumbar spine, or whole body sites. The significant effect of the strength program was found at the hip (intertrochanter hip site). Judge et al. (2005) tested the effect of the resistance home-based training on the femoral BMD in long-term users of hormone therapy. The exercise decreased bone turnover and increased femur BMD. Korpelainen et al. (2006) didn't found the effect of long-term impact exercise on BMD at the radius and hip, while there was a positive effect on bone mineral content at the trochanter. High-impact loading exercise in osteopenic postmenopausal women was assessed by Chien et al. (2000) and Vainionpää et al. (2005). A 24-week program had a positive effect on the deceleration of the decline in BMD (Chien et al., 2000). Vainionpää et al. (2005) suggested that this type of exercise may be an efficient way to prevent osteoporosis. Martyn-St James and Carroll (2009) assessed the effects of mixed exercise programmes on postmenopausal bone loss at the hip and spine. The exercise programmes combining jogging with other low-impact loading activity and programmes mixing impact activity with high-magnitude exercise could be effective in reducing bone loss at the hip and spine. The effects of slow (strength) and fast (power) resistance exercises on various osteodensitometric parameters were compared by Von Stengel et al. (2005) and Von Stengel et al. (2007). The changes in BMD after 1 year of training were not significant for the power exercise group, whereas the BMD value in strength exercise group was significantly lower.

The Effect of Exercise on Bone Mineral Density, Bone

shopping 0.3 hr).

**5.1.3 Medication** 

individuality of the given patient.

**5.2 Exercise and balance** 

is regular physical activity.

exercise must be complemented by application of calcium.

Markers and Postural Stability in Subjects with Osteoporosis 507

conducted within the study research, whose rate of return was, however, only approx. 25%, showed that in the run of one day, every woman had on average about 4.5 hours of physical activity (walking 1.2 hr; tidying up/cleaning 1.2 hr; meal preparation 1.1 hr; gardening 0.7 hr;

Regrettably, these common everyday activities of monitored women are, in many studies, neither taken into account nor specified nor quantified. Most authors limit themselves to stating that the monitored applicants lead a sedentary type of life. It is, however, evident

Williams (1999) claims that women who never exercised can increase their BMD through physical training by 3-5% per year. Women who exercised regularly already have higher BMD and in order to maintain this level, they have to walk or run for 30 min a day, at least 5 times a week. The individual extent of physical activity in monitored patients can differ significantly with regards to the previous style of life. Kerry (2003) did not find any positive effect of physical activities related to house chores on the quality of bone tissue. On the other

In the event that a patient does not suffer from any associated health disorder and is sufficiently hydrated, we do not expect significant changes in values of Ca, P and creatinine brought about by medications. Indicators of Ca and P do not have any direct relation to the level of bone remodelling (Štěpán et al., 2002). Changes in the values of osteocalcin and crosslaps express the activity of bone metabolism. In this case, a wide range of physiological values can be found, determining the standards in post-menopausal women (0.251-0.760 ng/ml resp. 4.9-30.5 ng/ml). It follows that it is necessary to evaluate measured changes in a strictly individual way. We have to keep this in mind also when evaluating statistically significant differences. Application of bisphosphonates (NEX/BP, EX/BP) is the most effective means for reduction of resorption expressed by the crosslaps parameter. Application of selective modulator (ralofixen; NEX/SERM, EX/SERM) influences these changes less and after a longer period of time. The decisive element is, however, a particular

Some authors regard, as the most effective way to prevent loss of BMD, the combination of physical activity and hormonal treatment (Angin & Erden, 2009; Yamazaki et al., 2004). Specker (1996) claims that in order to create positive effect of physical activity on BMD,

Results presented in this study confirm the opinion that exercise can in women after menopause minimize or inhibit the loss of BMD, it cannot, however, substitute

Risks of fall count among the most momentous problems in people with osteoporosis. Decrease of BMD of colli femoris in elderly people increases the risks of occurrence of fractures up to 2.6 times (Cummings et al., 1993). Awareness of the risks of fall can lead to intentional decrease in daily living activities, which is reflected in reduction of life quality. That is why it is essential to try and improve, using non-invasive interventions, the level of postural stability. One of the options bearing positive impact on improving balance control

pharmacological treatment and ensure increase in BMD (Bloomfield, 2005).

that such a definition of the level of everyday activities may not be sufficient.

hand, most other researches do confirm the above-mentioned positive effect.

A comparison of the effect of exercise on BMD in postmenopausal women described in various studies is very difficult because of different number of subjects, exercise intensity, type of exercise, medication etc. In future research it will be necessary to exactly determine all factors involved and attempt to assess their influence on research results. Physical activity should be observed not only during exercise units but also during ordinary daily activities. However, results of most studies show that exercise has an important positive effect on the deceleration of decline in BMD.

### **5.1.2 Type, intensity and method of exercise**

In order to evaluate the effect of physical activity on the change of bone markers, it is also important to take into consideration its parameters (type, intensity, duration …). In our case the exercise was of a lower intensity and was focused mainly on rehabilitation. And so the major effect did not lie in changing the physiology of the load but rather in improving body posture, adjusting muscle imbalances and postural stability.

Melendez-Ortega (2007) states that the amplitude of the load plays a more important role for bone density than number of repetitions. Repeated strain of bones above the physiological limit might lead to injury or even bone fracture. Englund et al. (2005) and other authors regard long-term weight-bearing training as the most suitable activity influencing the BMD. Vainionpää et al. (2005) proved that this type of exercise not only affects the bone density but also improves its architecture. To the contrary, Schwab and Klein (2008) claim that short repetitive loading of the bone has a positive impact on the biology of the bone.

Intensive aerobic activity, heavy-load and resistance exercises are, according to Yamazaki et al. (2004), much more effective in increasing BMD than physical activity with lower intensity (e.g. slow walking). Similar results were ascertained by Maddalozzo and Snow (2000) who believed that the highest effect is brought through a programme with high intensity of exercises. Heinonen et al. (1996) and Chien et al. (2000) determined that intensity of physical activity should hover above the aerobic threshold, i.e. above 60-70% of maximum aerobic capacity.

Brooke-Wavell et al. (2001), Yamazaki et al. (2004) and other authors recommend walking as a suitable activity for increasing bone density. Walking is the easiest and best available form of physical activity, which can be practiced virtually anywhere, poses only small risks of injury and requires negligible financial demands (it is, however, necessary to take into account risks of fall on uneven or slippery terrains). The most effective method of prevention of osteoporosis is brisk walking (Brooke-Wavell at al., 2001). Feskanich et al. (2002) point out, however, at increasing risks of fall at higher walking speed. Nevertheless, there exist studies which did not prove effect of walking on the increase of BMD (Martyn-St James & Carroll, 2008).

Exercise regimes encompassing a combination of weight-bearing, balance and coordination exercises but excluding jumping activities, improve BMD, enhance muscular strength and walking ability and thus reduce the risks of fall and suffering consequent fractures (Englund et al., 2005). According to Feskanich et al. (2002), activities improving balance and flexibility significantly contribute to reducing the risks of fall, whereas heavy-load and resistance exercises enhance muscular strength and BMD.

One of the shortcomings of the presented study is its limited scope of quantifying physical activity performed by women in the course of the monitored period. Common daily activities can have the same or even higher impact than directed exercise intervention. A survey conducted within the study research, whose rate of return was, however, only approx. 25%, showed that in the run of one day, every woman had on average about 4.5 hours of physical activity (walking 1.2 hr; tidying up/cleaning 1.2 hr; meal preparation 1.1 hr; gardening 0.7 hr; shopping 0.3 hr).

Regrettably, these common everyday activities of monitored women are, in many studies, neither taken into account nor specified nor quantified. Most authors limit themselves to stating that the monitored applicants lead a sedentary type of life. It is, however, evident that such a definition of the level of everyday activities may not be sufficient.

Williams (1999) claims that women who never exercised can increase their BMD through physical training by 3-5% per year. Women who exercised regularly already have higher BMD and in order to maintain this level, they have to walk or run for 30 min a day, at least 5 times a week. The individual extent of physical activity in monitored patients can differ significantly with regards to the previous style of life. Kerry (2003) did not find any positive effect of physical activities related to house chores on the quality of bone tissue. On the other hand, most other researches do confirm the above-mentioned positive effect.

### **5.1.3 Medication**

506 Osteoporosis

A comparison of the effect of exercise on BMD in postmenopausal women described in various studies is very difficult because of different number of subjects, exercise intensity, type of exercise, medication etc. In future research it will be necessary to exactly determine all factors involved and attempt to assess their influence on research results. Physical activity should be observed not only during exercise units but also during ordinary daily activities. However, results of most studies show that exercise has an important positive

In order to evaluate the effect of physical activity on the change of bone markers, it is also important to take into consideration its parameters (type, intensity, duration …). In our case the exercise was of a lower intensity and was focused mainly on rehabilitation. And so the major effect did not lie in changing the physiology of the load but rather in improving body

Melendez-Ortega (2007) states that the amplitude of the load plays a more important role for bone density than number of repetitions. Repeated strain of bones above the physiological limit might lead to injury or even bone fracture. Englund et al. (2005) and other authors regard long-term weight-bearing training as the most suitable activity influencing the BMD. Vainionpää et al. (2005) proved that this type of exercise not only affects the bone density but also improves its architecture. To the contrary, Schwab and Klein (2008) claim that short

Intensive aerobic activity, heavy-load and resistance exercises are, according to Yamazaki et al. (2004), much more effective in increasing BMD than physical activity with lower intensity (e.g. slow walking). Similar results were ascertained by Maddalozzo and Snow (2000) who believed that the highest effect is brought through a programme with high intensity of exercises. Heinonen et al. (1996) and Chien et al. (2000) determined that intensity of physical activity should hover above the aerobic threshold, i.e. above 60-70% of maximum aerobic

Brooke-Wavell et al. (2001), Yamazaki et al. (2004) and other authors recommend walking as a suitable activity for increasing bone density. Walking is the easiest and best available form of physical activity, which can be practiced virtually anywhere, poses only small risks of injury and requires negligible financial demands (it is, however, necessary to take into account risks of fall on uneven or slippery terrains). The most effective method of prevention of osteoporosis is brisk walking (Brooke-Wavell at al., 2001). Feskanich et al. (2002) point out, however, at increasing risks of fall at higher walking speed. Nevertheless, there exist studies which did not prove effect of walking on the increase of BMD (Martyn-St

Exercise regimes encompassing a combination of weight-bearing, balance and coordination exercises but excluding jumping activities, improve BMD, enhance muscular strength and walking ability and thus reduce the risks of fall and suffering consequent fractures (Englund et al., 2005). According to Feskanich et al. (2002), activities improving balance and flexibility significantly contribute to reducing the risks of fall, whereas heavy-load and resistance

One of the shortcomings of the presented study is its limited scope of quantifying physical activity performed by women in the course of the monitored period. Common daily activities can have the same or even higher impact than directed exercise intervention. A survey

repetitive loading of the bone has a positive impact on the biology of the bone.

effect on the deceleration of decline in BMD.

capacity.

James & Carroll, 2008).

exercises enhance muscular strength and BMD.

**5.1.2 Type, intensity and method of exercise** 

posture, adjusting muscle imbalances and postural stability.

In the event that a patient does not suffer from any associated health disorder and is sufficiently hydrated, we do not expect significant changes in values of Ca, P and creatinine brought about by medications. Indicators of Ca and P do not have any direct relation to the level of bone remodelling (Štěpán et al., 2002). Changes in the values of osteocalcin and crosslaps express the activity of bone metabolism. In this case, a wide range of physiological values can be found, determining the standards in post-menopausal women (0.251-0.760 ng/ml resp. 4.9-30.5 ng/ml). It follows that it is necessary to evaluate measured changes in a strictly individual way. We have to keep this in mind also when evaluating statistically significant differences. Application of bisphosphonates (NEX/BP, EX/BP) is the most effective means for reduction of resorption expressed by the crosslaps parameter. Application of selective modulator (ralofixen; NEX/SERM, EX/SERM) influences these changes less and after a longer period of time. The decisive element is, however, a particular individuality of the given patient.

Some authors regard, as the most effective way to prevent loss of BMD, the combination of physical activity and hormonal treatment (Angin & Erden, 2009; Yamazaki et al., 2004). Specker (1996) claims that in order to create positive effect of physical activity on BMD, exercise must be complemented by application of calcium.

Results presented in this study confirm the opinion that exercise can in women after menopause minimize or inhibit the loss of BMD, it cannot, however, substitute pharmacological treatment and ensure increase in BMD (Bloomfield, 2005).

### **5.2 Exercise and balance**

Risks of fall count among the most momentous problems in people with osteoporosis. Decrease of BMD of colli femoris in elderly people increases the risks of occurrence of fractures up to 2.6 times (Cummings et al., 1993). Awareness of the risks of fall can lead to intentional decrease in daily living activities, which is reflected in reduction of life quality. That is why it is essential to try and improve, using non-invasive interventions, the level of postural stability. One of the options bearing positive impact on improving balance control is regular physical activity.

The Effect of Exercise on Bone Mineral Density, Bone

(Véle, 1995).

**5.3 Future research** 

**6. Conclusion** 

the monitored period.

changes of the COP positions.

**7. Acknowledgments** 

parameters should be employed.

Markers and Postural Stability in Subjects with Osteoporosis 509

10%, which is considered as marginal for determining the asymmetry of weight-bearing

Similar researches stated in literature do not pay sufficient attention to analysing daily living activities of patients. But in fact, the style of life of the monitored women can significantly influence obtained results. That is why it is necessary for any further research to evaluate physical activities performed above the scope of the targeted intervention. In order to determine their range and intensity, devices enabling quantification of these

In our research, the final measurements were conducted one year after the initial measurements, i.e. in the same season of the year. In the event of control measurements, which are conducted in shorter time intervals or under significantly different climatic conditions, it is

Taking into account the level of motor skills and fitness of monitored people, it is necessary, when evaluating postural stability, to perform more demanding motor tasks (while abiding by all safety rules). When examining the effect of exercise, measuring dynamic stability could be more conclusive. Another option is to determine the level of stability when performing a specific task (dual task), whether motor or cognitive. Patients would then concentrate not only on their stance, but also on the performance of these tasks. Another means of achieving more reliable results could be a combination of exclusion or limitation of two sensory systems, as

BMD in the L1-L4 area and colli femoris increased in all monitored groups (exercising as well as non-exercising). The change was caused by application of nonspecific (Ca+D3) and specific (Fosamax, Evista) pharmacological treatment. Increase was higher for the area of lumbar spine. Sizes of measured bone markers did not significantly change in the course of

A significant effect of exercise applied in the course of one year on the level of bone mineralisation was not confirmed. Thus, physical activity is a necessary requirement for

Effect of repeated exercise units focused on postural stability did not manifest in the sizes of the COP sway in a bipedal stance, however, it had an effect on decrease in the velocity

In order to evaluate the postural stability in women with osteoporosis (osteopenia) without any significant limitations in the motor control area, it is essential to complement the

This study was supported by the research grant No MSM 6198959221 of the Ministry of Education, Youth and Sport, Czech Republic, "Physical activity and inactivity of inhabitants

positive changes of BMD in women after menopause, it is, however, not sufficient.

execution of current tests with a simultaneous solution of other tasks.

of the Czech Republic in the context of behavioural changes".

important to determine the effect of these changes on the measured parameters.

well as the modification of the visual signal with the use of special tools.

Among interventions focused on reduction of the risks of fall counts, among others, training of balance keeping and walking (Messinger-Rapport & Thacker, 2003). For better stability, balance training is more effective than general exercise programmes including merely aerobic, weight-bearing or stretching activities (Rogers et al., 2003; Madureira et al., 2007).

In order to evaluate the stability in various modifications of stand, we used parameters of confidence ellipses created on the basis of COP movement. Differences in sizes of COP sway between both monitored groups are not significant. These findings differ from conclusions of other authors.

Effect of physical activity on improving balance and quality of postural stability is reported by Binder et al. (1994), Hopkins et al. (1990) and Gerdhem et al. (2003). Reducing COP sway after performing targeted exercises was noted by Perrin et al. (1999). Park et al. (2008) inquired into the effect of physical activity (48 weeks) on balance and compared postural sway between participants who did or did not do exercises. He found a significant difference in the COP sway in medio-lateral direction, whereas antero-posterior sway remained unchanged. Kuczyński & Ostrowska (2006) recorded the size of COP sway in medio-lateral direction higher by 50% in patients with osteoporosis than in healthy individuals. These authors also discovered that medio-lateral sways are higher in people who had fallen at least once in the past than in people without such history. Limitation or loss of lateral stability thus increases the probability of fall occurrence (Melzer et al., 2004). According to Hu and Woollacott (1994), multisensory training influences postural stability in a form of improving its parameters, among others, also when standing with head extended.

Differences in size of COP sway measured in our study, which are different from trends in the above-mentioned studies, can be caused by low demands of selected types of postures and by incoherence of the monitored group. The group was put together on the basis of diagnostics of osteoporosis or osteopenia, excluding women with neurological, cognitive and sensory disorders. When putting the groups together, associated disorders and occurrence of suffered injuries in the past were not taken into account. The monitored group represents just a small sample and the numbers of women in the exercising and nonexercising groups were not even.

Conclusions concerning deterioration of posture stability with closed eyes, which were ascertained for various groups of population, from few-month-old babies (Jouen, 1988) up to elderly people (Lord & Menz, 2000) were not confirmed. Influence of vision is further accentuated also in situations when the proprioceptive element of the stability control is reduced (Redfern et al., 2001).

Unlike the size of COP sways, effect of balance exercises was discovered for the speed of COP sway. In the stance with closed eyes and stance on foam, the exercising group significantly reduced speed of COP sway in comparison with the non-exercising group. Significant differences in reduction of the COP velocity in the exercising group were found also by Rogers et al. (2001).

Postural stability decreases with increasing asymmetry in distribution of physical weight (Genthon & Rougier, 2005). In our study, we did not find any significant differences between weight-bearing distribution on left and right legs in individual types of stands in any of the measured groups. Ascertained differences are significantly lower than the size 10%, which is considered as marginal for determining the asymmetry of weight-bearing (Véle, 1995).

### **5.3 Future research**

508 Osteoporosis

Among interventions focused on reduction of the risks of fall counts, among others, training of balance keeping and walking (Messinger-Rapport & Thacker, 2003). For better stability, balance training is more effective than general exercise programmes including merely aerobic, weight-bearing or stretching activities (Rogers et al., 2003; Madureira et

In order to evaluate the stability in various modifications of stand, we used parameters of confidence ellipses created on the basis of COP movement. Differences in sizes of COP sway between both monitored groups are not significant. These findings differ from conclusions

Effect of physical activity on improving balance and quality of postural stability is reported by Binder et al. (1994), Hopkins et al. (1990) and Gerdhem et al. (2003). Reducing COP sway after performing targeted exercises was noted by Perrin et al. (1999). Park et al. (2008) inquired into the effect of physical activity (48 weeks) on balance and compared postural sway between participants who did or did not do exercises. He found a significant difference in the COP sway in medio-lateral direction, whereas antero-posterior sway remained unchanged. Kuczyński & Ostrowska (2006) recorded the size of COP sway in medio-lateral direction higher by 50% in patients with osteoporosis than in healthy individuals. These authors also discovered that medio-lateral sways are higher in people who had fallen at least once in the past than in people without such history. Limitation or loss of lateral stability thus increases the probability of fall occurrence (Melzer et al., 2004). According to Hu and Woollacott (1994), multisensory training influences postural stability in a form of improving its parameters, among others, also when standing with head

Differences in size of COP sway measured in our study, which are different from trends in the above-mentioned studies, can be caused by low demands of selected types of postures and by incoherence of the monitored group. The group was put together on the basis of diagnostics of osteoporosis or osteopenia, excluding women with neurological, cognitive and sensory disorders. When putting the groups together, associated disorders and occurrence of suffered injuries in the past were not taken into account. The monitored group represents just a small sample and the numbers of women in the exercising and non-

Conclusions concerning deterioration of posture stability with closed eyes, which were ascertained for various groups of population, from few-month-old babies (Jouen, 1988) up to elderly people (Lord & Menz, 2000) were not confirmed. Influence of vision is further accentuated also in situations when the proprioceptive element of the stability control is

Unlike the size of COP sways, effect of balance exercises was discovered for the speed of COP sway. In the stance with closed eyes and stance on foam, the exercising group significantly reduced speed of COP sway in comparison with the non-exercising group. Significant differences in reduction of the COP velocity in the exercising group were found

Postural stability decreases with increasing asymmetry in distribution of physical weight (Genthon & Rougier, 2005). In our study, we did not find any significant differences between weight-bearing distribution on left and right legs in individual types of stands in any of the measured groups. Ascertained differences are significantly lower than the size

al., 2007).

extended.

exercising groups were not even.

reduced (Redfern et al., 2001).

also by Rogers et al. (2001).

of other authors.

Similar researches stated in literature do not pay sufficient attention to analysing daily living activities of patients. But in fact, the style of life of the monitored women can significantly influence obtained results. That is why it is necessary for any further research to evaluate physical activities performed above the scope of the targeted intervention. In order to determine their range and intensity, devices enabling quantification of these parameters should be employed.

In our research, the final measurements were conducted one year after the initial measurements, i.e. in the same season of the year. In the event of control measurements, which are conducted in shorter time intervals or under significantly different climatic conditions, it is important to determine the effect of these changes on the measured parameters.

Taking into account the level of motor skills and fitness of monitored people, it is necessary, when evaluating postural stability, to perform more demanding motor tasks (while abiding by all safety rules). When examining the effect of exercise, measuring dynamic stability could be more conclusive. Another option is to determine the level of stability when performing a specific task (dual task), whether motor or cognitive. Patients would then concentrate not only on their stance, but also on the performance of these tasks. Another means of achieving more reliable results could be a combination of exclusion or limitation of two sensory systems, as well as the modification of the visual signal with the use of special tools.

### **6. Conclusion**

BMD in the L1-L4 area and colli femoris increased in all monitored groups (exercising as well as non-exercising). The change was caused by application of nonspecific (Ca+D3) and specific (Fosamax, Evista) pharmacological treatment. Increase was higher for the area of lumbar spine. Sizes of measured bone markers did not significantly change in the course of the monitored period.

A significant effect of exercise applied in the course of one year on the level of bone mineralisation was not confirmed. Thus, physical activity is a necessary requirement for positive changes of BMD in women after menopause, it is, however, not sufficient.

Effect of repeated exercise units focused on postural stability did not manifest in the sizes of the COP sway in a bipedal stance, however, it had an effect on decrease in the velocity changes of the COP positions.

In order to evaluate the postural stability in women with osteoporosis (osteopenia) without any significant limitations in the motor control area, it is essential to complement the execution of current tests with a simultaneous solution of other tasks.

### **7. Acknowledgments**

This study was supported by the research grant No MSM 6198959221 of the Ministry of Education, Youth and Sport, Czech Republic, "Physical activity and inactivity of inhabitants of the Czech Republic in the context of behavioural changes".

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**25** 

*Brazil* 

**Impaired Ability to Perform the** 

Júlia Guimarães Reis, Gustavo de Carvalho da Costa

and Daniela Cristina Carvalho de Abreu

*School of Medicine at Ribeirão Preto FMRP – USP* 

*University of São Paulo,* 

**Sit-to-Stand Task in Osteoporotic Women** 

Deborah Colucci Trevisan, Francisco José Albuquerque de Paula,

The process of aging causes several physiological alterations and body modification in elderly people. These changes include decrease in bone mass and muscular strength, rigidity in joints, and range of movement reduction in addition to changes in the central nervous system such as slow nerve conduction velocity (Deschenes, 2011), co- contraction of antagonist muscles, and alterations in the sensorial systems (visual, somatosensitive, vestibular functions), all contributing for the impairment of postural control and functional

The maintenance of the postural stability is important during functional activities such as sitting down and standing up, walking, as well as for performing volitional movements coordinately, which is essential for daily tasks. The increase of postural control system deficit, which is associated to aging, has a strong relation to the risk of falls. In Brazil, data from the Ministry of Health shown that 28,459 elderly persons had died between 1979 and 1995 due

Changes in postural control and decreased muscle strength and power are important risk factors for falls, especially in the elderly, since there is a reduction in muscle strength of 30-50% between 30 -80 years, especially in the lower limbs (Burke et al., 2010; Janssen et al., 2002). The reduction in muscle strength occurs due to the reduction in the number and size of muscle fibers. Mainly type II fibers (fast contraction), which are most affected in relation to

The intensity of the muscle fibers loss depends on the degree of physical activity, nutrition, hereditary factor and lifestyle throughout life. In addition to losing in maximum muscle strength due to the aging process, there is also the loss of muscle power (force x speed), leading to a greater impairment in performance of functional activities, which requires agility, such as standing and walking, and increase susceptibility to falls (Marsh, 2000;

The sit-to-stand test is a widely used tool in clinical practice because it is easy to apply and it requires simple matters, which are chair (without armrests) and a stopwatch. There are several ways to perform the test, but the way that is most commonly used, is to perform five

to falls and, in February 2000, the inpatient mortality rate for falls was 2.58%.

type I fibers (slow contraction) (Frontera et al., 1991).

**1. Introduction**

Hunter et al., 2004).

activities (Gauchard et al., 2003).


## **Impaired Ability to Perform the Sit-to-Stand Task in Osteoporotic Women**

Deborah Colucci Trevisan, Francisco José Albuquerque de Paula, Júlia Guimarães Reis, Gustavo de Carvalho da Costa and Daniela Cristina Carvalho de Abreu *University of São Paulo, School of Medicine at Ribeirão Preto FMRP – USP Brazil* 

### **1. Introduction**

516 Osteoporosis

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pp. 500-508.

The process of aging causes several physiological alterations and body modification in elderly people. These changes include decrease in bone mass and muscular strength, rigidity in joints, and range of movement reduction in addition to changes in the central nervous system such as slow nerve conduction velocity (Deschenes, 2011), co- contraction of antagonist muscles, and alterations in the sensorial systems (visual, somatosensitive, vestibular functions), all contributing for the impairment of postural control and functional activities (Gauchard et al., 2003).

The maintenance of the postural stability is important during functional activities such as sitting down and standing up, walking, as well as for performing volitional movements coordinately, which is essential for daily tasks. The increase of postural control system deficit, which is associated to aging, has a strong relation to the risk of falls. In Brazil, data from the Ministry of Health shown that 28,459 elderly persons had died between 1979 and 1995 due to falls and, in February 2000, the inpatient mortality rate for falls was 2.58%.

Changes in postural control and decreased muscle strength and power are important risk factors for falls, especially in the elderly, since there is a reduction in muscle strength of 30-50% between 30 -80 years, especially in the lower limbs (Burke et al., 2010; Janssen et al., 2002).

The reduction in muscle strength occurs due to the reduction in the number and size of muscle fibers. Mainly type II fibers (fast contraction), which are most affected in relation to type I fibers (slow contraction) (Frontera et al., 1991).

The intensity of the muscle fibers loss depends on the degree of physical activity, nutrition, hereditary factor and lifestyle throughout life. In addition to losing in maximum muscle strength due to the aging process, there is also the loss of muscle power (force x speed), leading to a greater impairment in performance of functional activities, which requires agility, such as standing and walking, and increase susceptibility to falls (Marsh, 2000; Hunter et al., 2004).

The sit-to-stand test is a widely used tool in clinical practice because it is easy to apply and it requires simple matters, which are chair (without armrests) and a stopwatch. There are several ways to perform the test, but the way that is most commonly used, is to perform five

Impaired Ability to Perform the Sit-to-Stand Task in Osteoporotic Women 519

*A* cross-sectional study, which sixty women were divided into three groups according to the World Health Organization (WHO) classification of osteoporosis: Group 1 (n = 20) consisted of women presenting T score greater than - 1 standard deviation (normal bone mineral density), Group 2 (n = 20) consisted of women presenting T score ranging from -1 and -2.5 standard deviation (osteopenia or low bone mineral density), and Group 3 (n=20) consisted of women presenting T score lesser than -2.5 standard deviation (osteoporosis). For Group 1, the mean age was 65.75 years (± 4.33), mean weight was 64.81 kg (± 6.83), and mean height was 157.0 cm (± 6.0). In Group 2, the mean age was 67.45 years (± 4.57), mean weight was 62.63 kg (± 10.21) and mean height was 156.0 cm (± 7.0). In Group 3, the mean age was 70.0 years (± 5.43), mean weight was 68.97 kg (± 15.01) and mean height was 155.0 cm (± 8.0). Women presenting vertebral fractures diagnosed by radiographs, diabetes mellitus, peripheral neuropathies, cardiovascular diseases, vestibulopathies, and neurological problems were excluded from this study. All women were sedentary, no smoker and none

The participants were selected from the general community and from the Centre of Health at the Ribeirao Preto School of Medicine, FMRP-USP (CSE-FMRP-USP) and affiliated Clinic Hospital. The research study was approved by the Human Research Ethics Committee of the Ribeirao Preto School of Medicine, University of São Paulo (protocol number 1953/2007), with

All the participants were submitted to evaluation of dynamic activity using the Polhemus system, in which the maximum antero-posterior dislocation of the trunk and time spent for

The Polhemus system (POLHEMS ® 3 SPACE ISOTRAK II, Conchester, Canada) (Abreu et al.; 2010) was employed for evaluation, which is based on emission and detection of magnetic fields by means of electromagnetic sensors (Figure 1). The emission system comprises three perpendicular coils (55 x 55 x 58 mm) and the detection system is also formed by other three perpendicular coils (2.9 x 28.3 x 15.2 mm), and an amplifier was used to obtain x (antero-posterior), y (medio-lateral), and z (vertical) orientations. The transmitting coil was positioned onto a support that was placed at 60 cm from the subject, whereas the sensory coil was fixed to the seventh cervical vertebra (C7). The equipment precisely measures every trunk movement: the attached transmitting coil emits magnetic fields which are detected by the sensor, considering that the distance between the

The dynamic activity was evaluated during the sit-to-stand (STS) (Bohannon, 2006) movements five times so that the maximum trunk antero-posterior dislocation and time spent for practicing the test could be obtained. An armless chair with seat height of 43 cm was used for this test. The subject started the test with her both feet on the floor and her arms crossed at the chest level. Then she was asked to perform the sit-to-stand movements five times consecutively as quickly as possible, and the test was concluded when the

Analysis of variance (ANOVA) was used for comparison between the groups. According to these statistical models, the residual differences between predicted and measured values have a normal distribution, with zero mean and constant variance. In the situations where such a presumption was not observed, changes in the response were taken into account. Post-hoc Tukey test were performed when needed. This procedure was performed by using

all the volunteers signing a free informed consent before participating in the study.

of them was included in any kind of rehabilitation program.

practicing the test were evaluated.

transmitting and sensory coils is known.

the SPSS 16.0.

evaluator asked the subject to remain in the chair (Figure 2).

**4. Methods** 

repetitions as quickly as possible, where the shorter the time to accomplish this task, the better the performance of the individual (Kim et al., 2010).

The risk of falls is increasing among elderly individuals who have difficulty in standing up from the chair (Campbell et al., 1989; Nevitt et al., 1989), since people with history of falls take more time to stand up from the chair and to stabilize their trunk after achieving the orthostatic position (Cheng et al., 2001). It is known that the action of standing up and sitting down is affected by decreased muscular strength and power, sensorial alterations, balance, and velocity in which this task is performed (Karikanta et al., 2005).

The incidence of falls increases with age and this fact is of great concern among the elderly, particularly among those with osteoporosis who present increased bone fragility, which increases the risk of fractures (Honig, 2010).

However, it is not clear if the osteoporotic women have a greater muscle function impairment compared to women with less bone losses and, consequently, have poorer dynamic postural control, which increases the risk of falls.

The muscle-bone unit has been suggested based on the mechanostatic theory, since muscle contractions promote tension in the bone, with consequent bone modeling activation. Therefore, the increase of muscle mass is also accompanied by increase of bone strength and improvement of bone geometrical characteristics (Hasegawa et al., 2001; Frost, 2003; Fricke & Schoenau, 2007). Also, the positive effect of some physical exercise on the increase of both muscle strength and bone mineral density (BMD) corroborates the relationship between bone and muscular systems.

Following these statements, the increased bone loss is accompanied by an increase of both muscle mass and muscle strength losses. However, based on the muscle-bone unit, the decrease of bone is consequence of both decrease of muscle mass and strength (Hamilton et al., 2010).

Therefore, in women with osteoporosis is expected an impairment during the functional activities performance, as sit-to-stand task, since they require the action of muscular system. The postural control impairment during functional tasks (standing up and sitting down) can make these individuals more susceptible to falls and subsequent fractures. For this reason, it is important to investigate factors that may worsen postural control in order to prevent falls, injuries and to improve the quality of life.

### **2. Objectives**

To evaluate whether osteoporotic women have impaired dynamic balance in relation to those women presenting less bone loss by using the sit-to-stand test.

### **3. Hypothesis**

Women with higher bone loss have greater impairment in postural control, needing to perform a greater flexion of the trunk to perform the sit-to-stand task, as a way of compensate for a probable weakness of the lower limb muscles, and spend more time to perform the test, compared to women with lower bone loss. The bone mineral density (BMD) loss can occur in association with a reduction of muscular capacity, due to the fact that muscular and skeletal systems act as a unique unit. The evaluation of dynamic balance through the sit-to-stand test can be an efficient method to detect the association between bone and muscular systems.

### **4. Methods**

518 Osteoporosis

repetitions as quickly as possible, where the shorter the time to accomplish this task, the

The risk of falls is increasing among elderly individuals who have difficulty in standing up from the chair (Campbell et al., 1989; Nevitt et al., 1989), since people with history of falls take more time to stand up from the chair and to stabilize their trunk after achieving the orthostatic position (Cheng et al., 2001). It is known that the action of standing up and sitting down is affected by decreased muscular strength and power, sensorial alterations,

The incidence of falls increases with age and this fact is of great concern among the elderly, particularly among those with osteoporosis who present increased bone fragility, which

However, it is not clear if the osteoporotic women have a greater muscle function impairment compared to women with less bone losses and, consequently, have poorer

The muscle-bone unit has been suggested based on the mechanostatic theory, since muscle contractions promote tension in the bone, with consequent bone modeling activation. Therefore, the increase of muscle mass is also accompanied by increase of bone strength and improvement of bone geometrical characteristics (Hasegawa et al., 2001; Frost, 2003; Fricke & Schoenau, 2007). Also, the positive effect of some physical exercise on the increase of both muscle strength and bone mineral density (BMD) corroborates the relationship between

Following these statements, the increased bone loss is accompanied by an increase of both muscle mass and muscle strength losses. However, based on the muscle-bone unit, the decrease of bone is consequence of both decrease of muscle mass and strength (Hamilton et

Therefore, in women with osteoporosis is expected an impairment during the functional activities performance, as sit-to-stand task, since they require the action of muscular system. The postural control impairment during functional tasks (standing up and sitting down) can make these individuals more susceptible to falls and subsequent fractures. For this reason, it is important to investigate factors that may worsen postural control in order to prevent falls,

To evaluate whether osteoporotic women have impaired dynamic balance in relation to

Women with higher bone loss have greater impairment in postural control, needing to perform a greater flexion of the trunk to perform the sit-to-stand task, as a way of compensate for a probable weakness of the lower limb muscles, and spend more time to perform the test, compared to women with lower bone loss. The bone mineral density (BMD) loss can occur in association with a reduction of muscular capacity, due to the fact that muscular and skeletal systems act as a unique unit. The evaluation of dynamic balance through the sit-to-stand test can be an efficient method to detect the association between

those women presenting less bone loss by using the sit-to-stand test.

balance, and velocity in which this task is performed (Karikanta et al., 2005).

better the performance of the individual (Kim et al., 2010).

dynamic postural control, which increases the risk of falls.

increases the risk of fractures (Honig, 2010).

bone and muscular systems.

injuries and to improve the quality of life.

al., 2010).

**2. Objectives** 

**3. Hypothesis** 

bone and muscular systems.

*A* cross-sectional study, which sixty women were divided into three groups according to the World Health Organization (WHO) classification of osteoporosis: Group 1 (n = 20) consisted of women presenting T score greater than - 1 standard deviation (normal bone mineral density), Group 2 (n = 20) consisted of women presenting T score ranging from -1 and -2.5 standard deviation (osteopenia or low bone mineral density), and Group 3 (n=20) consisted of women presenting T score lesser than -2.5 standard deviation (osteoporosis). For Group 1, the mean age was 65.75 years (± 4.33), mean weight was 64.81 kg (± 6.83), and mean height was 157.0 cm (± 6.0). In Group 2, the mean age was 67.45 years (± 4.57), mean weight was 62.63 kg (± 10.21) and mean height was 156.0 cm (± 7.0). In Group 3, the mean age was 70.0 years (± 5.43), mean weight was 68.97 kg (± 15.01) and mean height was 155.0 cm (± 8.0).

Women presenting vertebral fractures diagnosed by radiographs, diabetes mellitus, peripheral neuropathies, cardiovascular diseases, vestibulopathies, and neurological problems were excluded from this study. All women were sedentary, no smoker and none of them was included in any kind of rehabilitation program.

The participants were selected from the general community and from the Centre of Health at the Ribeirao Preto School of Medicine, FMRP-USP (CSE-FMRP-USP) and affiliated Clinic Hospital. The research study was approved by the Human Research Ethics Committee of the Ribeirao Preto School of Medicine, University of São Paulo (protocol number 1953/2007), with all the volunteers signing a free informed consent before participating in the study.

All the participants were submitted to evaluation of dynamic activity using the Polhemus system, in which the maximum antero-posterior dislocation of the trunk and time spent for practicing the test were evaluated.

The Polhemus system (POLHEMS ® 3 SPACE ISOTRAK II, Conchester, Canada) (Abreu et al.; 2010) was employed for evaluation, which is based on emission and detection of magnetic fields by means of electromagnetic sensors (Figure 1). The emission system comprises three perpendicular coils (55 x 55 x 58 mm) and the detection system is also formed by other three perpendicular coils (2.9 x 28.3 x 15.2 mm), and an amplifier was used to obtain x (antero-posterior), y (medio-lateral), and z (vertical) orientations. The transmitting coil was positioned onto a support that was placed at 60 cm from the subject, whereas the sensory coil was fixed to the seventh cervical vertebra (C7). The equipment precisely measures every trunk movement: the attached transmitting coil emits magnetic fields which are detected by the sensor, considering that the distance between the transmitting and sensory coils is known.

The dynamic activity was evaluated during the sit-to-stand (STS) (Bohannon, 2006) movements five times so that the maximum trunk antero-posterior dislocation and time spent for practicing the test could be obtained. An armless chair with seat height of 43 cm was used for this test. The subject started the test with her both feet on the floor and her arms crossed at the chest level. Then she was asked to perform the sit-to-stand movements five times consecutively as quickly as possible, and the test was concluded when the evaluator asked the subject to remain in the chair (Figure 2).

Analysis of variance (ANOVA) was used for comparison between the groups. According to these statistical models, the residual differences between predicted and measured values have a normal distribution, with zero mean and constant variance. In the situations where such a presumption was not observed, changes in the response were taken into account. Post-hoc Tukey test were performed when needed. This procedure was performed by using the SPSS 16.0.

**5. Results** 

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

**Trunk oscilation** 

Impaired Ability to Perform the Sit-to-Stand Task in Osteoporotic Women 521

The results showed that variables such as weight and height showed no significant differences between the groups (*P >* 0.05), but age was found to be different between the control and osteoporotic groups (*P <* 0.01). For this reason, the variables maximum anteroposterior dislocation (cm) during standing up and sitting down tasks and time (seconds)

Post-hoc Tukey test showed that women with T score lesser than - 2.5 SD (osteoporosis) had greater movement of the trunk during standing up and sitting down tasks compared to other groups of women. Also, women with T score between -1 and - 2.5 SD had greater movement of the trunk in relation to the group of women presenting normal bone mineral

**Osteoporosis Osteopenia Control**

\*\*

**Groups**

<sup>A</sup> \*

B)

**Osteoporosis Osteopenia Control**

**Groups**

density (T score greater than – 1 SD) during stand up from the chair (Figure 3).

spent for practicing the test were normalized by age.

\*P < 0.05 osteoporosis versus osteopenia and control

Fig. 3. Antero-posterior dislocation (cm) during the standing up (A) and sitting down (B)

\*\* P < 0.05 osteopenia versus control

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

**Trunk oscialtion**

tasks. Values were normalized by age.

Fig. 1. Illustration of the Polhemus system. a) sensor coil; b) transmitting coil.

Fig. 2. Illustration of initial position for the sit-to-stand test. Arrows indicate the positions of sensor coil on the seventh cervical vertebra and the transmitting coil.

### **5. Results**

520 Osteoporosis

b

Fig. 1. Illustration of the Polhemus system. a) sensor coil; b) transmitting coil.

a

Fig. 2. Illustration of initial position for the sit-to-stand test. Arrows indicate the positions of

sensor coil on the seventh cervical vertebra and the transmitting coil.

The results showed that variables such as weight and height showed no significant differences between the groups (*P >* 0.05), but age was found to be different between the control and osteoporotic groups (*P <* 0.01). For this reason, the variables maximum anteroposterior dislocation (cm) during standing up and sitting down tasks and time (seconds) spent for practicing the test were normalized by age.

Post-hoc Tukey test showed that women with T score lesser than - 2.5 SD (osteoporosis) had greater movement of the trunk during standing up and sitting down tasks compared to other groups of women. Also, women with T score between -1 and - 2.5 SD had greater movement of the trunk in relation to the group of women presenting normal bone mineral density (T score greater than – 1 SD) during stand up from the chair (Figure 3).

\*P < 0.05 osteoporosis versus osteopenia and control \*\* P < 0.05 osteopenia versus control

Fig. 3. Antero-posterior dislocation (cm) during the standing up (A) and sitting down (B) tasks. Values were normalized by age.

Impaired Ability to Perform the Sit-to-Stand Task in Osteoporotic Women 523

The sit-to-stand (STS) test is easy to apply and it is one of the most used methods to assess the functional muscle strength as well as the balance and the functional mobility of elderly people (Bohannon, 2006; Buatois et al., 2006), thus allowing identification of those individuals with impaired balance (Whitney et al., 2005). In a study carried out by Aslan et al., 2008, who applied the sit-to-stand test to young and older adults, the results showed that elderly individuals spent more time to perform the tasks compared to the young ones. Zech et al., 2011 also shown that the sit-to-stand power test can be efficient to distingue between nonfrail elderly and prefrail. In elderly women with 60 years and older, both higher muscle mass and lower body fat were positively associated with physical function, evaluated by

The five-repetition sit-to-stand test has been used to evaluate muscle strength and balance. However, the action of sitting and standing involves a complex integration of muscular strength and muscle power, range of movement, postural control and coordination pattern (Karikanta et al., 2005). Some studies shown that the muscle contraction speed is very important to perform the sit-to-stand test, as fast as possible, and the weak power probably contributes to loss of mobility and it can better predict falls than muscle strength analysis (Skelton et al., 2002; Petrella et al., 2005). Also, the sit-to-stand test is adequate to evaluate

In a study conducted by Netz et al., 2004, they observed that the sit-to-stand test when performed 10 times consecutively, as fast as possible, is not able to predict knee extensor strength, but it can be used to predict general endurance. Also, they suggest that the peak aerobic capacity is related to the performance of the test. However, the sit-to-stand test 10 times is a longer activity that increase the chance of both muscle fatigue and change of coordination pattern, and possibly requires more of the cardiorespiratory system. Therefore, future studies must be performed to compare the methodologies (five versus ten times sit-

Nevertheless, it is not clear if the reduction of both muscle function and postural stability is more pronounced in women with osteoporosis. The impairment on the ability to perform functional tasks (for example: standing up and sitting down) can make these individuals more susceptible to falls and subsequent fractures. The rate of falls among the elderly is high and the fractures occurrence and severe lesions lead to a partial or total decrease in their daily activity performance and autonomy, with a negative impact in their quality of life

Therefore, in order to evaluate the association between bone mineral density and dynamic balance of elderly women, the sit-to-stand test was used, since it seems to be a clinical test capable of evaluating muscle function and balance. The variables obtained were maximum antero-posterior trunk movement during the sit-to-stand tasks and time spent during the test. The data shown that women with osteoporosis had greater movement of the trunk during standing up and sitting down tasks compared to other groups of women. The results suggest that the decrease in BMD can occur in association with a reduction in the functional capacity of muscular system, due to the fact that muscular and skeletal systems act as a unique unit. A previous study shown that osteoporotic women are more likely to fall than the non-osteoporotic ones within the same age group, due to the fact that osteoporotic women have greater weakness of the quadriceps and impaired postural control (Lynn et al, 1997). The quadriceps muscle is important for performing the sitting down/standing up movement, which might explain why the group of osteoporotic had a greater anterior-

walking speed and sit-to-stand test (Visser et al., 2000).

muscle power in elderly population (Zech et al., 2011).

to-stand test).

(Shimada et al., 2003).

The results showed that there were no differences in the time spent to perform the sit-tostand movements (*P >* 0.05) between the groups (Figure 4).

In the Group 3 (women with osteoporosis), the time spent for performing the STS test was 15.14 ± 4.18 sec (0.22 ± 0.06 sec after normalized by age) and the antero-posterior movements of the trunk during standing up and sitting down tasks were, respectively, 33.03 ± 7.04 cm (0.48 ± 0.11 cm after normalized by age) and 34.15 ± 6.27 cm (0.49 ± 0.10 cm after normalized by age). In Group 2 (women with osteopenia), the overall time spent was 13.34 ± 3.34 sec (0.20 ± 0.07 sec after normalized by age), with antero-posterior movements of the trunk during standing up and sitting down tasks being, respectively, 16.98 ± 11.03 cm (0.25 ± 0.17 cm after normalized by age) and 16.61 ± 11.61 cm (0.25 ± 0.17 after normalized by age). With regard to Group 1 (women with normal BMD), the time spent for performing the STS test was 11.95 ± 2.1 sec (0.18 ± 0.03 sec after normalized by age) and the antero-posterior movements of the trunk were 9.86 ± 9.12 cm (0.15 ± 0.13 after normalized by age) and 10.96 ± 9.74 cm (0.17 ± 0.16 after normalized by age) during standing up and sitting down tasks, respectively.

Fig. 4. Time spent (sec) during the sit-to-stand task. Values were normalized by age.

### **6. Discussion**

The aging process is associated to many changes of body function, which include alterations in the postural control during posture maintenance and activities, which interfere directly with balance and lead to an increase in corporal oscillation in elderly persons (Gill et al., 2001). The postural control system requires the association of perception (of body position and body movement) (Faraldo-García et al., 2011), action (capacity of muscle activation) and cognition (movement planning and execution). In order to have an efficient action it is necessary, besides muscle function, other biomechanical aspects, as adequate range of movement and posture. The muscle deficits can have a negative influence on postural control and functionality, because they decrease the ability to perform functional movement with safety and efficiency which increase the risk of falls (Shumway-Cook &, Woollacott, 2000). Additionally, the decrease of muscle strength and power in elderly persons has a negative impact on the ability to restore the state of balance after external perturbations.

The results showed that there were no differences in the time spent to perform the sit-to-

In the Group 3 (women with osteoporosis), the time spent for performing the STS test was 15.14 ± 4.18 sec (0.22 ± 0.06 sec after normalized by age) and the antero-posterior movements of the trunk during standing up and sitting down tasks were, respectively, 33.03 ± 7.04 cm (0.48 ± 0.11 cm after normalized by age) and 34.15 ± 6.27 cm (0.49 ± 0.10 cm after normalized by age). In Group 2 (women with osteopenia), the overall time spent was 13.34 ± 3.34 sec (0.20 ± 0.07 sec after normalized by age), with antero-posterior movements of the trunk during standing up and sitting down tasks being, respectively, 16.98 ± 11.03 cm (0.25 ± 0.17 cm after normalized by age) and 16.61 ± 11.61 cm (0.25 ± 0.17 after normalized by age). With regard to Group 1 (women with normal BMD), the time spent for performing the STS test was 11.95 ± 2.1 sec (0.18 ± 0.03 sec after normalized by age) and the antero-posterior movements of the trunk were 9.86 ± 9.12 cm (0.15 ± 0.13 after normalized by age) and 10.96 ± 9.74 cm (0.17 ± 0.16 after normalized by age) during standing up and sitting down tasks,

Fig. 4. Time spent (sec) during the sit-to-stand task. Values were normalized by age.

The aging process is associated to many changes of body function, which include alterations in the postural control during posture maintenance and activities, which interfere directly with balance and lead to an increase in corporal oscillation in elderly persons (Gill et al., 2001). The postural control system requires the association of perception (of body position and body movement) (Faraldo-García et al., 2011), action (capacity of muscle activation) and cognition (movement planning and execution). In order to have an efficient action it is necessary, besides muscle function, other biomechanical aspects, as adequate range of movement and posture. The muscle deficits can have a negative influence on postural control and functionality, because they decrease the ability to perform functional movement with safety and efficiency which increase the risk of falls (Shumway-Cook &, Woollacott, 2000). Additionally, the decrease of muscle strength and power in elderly persons has a negative impact on the ability to restore the state of balance after external perturbations.

**Osteoporosis Osteopenia Control**

**Groups**

stand movements (*P >* 0.05) between the groups (Figure 4).

respectively.

**Time** 

**6. Discussion** 

0

0.05 0.1 0.15 0.2 0.25 0.3 The sit-to-stand (STS) test is easy to apply and it is one of the most used methods to assess the functional muscle strength as well as the balance and the functional mobility of elderly people (Bohannon, 2006; Buatois et al., 2006), thus allowing identification of those individuals with impaired balance (Whitney et al., 2005). In a study carried out by Aslan et al., 2008, who applied the sit-to-stand test to young and older adults, the results showed that elderly individuals spent more time to perform the tasks compared to the young ones. Zech et al., 2011 also shown that the sit-to-stand power test can be efficient to distingue between nonfrail elderly and prefrail. In elderly women with 60 years and older, both higher muscle mass and lower body fat were positively associated with physical function, evaluated by walking speed and sit-to-stand test (Visser et al., 2000).

The five-repetition sit-to-stand test has been used to evaluate muscle strength and balance. However, the action of sitting and standing involves a complex integration of muscular strength and muscle power, range of movement, postural control and coordination pattern (Karikanta et al., 2005). Some studies shown that the muscle contraction speed is very important to perform the sit-to-stand test, as fast as possible, and the weak power probably contributes to loss of mobility and it can better predict falls than muscle strength analysis (Skelton et al., 2002; Petrella et al., 2005). Also, the sit-to-stand test is adequate to evaluate muscle power in elderly population (Zech et al., 2011).

In a study conducted by Netz et al., 2004, they observed that the sit-to-stand test when performed 10 times consecutively, as fast as possible, is not able to predict knee extensor strength, but it can be used to predict general endurance. Also, they suggest that the peak aerobic capacity is related to the performance of the test. However, the sit-to-stand test 10 times is a longer activity that increase the chance of both muscle fatigue and change of coordination pattern, and possibly requires more of the cardiorespiratory system. Therefore, future studies must be performed to compare the methodologies (five versus ten times sitto-stand test).

Nevertheless, it is not clear if the reduction of both muscle function and postural stability is more pronounced in women with osteoporosis. The impairment on the ability to perform functional tasks (for example: standing up and sitting down) can make these individuals more susceptible to falls and subsequent fractures. The rate of falls among the elderly is high and the fractures occurrence and severe lesions lead to a partial or total decrease in their daily activity performance and autonomy, with a negative impact in their quality of life (Shimada et al., 2003).

Therefore, in order to evaluate the association between bone mineral density and dynamic balance of elderly women, the sit-to-stand test was used, since it seems to be a clinical test capable of evaluating muscle function and balance. The variables obtained were maximum antero-posterior trunk movement during the sit-to-stand tasks and time spent during the test.

The data shown that women with osteoporosis had greater movement of the trunk during standing up and sitting down tasks compared to other groups of women. The results suggest that the decrease in BMD can occur in association with a reduction in the functional capacity of muscular system, due to the fact that muscular and skeletal systems act as a unique unit. A previous study shown that osteoporotic women are more likely to fall than the non-osteoporotic ones within the same age group, due to the fact that osteoporotic women have greater weakness of the quadriceps and impaired postural control (Lynn et al, 1997). The quadriceps muscle is important for performing the sitting down/standing up movement, which might explain why the group of osteoporotic had a greater anterior-

Impaired Ability to Perform the Sit-to-Stand Task in Osteoporotic Women 525

already been raised by Netz et al., 2004, since they discussed that the STS ten times not

Hence, the evaluation of spent time to perform the STS test by itself would not be enough to identify impairment in the dynamic activity in women with greater bone losses and wrong conclusions about the muscle strength and balance characteristics could have been done. In relation to the muscular system, the aging process interferes negatively in muscle characteristics (Zech et al., 2011; Clark BC & Taylor, 2011; Buffa et al., 2011), and following the muscle-bone unit theory, women with greater bone losses also present greater muscle function alterations. Therefore, the compensatory movement (increase of the trunk dislocation) observed during the sit-to-stand test can also be associated to a decrease of muscle function, which includes strength, power and muscle mass, without disconsidering the other components involved during the test. However, future research is needed to verify

Our hypothesis was in part confirmed, since women with different classifications of BMD presented different anterior-posterior displacements of the trunk, but not presented

Besides, the results show that women with osteopenia also have increase in the trunk dislocation, and based on a study by Siris et al, 2001 which shown that osteopenic women had 1.8-fold higher rate of fracture than women with normal BMD, a careful attention

A recent study evaluated the physical performance of women aged 45 to 64 years, through evaluations that included sit-to-stand test (Khazzani et al., 2009). The results showed that low physical performance was associated with low BMD of spine and hip. In addition, some studies shown that regular training to strengthen the muscles of the lower limbs, especially the quadriceps, are effective for increasing muscle power, static and dynamic balance, thus improving performance activities of daily living, which includes the act of sitting down and up (Khazzani et al., 2009; Teixeira et al., 2010). Also, high-impact loading exercise has shown to be efficient to increase bone mass and geometry in postmenopausal women (Hamilton et al., 2010; Iwamoto et al., 2010). Another study that conducted a 11-month exercise program, which included strength, aerobic capacity, balance, joint mobility on ground and in the water on postmenopausal women shown an improvement of physical function capacity,

Those studies ratify the importance of exercise programs in order to improve muscular and bone systems and to improve balance and functional capacity. The conservation of muscle function seems to be essential to keep a sufficient mechanical stimulus on bone, and

These data emphasize the need to encourage women with different levels of bone loss to adhere to exercise programs in order to improve their balance, functionality and bone

The results suggest that osteoporotic women exhibit a greater trunk movement compared to women with less bone loss, which is associated to impairment of both postural control and muscle function. However, women with T score ranging from -1 to - 2.5 SD (low bone mineral density) had a greater impairment compared to the group of women with T score

the muscle function in women with different levels of bone mineral density.

differences of time spent to perform the sit-to-stand test.

should be paid to this population in order to reduce the risk of falls.

associated to a reduction of physiological bone loss (Tolomio et al., 2010).

characteristics, thus reducing the risk of falls and fractures consequently.

consequently, to minimize the bone decline over time.

**7. Conclusions** 

greater than -1 SD.

include the trunk control analysis.

posterior movement of the trunk as a way of compensating for such a muscle weakness (Bohannon, 2006; Lord et al.; 2002).

Moreover, the women with T score between -1 and - 2.5 SD (osteopenia) had greater movement of the trunk in relation to the group of women presenting normal bone mineral density (T score greater than – 1 SD) during stand up from the chair. This finding is very relevant, since it shown that women with osteopenia already perform compensation during the dynamic activity. The fact of women with osteoporosis have greater movement of the trunk during standing up and sitting down suggests a quadriceps function deficit during concentric and eccentric contractions, while the fact that women with osteopenia have greater movement of the trunk only during standing up suggests some quadriceps muscle function deficit only during concentric contraction.

Based on the literature, the aging process affect negatively all contraction muscle types (concentric, eccentric and isometric strengths) (Lindle et al., 1997; Porter et al., 1995), however, the concentric knee extension strength decreases more than eccentric strength. Therefore, it seems that women with osteoporosis have a more pronounced decline of muscle contraction strength, with impairment during concentric and eccentric movements.

The compensatory movement by the trunk dislocation is worrying, since the high degrees of trunk flexion movement displaces the centre of gravity anteriorly, and associated to the decrease of postural stability and muscle function, the control of body mass centre is prejudiced, resulting in difficulty to maintain the state of balance during the sit-to-stand task, which increases the risk of fall among the osteoporotic women.

There was no difference between groups when compared the time spent during the sit-tostand movements (*P >* 0.05), probably due to the higher trunk flexion performed by groups with osteoporosis and osteopenia, which compensate the lower limb muscles deficit and, consequently, allowed them to achieve the same time during the test. However, in some studies in which the sit-to-stand test was applied to elderly individuals, the results regarding the time spent for performing the tasks are close to those obtained in the present study (Whitney et al., 2005; Aslan et al., 2008; Schaubert & Bohannon, 2005), which suggests that the decrease of the movement velocity is associated to many factors of aging process and not to the bone mineral density (BMD) directly.

The spent time to perform the five-chair sit-to-stand test in women aged 65 years or older with osteopenia (Chyu et al., 2010; Alp et al., 2007) was similar to the present study. In another study conducted with osteoporotic women (Alp et al., 2007), the sit-to-stand test was performed 10 times as quickly as possible, and the values obtained was approximately twice the time spent by women in our study (in our study they performed the sit-to-stand movements five times consecutively as quickly as possible).

Lindsey et al, 2005 did not observe a correlation between sit-to-stand test performance and BMD of any skeletal site in older women, which is in agreement with our findings, since we did not find differences in time spent during the sit-to-stand test between groups. Also, in a systematic literature review conducted by Hyehyung et al., 2011, no correlation was observed between lower femoral/lumbar BMD and slower sit-to-stand test in age-adjusted models.

The obtained results point out an interesting discussion on which parameters should be considered in assessments of dynamic balance and functional activity, since the compensatory movements can mask the deficits of analyzed variables. In our study, the antero-posterior trunk dislocation probably was the compensatory movement due to the lower limbs muscle weakness. The lack of difference in the spent time during the sit-tostand test is probably a consequence of the compensatory movement. This aspect has

posterior movement of the trunk as a way of compensating for such a muscle weakness

Moreover, the women with T score between -1 and - 2.5 SD (osteopenia) had greater movement of the trunk in relation to the group of women presenting normal bone mineral density (T score greater than – 1 SD) during stand up from the chair. This finding is very relevant, since it shown that women with osteopenia already perform compensation during the dynamic activity. The fact of women with osteoporosis have greater movement of the trunk during standing up and sitting down suggests a quadriceps function deficit during concentric and eccentric contractions, while the fact that women with osteopenia have greater movement of the trunk only during standing up suggests some quadriceps muscle

Based on the literature, the aging process affect negatively all contraction muscle types (concentric, eccentric and isometric strengths) (Lindle et al., 1997; Porter et al., 1995), however, the concentric knee extension strength decreases more than eccentric strength. Therefore, it seems that women with osteoporosis have a more pronounced decline of muscle contraction strength, with impairment during concentric and eccentric movements. The compensatory movement by the trunk dislocation is worrying, since the high degrees of trunk flexion movement displaces the centre of gravity anteriorly, and associated to the decrease of postural stability and muscle function, the control of body mass centre is prejudiced, resulting in difficulty to maintain the state of balance during the sit-to-stand

There was no difference between groups when compared the time spent during the sit-tostand movements (*P >* 0.05), probably due to the higher trunk flexion performed by groups with osteoporosis and osteopenia, which compensate the lower limb muscles deficit and, consequently, allowed them to achieve the same time during the test. However, in some studies in which the sit-to-stand test was applied to elderly individuals, the results regarding the time spent for performing the tasks are close to those obtained in the present study (Whitney et al., 2005; Aslan et al., 2008; Schaubert & Bohannon, 2005), which suggests that the decrease of the movement velocity is associated to many factors of aging process

The spent time to perform the five-chair sit-to-stand test in women aged 65 years or older with osteopenia (Chyu et al., 2010; Alp et al., 2007) was similar to the present study. In another study conducted with osteoporotic women (Alp et al., 2007), the sit-to-stand test was performed 10 times as quickly as possible, and the values obtained was approximately twice the time spent by women in our study (in our study they performed the sit-to-stand

Lindsey et al, 2005 did not observe a correlation between sit-to-stand test performance and BMD of any skeletal site in older women, which is in agreement with our findings, since we did not find differences in time spent during the sit-to-stand test between groups. Also, in a systematic literature review conducted by Hyehyung et al., 2011, no correlation was observed between lower femoral/lumbar BMD and slower sit-to-stand test in age-adjusted models. The obtained results point out an interesting discussion on which parameters should be considered in assessments of dynamic balance and functional activity, since the compensatory movements can mask the deficits of analyzed variables. In our study, the antero-posterior trunk dislocation probably was the compensatory movement due to the lower limbs muscle weakness. The lack of difference in the spent time during the sit-tostand test is probably a consequence of the compensatory movement. This aspect has

(Bohannon, 2006; Lord et al.; 2002).

function deficit only during concentric contraction.

and not to the bone mineral density (BMD) directly.

movements five times consecutively as quickly as possible).

task, which increases the risk of fall among the osteoporotic women.

already been raised by Netz et al., 2004, since they discussed that the STS ten times not include the trunk control analysis.

Hence, the evaluation of spent time to perform the STS test by itself would not be enough to identify impairment in the dynamic activity in women with greater bone losses and wrong conclusions about the muscle strength and balance characteristics could have been done.

In relation to the muscular system, the aging process interferes negatively in muscle characteristics (Zech et al., 2011; Clark BC & Taylor, 2011; Buffa et al., 2011), and following the muscle-bone unit theory, women with greater bone losses also present greater muscle function alterations. Therefore, the compensatory movement (increase of the trunk dislocation) observed during the sit-to-stand test can also be associated to a decrease of muscle function, which includes strength, power and muscle mass, without disconsidering the other components involved during the test. However, future research is needed to verify the muscle function in women with different levels of bone mineral density.

Our hypothesis was in part confirmed, since women with different classifications of BMD presented different anterior-posterior displacements of the trunk, but not presented differences of time spent to perform the sit-to-stand test.

Besides, the results show that women with osteopenia also have increase in the trunk dislocation, and based on a study by Siris et al, 2001 which shown that osteopenic women had 1.8-fold higher rate of fracture than women with normal BMD, a careful attention should be paid to this population in order to reduce the risk of falls.

A recent study evaluated the physical performance of women aged 45 to 64 years, through evaluations that included sit-to-stand test (Khazzani et al., 2009). The results showed that low physical performance was associated with low BMD of spine and hip. In addition, some studies shown that regular training to strengthen the muscles of the lower limbs, especially the quadriceps, are effective for increasing muscle power, static and dynamic balance, thus improving performance activities of daily living, which includes the act of sitting down and up (Khazzani et al., 2009; Teixeira et al., 2010). Also, high-impact loading exercise has shown to be efficient to increase bone mass and geometry in postmenopausal women (Hamilton et al., 2010; Iwamoto et al., 2010). Another study that conducted a 11-month exercise program, which included strength, aerobic capacity, balance, joint mobility on ground and in the water on postmenopausal women shown an improvement of physical function capacity, associated to a reduction of physiological bone loss (Tolomio et al., 2010).

Those studies ratify the importance of exercise programs in order to improve muscular and bone systems and to improve balance and functional capacity. The conservation of muscle function seems to be essential to keep a sufficient mechanical stimulus on bone, and consequently, to minimize the bone decline over time.

These data emphasize the need to encourage women with different levels of bone loss to adhere to exercise programs in order to improve their balance, functionality and bone characteristics, thus reducing the risk of falls and fractures consequently.

### **7. Conclusions**

The results suggest that osteoporotic women exhibit a greater trunk movement compared to women with less bone loss, which is associated to impairment of both postural control and muscle function. However, women with T score ranging from -1 to - 2.5 SD (low bone mineral density) had a greater impairment compared to the group of women with T score greater than -1 SD.

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### **8. Acknowledgements**

The authors would like to thank the Bioengineering Unit and the State of São Paulo Foundation for Research (FAPESP; #2007/54596-0, #2007/57685-4) for the support provided.

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**1. Introduction** 

on osteoporosis and arterial stiffness.

**2. Arterial structure** 

which is the inner arterial wall.

**3. Collagen and elastin on bone and arteries** 

**26** 

*Japan* 

Takanobu Okamoto

*Nippon Sport Science University* 

**Osteoporosis and Arterial Stiffness:** 

In addition to menopause and advanced age, risk factors for atherosclerosis are also associated with osteoporosis. Osteoporosis and atherosclerosis are major public health problems that lead to increased rates of morbidity and mortality. Because these diseases progress with aging and share common risk factors, both seem to correlate with aging. Although historically considered as independent conditions, clinical and epidemiological studies indicate that common pathophysiological mechanisms underlie these diseases. Physical activity is of primary importance to reach optimal peak bone mass and decrease arterial stiffness, an independent risk factor of atherosclerosis. Exercising that incorporates levels of whole body accelerations exceeding 3.9 g at a frequency of 100 per day has been shown to have positive effects on cardiovascular fitness, femoral bone density and balance (Jämsä et al, 2006; Vainionpää et al, 2006; Heikkinen et al, 2007). These acceleration levels are normally reported in activities such as running or jumping, which may be appropriate for middle aged and younger individuals, but may be more difficult for many older people or those with chronic lower limb injuries to achieve. This chapter explains the effect of exercise

Arteries are flexible, muscular blood vessels that carry blood from the heart and oxygenated blood to tissues throughout the body (Murray, TD. & Murray JM. 1998). The arterial wall comprises three layers (Fig. 1). The outermost adventitia primarily consists of connective tissue made of collagen, a structural protein that helps to maintain vessel integrity and provide flexibility. The elastin media is the middle layer, which mostly comprises smooth muscle tissue that confers the ability to contract and relax. This helps to regulate the size of the vessel lumen and thus alter blood pressure and flow. The inner intima layer comprises smooth epithelial tissue that facilitates blood flow. This layer includes the endothelium,

About 80% of the total protein in bone consists of collagen, about 95% of which is type I. Bone strength depends on the orientation of osteons (and thus collagen fibers) within

**Effects of Exercise Training** 


## **Osteoporosis and Arterial Stiffness: Effects of Exercise Training**

Takanobu Okamoto

*Nippon Sport Science University Japan* 

### **1. Introduction**

528 Osteoporosis

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In addition to menopause and advanced age, risk factors for atherosclerosis are also associated with osteoporosis. Osteoporosis and atherosclerosis are major public health problems that lead to increased rates of morbidity and mortality. Because these diseases progress with aging and share common risk factors, both seem to correlate with aging. Although historically considered as independent conditions, clinical and epidemiological studies indicate that common pathophysiological mechanisms underlie these diseases. Physical activity is of primary importance to reach optimal peak bone mass and decrease arterial stiffness, an independent risk factor of atherosclerosis. Exercising that incorporates levels of whole body accelerations exceeding 3.9 g at a frequency of 100 per day has been shown to have positive effects on cardiovascular fitness, femoral bone density and balance (Jämsä et al, 2006; Vainionpää et al, 2006; Heikkinen et al, 2007). These acceleration levels are normally reported in activities such as running or jumping, which may be appropriate for middle aged and younger individuals, but may be more difficult for many older people or those with chronic lower limb injuries to achieve. This chapter explains the effect of exercise on osteoporosis and arterial stiffness.

### **2. Arterial structure**

Arteries are flexible, muscular blood vessels that carry blood from the heart and oxygenated blood to tissues throughout the body (Murray, TD. & Murray JM. 1998). The arterial wall comprises three layers (Fig. 1). The outermost adventitia primarily consists of connective tissue made of collagen, a structural protein that helps to maintain vessel integrity and provide flexibility. The elastin media is the middle layer, which mostly comprises smooth muscle tissue that confers the ability to contract and relax. This helps to regulate the size of the vessel lumen and thus alter blood pressure and flow. The inner intima layer comprises smooth epithelial tissue that facilitates blood flow. This layer includes the endothelium, which is the inner arterial wall.

### **3. Collagen and elastin on bone and arteries**

About 80% of the total protein in bone consists of collagen, about 95% of which is type I. Bone strength depends on the orientation of osteons (and thus collagen fibers) within

Osteoporosis and Arterial Stiffness: Effects of Exercise Training 531

cerebrovascular events in healthy populations. Several studies have examined associations between atherosclerosis at different sites and osteoporosis or low bone mineral density (BMD) in women, and the findings suggest that the development of osteoporosis is a risk for advanced atherosclerosis after menopause (Hak et al, 2000; Sanada et al, 2004). The Osteo Sono-Assessment Index, which reflects elastic properties of bone tissues, negatively correlates with pulse wave velocity (PWV) in both sexes; this association is more prominent in females than in males and becomes even closer in post-menopausal females (Hirose et al,

Fig. 2. Correlation between osteo-sono assessment index (OSI) and brachial-ankle pulse

Increased central arterial stiffness reduces the arterial buffering function of the pulsation of blood pressure and blood flow, which contributes to increases in systolic blood pressure and in pulse pressure. Increased arterial stiffness alters the cyclical dynamics of arterial wall connective tissues, promotes vascular remodeling, and increases arterial wall thickness and plaque formation. Patients with osteoporosis have the most arterial stiffness. The reciprocal association between osteoporosis and arterial stiffness is supported by the relationship between bone mineral loss and each of vascular calcification, atherosclerosis and cardiovascular disease (CVD). Arterial calcification leading to increased arterial stiffness, a powerful risk factor for CVD, might underlie the association between osteoporosis and CVD in post-menopausal women. Osteoprotegerin might be a molecular link between bone loss and vascular calcification. In fact, intimal calcification is associated with advanced atherosclerosis. In addition, Frost et al. (2008) suggested that decreased BMD is associated with arterial calcification and stiffening and raised the possibility that osteoprotegerin is a marker of arterial stiffening, independently of any association with BMD. Osteoporotic postmenopausal women free of CVD and risk factors had increased augmentation index, a measure of wave reflections and arterial stiffness, and central aortic systolic and pulse

wave velocity (baPWV) in both genders (Quotation from Hirose et al, 2003).

2003, Fig. 2).

cortical bone. Various determinants of bone quality are interrelated, especially minerals and collagen (Viguet-Carrin et al, 2007).

#### Fig. 1. Arterial structure

Collagen and elastin are two vital components of blood vessels (Greenwald, 2007). Elastic arterial fibers comprise 90% elastin, which enables tissues to resume shape after stretching or contraction (Milewicz et al, 2000). Collagen is the most common protein in mammals (25% to 35% of total body protein content) as it is the main component of connective tissue. Elastin and collagen play crucial roles in arterial remodeling. Moreover, arterial stiffness depends upon the composition of the elastin and collagen, and the calcium content of elastin. As collagen ages, specific physical and biochemical changes reduce extensibility and increase rigidity. Thus, aging increases the diameter of collagen fibers in various tissues. Fibrils also become more crystalline, which strengthens intermolecular bonds and increases resistance to further deformation. Furthermore, aging is believed to be associated with an increased number of intramolecular and intermolecular cross-links that restrict the ability of collagen molecules to glide past each other. Collagen fibers are only slightly extensible but are very resistant to tensile stress. Therefore, they are the main constituents of structures such as ligaments, tendons and arteries that are subjected to pulling forces. As a result of aging, elastic fibers lose resilience and undergo various other changes, including fragmentation, fraying, classification and other types of mineralization and increased crosslinkages (Knott et al. 1997).

#### **4. Osteoporosis and arterial stiffness**

The multifactorial and degenerative entities of osteoporosis and atherosclerosis are major public health problems. These diseases accompany the aging process and share common risk factors. Increased arterial stiffness independently predicts cardiovascular and

cortical bone. Various determinants of bone quality are interrelated, especially minerals and

adventitia connective tissue

media

intima

smooth muscle

connective tissue endothelial cell

Collagen and elastin are two vital components of blood vessels (Greenwald, 2007). Elastic arterial fibers comprise 90% elastin, which enables tissues to resume shape after stretching or contraction (Milewicz et al, 2000). Collagen is the most common protein in mammals (25% to 35% of total body protein content) as it is the main component of connective tissue. Elastin and collagen play crucial roles in arterial remodeling. Moreover, arterial stiffness depends upon the composition of the elastin and collagen, and the calcium content of elastin. As collagen ages, specific physical and biochemical changes reduce extensibility and increase rigidity. Thus, aging increases the diameter of collagen fibers in various tissues. Fibrils also become more crystalline, which strengthens intermolecular bonds and increases resistance to further deformation. Furthermore, aging is believed to be associated with an increased number of intramolecular and intermolecular cross-links that restrict the ability of collagen molecules to glide past each other. Collagen fibers are only slightly extensible but are very resistant to tensile stress. Therefore, they are the main constituents of structures such as ligaments, tendons and arteries that are subjected to pulling forces. As a result of aging, elastic fibers lose resilience and undergo various other changes, including fragmentation, fraying, classification and other types of mineralization and increased cross-

The multifactorial and degenerative entities of osteoporosis and atherosclerosis are major public health problems. These diseases accompany the aging process and share common risk factors. Increased arterial stiffness independently predicts cardiovascular and

collagen (Viguet-Carrin et al, 2007).

Fig. 1. Arterial structure

linkages (Knott et al. 1997).

**4. Osteoporosis and arterial stiffness** 

cerebrovascular events in healthy populations. Several studies have examined associations between atherosclerosis at different sites and osteoporosis or low bone mineral density (BMD) in women, and the findings suggest that the development of osteoporosis is a risk for advanced atherosclerosis after menopause (Hak et al, 2000; Sanada et al, 2004). The Osteo Sono-Assessment Index, which reflects elastic properties of bone tissues, negatively correlates with pulse wave velocity (PWV) in both sexes; this association is more prominent in females than in males and becomes even closer in post-menopausal females (Hirose et al, 2003, Fig. 2).

Fig. 2. Correlation between osteo-sono assessment index (OSI) and brachial-ankle pulse wave velocity (baPWV) in both genders (Quotation from Hirose et al, 2003).

Increased central arterial stiffness reduces the arterial buffering function of the pulsation of blood pressure and blood flow, which contributes to increases in systolic blood pressure and in pulse pressure. Increased arterial stiffness alters the cyclical dynamics of arterial wall connective tissues, promotes vascular remodeling, and increases arterial wall thickness and plaque formation. Patients with osteoporosis have the most arterial stiffness. The reciprocal association between osteoporosis and arterial stiffness is supported by the relationship between bone mineral loss and each of vascular calcification, atherosclerosis and cardiovascular disease (CVD). Arterial calcification leading to increased arterial stiffness, a powerful risk factor for CVD, might underlie the association between osteoporosis and CVD in post-menopausal women. Osteoprotegerin might be a molecular link between bone loss and vascular calcification. In fact, intimal calcification is associated with advanced atherosclerosis. In addition, Frost et al. (2008) suggested that decreased BMD is associated with arterial calcification and stiffening and raised the possibility that osteoprotegerin is a marker of arterial stiffening, independently of any association with BMD. Osteoporotic postmenopausal women free of CVD and risk factors had increased augmentation index, a measure of wave reflections and arterial stiffness, and central aortic systolic and pulse

Osteoporosis and Arterial Stiffness: Effects of Exercise Training 533

Fig. 3. Chronological changes in brachial-ankle pulse wave velocity (baPWV) in healthy men

age

Female Male

Health organizations such as the American Heart Association (AHA) and the American College of Sports Medicine (ACSM) recommend habitual exercise to prevent and treat CVD and frailty associated with aging. In contrast to age, regular physical exercise in general, and aerobic exercise/fitness in particular, are associated with enhanced vascular function and a reduced risk of CVD. However, in contrast to the beneficial effects of aerobic exercise, highintensity resistance training increases arterial stiffness in young and middle-aged healthy

To date, the predominant medical strategies to prevent and/or treat post-menopausal bone loss have focused on antiresorptive medications (i.e., bisphosphonates). However, these treatments might be limited due to adverse side effects, questionable compliance and longterm safety concerns. Various types of exercise, such as walking, jogging or resistance training, could provide an important role in maintaining and/or increasing bone density in women. Therefore, implementing non-pharmacological treatment strategies such as exercise that have few or no inherent side effects is critical. Exercise plays an important role in maintaining or increasing bone density. Physical activity increases growth in the width and mineral content of bones in girls and adolescent females, particularly when initiated before puberty, carried out in volumes and at intensities seen in athletes, and accompanied by adequate caloric and calcium intake. The differences are regularly the largest in gymnasts whose hip and spine BMD values are 30% – 40% higher than those of long-distance runners (Robinson et al, 1995); a plausible explanation for this is the greater magnitude of impact forces generated in gymnastic movements (10- to 12-fold body weight) compared with

and women (Quotation from Tomiyama et al, 2003).

men and in pre-menopausal women.

baPWV (cm/sec)

**6. Exercise** 

pressures, which show a higher estimated aortic PWV indicating a stiffer aorta (Mangiafico et al, 2008, Tab. 1). Such alterations may increase the risk of CVD in postmenopausal osteoporosis. Therefore, the prevention and treatment of increased arterial stiffness and/or osteoporosis are important.


Table 1. Peripheral and central haemodynamic parameters of osteoporotic patients and control subjects (Quotation from Mangiafico et al, 2008)

#### **5. Effects of aging on osteoporosis and arterial stiffness**

In addition to menopause and advanced age, risk factors for CVD such as obesity and diabetes are also associated with osteoporosis. Thus, osteoporosis and atherosclerosis seem to correlate with aging. Osteoporosis-related fractures represent a major health concern, particularly among elderly populations. Post-menopausal osteoporosis in women with increased availability of circulating osteoprogenitor cells has a detrimental influence on arterial compliance. Lifestyle modification includes measures to reduce falls and bone loss such as participating in exercise, adequate dietary calcium intake and avoiding smoking and excessive alcohol consumption. Osteoporosis is characterized by the progressive loss of bone tissue and micro-architectural deterioration that reduces the quality of life for the elderly and thus it is a persistent public health issue. BMD at the femoral neck and spine in aging women decreases by 1 - 2 % per year (Finkelstein et al, 2008). Decreasing estrogen concentrations after menopause can cause a decline in BMD, which leads to osteoporosis. Epidemiological data suggest that estrogen deficiency is a risk factor for CVD and osteoporosis.

Changes in arterial function with age include a decrease in major artery compliance and increased arterial stiffness will result in an increase in resting and exercise blood pressure. Large arteries that convey blood at high pressure have relatively thick walls. Arterial stiffness, an independent risk factor for CVD, increases with advancing age (Tomiyama et al, 2003, Fig. 3). This age-related increase is greater in post-menopausal women, which increases their vulnerability to CVD. The cause of progressive age-related stiffness is the obviously increased thickness of the artery walls and interstitial collagen. Vessel structure also changes when an increase in blood pressure augments vascular tension. Increased arterial stiffness might be due to age-associated structural changes in the arterial walls. Aging is associated with a decrease in elastin and a concomitant increase in collagen and connective tissues in the arterial walls and an increase in arterial stiffness due to menopause.

Fig. 3. Chronological changes in brachial-ankle pulse wave velocity (baPWV) in healthy men and women (Quotation from Tomiyama et al, 2003).

### **6. Exercise**

532 Osteoporosis

pressures, which show a higher estimated aortic PWV indicating a stiffer aorta (Mangiafico et al, 2008, Tab. 1). Such alterations may increase the risk of CVD in postmenopausal osteoporosis. Therefore, the prevention and treatment of increased arterial stiffness and/or

Table 1. Peripheral and central haemodynamic parameters of osteoporotic patients and

In addition to menopause and advanced age, risk factors for CVD such as obesity and diabetes are also associated with osteoporosis. Thus, osteoporosis and atherosclerosis seem to correlate with aging. Osteoporosis-related fractures represent a major health concern, particularly among elderly populations. Post-menopausal osteoporosis in women with increased availability of circulating osteoprogenitor cells has a detrimental influence on arterial compliance. Lifestyle modification includes measures to reduce falls and bone loss such as participating in exercise, adequate dietary calcium intake and avoiding smoking and excessive alcohol consumption. Osteoporosis is characterized by the progressive loss of bone tissue and micro-architectural deterioration that reduces the quality of life for the elderly and thus it is a persistent public health issue. BMD at the femoral neck and spine in aging women decreases by 1 - 2 % per year (Finkelstein et al, 2008). Decreasing estrogen concentrations after menopause can cause a decline in BMD, which leads to osteoporosis. Epidemiological data

Changes in arterial function with age include a decrease in major artery compliance and increased arterial stiffness will result in an increase in resting and exercise blood pressure. Large arteries that convey blood at high pressure have relatively thick walls. Arterial stiffness, an independent risk factor for CVD, increases with advancing age (Tomiyama et al, 2003, Fig. 3). This age-related increase is greater in post-menopausal women, which increases their vulnerability to CVD. The cause of progressive age-related stiffness is the obviously increased thickness of the artery walls and interstitial collagen. Vessel structure also changes when an increase in blood pressure augments vascular tension. Increased arterial stiffness might be due to age-associated structural changes in the arterial walls. Aging is associated with a decrease in elastin and a concomitant increase in collagen and connective tissues in the arterial walls and an increase in arterial stiffness due to menopause.

control subjects (Quotation from Mangiafico et al, 2008)

**5. Effects of aging on osteoporosis and arterial stiffness** 

suggest that estrogen deficiency is a risk factor for CVD and osteoporosis.

osteoporosis are important.

Health organizations such as the American Heart Association (AHA) and the American College of Sports Medicine (ACSM) recommend habitual exercise to prevent and treat CVD and frailty associated with aging. In contrast to age, regular physical exercise in general, and aerobic exercise/fitness in particular, are associated with enhanced vascular function and a reduced risk of CVD. However, in contrast to the beneficial effects of aerobic exercise, highintensity resistance training increases arterial stiffness in young and middle-aged healthy men and in pre-menopausal women.

To date, the predominant medical strategies to prevent and/or treat post-menopausal bone loss have focused on antiresorptive medications (i.e., bisphosphonates). However, these treatments might be limited due to adverse side effects, questionable compliance and longterm safety concerns. Various types of exercise, such as walking, jogging or resistance training, could provide an important role in maintaining and/or increasing bone density in women. Therefore, implementing non-pharmacological treatment strategies such as exercise that have few or no inherent side effects is critical. Exercise plays an important role in maintaining or increasing bone density. Physical activity increases growth in the width and mineral content of bones in girls and adolescent females, particularly when initiated before puberty, carried out in volumes and at intensities seen in athletes, and accompanied by adequate caloric and calcium intake. The differences are regularly the largest in gymnasts whose hip and spine BMD values are 30% – 40% higher than those of long-distance runners (Robinson et al, 1995); a plausible explanation for this is the greater magnitude of impact forces generated in gymnastic movements (10- to 12-fold body weight) compared with

Osteoporosis and Arterial Stiffness: Effects of Exercise Training 535

Fig. 5. Arterial compliance (a) and ß-stiffness index (b) before and after aerobic exercise

The ACSM position on physical activity and bone health recommends regular weightbearing endurance activities, including jogging and jumping to preserving bone mass during adulthood. Moreover, although vascular function is not improved by aerobic exercise before resistance training, aerobic exercise thereafter can prevent vascular function from deterioratin (Okamoto et al. 2007, Fig. 6). Adaptive bone responses might require dynamic, rather than static mechanical stimulation. Aerobic exercise combined with highimpact exercise training seems to be effective against osteoporosis and/or for improving

intervention. \*P<0.01 vs before training. (Quotation from Tanaka et al, 2000)

vascular health.

running (3- to 5-fold body weight) (Duncan et al, 2002). Moreover, not only are high-impact sports associated with a greater BMD, but athletes involved in high-impact sports also have a greater section modulus (a predictor of strength in bending) (Nikander et al, 2005, Fig. 4). Since the two mechanisms that principally determine adult bone health are peak BMD at skeletal maturity and the rate of bone loss with advancing age, maximizing pre-menopausal BMD is a critical strategy for preventing osteoporosis and resultant fractures later in life.

Fig. 4. Differences in cross-sectional area ( ) and section modulus (a predictor of strength in bending; ( ) between athletes participating in sports of different loading modalities and controls. Values are means and 95% confidence interval (CI) represented by horizontal bars. Where the 95% CI does not cross the zero line (the value for the controls) the difference was significant (*P*<0·05) (Quotation from Nikander et al, 2005) .

### **6.1 Aerobic exercise and arterial stiffness**

Physical activity can be used as a prophylactic tool against osteoporosis and to improve skeletal resistance to bone fractures. A physically active lifestyle is associated with a 30% to 50% decrease in the risk of vertebral or hip fractures. Aerobic exercise positively affects blood pressure and arterial stiffness. Regular aerobic exercise is recommended to prevent and treat CVD and the frailty associated with aging. Regular aerobic exercise is beneficial for reversing arterial stiffening in middle-aged and older adults (Tanaka et al, 2000, Fig. 5). Moderate, shortterm aerobic exercise could restore carotid arterial compliance in previously sedentary postmenopausal women taking hormone replacement therapy(Moreau et al, 2002).

running (3- to 5-fold body weight) (Duncan et al, 2002). Moreover, not only are high-impact sports associated with a greater BMD, but athletes involved in high-impact sports also have a greater section modulus (a predictor of strength in bending) (Nikander et al, 2005, Fig. 4). Since the two mechanisms that principally determine adult bone health are peak BMD at skeletal maturity and the rate of bone loss with advancing age, maximizing pre-menopausal BMD is a critical strategy for preventing osteoporosis and resultant fractures later in life.

Fig. 4. Differences in cross-sectional area ( ) and section modulus (a predictor of strength in bending; ( ) between athletes participating in sports of different loading modalities and controls. Values are means and 95% confidence interval (CI) represented by horizontal bars. Where the 95% CI does not cross the zero line (the value for the controls) the difference was

Physical activity can be used as a prophylactic tool against osteoporosis and to improve skeletal resistance to bone fractures. A physically active lifestyle is associated with a 30% to 50% decrease in the risk of vertebral or hip fractures. Aerobic exercise positively affects blood pressure and arterial stiffness. Regular aerobic exercise is recommended to prevent and treat CVD and the frailty associated with aging. Regular aerobic exercise is beneficial for reversing arterial stiffening in middle-aged and older adults (Tanaka et al, 2000, Fig. 5). Moderate, shortterm aerobic exercise could restore carotid arterial compliance in previously sedentary post-

menopausal women taking hormone replacement therapy(Moreau et al, 2002).

significant (*P*<0·05) (Quotation from Nikander et al, 2005) .

**6.1 Aerobic exercise and arterial stiffness** 

Fig. 5. Arterial compliance (a) and ß-stiffness index (b) before and after aerobic exercise intervention. \*P<0.01 vs before training. (Quotation from Tanaka et al, 2000)

The ACSM position on physical activity and bone health recommends regular weightbearing endurance activities, including jogging and jumping to preserving bone mass during adulthood. Moreover, although vascular function is not improved by aerobic exercise before resistance training, aerobic exercise thereafter can prevent vascular function from deterioratin (Okamoto et al. 2007, Fig. 6). Adaptive bone responses might require dynamic, rather than static mechanical stimulation. Aerobic exercise combined with highimpact exercise training seems to be effective against osteoporosis and/or for improving vascular health.

Osteoporosis and Arterial Stiffness: Effects of Exercise Training 537

 Fig. 7. Changes in carotid arterial compliance (top) and β-stiffness index (bottom) in the intervention group (black circles) and control group (white triangles). Values are mean±SEM. \*P<0.05 vs baseline; †P<0.05 vs resistance training period (2- and 4-month

Physical activity stimulates increases in bone diameter throughout life and diminishes the risk of fractures by mechanically counteracting the rates of bone thinning and bone porosity. Exercise can be associated with an increase in muscle contraction and thus with more strain applied to bone, which is important for bone mass stimulation. Whole body vibration has been investigated from the viewpoints of sport, rehabilitation and treatment for osteoporosis. Whole-body vibration is a new training modality that increases muscle strength and mass to the same extent as resistance training at moderate intensity, which can be of clinical importance in individuals who cannot perform high-intensity and prolonged traditional exercise. Whole body vibration acutely decreases arterial stiffness (Otsuki et al. 2008, Fig. 8). Moreover, whole-body vibration prevents increases in leg arterial stiffness and attenuates increases in systemic arterial stiffness (Figueroa et al, 2011). Thus, whole body vibration is beneficial not only to the skeletal system and musculature but also to the

Whole body vibration is feasible not only in healthy humans but also in vulnerable populations such as those with osteogenesis imperfecta (Semler et al, 2007 ). Whole body vibration reflexes to the lumbar spine can be induced by upright standing on a vibrating platform. The application of vibrations increased bone formation and the metabolism in skeletal muscles and skin (Bleeker et al, 2005; Kerschau-Schindl et al, 2001). As whole body vibration -induced oscillation is propagated at least to the lumbar spine (Rubin et al, 2003 ), it is reasonable to consider that whole body vibration mechanically stimulates abdominal and leg arteries. Therefore, whole body vibration may reduce arterial tone and decrease

values) (Quotation from Miyachi et al. 2004).

cardiovascular system.

**6.3 Other types of exercise and arterial stiffness** 

arterial stiffness via mechanical stimuli to arteries.

Fig. 6. Changes in brachial-ankle pulse wave velocity (baPWV), percent flow-mediated dilation (%FMD), and normalized FMD in groups that ran before resistance training (RT) (BRT;●), ran after RT (ART;■), or remained sedentary (SED;▲). Values are means ± SE. \**P* < 0.05; \*\**P* < 0.01 vs. baseline. †*P* < 0.05; ††*P* < 0.01 vs. BRT group (Quotation from Okamoto et al. 2007).

#### **6.2 Resistance exercise and arterial stiffness**

Physical activity could increase bone strength by increasing muscle mass (Bennell et al, 2000). Physical activity reduces skeletal fragility and a predisposition to falling through a combination of increased BMD and improved coordination, balance, reaction time and muscle function (Liu-Ambrose et al, 2004). Resistance training is a critical component in exercise prescription programmes for healthy adults. Resistance training is widely recommended to prevent sarcopenia and osteoporosis (Pollock et al, 2000). Resistance exercise at high intensity [one repetition maximum (1RM), 80%] has generally been regarded as optimal for gaining muscular size and strength (McDonagh, & Davies, 1984). However, high intensity resistance training has been associated with the stiffening of large arteries in young and middle-aged adults (Miyachi et al. 2004, Fig. 7). In contrast, Cortez-Cooper et al (2008) reported that 13 weeks of moderate-intensity resistance training two or three times per week does not reduce central arterial compliance in middle-aged and older adults. In addition, Yoshizawa et al (2009) demonstrated that 12 weeks of moderateintensity resistance training did not affect arterial stiffness in middle-aged women. Moreover, low-intensity resistance training with short inter-set rest periods reduces arterial stiffness and improves vascular endothelial function (Okamoto et al, 2011). These conflicting result might be due to differences in the intensity of resistance training. Therefore, resistance training might need to be carefully prescribed based on individual pre-existing conditions and the anticipated outcome of the exercise program. Moderate and low intensity resistance training is recommended from the general viewpoints of health promotion and safety.

Fig. 6. Changes in brachial-ankle pulse wave velocity (baPWV), percent flow-mediated dilation (%FMD), and normalized FMD in groups that ran before resistance training (RT) (BRT;●), ran after RT (ART;■), or remained sedentary (SED;▲). Values are means ± SE. \**P* < 0.05; \*\**P* < 0.01 vs. baseline. †*P* < 0.05; ††*P* < 0.01 vs. BRT group (Quotation from Okamoto et

Physical activity could increase bone strength by increasing muscle mass (Bennell et al, 2000). Physical activity reduces skeletal fragility and a predisposition to falling through a combination of increased BMD and improved coordination, balance, reaction time and muscle function (Liu-Ambrose et al, 2004). Resistance training is a critical component in exercise prescription programmes for healthy adults. Resistance training is widely recommended to prevent sarcopenia and osteoporosis (Pollock et al, 2000). Resistance exercise at high intensity [one repetition maximum (1RM), 80%] has generally been regarded as optimal for gaining muscular size and strength (McDonagh, & Davies, 1984). However, high intensity resistance training has been associated with the stiffening of large arteries in young and middle-aged adults (Miyachi et al. 2004, Fig. 7). In contrast, Cortez-Cooper et al (2008) reported that 13 weeks of moderate-intensity resistance training two or three times per week does not reduce central arterial compliance in middle-aged and older adults. In addition, Yoshizawa et al (2009) demonstrated that 12 weeks of moderateintensity resistance training did not affect arterial stiffness in middle-aged women. Moreover, low-intensity resistance training with short inter-set rest periods reduces arterial stiffness and improves vascular endothelial function (Okamoto et al, 2011). These conflicting result might be due to differences in the intensity of resistance training. Therefore, resistance training might need to be carefully prescribed based on individual pre-existing conditions and the anticipated outcome of the exercise program. Moderate and low intensity resistance training is recommended from the general viewpoints of health promotion and safety.

al. 2007).

**6.2 Resistance exercise and arterial stiffness** 

Fig. 7. Changes in carotid arterial compliance (top) and β-stiffness index (bottom) in the intervention group (black circles) and control group (white triangles). Values are mean±SEM. \*P<0.05 vs baseline; †P<0.05 vs resistance training period (2- and 4-month values) (Quotation from Miyachi et al. 2004).

#### **6.3 Other types of exercise and arterial stiffness**

Physical activity stimulates increases in bone diameter throughout life and diminishes the risk of fractures by mechanically counteracting the rates of bone thinning and bone porosity. Exercise can be associated with an increase in muscle contraction and thus with more strain applied to bone, which is important for bone mass stimulation. Whole body vibration has been investigated from the viewpoints of sport, rehabilitation and treatment for osteoporosis. Whole-body vibration is a new training modality that increases muscle strength and mass to the same extent as resistance training at moderate intensity, which can be of clinical importance in individuals who cannot perform high-intensity and prolonged traditional exercise. Whole body vibration acutely decreases arterial stiffness (Otsuki et al. 2008, Fig. 8). Moreover, whole-body vibration prevents increases in leg arterial stiffness and attenuates increases in systemic arterial stiffness (Figueroa et al, 2011). Thus, whole body vibration is beneficial not only to the skeletal system and musculature but also to the cardiovascular system.

Whole body vibration is feasible not only in healthy humans but also in vulnerable populations such as those with osteogenesis imperfecta (Semler et al, 2007 ). Whole body vibration reflexes to the lumbar spine can be induced by upright standing on a vibrating platform. The application of vibrations increased bone formation and the metabolism in skeletal muscles and skin (Bleeker et al, 2005; Kerschau-Schindl et al, 2001). As whole body vibration -induced oscillation is propagated at least to the lumbar spine (Rubin et al, 2003 ), it is reasonable to consider that whole body vibration mechanically stimulates abdominal and leg arteries. Therefore, whole body vibration may reduce arterial tone and decrease arterial stiffness via mechanical stimuli to arteries.

Osteoporosis and Arterial Stiffness: Effects of Exercise Training 539

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Fig. 8. Brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, before and 20, 40 and 60 min after control (a) and whole-body vibration (WBV, b) sessions. Open circles are individual values and closed circles are mean ± SE. \**P* < 0.05 vs. baseline (Quotation from Otsuki et al. 2008).

#### **7. Summary**

Based on these results, we encourage the clinical prescription of specific exercise programs to impede the progression of osteoporosis and/or atherosclerosis and to confer health benefits that will assure a better long-term quality of life and decrease the public health burden.

#### **8. References**


Fig. 8. Brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, before and 20, 40 and 60 min after control (a) and whole-body vibration (WBV, b) sessions. Open circles are individual values and closed circles are mean ± SE. \**P* < 0.05 vs. baseline (Quotation

Based on these results, we encourage the clinical prescription of specific exercise programs to impede the progression of osteoporosis and/or atherosclerosis and to confer health benefits

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from Otsuki et al. 2008).

**7. Summary** 

**8. References** 


**27** 

*1USA, 2Japan* 

**Osteoporotic Pain** 

Sumihisa Orita1,2, Seiji Ohtori2, Gen Inoue2 and Kazuhisa Takahashi2

*1Dept. of Anesthesiology, School of Medicine, University of California, San Diego, La Jolla, 2Dept. of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba,* 

Pain derived from musculoskeletal disorders play a major role in the health profile of the general population (Badley et al., 1994). Generally, osteoporosis patients experience several kinds of pain, including LBP: pain derived from external injury such as from fractures of the compressed vertebrae or femoral neck, and pain from internal consequences of the osteoporotic state without injury, which has been reported to account for pain in 89% of menopausal osteoporosis patients (Scharla et al., 2006). The exact mechanism for that pain still remains unknown, but some studies have tried to clarify that. In a previous study in which SPECT RI, bone scintigraphy, and X-rays were used, pain from injury was reported to be caused by collapsed vertebral bodies and degenerated intervertebral disc and facet joints (Ryan et al., 1992), which proved one of the evidence of injury-derived pain. The injuryderived pain in osteoporosis patients tends to turn into acute pain, whereas the non-injuryderived pain tends to take a chronic course, among which the latter must be sought for its pathogenesis. Here, we define pain derived from osteoporosis without any fractures or injuries as "osteoporotic pain." In this chapter, we review osteoporotic pain by showing the association between its possible mechanism and treatment. Regarding the detailed pharmacological character and use of each anti-osteoporosis agent, please refer to the other

**2. Mechanism and pharmacological management of osteoporotic pain** 

In the bone tissue, nociceptors respond to mechanical, thermal, and chemical stimuli. Injury or inflammation results in the release of a variety of chemical mediators (e.g., prostaglandins, cytokines, and growth factors), which not only stimulate osteoclast activity but also activate nociceptors and decrease their threshold for activation (Haegerstam, 2001; Payne, 1997). The alteration in bone turnover leads to microfractures of bone, which may be one of the possible accepted origins of osteoporotic pain. Furthermore, other mechanisms

Menopause is well known to be one of the essential causes of osteoporosis in humans (Albright, 1989), and the most important change after menopause is the depletion of estrogen that regulates the expression of various genes (Beato, 1989), which leads to a decrease in the amounts of gene products, including receptors and peptides, required for

**1. Introduction** 

appropriate chapters.

for osteoporotic pain are reviewed in this section.

**2.1 Overview** 


## **Osteoporotic Pain**

Sumihisa Orita1,2, Seiji Ohtori2, Gen Inoue2 and Kazuhisa Takahashi2

*1Dept. of Anesthesiology, School of Medicine, University of California, San Diego, La Jolla, 2Dept. of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, 1USA, 2Japan* 

### **1. Introduction**

540 Osteoporosis

Murray, TD. & Murray JM. (1998) *Cardiocascular anatomy. In: American College of Sports* 

Nikander, R. Sievanen, H. & Heinonen, A. et al. (2005) Femoral neck structure in adult

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Otsuki, T. Takanami, Y. & Aoi, W. et al. (2008) Arterial stiffness acutely decreases after

Pollock, ML. Franklin, BA. & Balady, GJ. et al. (2000) AHA Science Advisory. Resistance

Robinson, TL. Snow-Harter, C. & Taaffe, DR. et al. (1995) Gymnasts exhibit higher bone

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Pain derived from musculoskeletal disorders play a major role in the health profile of the general population (Badley et al., 1994). Generally, osteoporosis patients experience several kinds of pain, including LBP: pain derived from external injury such as from fractures of the compressed vertebrae or femoral neck, and pain from internal consequences of the osteoporotic state without injury, which has been reported to account for pain in 89% of menopausal osteoporosis patients (Scharla et al., 2006). The exact mechanism for that pain still remains unknown, but some studies have tried to clarify that. In a previous study in which SPECT RI, bone scintigraphy, and X-rays were used, pain from injury was reported to be caused by collapsed vertebral bodies and degenerated intervertebral disc and facet joints (Ryan et al., 1992), which proved one of the evidence of injury-derived pain. The injuryderived pain in osteoporosis patients tends to turn into acute pain, whereas the non-injuryderived pain tends to take a chronic course, among which the latter must be sought for its pathogenesis. Here, we define pain derived from osteoporosis without any fractures or injuries as "osteoporotic pain." In this chapter, we review osteoporotic pain by showing the association between its possible mechanism and treatment. Regarding the detailed pharmacological character and use of each anti-osteoporosis agent, please refer to the other appropriate chapters.

### **2. Mechanism and pharmacological management of osteoporotic pain**

### **2.1 Overview**

In the bone tissue, nociceptors respond to mechanical, thermal, and chemical stimuli. Injury or inflammation results in the release of a variety of chemical mediators (e.g., prostaglandins, cytokines, and growth factors), which not only stimulate osteoclast activity but also activate nociceptors and decrease their threshold for activation (Haegerstam, 2001; Payne, 1997). The alteration in bone turnover leads to microfractures of bone, which may be one of the possible accepted origins of osteoporotic pain. Furthermore, other mechanisms for osteoporotic pain are reviewed in this section.

Menopause is well known to be one of the essential causes of osteoporosis in humans (Albright, 1989), and the most important change after menopause is the depletion of estrogen that regulates the expression of various genes (Beato, 1989), which leads to a decrease in the amounts of gene products, including receptors and peptides, required for

Osteoporotic Pain 543

Calcitonin is a polypeptide hormone involved primarily in the regulation of calcium homeostasis; it is secreted into the general circulation by the parafollicular C cells of the mammalian thyroid gland, and regulates the blood calcium concentration and bone metabolism by suppressing the activity of osteoclasts by binding calcitonin receptor on them. Thus, it reduces the blood calcium concentration in hypercalcemia and improves bone mass in osteoporosis. It is usually administered via a subcutaneous injection, and its analgesic effect as well as the resulting increase in bone mineral density (BMD) has been observed and reported in clinical situations; some RCT studies showed that calcitonin produced an analgesic effect in patients with osteoporotic vertebral compression fractures (Knopp et al., 2005; Lyritis et al., 1999), reflex sympathetic dystrophy(or Complex regional

pain syndrome: CRPS) (Gobelet et al., 1992) , and cancer pain (Roth & Kolarić, 1986).

1986; Sugiura et al., 1989; Yoshimura & Jessell, 1990; Yoshimura & Jessell, 1989).

Fig. 2. Schematic diagram of the neuronal organization of the superficial dorsal horn in the spinal cord and the afferent input to the same. Substantia gelatinosa exists in lamina II, in which myelinated A-afferent fibers and unmyelinated C-afferent fibers terminate

In osteoporosis, estrogen deficiency not only causes bone loss but also alters the spinal serotonergic system by suppressing 5-HT receptor expression, which usually plays an important role in descending pain inhibitory system; this results in hyperalgesia. In other words, the hyperalgesia observed in the osteoporotic model is, at least in part, mediated by

preferentially (Cervero & Iggo, 1980)

The analgesic effect of calcitonin is reported to be related to the serotonergic system in the spinal cord: a presynaptic serotonin (5-HT)-induced inhibition of excitatory glutamatergic transmission evoked monosynaptically by stimulating C-afferent fibers in the substantia gelatinosa (SG) neurons existing in the lamina II of the spinal dorsal horn (Fig. 2). Incidentally SG neurons play an important role in the modulation of nociceptive transmission from the periphery to the central nervous system (CNS), in which nociceptive information is transmitted by fine myelinated A-afferent and unmyelinated C-afferent fibers terminating preferentially (Kumazawa & Perl, 1978; Light et al., 1979; Sugiura et al.,

**2.2 Calcitonin** 

modulation of nociceptive transmission. Furthermore, estrogen modulates osteoclast formation both by directly suppressing Receptor activator of NF-B ligand (RANKL) induced osteoclast differentiation and by down-regulating the expression of osteoclastogenic cytokines from supportive cells (Shevde, et al., 2000).

In basic studies, ovariectomized (OVX) rats are often used as well-known osteoporosis pathological model, which exhibit the same hormonal changes observed in humans with osteoporosis. Regarding pain perception, a significant reduction in the latencies of tail withdrawal from hot water (Forman et al., 1989) and long-term formalin-induced licking has also been reported to be increased in OVX rats (Franceschini et al., 1983), and because of this, OVX is thought to induce hyperalgesia in rats. These increased pain perception should be another reason for the osteoporotic pain.

Osteoporosis treatment against pain itself potentially includes the prevention of possible fracture-induced pain by increasing bone mass density (BMD), which each agent originally aims to acquire. Furthermore, each anti-osteoporosis agent has been reported to have its own specific pain-related active site, which will be described further in the following sections.

In this section we will review the possible mechanism underlying osteoporotic pain with the relation to the osteoporosis agents, details of which have been obtained from several studies in which some of the mechanisms overlap and remain unclear, that tells us the several sources of osteoporotic pain in the central/peripheral nervous system for its manifestation in local sites of osteoporosis. Fig. 1 below shows us the general view of several sources of osteoporotic pain in the central/peripheral nervous system. Regarding the detail of the each agent, please refer to the following subsections.

Fig. 1. Possible mechanism underlying osteoporotic pain. Green boxes show the roles of osteoporosis agents.

modulation of nociceptive transmission. Furthermore, estrogen modulates osteoclast formation both by directly suppressing Receptor activator of NF-B ligand (RANKL) induced osteoclast differentiation and by down-regulating the expression of

In basic studies, ovariectomized (OVX) rats are often used as well-known osteoporosis pathological model, which exhibit the same hormonal changes observed in humans with osteoporosis. Regarding pain perception, a significant reduction in the latencies of tail withdrawal from hot water (Forman et al., 1989) and long-term formalin-induced licking has also been reported to be increased in OVX rats (Franceschini et al., 1983), and because of this, OVX is thought to induce hyperalgesia in rats. These increased pain perception should

Osteoporosis treatment against pain itself potentially includes the prevention of possible fracture-induced pain by increasing bone mass density (BMD), which each agent originally aims to acquire. Furthermore, each anti-osteoporosis agent has been reported to have its own specific pain-related active site, which will be described further in the following sections. In this section we will review the possible mechanism underlying osteoporotic pain with the relation to the osteoporosis agents, details of which have been obtained from several studies in which some of the mechanisms overlap and remain unclear, that tells us the several sources of osteoporotic pain in the central/peripheral nervous system for its manifestation in local sites of osteoporosis. Fig. 1 below shows us the general view of several sources of osteoporotic pain in the central/peripheral nervous system. Regarding the detail of the each

Fig. 1. Possible mechanism underlying osteoporotic pain. Green boxes show the roles of

osteoclastogenic cytokines from supportive cells (Shevde, et al., 2000).

be another reason for the osteoporotic pain.

agent, please refer to the following subsections.

osteoporosis agents.

#### **2.2 Calcitonin**

Calcitonin is a polypeptide hormone involved primarily in the regulation of calcium homeostasis; it is secreted into the general circulation by the parafollicular C cells of the mammalian thyroid gland, and regulates the blood calcium concentration and bone metabolism by suppressing the activity of osteoclasts by binding calcitonin receptor on them. Thus, it reduces the blood calcium concentration in hypercalcemia and improves bone mass in osteoporosis. It is usually administered via a subcutaneous injection, and its analgesic effect as well as the resulting increase in bone mineral density (BMD) has been observed and reported in clinical situations; some RCT studies showed that calcitonin produced an analgesic effect in patients with osteoporotic vertebral compression fractures (Knopp et al., 2005; Lyritis et al., 1999), reflex sympathetic dystrophy(or Complex regional pain syndrome: CRPS) (Gobelet et al., 1992) , and cancer pain (Roth & Kolarić, 1986).

The analgesic effect of calcitonin is reported to be related to the serotonergic system in the spinal cord: a presynaptic serotonin (5-HT)-induced inhibition of excitatory glutamatergic transmission evoked monosynaptically by stimulating C-afferent fibers in the substantia gelatinosa (SG) neurons existing in the lamina II of the spinal dorsal horn (Fig. 2). Incidentally SG neurons play an important role in the modulation of nociceptive transmission from the periphery to the central nervous system (CNS), in which nociceptive information is transmitted by fine myelinated A-afferent and unmyelinated C-afferent fibers terminating preferentially (Kumazawa & Perl, 1978; Light et al., 1979; Sugiura et al., 1986; Sugiura et al., 1989; Yoshimura & Jessell, 1990; Yoshimura & Jessell, 1989).

Fig. 2. Schematic diagram of the neuronal organization of the superficial dorsal horn in the spinal cord and the afferent input to the same. Substantia gelatinosa exists in lamina II, in which myelinated A-afferent fibers and unmyelinated C-afferent fibers terminate preferentially (Cervero & Iggo, 1980)

In osteoporosis, estrogen deficiency not only causes bone loss but also alters the spinal serotonergic system by suppressing 5-HT receptor expression, which usually plays an important role in descending pain inhibitory system; this results in hyperalgesia. In other words, the hyperalgesia observed in the osteoporotic model is, at least in part, mediated by

Osteoporotic Pain 545

Fig. 3. CGRP production in ovariectomized (OVX) rats. Average CGRP production is

RIS and EXE (described in section 3) (Orita et al., 2010).

cord should be the another reason for osteoporotic pain.

osteoporotic patients by suppressing peripheral nerve function.

suppressed in the BP-treated group than in the vehicle-treated OVX group or physical exercise (EXE)-only treated group. TheCGRP production was mostly suppressed by the combination of

microenvironments by inflammation (Rousselle & Heymann, 2002; Teitelbaum, 2000), which should evoke the stimulation of TRPV1. Furthermore, this acidic microenvironment stimulates acid-sensing ion channels (ASICs). Increased activities of osteoporotic osteoclasts also lead to these upregulation of pain-related nociceptors and channels; hence, BP should downregulate their activity by suppressing osteoclasts. Indeed, the effect of BP on the increased number of TRPV1 has not been clarified; however, BP should have an effect on TRPV1 because the receptor has been reported to modulate the synthesis and release of CGRP in sensory nerves. Furthermore, activation of these pain-related molecules induces increased production of c-Fos protein in the spinal dorsal horn, which is expressed by both noxious and non-noxious stimuli in the postsynaptic neurons of the spinal dorsal horn (Hunt et al., 1987). It is upregulated in response to various stimuli from the primary afferent neurons (Hunt et al., 1987; Menétrey et al., 1989; Morgan & Curran, 1991), thus it is used for a marker for neuronal excitation including pain. These findings such as increased production of pain-related channels, receptors, and proteins in DRG and activated spinal

Furthermore, BP is indicated to have a direct suppressive effect on pain-related sensory neurons. We demonstrated that risedronate inhibited axonal growth of neurite of painrelated small-sized DRG neurons isolated from rat neonates *in vitro* (Orita et al., 2010). The underlying mechanism remains unclear, but BP itself can produce an analgesic effect in

disinhibition of pain transmission in the spinal cord. Calcitonin recovers these changes in the dorsal horn leading to a resumption of synthesis of 5-HT receptors followed by the recovery of descending inhibiting pathway; this in turn produces the analgesic effect (Ito et al., 2000).

Other previous studies demonstrate the analgesic effect of calcitonin. One basic study shows that calcitonin decreased hyperalgesia in ovariectomized rats by upregulating the activity of the descending serotonergic inhibitory system (Takayama et al., 2008) , and another clinical study reported that it produced an effect comparative to morphine analgesia (Martin et al., 1995) . Furthermore, calcitonin has been reported to significantly increase the plasma -endorphin levels in patients with postmenopausal osteoporosis (Ofluoglu et al., Akyuz, Unay, & Kayhan, 2007) . These facts prove the analgesic effect of calcitonin in osteoporotic pain.

Additionally, calcitonin is administered subcutaneously in the clinical situation. That makes easier to use for those osteoporotic pain patients with symptoms of gastroesophageal reflux disease and in elderly patients with kyphosis (Yamane et al., 2011) or with low medical compliance, which often makes it difficult to use other internal agents.

#### **2.3 Bisphosphonate**

Bisphosphonate (BP) regulates bone turnover by suppressing osteoclast activity, and its antifracture efficacy has been reported in osteoporosis patients. BP exerts its anti-osteoporosis effects by binding to hydroxyapatite in the bone tissue, inhibiting osteoclast activity, and inducing apoptosis of osteoclasts. Recently, it has been reported to produce suppressive effects on monocytes and macrophages as well; this in turn leads to the suppression of more acute conditions (Roelofs et al., 2010)

Clinically BP has the potential to prevent or relieve back pain in patients with spinal osteoporosis. For instance, risedronate produced an analgesic effect on osteoporosis patients with chronic low back pain who had no evidence of fractures (Ohtori et al., 2010). Alendronate resulted in a rapid decrease in back pain and improvement in QOL in postmenopausal women with osteoporosis (Iwamoto et al., 2010). In addition, an RCT study showed that alendronate produced a stronger analgesic effect than calcitonin in postmenopausal osteoporotic women (J. Iwamoto et al., 2010).

Recent studies tell us that several factors are involved in the analgesic mechanism of BP. First, it is caused by the modulation of pain-transmitting neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) and inflammatory cytokines such as tumor necrosis factor (TNF)- Regarding the effect on pain-related neuropeptide, ibandronate is reported to suppress the expression of substance P mRNA and TNF- in dorsal root ganglia (DRG) in a rat model of persistent inflammation (Bianchi et al., 2008). Here estrogen has reported to suppress CGRP production in DRG using OVX rats (Yang et al., 1998); hence, it is acceptable that estrogen deficiency in osteoporosis patients induces increased CGRP production. Herein we demonstrated that risedronate has suppressed the CGRP production (Fig. 3).(Orita et al., 2010).

Also, transient-receptor potential vanilloid 1 (TRPV1) is also upregulated in the DRGs of OVX rats (Orita et al., 2010). TRPV1 is a ligand-gated non-selective cation channel preferentially expressed in small-diameter primary afferent neurons (Tominaga et al., 1998). It responds to capsaicin, noxious heat and acid. Osteoporotic osteoclasts degrade bone minerals by secreting protons through the vacuolar H+-ATPase creating local acidic

disinhibition of pain transmission in the spinal cord. Calcitonin recovers these changes in the dorsal horn leading to a resumption of synthesis of 5-HT receptors followed by the recovery of descending inhibiting pathway; this in turn produces the analgesic effect (Ito et

Other previous studies demonstrate the analgesic effect of calcitonin. One basic study shows that calcitonin decreased hyperalgesia in ovariectomized rats by upregulating the activity of the descending serotonergic inhibitory system (Takayama et al., 2008) , and another clinical study reported that it produced an effect comparative to morphine analgesia (Martin et al., 1995) . Furthermore, calcitonin has been reported to significantly increase the plasma -endorphin levels in patients with postmenopausal osteoporosis (Ofluoglu et al., Akyuz, Unay, & Kayhan, 2007) . These facts prove the analgesic effect of

Additionally, calcitonin is administered subcutaneously in the clinical situation. That makes easier to use for those osteoporotic pain patients with symptoms of gastroesophageal reflux disease and in elderly patients with kyphosis (Yamane et al., 2011) or with low medical

Bisphosphonate (BP) regulates bone turnover by suppressing osteoclast activity, and its antifracture efficacy has been reported in osteoporosis patients. BP exerts its anti-osteoporosis effects by binding to hydroxyapatite in the bone tissue, inhibiting osteoclast activity, and inducing apoptosis of osteoclasts. Recently, it has been reported to produce suppressive effects on monocytes and macrophages as well; this in turn leads to the suppression of more

Clinically BP has the potential to prevent or relieve back pain in patients with spinal osteoporosis. For instance, risedronate produced an analgesic effect on osteoporosis patients with chronic low back pain who had no evidence of fractures (Ohtori et al., 2010). Alendronate resulted in a rapid decrease in back pain and improvement in QOL in postmenopausal women with osteoporosis (Iwamoto et al., 2010). In addition, an RCT study showed that alendronate produced a stronger analgesic effect than calcitonin in

Recent studies tell us that several factors are involved in the analgesic mechanism of BP. First, it is caused by the modulation of pain-transmitting neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) and inflammatory cytokines such as tumor necrosis factor (TNF)- Regarding the effect on pain-related neuropeptide, ibandronate is reported to suppress the expression of substance P mRNA and TNF- in dorsal root ganglia (DRG) in a rat model of persistent inflammation (Bianchi et al., 2008). Here estrogen has reported to suppress CGRP production in DRG using OVX rats (Yang et al., 1998); hence, it is acceptable that estrogen deficiency in osteoporosis patients induces increased CGRP production. Herein we demonstrated that risedronate has suppressed the CGRP production

Also, transient-receptor potential vanilloid 1 (TRPV1) is also upregulated in the DRGs of OVX rats (Orita et al., 2010). TRPV1 is a ligand-gated non-selective cation channel preferentially expressed in small-diameter primary afferent neurons (Tominaga et al., 1998). It responds to capsaicin, noxious heat and acid. Osteoporotic osteoclasts degrade bone minerals by secreting protons through the vacuolar H+-ATPase creating local acidic

compliance, which often makes it difficult to use other internal agents.

postmenopausal osteoporotic women (J. Iwamoto et al., 2010).

al., 2000).

calcitonin in osteoporotic pain.

acute conditions (Roelofs et al., 2010)

(Fig. 3).(Orita et al., 2010).

**2.3 Bisphosphonate** 

Fig. 3. CGRP production in ovariectomized (OVX) rats. Average CGRP production is suppressed in the BP-treated group than in the vehicle-treated OVX group or physical exercise (EXE)-only treated group. TheCGRP production was mostly suppressed by the combination of RIS and EXE (described in section 3) (Orita et al., 2010).

microenvironments by inflammation (Rousselle & Heymann, 2002; Teitelbaum, 2000), which should evoke the stimulation of TRPV1. Furthermore, this acidic microenvironment stimulates acid-sensing ion channels (ASICs). Increased activities of osteoporotic osteoclasts also lead to these upregulation of pain-related nociceptors and channels; hence, BP should downregulate their activity by suppressing osteoclasts. Indeed, the effect of BP on the increased number of TRPV1 has not been clarified; however, BP should have an effect on TRPV1 because the receptor has been reported to modulate the synthesis and release of CGRP in sensory nerves. Furthermore, activation of these pain-related molecules induces increased production of c-Fos protein in the spinal dorsal horn, which is expressed by both noxious and non-noxious stimuli in the postsynaptic neurons of the spinal dorsal horn (Hunt et al., 1987). It is upregulated in response to various stimuli from the primary afferent neurons (Hunt et al., 1987; Menétrey et al., 1989; Morgan & Curran, 1991), thus it is used for a marker for neuronal excitation including pain. These findings such as increased production of pain-related channels, receptors, and proteins in DRG and activated spinal cord should be the another reason for osteoporotic pain.

Furthermore, BP is indicated to have a direct suppressive effect on pain-related sensory neurons. We demonstrated that risedronate inhibited axonal growth of neurite of painrelated small-sized DRG neurons isolated from rat neonates *in vitro* (Orita et al., 2010). The underlying mechanism remains unclear, but BP itself can produce an analgesic effect in osteoporotic patients by suppressing peripheral nerve function.

Osteoporotic Pain 547

combination with other osteoporosis treatment strategies to alleviate pain. Recently a new SERM, bazedoxifene, has been used in the clinical situation. Its analgesic effect is also should

Parathyroid hormone (PTH) stimulates bone formation by increasing the number of osteoblasts, partly by delaying osteoblast apoptosis (Jilka, 2007). Teriparatide, a recombinant of human PTH fragment 1-34 [rhPTH(1-34)], act as a bone anabolic agent which prevents, arrests, or partially reverses bone loss inducing new bone formation and improving bone microarchitecture (Peiqi Chen et al., 2007; Dempster, et al., 1993; Neer et al., 2001). The detailed mechanism of action of rhPTH is still under investigation, however the drug probably affects multiple pathways and alters the activity of osteoblasts, bone lining cells and osteocytes. Bone formation induced by PTH analogues not only increases BMD or bone mass but also improves the microarchitecture of the skeleton, thereby leading to improved bone strength and mechanical resistance (Kraenzlin & C. Meier, 2011). Hence, teriparatide has come to be used as one of the few anabolic agents for osteoporosis. A previous study reported that osteoporosis patients treated with teriparatide showed a greater analgesic effect on LBP than alendronate (Miller et al., 2005). Recently, a meta-analysis of five teriparatide trials showed that patients randomized to teriparatide had a reduced risk of new or worsening back pain during the active treatment phase compared with patients

Teriparatide can increase or decrease bone mass, depending on the mode of administration (Hock & Gera, 1992; Podbesek et al., 1983). Continuous infusions, which result in a persistent elevation of the serum parathyroid hormone concentration, lead to greater bone resorption than do daily injections, which cause only transient increases in the serum parathyroid hormone concentration(Tam et al., 1982). A previous study reported that a dose of 40 g increased BMD to a greater extent than a dose of 20 g but had similar effects on the risk of fracture and was more likely to produce side effects such as nausea and headache (Neer et al., 2001); this shows that physicians should be careful in prescribing the agent.

NSAIDs are commonly used in clinical situations to reduce inflammation and pain. The mechanism of NSAIDs is mainly based on inhibition of cyclooxygenase (COX) enzymes, which convert arachidonic acid into prostaglandins (PG). In particular the COX-2 isoform is accepted as a proinflammatory enzyme that is induced by inflammatory stimuli and responsible for the generation of proinflammatory PGE2 (Niederberger et al., 2008). PGE2 induces proliferation and activation of osteoclasts via osteoblast activation, hence its inhibition can lead to inhibiting osteoclast formation, which lead to analgesic effect (Kaji et al., 1996). However, they are often ineffective on osteoporotic pain because osteoporotic pain involves multiple mechanisms described above. Hence, clinical physicians dealing with pain should consider the existence of osteoporotic pain when NSAIDs are barely able to produce an analgesic effect on patients complaining of chronic pain for several months. Such patients would be an osteoporosis patients with osteoporotic pain who have no evidence of injuries (Ohtori et al., 2010). Long-term administration of NSAIDs can produce some side effects such as gastric ulcers or renal function disorder; hence, physicians should be careful when prescribing NSAIDs to pain patients and should always try to target the origin of their pain.

be investigated for osteoporotic pain patients.

**2.5 Parathyroid hormone (PTH) and PTH analogue** 

randomized to placebo or antiresorptive therapy (Nevitt et al., 2006).

**2.6 Non-steroidal anti-inflammatory drugs (NSAIDs)** 

The analgesic effect of BP has come to be studied and recognized as reviewed here. Hence, BP can be a useful agent for dealing with osteoporotic pain.

When using BP, we have to be careful of its side effects such as gastroesophageal reflux disease in elderly patients with kyphosis, and jaw necrosis. However, BP should be of use after the exclusion of these possible side effects.

#### **2.4 Hormone replacement treatment (HRT) and selective estrogen receptor modifier (SERM)**

Estrogen deficiency is the most major pathology in osteoporosis. Thus there should be suggesting that hormone replacement treatment (HRT) could be an alternative treatment. However HRT is not recommended by several studies for its side effects: breast cancer, coronary heart disease, stroke, and pulmonary embolism (Rossouw et al., 2002). Regarding pain, several clinical reviews indicate that the low back pain treatment with HRT is not significantly effective (Symmons, et al., 1991) and not recommended (Gamble, 1995; South-Paul, 2001; Willhite, 1998).

Instead of HRT using estrogen, selective estrogen receptor modifier (SERM) has been used for the treatment and prevention of osteoporosis. Raloxifene is a benzothiophene-derivative SERM that binds to estrogen receptors and and exerts estrogen agonist effects or antagonist effects, depending on the target tissue: in bone tissue, raloxifene produces estrogenlike effects while it does not induce breast cancer(Cummings et al., 1999). Estrogen produces a suppressive effect on osteoclast activity by suppressing osteoclast differentiation and bone resorption (Luo et al., 2011). Hence, as an anti-osteoporosis agent, SERM increases BMD at the lumbar spine and hip region (Delmas et al., 1997), decreases bone turnover (Draper et al., 1996), reduces the risk of vertebral fractures in postmenopausal women with osteoporosis (Ettinger et al., 1999), and improves the lipid profile in healthy postmenopausal women (Walsh et al., 1998). Furthermore some possible mechanisms regarding the analgesic effect of raloxifene have been reported. First, it subserves the decreasing estrogen, which affects the sensitivity of nociceptive receptors (Hapidou & De Catanzaro, 1988) by facilitating pain production through pain-related neurotransmitters (Duval et al., 1996; Kawata et al., 1994). Second, pain modulation via central interactions using the endogenous opioids pathway system is reported (Quiñones-Jenab et al., 1997). By mimicking estrogen, raloxifene increases the number of glutamate receptors in the rostral cortex, nucleus accumbens, and striatum (Cyr et al., 2001), which are regions of the brain that have recently known to be involved in the nociceptive processing system (Chudler & Dong, 1995). Also, raloxifene affects dopamine receptors in the striatum and nucleus accumbens (Landry et al., 2002), which play an important role in nociception in acute and chronic pain conditions (Magnusson & Fisher, 2000). Furthermore, clinical studies suggested that raloxifene produces estrogen-like upregulating effects on plasma levels of -endorphin (Florio et al., 2001), which acts as a neurotransmitter in the endogenous antinociceptive system. Hence, raloxifene affects nociceptive processing in CNS, possibly producing an analgesic effect. In addition, osteoclasts suppressed because of the estrogen-like effect of raloxifene should produce an analgesic condition through the reduced secretion of cytokines and reduce the risk of fractures.

While one study reported that raloxifene produced an analgesic effect in osteoporosis patients (Fujita et al., 2010), another study reported that the effect produced was not significant (Papadokostakis et al., 2006). This instability in estrogen or its alternative treatment should be due to the gradual decrease of estrogen receptor after menopause. And this shows that SERM should have some analgesic effect but might be better to be used in

The analgesic effect of BP has come to be studied and recognized as reviewed here. Hence,

When using BP, we have to be careful of its side effects such as gastroesophageal reflux disease in elderly patients with kyphosis, and jaw necrosis. However, BP should be of use

**2.4 Hormone replacement treatment (HRT) and selective estrogen receptor modifier** 

Estrogen deficiency is the most major pathology in osteoporosis. Thus there should be suggesting that hormone replacement treatment (HRT) could be an alternative treatment. However HRT is not recommended by several studies for its side effects: breast cancer, coronary heart disease, stroke, and pulmonary embolism (Rossouw et al., 2002). Regarding pain, several clinical reviews indicate that the low back pain treatment with HRT is not significantly effective (Symmons, et al., 1991) and not recommended (Gamble, 1995; South-

Instead of HRT using estrogen, selective estrogen receptor modifier (SERM) has been used for the treatment and prevention of osteoporosis. Raloxifene is a benzothiophene-derivative SERM that binds to estrogen receptors and and exerts estrogen agonist effects or antagonist effects, depending on the target tissue: in bone tissue, raloxifene produces estrogenlike effects while it does not induce breast cancer(Cummings et al., 1999). Estrogen produces a suppressive effect on osteoclast activity by suppressing osteoclast differentiation and bone resorption (Luo et al., 2011). Hence, as an anti-osteoporosis agent, SERM increases BMD at the lumbar spine and hip region (Delmas et al., 1997), decreases bone turnover (Draper et al., 1996), reduces the risk of vertebral fractures in postmenopausal women with osteoporosis (Ettinger et al., 1999), and improves the lipid profile in healthy postmenopausal women (Walsh et al., 1998). Furthermore some possible mechanisms regarding the analgesic effect of raloxifene have been reported. First, it subserves the decreasing estrogen, which affects the sensitivity of nociceptive receptors (Hapidou & De Catanzaro, 1988) by facilitating pain production through pain-related neurotransmitters (Duval et al., 1996; Kawata et al., 1994). Second, pain modulation via central interactions using the endogenous opioids pathway system is reported (Quiñones-Jenab et al., 1997). By mimicking estrogen, raloxifene increases the number of glutamate receptors in the rostral cortex, nucleus accumbens, and striatum (Cyr et al., 2001), which are regions of the brain that have recently known to be involved in the nociceptive processing system (Chudler & Dong, 1995). Also, raloxifene affects dopamine receptors in the striatum and nucleus accumbens (Landry et al., 2002), which play an important role in nociception in acute and chronic pain conditions (Magnusson & Fisher, 2000). Furthermore, clinical studies suggested that raloxifene produces estrogen-like upregulating effects on plasma levels of -endorphin (Florio et al., 2001), which acts as a neurotransmitter in the endogenous antinociceptive system. Hence, raloxifene affects nociceptive processing in CNS, possibly producing an analgesic effect. In addition, osteoclasts suppressed because of the estrogen-like effect of raloxifene should produce an analgesic

condition through the reduced secretion of cytokines and reduce the risk of fractures.

While one study reported that raloxifene produced an analgesic effect in osteoporosis patients (Fujita et al., 2010), another study reported that the effect produced was not significant (Papadokostakis et al., 2006). This instability in estrogen or its alternative treatment should be due to the gradual decrease of estrogen receptor after menopause. And this shows that SERM should have some analgesic effect but might be better to be used in

BP can be a useful agent for dealing with osteoporotic pain.

after the exclusion of these possible side effects.

**(SERM)** 

Paul, 2001; Willhite, 1998).

combination with other osteoporosis treatment strategies to alleviate pain. Recently a new SERM, bazedoxifene, has been used in the clinical situation. Its analgesic effect is also should be investigated for osteoporotic pain patients.

### **2.5 Parathyroid hormone (PTH) and PTH analogue**

Parathyroid hormone (PTH) stimulates bone formation by increasing the number of osteoblasts, partly by delaying osteoblast apoptosis (Jilka, 2007). Teriparatide, a recombinant of human PTH fragment 1-34 [rhPTH(1-34)], act as a bone anabolic agent which prevents, arrests, or partially reverses bone loss inducing new bone formation and improving bone microarchitecture (Peiqi Chen et al., 2007; Dempster, et al., 1993; Neer et al., 2001). The detailed mechanism of action of rhPTH is still under investigation, however the drug probably affects multiple pathways and alters the activity of osteoblasts, bone lining cells and osteocytes. Bone formation induced by PTH analogues not only increases BMD or bone mass but also improves the microarchitecture of the skeleton, thereby leading to improved bone strength and mechanical resistance (Kraenzlin & C. Meier, 2011). Hence, teriparatide has come to be used as one of the few anabolic agents for osteoporosis. A previous study reported that osteoporosis patients treated with teriparatide showed a greater analgesic effect on LBP than alendronate (Miller et al., 2005). Recently, a meta-analysis of five teriparatide trials showed that patients randomized to teriparatide had a reduced risk of new or worsening back pain during the active treatment phase compared with patients randomized to placebo or antiresorptive therapy (Nevitt et al., 2006).

Teriparatide can increase or decrease bone mass, depending on the mode of administration (Hock & Gera, 1992; Podbesek et al., 1983). Continuous infusions, which result in a persistent elevation of the serum parathyroid hormone concentration, lead to greater bone resorption than do daily injections, which cause only transient increases in the serum parathyroid hormone concentration(Tam et al., 1982). A previous study reported that a dose of 40 g increased BMD to a greater extent than a dose of 20 g but had similar effects on the risk of fracture and was more likely to produce side effects such as nausea and headache (Neer et al., 2001); this shows that physicians should be careful in prescribing the agent.

### **2.6 Non-steroidal anti-inflammatory drugs (NSAIDs)**

NSAIDs are commonly used in clinical situations to reduce inflammation and pain. The mechanism of NSAIDs is mainly based on inhibition of cyclooxygenase (COX) enzymes, which convert arachidonic acid into prostaglandins (PG). In particular the COX-2 isoform is accepted as a proinflammatory enzyme that is induced by inflammatory stimuli and responsible for the generation of proinflammatory PGE2 (Niederberger et al., 2008). PGE2 induces proliferation and activation of osteoclasts via osteoblast activation, hence its inhibition can lead to inhibiting osteoclast formation, which lead to analgesic effect (Kaji et al., 1996). However, they are often ineffective on osteoporotic pain because osteoporotic pain involves multiple mechanisms described above. Hence, clinical physicians dealing with pain should consider the existence of osteoporotic pain when NSAIDs are barely able to produce an analgesic effect on patients complaining of chronic pain for several months. Such patients would be an osteoporosis patients with osteoporotic pain who have no evidence of injuries (Ohtori et al., 2010). Long-term administration of NSAIDs can produce some side effects such as gastric ulcers or renal function disorder; hence, physicians should be careful when prescribing NSAIDs to pain patients and should always try to target the origin of their pain.

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### **3. Non-pharmacological treatment and osteoporotic pain**

Non-pharmacological treatment strategies such as physical exercise, nutrition, diet, and following of certain habits are also used. These non-pharmacological approaches can improve BMD by preventing a fracture. Considerable evidence indicates that physical exercise can be most useful among these approaches. The major objective of physical exercise in the prevention or treatment of osteoporosis is to reduce the incidence of fractures. Additionally it has been reported that physical exercises produce an analgesic effect for osteoporotic pain besides bringing about improved physical function and vitality (Li et al., 2009). A basic study using OVX rats showed that physical exercise (5 days a week for 30 min on a treadmill for 30 days) led to a significant decrease in CGRP production when combined with risedronate; this combination suppressed CGRP production more than risedronate alone.Furthermore, this combination led to the maximum improvement in BMD (Fig. 3) (Orita et al., 2010). This is attributable to the activation of osteoblasts by both BP and physical exercise. BP is reported to increase total cellular protein, alkaline phosphatase activity, and type I collagen secretion in vitro (Iwamoto et al., 2005), and adequate mechanical stress is reported to activate osteoblasts (Ban et al., 2011); this is the reason why BP and exercise make an effective combination, which coincides with that of a previous report (Fuchs et al., 2007; Tamaki et al., Akamine et al., 1998). Other combinations of physical exercise and osteoporosis treatment strategies should be effective. However, another study reports that excessive physical exercise such as running for long periods has a negative effect on bone metabolism and proinflammatory status, and leads to increased osteoclast activity and elevated production of TNF- and interferon- by CD8+ T cells (Sipos et al., 2008); further, excessive physical exercise can lead to fractures. Hence, the medical staff should suggest physical exercise programs suited to each patient.

### **4. Conclusion**

Osteoporotic pain is a clinically-known condition, but investigation of its mechanism and origin has only been performed in recent years. Osteoporosis treatment predominantly aims to increase the BMD of patients in order to prevent possible fragile fractures that sometimes lead to a critical condition or result in a poor quality of life (QOL). Considerable evidence shows that using pharmacological or non-pharmacological treatment strategies for these patients not only improve their BMD but also relieve their pain. Physicians should always bear these matters in mind when choosing a treatment strategy that would best benefit patients with osteoporotic pain.

### **5. References**


Non-pharmacological treatment strategies such as physical exercise, nutrition, diet, and following of certain habits are also used. These non-pharmacological approaches can improve BMD by preventing a fracture. Considerable evidence indicates that physical exercise can be most useful among these approaches. The major objective of physical exercise in the prevention or treatment of osteoporosis is to reduce the incidence of fractures. Additionally it has been reported that physical exercises produce an analgesic effect for osteoporotic pain besides bringing about improved physical function and vitality (Li et al., 2009). A basic study using OVX rats showed that physical exercise (5 days a week for 30 min on a treadmill for 30 days) led to a significant decrease in CGRP production when combined with risedronate; this combination suppressed CGRP production more than risedronate alone.Furthermore, this combination led to the maximum improvement in BMD (Fig. 3) (Orita et al., 2010). This is attributable to the activation of osteoblasts by both BP and physical exercise. BP is reported to increase total cellular protein, alkaline phosphatase activity, and type I collagen secretion in vitro (Iwamoto et al., 2005), and adequate mechanical stress is reported to activate osteoblasts (Ban et al., 2011); this is the reason why BP and exercise make an effective combination, which coincides with that of a previous report (Fuchs et al., 2007; Tamaki et al., Akamine et al., 1998). Other combinations of physical exercise and osteoporosis treatment strategies should be effective. However, another study reports that excessive physical exercise such as running for long periods has a negative effect on bone metabolism and proinflammatory status, and leads to increased osteoclast activity and elevated production of TNF- and interferon- by CD8+ T cells (Sipos et al., 2008); further, excessive physical exercise can lead to fractures. Hence, the medical

**3. Non-pharmacological treatment and osteoporotic pain** 

staff should suggest physical exercise programs suited to each patient.

Osteoporotic pain is a clinically-known condition, but investigation of its mechanism and origin has only been performed in recent years. Osteoporosis treatment predominantly aims to increase the BMD of patients in order to prevent possible fragile fractures that sometimes lead to a critical condition or result in a poor quality of life (QOL). Considerable evidence shows that using pharmacological or non-pharmacological treatment strategies for these patients not only improve their BMD but also relieve their pain. Physicians should always bear these matters in mind when choosing a treatment strategy that would best benefit

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Eriksen, F., Ish-Shalom, S., Genant, K., Wang, O., Mitlak, H. (2001). Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. *The New England journal of medicine*,

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endorphin levels in postmenopausal osteoporotic patients with back pain. *Clinical* 

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Kamoda H., Arai G., Ishikawa T., Miyagi M., Ochiai N., Kishida S., Takaso M., Aoki Y., Toyone T., & Takahashi K. (2010). The Effects of Risedronate and Exercise on Osteoporotic Lumbar Rat Vertebrae and Their Sensory Innervation. *Spine*, Vol.35,

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**28** 

*Spain* 

**Pharmacological Treatment of Osteoporosis** 

Osteoporosis can be classified into two big categories, clinical osteoporosis and densitometric osteoporosis. Clinical osteoporosis involves a fragility fracture, and no densitometry is needed to start treatment. Densitometric osteoporosis is defined by means of a bone mineral density assessment. Treatment should be considered depending on the

The first step in the pharmacological treatment of osteoporosis is to identify whether it is a primary disease or whether the bone mass loss is secondary to another disease. In the case of a secondary osteoporosis, treatment of the primary disease is the most important step. Pharmacological treatment should then be considered if the fracture risk is too high. The purpose of pharmacological treatment in osteoporosis is to reduce the risk of fracture. According to the World Health Organization's more than half of the patients suffering a fragility fracture do not have densitometric osteoporosis. (Siris et al., 2004) When any medication is started for osteoporosis treatment it must be remembered that this illness will require treatment for a long time and that the drug has to be given in conjunction with advise regarding lifestyle changes. It is therefore imperative to evaluate and make decisions based on issues such as cost, evaluation of cost-efficiency, and patient adaptability to drug safety.

Calcitonin is a 32 amino acid polypeptide. It binds to osteoclasts and inhibits bone resorption. Calcitonins from many species are effective in humans, but salmon calcitonin is the most widely used. It is extremely potent in humans due to its higher affinity (forty times that of human calcitonin) for the human calcitonin receptor. The only other calcitonin clinically used is human calcitonin, less potent but also less antigenic than salmon calcitonin. (Carstens & Feinblatt, 1991) It can be administered by intramuscular, intravenous or nasal route. The bioavailability of nasal salmon calcitonin is only about 25 percent that of intramuscular calcitonin; thus, the biological effect of 50 international units (IU) of intramuscular salmon calcitonin is comparable to that of 200 IU of nasal salmon calcitonin.

global fracture risk, and taking the densitometric results into account.

**1. Introduction** 

**2. Antiresorptives** 

(Overgaard et al., 1991)

**2.1 Calcitonin** 

Jorge Malouf-Sierra1 and Roberto Güerri-Fernández2

*1Universitat Autònoma de Barcelona,* 

*2Universitat Autònoma de Barcelona, IMIM-Hospital del Mar Barcelona,* 

*Hospital de la Santa Creu i Sant Pau Barcelona,* 


## **Pharmacological Treatment of Osteoporosis**

Jorge Malouf-Sierra1 and Roberto Güerri-Fernández2

*1Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau Barcelona, 2Universitat Autònoma de Barcelona, IMIM-Hospital del Mar Barcelona, Spain* 

### **1. Introduction**

554 Osteoporosis

Tamaki, H.; Akamine, T., Goshi, N., Kurata, H., & Sakou, T. (1998). Effects of exercise

Teitelbaum, L. (2000). Bone Resorption by Osteoclasts. *Science*, Vol. 289, No.5484, (September

Tominaga, M.; Caterina, J., Malmberg, B., Rosen, A, Gilbert, H., Skinner, K., Raumann, E.,

Walsh, W.; Kuller, H., Wild, A., Paul, S., Farmer, M., Lawrence, J. B., Shah, & Anderson W.

Willhite, L. (1998). Osteoporosis in women: prevention and treatment. *Journal of the American* 

Yamane, Y.; Yamaguchi, T., Tsumori, M., Yamauchi, M., Yano, S., Yamamoto, M., Honda, C.,

*Brain research*, Vol.791, No.1-2, (April 1998), pp. 35-42. ISSN 0006-8993 Yoshimura, M, & Jessell, T. (1990). Amino acid-mediated EPSPs at primary afferent synapses

Yoshimura, M. & Jessell, M. (1989). Primary afferent-evoked synaptic responses and slow

October 1998), pp. 614-623; quiz 623-624. ISSN 1086-5802

*neurophysiology*, Vol.62, No.1, pp. 96-108. ISSN 0022-3077

2000), pp. 1504-1508. ISSN 0036-8075

Vol.430, pp. 315-35, ISSN 1469-7793

0896-6273

0098-7484

training and etidronate treatment on bone mineral density and trabecular bone in ovariectomized rats. *Bone*, Vol.23, No,2, (August 1998), pp. 147-153. ISSN 8756-3282

Basbaum, I., & Julius, D. (1998). The cloned capsaicin receptor integrates multiple pain-producing stimuli. *Neuron*, Vol.21, No.3, (September 1998), pp. 531-543. ISSN

(1998). Effects of Raloxifene on Serum Lipids and Coagulation Factors in Healthy Postmenopausal Women. *JAMA*, Vol.279, No.18, (May 1998), pp. 1445-1451. ISSN

*Pharmaceutical Association (Washington,D.C. : 1996),* Vol.38, No.5, (September-

et al. (2011). Elcatonin is effective for lower back pain and the symptoms of gastroesophageal reflux disease in elderly osteoporotic patients with kyphosis. *Geriatrics & gerontology international*, Vol.11, No.2, pp.215-220. ISSN 1447-0594 Yang, Y.; Ozawa, H., Lu, H., Yuri, K., Hayashi, S., Nihonyanagi, K., & Kawata, M. (1998).

Immunocytochemical analysis of sex differences in calcitonin gene-related peptide in the rat dorsal root ganglion, with special reference to estrogen and its receptor.

with substantia gelatinosa neurones in the rat spinal cord. *The Journal of physiology*,

potential generation in rat substantia gelatinosa neurons in vitro. *Journal of* 

Osteoporosis can be classified into two big categories, clinical osteoporosis and densitometric osteoporosis. Clinical osteoporosis involves a fragility fracture, and no densitometry is needed to start treatment. Densitometric osteoporosis is defined by means of a bone mineral density assessment. Treatment should be considered depending on the global fracture risk, and taking the densitometric results into account.

The first step in the pharmacological treatment of osteoporosis is to identify whether it is a primary disease or whether the bone mass loss is secondary to another disease. In the case of a secondary osteoporosis, treatment of the primary disease is the most important step. Pharmacological treatment should then be considered if the fracture risk is too high. The purpose of pharmacological treatment in osteoporosis is to reduce the risk of fracture. According to the World Health Organization's more than half of the patients suffering a fragility fracture do not have densitometric osteoporosis. (Siris et al., 2004) When any medication is started for osteoporosis treatment it must be remembered that this illness will require treatment for a long time and that the drug has to be given in conjunction with advise regarding lifestyle changes. It is therefore imperative to evaluate and make decisions based on issues such as cost, evaluation of cost-efficiency, and patient adaptability to drug safety.

### **2. Antiresorptives**

### **2.1 Calcitonin**

Calcitonin is a 32 amino acid polypeptide. It binds to osteoclasts and inhibits bone resorption. Calcitonins from many species are effective in humans, but salmon calcitonin is the most widely used. It is extremely potent in humans due to its higher affinity (forty times that of human calcitonin) for the human calcitonin receptor. The only other calcitonin clinically used is human calcitonin, less potent but also less antigenic than salmon calcitonin. (Carstens & Feinblatt, 1991) It can be administered by intramuscular, intravenous or nasal route. The bioavailability of nasal salmon calcitonin is only about 25 percent that of intramuscular calcitonin; thus, the biological effect of 50 international units (IU) of intramuscular salmon calcitonin is comparable to that of 200 IU of nasal salmon calcitonin. (Overgaard et al., 1991)

Pharmacological Treatment of Osteoporosis 557

(RR=0.39; CI 95%: 0.24 to 0.64), but a non-significant hip fracture risk reduction (RR=0.64; CI 95%: 0.32 to 1.04). The WHI study (Women's Health Initiative), a randomized clinical trial (RCT) that evaluated postmenopausal women randomized to combined HRT (combined equine estrogen 0.625 mg daily plus medroxyprogesterone 2.5 mg daily) or placebo, demonstrated, after 5.2 years of treatment, a hip fracture risk reduction of 34% (hazard ratio [HR]=0.66; CI 95%: 0.45 to 0.98), of clinical vertebral fractures of 34% (HR=0.66; CI 95%: 0.44 to 0.98) and a reduction in any fracture of 24% (HR=0.76; CI 95%: 0.69 to 0.85). (Rossouw et al., 2002; Cauley et al., 2003) In the same study, the branch using estrogen alone showed similar results, but it was suspended due to an unfavorable risk benefit ratio. (Anderson et al., 2004) In two meta-analysis of RCTs a reduction of 27% (RR=0.73; CI 95%: 0.56 to 0.94) in non-vertebral fractures and a tendency towards the decrease of vertebral fractures (RR=0.66; CI 95%: 0.41 to 1.07) was described. (MacLean et al., 2008) Nevertheless, from the HERS (The Heart and Estrogen + Progestin Replacement Study) RCT and from the cohort followed, the HERS II study (Hulley et al., 1998), no reduction of the risk of hip fractures or of other locations (RR=1.04; CI 95%: 0.87 to 1.25) in women with cardiovascular disease history,

Another meta-analysis, which included information from two publications of the WHI study (women with and without osteoporosis, without DMO measurements) found a reduction of 25% of the relative risk of non-vertebral fractures (RR=0.75; CI 95%: 0.70 to 0.81) in a sample of 31,333 patients followed up for a maximum of 7 years and a 36% relative risk reduction for hip fractures (RR=0.64; CI 95%: 0.49 to 0.84) in a sample of 27,347 patients. (Liberman et al., 2006) The British National Institute of Health and Clinical Excellence presented a meta-analysis of RCTs on the efficacy of HRT (with estrogen alone or combined) vs. placebo / not treatment in postmenopausal women or with surgical menopause. (National Institute for Clinical Excellence [NICE], 2008) The results were presented by fracture location and specified the RCT used for the estimation of the relative risk. The

A systematic review of five RCTs, studying HRT with estrogen and two with combined HRT estrogen plus progesterone, did not demonstrate significant differences in the incidence of acute coronary events (including acute myocardial infarction) between the group of intervention and the control group. (MacLean et al., 2008) Two of the essays with estrogen and two of combined therapy (estrogen plus progesterone) that reported the incidence of death of cardiac origin did not demonstrate significant differences between the intervention group and control group. Combined results of three essays comparing estrogenic therapy with placebo (Anderson et al., 2004; Mosekilde et al., 2000; Cherry et al., 2002) presented an odds ratio (OR) of 1.34 (IC 95%: 1.07 to 1.68) for cerebral vascular events. The combined results of the essays that compared combined therapy estrogen plus progesterone with placebo (Rossouw et al., 2002; Hulley et al., 1998), demonstrated a higher risk of ictus (OR=1.28; CI 95%: 1.05 to 1.57) in the intervention group. Of 4 systematic reviews of observational studies in women receiving HRT (Stampfer et al., 1991; Grady et al., 2002; Barrett-Connor, 1992; Humphrey et al., 2002), three demonstrated an important reduction in the global risk of mortality for acute coronary events. The most recent systematic review, that controlled selection bias of inclusion and analysis, did not show any

could be demonstrated. (Cauley et al., 2001)

results are summarized in table 1.

**2.2.2 Safety** 

**2.2.2.1 Vascular illness** 

#### **2.1.1 Clinical data**

There is evidence that calcitonin is effective in the treatment of established osteoporosis. In one study of calcitonin in osteoporosis, 208 elderly osteopenic women were treated with calcium and either intranasal placebo, or 50, 100, or 200 IU of daily salmon calcitonin for two years. Mean spine bone mineral density (BMD) was increased by salmon calcitonin in a dose-dependent manner, and a maximum effect was seen with the 200 IU dose. (Overgaard et al., 1992)

The largest clinical trial with calcitonin for the treatment of osteoporosis was a five-year trial comprising 1,255 women with a lumbar spine T score of <-2 and at least one vertebral fracture. They were randomly assigned to placebo or 100, 200, or 400 IU of intranasal calcitonin per day. There was a small increase in spine BMD (1% to 1.5%) in all groups. The risk of vertebral fracture was significantly lower than placebo only in the group taking 200 IU per day, and the risk of non-vertebral fractures was significantly lower than placebo only in the group taking 100 IU per day. Thus, the beneficial effect of nasal calcitonin on vertebral BMD and vertebral fracture risk was small and inconsistent. (Chesnut et al., 2000)

Nowadays calcitonin is not a current therapy for osteoporosis. It has been displaced by other treatments. However, one beneficial short-term effect of calcitonin therapy is pain reduction in patients who have sustained a fracture. In one study, looking for pain effect of calcitonin, 56 osteoporotic women who sustained an atraumatic vertebral fracture were randomly assigned to treatment with placebo or 100 IU of intramuscular salmon calcitonin daily for two weeks. Mean pain scores and analgesic consumption in the calcitonin group were significantly lower than in the placebo group by the fourth day. Similar benefits on bone pain have been observed in several other small, randomized trials of parental and nasal calcitonin. The ability to relieve pain may represent a truly distinguishing feature from other drugs used in the treatment of osteoporosis and maybe today it is one of its main indications. (Lyritis et al., 1991)

### **2.1.2 Adverse effects**

The most frequent adverse effects of calcitonin appear during or shortly after its parenteral administration: digestive disorders, nausea, vomiting, abdominal pains, diarrhea, vasomotor disorders or facial flushing among others. Allergy to calcitonin is possible but exceptional. Thus, calcitonin may be the antiresorptive agent of choice in patients with pain from an acute osteoporotic fracture. Why pain relief occurs is not well understood; one possibility is a rise in endorphin levels induced by calcitonin.

### **2.2 Hormonal replacement therapy (HRT)**

The HRT is a treatment option that includes different estrogen doses, in combination, or not, with progestagens. Hormonal replacement therapy is described in detail in another chapter. Therefore, in this chapter we are just going to make a review of the antifracture efficacy of HRT along with the safety data from different meta-analysis, systematic reviews and clinical guides.

#### **2.2.1 Hormone replacement therapy (HRT) for fracture prevention**

The estimations of fracture risk, derived from the principal cohort studies of postmenopausal women, using HRT for long periods of time, show a significant vertebral fracture risk reduction (RR=0.6; CI 95%: 0.36 to 0.99) and wrist fracture risk reduction

There is evidence that calcitonin is effective in the treatment of established osteoporosis. In one study of calcitonin in osteoporosis, 208 elderly osteopenic women were treated with calcium and either intranasal placebo, or 50, 100, or 200 IU of daily salmon calcitonin for two years. Mean spine bone mineral density (BMD) was increased by salmon calcitonin in a dose-dependent manner, and a maximum effect was seen with the 200 IU dose. (Overgaard

The largest clinical trial with calcitonin for the treatment of osteoporosis was a five-year trial comprising 1,255 women with a lumbar spine T score of <-2 and at least one vertebral fracture. They were randomly assigned to placebo or 100, 200, or 400 IU of intranasal calcitonin per day. There was a small increase in spine BMD (1% to 1.5%) in all groups. The risk of vertebral fracture was significantly lower than placebo only in the group taking 200 IU per day, and the risk of non-vertebral fractures was significantly lower than placebo only in the group taking 100 IU per day. Thus, the beneficial effect of nasal calcitonin on vertebral

Nowadays calcitonin is not a current therapy for osteoporosis. It has been displaced by other treatments. However, one beneficial short-term effect of calcitonin therapy is pain reduction in patients who have sustained a fracture. In one study, looking for pain effect of calcitonin, 56 osteoporotic women who sustained an atraumatic vertebral fracture were randomly assigned to treatment with placebo or 100 IU of intramuscular salmon calcitonin daily for two weeks. Mean pain scores and analgesic consumption in the calcitonin group were significantly lower than in the placebo group by the fourth day. Similar benefits on bone pain have been observed in several other small, randomized trials of parental and nasal calcitonin. The ability to relieve pain may represent a truly distinguishing feature from other drugs used in the treatment of osteoporosis and maybe today it is one of its main

The most frequent adverse effects of calcitonin appear during or shortly after its parenteral administration: digestive disorders, nausea, vomiting, abdominal pains, diarrhea, vasomotor disorders or facial flushing among others. Allergy to calcitonin is possible but exceptional. Thus, calcitonin may be the antiresorptive agent of choice in patients with pain from an acute osteoporotic fracture. Why pain relief occurs is not well understood; one

The HRT is a treatment option that includes different estrogen doses, in combination, or not, with progestagens. Hormonal replacement therapy is described in detail in another chapter. Therefore, in this chapter we are just going to make a review of the antifracture efficacy of HRT along with the safety data from different meta-analysis, systematic reviews and clinical

The estimations of fracture risk, derived from the principal cohort studies of postmenopausal women, using HRT for long periods of time, show a significant vertebral fracture risk reduction (RR=0.6; CI 95%: 0.36 to 0.99) and wrist fracture risk reduction

possibility is a rise in endorphin levels induced by calcitonin.

**2.2.1 Hormone replacement therapy (HRT) for fracture prevention** 

**2.2 Hormonal replacement therapy (HRT)** 

BMD and vertebral fracture risk was small and inconsistent. (Chesnut et al., 2000)

**2.1.1 Clinical data** 

indications. (Lyritis et al., 1991)

**2.1.2 Adverse effects** 

guides.

et al., 1992)

(RR=0.39; CI 95%: 0.24 to 0.64), but a non-significant hip fracture risk reduction (RR=0.64; CI 95%: 0.32 to 1.04). The WHI study (Women's Health Initiative), a randomized clinical trial (RCT) that evaluated postmenopausal women randomized to combined HRT (combined equine estrogen 0.625 mg daily plus medroxyprogesterone 2.5 mg daily) or placebo, demonstrated, after 5.2 years of treatment, a hip fracture risk reduction of 34% (hazard ratio [HR]=0.66; CI 95%: 0.45 to 0.98), of clinical vertebral fractures of 34% (HR=0.66; CI 95%: 0.44 to 0.98) and a reduction in any fracture of 24% (HR=0.76; CI 95%: 0.69 to 0.85). (Rossouw et al., 2002; Cauley et al., 2003) In the same study, the branch using estrogen alone showed similar results, but it was suspended due to an unfavorable risk benefit ratio. (Anderson et al., 2004) In two meta-analysis of RCTs a reduction of 27% (RR=0.73; CI 95%: 0.56 to 0.94) in non-vertebral fractures and a tendency towards the decrease of vertebral fractures (RR=0.66; CI 95%: 0.41 to 1.07) was described. (MacLean et al., 2008) Nevertheless, from the HERS (The Heart and Estrogen + Progestin Replacement Study) RCT and from the cohort followed, the HERS II study (Hulley et al., 1998), no reduction of the risk of hip fractures or of other locations (RR=1.04; CI 95%: 0.87 to 1.25) in women with cardiovascular disease history, could be demonstrated. (Cauley et al., 2001)

Another meta-analysis, which included information from two publications of the WHI study (women with and without osteoporosis, without DMO measurements) found a reduction of 25% of the relative risk of non-vertebral fractures (RR=0.75; CI 95%: 0.70 to 0.81) in a sample of 31,333 patients followed up for a maximum of 7 years and a 36% relative risk reduction for hip fractures (RR=0.64; CI 95%: 0.49 to 0.84) in a sample of 27,347 patients. (Liberman et al., 2006) The British National Institute of Health and Clinical Excellence presented a meta-analysis of RCTs on the efficacy of HRT (with estrogen alone or combined) vs. placebo / not treatment in postmenopausal women or with surgical menopause. (National Institute for Clinical Excellence [NICE], 2008) The results were presented by fracture location and specified the RCT used for the estimation of the relative risk. The results are summarized in table 1.

#### **2.2.2 Safety**

#### **2.2.2.1 Vascular illness**

A systematic review of five RCTs, studying HRT with estrogen and two with combined HRT estrogen plus progesterone, did not demonstrate significant differences in the incidence of acute coronary events (including acute myocardial infarction) between the group of intervention and the control group. (MacLean et al., 2008) Two of the essays with estrogen and two of combined therapy (estrogen plus progesterone) that reported the incidence of death of cardiac origin did not demonstrate significant differences between the intervention group and control group. Combined results of three essays comparing estrogenic therapy with placebo (Anderson et al., 2004; Mosekilde et al., 2000; Cherry et al., 2002) presented an odds ratio (OR) of 1.34 (IC 95%: 1.07 to 1.68) for cerebral vascular events. The combined results of the essays that compared combined therapy estrogen plus progesterone with placebo (Rossouw et al., 2002; Hulley et al., 1998), demonstrated a higher risk of ictus (OR=1.28; CI 95%: 1.05 to 1.57) in the intervention group. Of 4 systematic reviews of observational studies in women receiving HRT (Stampfer et al., 1991; Grady et al., 2002; Barrett-Connor, 1992; Humphrey et al., 2002), three demonstrated an important reduction in the global risk of mortality for acute coronary events. The most recent systematic review, that controlled selection bias of inclusion and analysis, did not show any

Pharmacological Treatment of Osteoporosis 559

The combined HRT group of the WHI study, showed an increase in the risk of invasive breast cancer. (Rossouw et al., 2002) This increase took place after the fourth year of treatment (RR=1.26; CI 95 %: 1.0 to 1.59), with a tendency to increase according to the duration of the treatment (38 cases compared with 30 for 10,000 women/year). The patients in the treatment group were diagnosed in more advanced stages. No significant differences were found for the in situ carcinoma. (Chlebowski et al., 2003) Moreover, other studies have demonstrated that both the sequential and the continuous administration of the

The administration of isolated estrogen increases the risk of developing endometrial hyperplasia and cancer. (Lethaby et al., 2004; Nelson, 2004) A meta-analysis including 29 observational studies showed a significant increase in the endometrial cancer risk with or without combined estrogens (RR=2.3; CI 95%: 2.1 to 2.5). (Grady et al., 1995) This risk is proportional to the duration of the treatment and remains elevated for up to 5 years or more after stopping treatment. In addition, an increase in endometrial cancer mortality was observed, but it was a non-significant increase (RR=2.7; CI 95 %: 0.9 to 8.0). The combined HRT group of the WHI study and its continuation for secondary prevention (HERS II) showed a relative risk of endometrial cancer of 1.58 without reaching statistical significance

In a systematic review of several case-control studies no association could be found between HRT and ovarian cancer. (Coughlin et al., 2000) In contrast, more recent systematic reviews of observational studies confirm the increase in the risk of ovarian cancer in women receiving treatment, especially long-term treatment (more than 10 years). (Garg et al., 1998; Negri et al., 1999) Two cohort studies of postmenopausal women treated for more than 10 years confirm this risk increase (RR=2.2; CI 95%: 1.53 to 3.17), as well as the mortality risk (RR=1.59; CI 95%: 1.13 to 2.25). (Lacey et al., 2002; Rodriguez et al., 2001) The combined HRT group of the WHI study also showed a non-significant increase in the risk of ovarian cancer

In summary, HRT is effective for the treatment of postmenopausal osteoporosis and the reduction of fracture risk. In spite of this, it is not advisable to use HRT (combined estrogen and progestagens) for more than 5 years due to the potential risks associated with the treatment of an equivalent dose of 50 picograms of estradiol per day. When HRT is indicated, it has to be prescribed at low doses (equivalent to estrogen transdermal patches of 25 mcg) and only if strictly necessary, higher doses. Estrogens and progestagens are recommended only in women with intact uteri. The progestagen dose must be calculated according to the estrogen dose. In those cases where a hysterectomy was performed due to endometrial cancer, HRT must not combine estrogen and progestagens. Continuous

So far two estrogen receptors have been described, alpha (ER) and beta (ER), which are at different levels and locations in different body tissues. The ER are mainly in the developing spongy bone, while ER are concentrated more on the cortical bone. In addition, these receptors have differences in their structure and function, which would explain other effects

of estrogen deficiency as vasomotor symptoms or alterations in the lipid profile.

progestagens, collaborate to increase breast cancer. (Li et al., 2003)

(IC 95%: 0.77 to 3.24). (Menopause and post menopause workgroup, 2004)

(RR=1.58; CI 95 %: 0.77 to 3.24). (Anderson et al., 2003)

**2.3 Selective estrogen receptor modulators (SERMs)** 

combined HRT must not be started until after one year of menopause.

**2.2.2.4 Endometrial cancer** 

**2.2.2.5 Ovarian cancer** 

association between the THS and the incidence, and mortality of acute coronary events. (Humphrey et al., 2002)

The WHI primary prevention study showed a significant increase in the risk of acute coronary events (41%), beginning the second year of treatment (29 cases in the treatment group, compared with 21 cases for 10.000 women/year in the general population). (Rossouw et al., 2002) This increase was higher in non-mortal coronary events (RR=1.50; CI 95%: 1.08 to 2.08) than in the mortal coronary events (RR=1.20; CI 95%: 0.58 to 2.50). The RCTs of HRT with estrogens alone, in primary prevention as well as in secondary prevention, did not show any benefit on the cerebrovascular illness. (Viscoli et al., 2001) The group of the WHI study with estrogen also showed an increase in the risk of cerebrovascular accidents. (Anderson et al., 2004)


Table 1. Relative risk of fractures in meta-analysis from the NICE

### **2.2.2.2 Venous thrombotic events**

In a systematic review, McLean et al., reported that estrogen treated patients present a higher risk of major venous thromboembolic events (OR=1.36; CI 95%: 1.01 to 1.86) compared to the placebo group. (MacLean et al., 2008) Another systematic review evaluating the effect of the HRT (estrogen with or without progestagens) included 12 studies (3 RCTs, 8 case-control studies and 1 cohort study) and showed an increase in the risk of thromboembolism (RR=2.14; CI 95%: 1.64 to 2.81). This risk is higher in the first two years of treatment and it is dose dependant. (Miller et al., 2002) The HERS study for secondary prevention showed an increase in the risk of thromboembolism in women with cardiovascular illness. (Hulley et al., 1998; Grady et al., 2002)

#### **2.2.2.3 Breast cancer**

A systematic review of 4 RCTs demonstrated that patients treated with estrogens alone present lower risk of breast cancer (OR=0.79; CI 95%: 0.66 to 0.93) compared to placebo. (MacLean et al., 2008) On the contrary, patients treated with estrogen and progestin present a higher risk of breast cancer (OR=1.28; CI 95%: 1.03 to 1.60) compared to placebo. (Rossouw et al., 2002; Hulley et al., 1998; Lufkin et al., 1992)

The combined HRT group of the WHI study, showed an increase in the risk of invasive breast cancer. (Rossouw et al., 2002) This increase took place after the fourth year of treatment (RR=1.26; CI 95 %: 1.0 to 1.59), with a tendency to increase according to the duration of the treatment (38 cases compared with 30 for 10,000 women/year). The patients in the treatment group were diagnosed in more advanced stages. No significant differences were found for the in situ carcinoma. (Chlebowski et al., 2003) Moreover, other studies have demonstrated that both the sequential and the continuous administration of the progestagens, collaborate to increase breast cancer. (Li et al., 2003)

#### **2.2.2.4 Endometrial cancer**

558 Osteoporosis

association between the THS and the incidence, and mortality of acute coronary events.

The WHI primary prevention study showed a significant increase in the risk of acute coronary events (41%), beginning the second year of treatment (29 cases in the treatment group, compared with 21 cases for 10.000 women/year in the general population). (Rossouw et al., 2002) This increase was higher in non-mortal coronary events (RR=1.50; CI 95%: 1.08 to 2.08) than in the mortal coronary events (RR=1.20; CI 95%: 0.58 to 2.50). The RCTs of HRT with estrogens alone, in primary prevention as well as in secondary prevention, did not show any benefit on the cerebrovascular illness. (Viscoli et al., 2001) The group of the WHI study with estrogen also showed an increase in the risk of

0.46 to 0.66

0.65 to 0.81

0.42 to 0.93

0.63 to 0.78

In a systematic review, McLean et al., reported that estrogen treated patients present a higher risk of major venous thromboembolic events (OR=1.36; CI 95%: 1.01 to 1.86) compared to the placebo group. (MacLean et al., 2008) Another systematic review evaluating the effect of the HRT (estrogen with or without progestagens) included 12 studies (3 RCTs, 8 case-control studies and 1 cohort study) and showed an increase in the risk of thromboembolism (RR=2.14; CI 95%: 1.64 to 2.81). This risk is higher in the first two years of treatment and it is dose dependant. (Miller et al., 2002) The HERS study for secondary prevention showed an increase in the risk of thromboembolism in women with

A systematic review of 4 RCTs demonstrated that patients treated with estrogens alone present lower risk of breast cancer (OR=0.79; CI 95%: 0.66 to 0.93) compared to placebo. (MacLean et al., 2008) On the contrary, patients treated with estrogen and progestin present a higher risk of breast cancer (OR=1.28; CI 95%: 1.03 to 1.60) compared to placebo. (Rossouw

(Wimalawansa, 1998; Mosekilde et al., 2000; Anderson et al., 1997; Lufkin et al., 1992)

(Wimalawansa, 1998; Anderson et al., 2003; Mosekilde et al., 2000)

(Anderson et al., 2003; Mosekilde et al., 2000)

(Anderson et al., 2003; Herrington et al., 2000; Ravn et al., 1999)

Fracture Location Nr of RCTs n RESULTS References

Vertebral fracture 4 RCTs 11,842 RR=0.55; CI 95%:

Non-vertebral fracture 3 RCTs 11,774 RR=0.73; CI 95%:

Hip fracture 2 RCTs 11,745 RR=0.63; CI 95%:

Any type of fracture 3 RCTs 11,556 RR=0.70; CI 95%:

Table 1. Relative risk of fractures in meta-analysis from the NICE

cardiovascular illness. (Hulley et al., 1998; Grady et al., 2002)

et al., 2002; Hulley et al., 1998; Lufkin et al., 1992)

**2.2.2.2 Venous thrombotic events** 

**2.2.2.3 Breast cancer** 

(Humphrey et al., 2002)

cerebrovascular accidents. (Anderson et al., 2004)

The administration of isolated estrogen increases the risk of developing endometrial hyperplasia and cancer. (Lethaby et al., 2004; Nelson, 2004) A meta-analysis including 29 observational studies showed a significant increase in the endometrial cancer risk with or without combined estrogens (RR=2.3; CI 95%: 2.1 to 2.5). (Grady et al., 1995) This risk is proportional to the duration of the treatment and remains elevated for up to 5 years or more after stopping treatment. In addition, an increase in endometrial cancer mortality was observed, but it was a non-significant increase (RR=2.7; CI 95 %: 0.9 to 8.0). The combined HRT group of the WHI study and its continuation for secondary prevention (HERS II) showed a relative risk of endometrial cancer of 1.58 without reaching statistical significance (IC 95%: 0.77 to 3.24). (Menopause and post menopause workgroup, 2004)

#### **2.2.2.5 Ovarian cancer**

In a systematic review of several case-control studies no association could be found between HRT and ovarian cancer. (Coughlin et al., 2000) In contrast, more recent systematic reviews of observational studies confirm the increase in the risk of ovarian cancer in women receiving treatment, especially long-term treatment (more than 10 years). (Garg et al., 1998; Negri et al., 1999) Two cohort studies of postmenopausal women treated for more than 10 years confirm this risk increase (RR=2.2; CI 95%: 1.53 to 3.17), as well as the mortality risk (RR=1.59; CI 95%: 1.13 to 2.25). (Lacey et al., 2002; Rodriguez et al., 2001) The combined HRT group of the WHI study also showed a non-significant increase in the risk of ovarian cancer (RR=1.58; CI 95 %: 0.77 to 3.24). (Anderson et al., 2003)

In summary, HRT is effective for the treatment of postmenopausal osteoporosis and the reduction of fracture risk. In spite of this, it is not advisable to use HRT (combined estrogen and progestagens) for more than 5 years due to the potential risks associated with the treatment of an equivalent dose of 50 picograms of estradiol per day. When HRT is indicated, it has to be prescribed at low doses (equivalent to estrogen transdermal patches of 25 mcg) and only if strictly necessary, higher doses. Estrogens and progestagens are recommended only in women with intact uteri. The progestagen dose must be calculated according to the estrogen dose. In those cases where a hysterectomy was performed due to endometrial cancer, HRT must not combine estrogen and progestagens. Continuous combined HRT must not be started until after one year of menopause.

#### **2.3 Selective estrogen receptor modulators (SERMs)**

So far two estrogen receptors have been described, alpha (ER) and beta (ER), which are at different levels and locations in different body tissues. The ER are mainly in the developing spongy bone, while ER are concentrated more on the cortical bone. In addition, these receptors have differences in their structure and function, which would explain other effects of estrogen deficiency as vasomotor symptoms or alterations in the lipid profile.

Pharmacological Treatment of Osteoporosis 561

increase in bone mineral density in spine and hip, while the placebo was associated with reduced bone mineral density at the same sites. (Delmas et al., 1997) Compared to placebo, the average change in BMD with 60 mg of raloxifene was 2.4% at the spine and 2.4% at the total hip (p <0.001 vs placebo). However, in two placebo-controlled trials with 145 5-year postmenopausal women 60 years or younger, treatment with raloxifene for three years showed a minor effect on spine and hip BMD. (Johnston et al., 2000) The change in BMD of the spine at three years was -1.32% with placebo, 0.71% with 30 mg of raloxifene, 1.28% with 60 mg raloxifene and 1.2% with 150 mg of raloxifene. Similar changes in hip BMD were observed in the respective treatment groups. In another analysis two studies involving 328 women with a mean age of 55 years and five years after menopause, treatment for five years with 60 mg of raloxifene was associated with preservation of BMD and a reduced risk of osteoporosis compared with the placebo group. The treatment with raloxifene compared to placebo showed an average increase in BMD of 2.8% at the lumbar spine and 2.6% at the hip

Raloxifene has shown to be effective in reducing the risk of invasive breast cancer in older women. Postmenopausal women with low bone mass and osteoporosis were studied in a trial named Multiple Outcomes of Raloxifene Evaluation (MORE, n=7,705) and its complementary study, called the Continuing Outcomes Relevant to Evista (CORE, n=4,011). (Burshell et al., 2008) In this study, women had an average age of 65 years (group with low bone mass) and 68 years (group with osteoporosis) and were followed for eight years. Regarding fractures, raloxifene reduced the risk of vertebral fracture; however, it did not show a reduction in non-vertebral fractures. Moreover, in a meta-analysis of RCTs comparing raloxifene to placebo, raloxifene consistently reduced the risk of vertebral

In the MORE trial, a subset of 6,828 of the women had lumbar spine x-rays at baseline and after 36 months of treatment. Among the women receiving 60 mg and 120 mg raloxifene new vertebral fractures were observed in 6.6% and 5.4%, respectively, compared with 10.1% in the placebo group. The risk of non-vertebral fracture was similar in the three groups. After four years of raloxifene treatment (60 mg per day), the cumulative relative risk of one

Compared with placebo, treatment with 60 mg of raloxifene was associated with a reduction of 65 to 78% in the incidence of invasive breast cancer and breast invasive cancer with positive estrogen receptor (both p <0.05). Therefore, the FDA approved raloxifene to reduce the risk of invasive breast cancer in postmenopausal women at high risk. (Barrett-Connor et al., 2006)

The combination of alendronate and raloxifene resulted in a greater increase in BMD when compared with either drug alone. (Johnell et al., 2002) However, the benefit of combined versus monotherapy for fracture reduction is unknown and there are additional costs and side effects of taking two agents. As explained previously, some trials have reported that raloxifene (either taken concurrently or prior to PTH) does not suppress the BMD

Several adverse events are associated with raloxifene. In the MORE and CORE studies an association between raloxifene and a 1.7 times increased risk of thromboembolism (TE),

or more vertebral fractures was 0.64 (IC 95%: 0.53 - 0.76), compared with placebo.

(in both p <0.001). (Jolly et al., 2003)

**2.4.1 Combination therapy** 

**2.4.2 Adverse events** 

response to PTH as much as alendronate.

fractures in postmenopausal women (OR=0.6; CI 95%: 0.5-0.7).

The selective estrogen receptor modulators are drugs with selective effects on the estrogen receptor. They can act as estrogen receptor agonists in some tissues while acting as estrogen receptor antagonists in others. SERMs embrace diverse molecules that lack the steroid structure of estrogens, but own a tertiary structure that allows them to bind to ER and/or ER with different potency. In contrast to estrogens and estrogen receptor agonists, these are partial agonists/antagonists. Due to their selective estrogen-agonist properties on different tissues, SERMs may be indicated for the prevention or treatment of diseases caused by estrogen deficiency, like osteoporosis, without some of the adverse effects of estrogens. In addition, due to their selective properties in the breast (estrogen receptor antagonists), SERMs can be also utilized to prevent or treat breast cancer, where estrogen-agonistic activity is not wanted.

#### **2.3.1 Differences between SERMs**

Currently there are two types of SERMs that are differentiated by their chemical structure: triphenylethylene derivatives, such as tamoxifen and toremifene, and a benzothiophene derivative, raloxifene. The first two are used for the treatment of breast cancer while raloxifene is indicated for the prevention and treatment of osteoporosis. All have been associated with an increased incidence of pulmonary thromboembolism and with the onset of hot flushes but they have a beneficial effect on the lipid profile.

Tamoxifen is not indicated for the treatment of osteoporosis due to increased incidence of endometrial cancer associated with prolonged treatment and the weak effect of this drug on bone that is not maintained over time. The results of the studies that evaluated the effect of tamoxifen on fracture risk were contradictory.

The SERMs differ significantly in terms of tissue specificity. Bazedoxifene seems to have less effect on the uterus than estradiol and raloxifene in animal experiments due to lower estrogen receptor alpha agonistic effects. Tamoxifen and toremifene are used to treat breast cancer. Raloxifene is indicated for the treatment and prevention of osteoporosis and for the prevention of breast cancer. Besides the SERMs described in this review, other new SERMS have had clinical trials suspended prematurely: levormeloxifene, for causing urinary incontinence and uterine prolapse, arzoxifene for lacking effectiveness, and idoxifene, for resulting in increased endometrial thickness on ultrasonography but without significant histological abnormality.

#### **2.4 Raloxifene**

Raloxifene has estrogenic activity in bone and other systems but not in reproductive tissue. In ovariectomized animals, raloxifene preserves bone density, lowers serum total cholesterol, and inhibits aortic cholesterol accumulation, without causing endometrial hyperplasia. The mechanism of selectivity of raloxifene is not fully understood. There are studies that suggest that raloxifene has different effects than estradiol at the estrogen receptor. It also seems to have a different modulation in DNA response.

Several studies have demonstrated the effectiveness of raloxifene in the preservation of bone in early postmenopause. In a meta-analysis of seven trials (four treatment and three prevention trials) examining the effects of raloxifene versus placebo on bone mineral density, raloxifene increased bone mineral density of the lumbar spine after two years of treatment. (Cranney et al., 2002) A study with 601 women, five years after menopause, that received a daily treatment with 30, 60 or 150 mg of raloxifene for two years, showed an

The selective estrogen receptor modulators are drugs with selective effects on the estrogen receptor. They can act as estrogen receptor agonists in some tissues while acting as estrogen receptor antagonists in others. SERMs embrace diverse molecules that lack the steroid structure of estrogens, but own a tertiary structure that allows them to bind to ER and/or ER with different potency. In contrast to estrogens and estrogen receptor agonists, these are partial agonists/antagonists. Due to their selective estrogen-agonist properties on different tissues, SERMs may be indicated for the prevention or treatment of diseases caused by estrogen deficiency, like osteoporosis, without some of the adverse effects of estrogens. In addition, due to their selective properties in the breast (estrogen receptor antagonists), SERMs can be also utilized to prevent or treat breast cancer, where estrogen-agonistic

Currently there are two types of SERMs that are differentiated by their chemical structure: triphenylethylene derivatives, such as tamoxifen and toremifene, and a benzothiophene derivative, raloxifene. The first two are used for the treatment of breast cancer while raloxifene is indicated for the prevention and treatment of osteoporosis. All have been associated with an increased incidence of pulmonary thromboembolism and with the onset

Tamoxifen is not indicated for the treatment of osteoporosis due to increased incidence of endometrial cancer associated with prolonged treatment and the weak effect of this drug on bone that is not maintained over time. The results of the studies that evaluated the effect of

The SERMs differ significantly in terms of tissue specificity. Bazedoxifene seems to have less effect on the uterus than estradiol and raloxifene in animal experiments due to lower estrogen receptor alpha agonistic effects. Tamoxifen and toremifene are used to treat breast cancer. Raloxifene is indicated for the treatment and prevention of osteoporosis and for the prevention of breast cancer. Besides the SERMs described in this review, other new SERMS have had clinical trials suspended prematurely: levormeloxifene, for causing urinary incontinence and uterine prolapse, arzoxifene for lacking effectiveness, and idoxifene, for resulting in increased endometrial thickness on ultrasonography but without significant

Raloxifene has estrogenic activity in bone and other systems but not in reproductive tissue. In ovariectomized animals, raloxifene preserves bone density, lowers serum total cholesterol, and inhibits aortic cholesterol accumulation, without causing endometrial hyperplasia. The mechanism of selectivity of raloxifene is not fully understood. There are studies that suggest that raloxifene has different effects than estradiol at the estrogen

Several studies have demonstrated the effectiveness of raloxifene in the preservation of bone in early postmenopause. In a meta-analysis of seven trials (four treatment and three prevention trials) examining the effects of raloxifene versus placebo on bone mineral density, raloxifene increased bone mineral density of the lumbar spine after two years of treatment. (Cranney et al., 2002) A study with 601 women, five years after menopause, that received a daily treatment with 30, 60 or 150 mg of raloxifene for two years, showed an

receptor. It also seems to have a different modulation in DNA response.

of hot flushes but they have a beneficial effect on the lipid profile.

activity is not wanted.

histological abnormality.

**2.4 Raloxifene** 

**2.3.1 Differences between SERMs** 

tamoxifen on fracture risk were contradictory.

increase in bone mineral density in spine and hip, while the placebo was associated with reduced bone mineral density at the same sites. (Delmas et al., 1997) Compared to placebo, the average change in BMD with 60 mg of raloxifene was 2.4% at the spine and 2.4% at the total hip (p <0.001 vs placebo). However, in two placebo-controlled trials with 145 5-year postmenopausal women 60 years or younger, treatment with raloxifene for three years showed a minor effect on spine and hip BMD. (Johnston et al., 2000) The change in BMD of the spine at three years was -1.32% with placebo, 0.71% with 30 mg of raloxifene, 1.28% with 60 mg raloxifene and 1.2% with 150 mg of raloxifene. Similar changes in hip BMD were observed in the respective treatment groups. In another analysis two studies involving 328 women with a mean age of 55 years and five years after menopause, treatment for five years with 60 mg of raloxifene was associated with preservation of BMD and a reduced risk of osteoporosis compared with the placebo group. The treatment with raloxifene compared to placebo showed an average increase in BMD of 2.8% at the lumbar spine and 2.6% at the hip (in both p <0.001). (Jolly et al., 2003)

Raloxifene has shown to be effective in reducing the risk of invasive breast cancer in older women. Postmenopausal women with low bone mass and osteoporosis were studied in a trial named Multiple Outcomes of Raloxifene Evaluation (MORE, n=7,705) and its complementary study, called the Continuing Outcomes Relevant to Evista (CORE, n=4,011). (Burshell et al., 2008) In this study, women had an average age of 65 years (group with low bone mass) and 68 years (group with osteoporosis) and were followed for eight years. Regarding fractures, raloxifene reduced the risk of vertebral fracture; however, it did not show a reduction in non-vertebral fractures. Moreover, in a meta-analysis of RCTs comparing raloxifene to placebo, raloxifene consistently reduced the risk of vertebral fractures in postmenopausal women (OR=0.6; CI 95%: 0.5-0.7).

In the MORE trial, a subset of 6,828 of the women had lumbar spine x-rays at baseline and after 36 months of treatment. Among the women receiving 60 mg and 120 mg raloxifene new vertebral fractures were observed in 6.6% and 5.4%, respectively, compared with 10.1% in the placebo group. The risk of non-vertebral fracture was similar in the three groups. After four years of raloxifene treatment (60 mg per day), the cumulative relative risk of one or more vertebral fractures was 0.64 (IC 95%: 0.53 - 0.76), compared with placebo.

Compared with placebo, treatment with 60 mg of raloxifene was associated with a reduction of 65 to 78% in the incidence of invasive breast cancer and breast invasive cancer with positive estrogen receptor (both p <0.05). Therefore, the FDA approved raloxifene to reduce the risk of invasive breast cancer in postmenopausal women at high risk. (Barrett-Connor et al., 2006)

#### **2.4.1 Combination therapy**

The combination of alendronate and raloxifene resulted in a greater increase in BMD when compared with either drug alone. (Johnell et al., 2002) However, the benefit of combined versus monotherapy for fracture reduction is unknown and there are additional costs and side effects of taking two agents. As explained previously, some trials have reported that raloxifene (either taken concurrently or prior to PTH) does not suppress the BMD response to PTH as much as alendronate.

#### **2.4.2 Adverse events**

Several adverse events are associated with raloxifene. In the MORE and CORE studies an association between raloxifene and a 1.7 times increased risk of thromboembolism (TE),

Pharmacological Treatment of Osteoporosis 563

was collected for 168 hours after each dose. The bioavailabilty of bazedoxifene was 6.2% for both oral formulations. (Patat et al., 2003) Finally, a study evaluated the longer-term pharmacokinetics of multiple doses of bazedoxifene. In a randomized, crossover study 23 postmenopausal women were given multiple doses of bazedoxifene (5, 20, 40 mg) for 14 days. Maximum concentration was achieved in 1–2 hours and t½ was approximately 28 hours. Protein binding was greater than 99%. Steady state concentrations were achieved by

Human studies with bazedoxifene have demonstrated a decreased thickness of the endometrium at doses of 30 to 40 mg/day compared to placebo or conjugated estrogen plus medroxyprogesterone (mean ± standard error of the mean increase after 168 days: 0.04 ± 0.12 mm for 30 mg, 0.12 ± 0.11 mm for 40 mg, 0.58 ± 0.21 mm for placebo, and 1.60 ± 0.23 mm for conjugated estrogen plus medroxyprogesterone acetate). (Ronkin et al., 2005) In a phase 2 study of healthy postmenopausal women, daily oral doses of bazedoxifene 2.5, 5.0, 10, 20, 30, or 40 mg were generally well tolerated and did not stimulate the endometrium. Furthermore, bazedoxifene 30 and 40 mg caused significantly smaller increases in endometrial thickness and significantly reduced the incidence of uterine bleeding compared with placebo. In a 2-year phase 3 study of postmenopausal women at risk of osteoporosis, bazedoxifene 10, 20, and 40 mg showed to prevent bone loss and reduce bone turnover and was associated with a favorable endometrial, ovarian, and breast safety profile. (Ronkin et

A phase III, multicenter, double-blind, randomized, placebo-controlled study was designed exclusively to evaluate the efficacy of bazedoxifene for the prevention of fractures (Silverman et al., 2008). The study comprised 7,492 healthy postmenopausal women with osteoporosis with or without prevalent vertebral fractures. Participants were randomized to 20 or 40 mg per day of bazedoxifene, 60 mg of raloxifene, or placebo plus 1200 mg of calcium and 400 IU of vitamin D. The primary endpoint was the incidence of new vertebral fractures after 36 months. Secondary outcomes included, clinical vertebral fractures, worsening of vertebral fractures, non-vertebral fractures, breast cancer incidence, and changes in height. Both bazedoxifene 20 and 40 mg prevented the incidence of vertebral fractures with a similar efficacy as raloxifene when compared to placebo. The 3-year incidence of new vertebral fractures were 2.3%, 2.5%, 2.3%, and 4.1% in the bazedoxifene 20 mg, bazedoxifene 40 mg, raloxifene 60 mg, and placebo groups, respectively, with a significant reduction in relative risk for new vertebral fracture of 42%, 37%, and 42%, respectively, versus placebo. There was in general no effect on nonvertebral fractures, with incidence rates of 5.7% and 5.6% for the bazedoxifene 20 and 40 mg groups, respectively, compared with 5.9% for the raloxifene treatment group and 6.3% for the placebo group. Though, in a post-hoc analysis of women with higher risk for fractures (low femoral neck T-score and multiple vertebral fractures, n=1,772) bazedoxifene 20 mg demonstrated a 50% and 44% reduction in non-vertebral fracture risk compared with placebo (HR=0.50; 95% CI: 0.28–0.90; p=0.02) or raloxifene 60 mg (HR=0.56; 95% CI: 0.31–1.01; p=0.05),

al., 2005; Pinkerton et al., 2009; Miller et al., 2008; Archer et al., 2009)

**2.5.3 Bazedoxifene and conjugated estrogen combination therapy** 

The rationale for selecting bazedoxifene as the SERM in this combination is that it may counterbalance estrogen stimulation of endometrial and breast tissue, without the

day 7. (Ermer et al., 2003)

**2.5.2 Bazedoxifene in humans** 

respectively. (Silverman et al., 2008)

compared with placebo, was observed (95% CI: 0.93-3.14; risk difference total of 0.9/1,000 women-years). (Martino et al., 2005) In a meta-analysis of nine studies, therapy with raloxifene was associated with an increase in the risk of deep venous thrombosis and pulmonary embolism (OR=1.5; CI 95%: 1.1-2.1 and OR=1.9; 95% CI: 1.0-3.5, respectively). (Adomaityte et al., 2008)

In the RUTH study (Raloxifene Use for The Heart), which included 10,101 postmenopausal women with coronary heart disease and an average age of 68 years, there was an association between Raloxifene and an increased risk of fatal stroke (HR=1.49; 95% CI: 1.00-2.24, an increase in the absolute risk of 0.7/1,000 women-years) and thromboembolism (HR=1.44; 95% CI: 1.06-1.95, an increase absolute risk of 1.2/1,000 women-years) compared with placebo. There was no increased risk of myocardial infarction or other coronary events in the RUTH study. However, as observed with thromboembolism and pulmonary embolism, the results of a recent analysis in a subgroup of the study showed an effect of age on incidence of coronary events, among women 60 years old or younger, the incidence of coronary events was significantly lower with raloxifene (50 cases), compared with the placebo group (84 cases; HR=0.59; 95% CI: 0.41 to 0.83, p=0.003). Raloxifene was also associated with an increase in hot flushes, particularly in women with new onset menopause. In MORE and CORE trials, 12.6% of women receiving raloxifene had hot flushes, compared with 6.9% in the placebo group (p<0.0001). (Collins et al., 2009)

In conclusion, raloxifene offers an alternative in the treatment of osteoporosis in selected patients. Its profile regarding heart disease and breast cancer is good but it should be carefully considered especially due to the high risk of venous thrombosis.

#### **2.5 Bazedoxifene**

Bazedoxifene is a novel, non-steroidal, indole based SERM that was developed using a rigorous preclinical screening process designed to select therapies with favorable effects on bone and lipid profiles while reducing the stimulation of uterus or breast tissue. (Komm et al. 2005; Komm & Lyttle, 2001) It is a third-generation SERM after the first generation tamoxifene, and the second-generation raloxifene. (Bazedoxifene: bazedoxifene acetate, 2008) Significant differences have been shown between the generations in terms of effects especially on the uterus and the breast tissue. (Vogel et al., 2006) It was developed using raloxifene as a template with the benzothiophene core substituted by an indole ring. (Gruber & Gruber 2004)

#### **2.5.1 Pharmacokinetics and pharmacodynamics**

Bazedoxifene is quickly absorbed with a t-max of approximately 2 hours and displays a linear increase in plasma concentrations after single doses from 0.5 mg up to 120 mg. (Chandrasekaran et al., 2009) It is highly bound (95.8% to 99.3%) to plasma proteins in vitro and it is extensively metabolized in women. Glucuronidation is the most important metabolic pathway. Slight or no cytochrome P450-mediated metabolism is apparent. Bazedoxifene-5-glucuronide is the major circulating metabolite and the concentrations of this glucuronide are approximately 10-fold higher than those of non-metabolized active substance in plasma. Bazedoxifene is excreted principally by feces and has a half-life of approximately 30 hours. Steady-state concentrations are achieved by the second week of once-daily administration. (Biskobing 2007; Shen et al., 2010) To study the bioavailability of bazedoxifene two oral formulations, a 10 mg tablet and two 5 mg capsules, and a 3 mg IV formulation were given to 18 postmenopausal women in a 3-way crossover design. Blood

compared with placebo, was observed (95% CI: 0.93-3.14; risk difference total of 0.9/1,000 women-years). (Martino et al., 2005) In a meta-analysis of nine studies, therapy with raloxifene was associated with an increase in the risk of deep venous thrombosis and pulmonary embolism (OR=1.5; CI 95%: 1.1-2.1 and OR=1.9; 95% CI: 1.0-3.5, respectively).

In the RUTH study (Raloxifene Use for The Heart), which included 10,101 postmenopausal women with coronary heart disease and an average age of 68 years, there was an association between Raloxifene and an increased risk of fatal stroke (HR=1.49; 95% CI: 1.00-2.24, an increase in the absolute risk of 0.7/1,000 women-years) and thromboembolism (HR=1.44; 95% CI: 1.06-1.95, an increase absolute risk of 1.2/1,000 women-years) compared with placebo. There was no increased risk of myocardial infarction or other coronary events in the RUTH study. However, as observed with thromboembolism and pulmonary embolism, the results of a recent analysis in a subgroup of the study showed an effect of age on incidence of coronary events, among women 60 years old or younger, the incidence of coronary events was significantly lower with raloxifene (50 cases), compared with the placebo group (84 cases; HR=0.59; 95% CI: 0.41 to 0.83, p=0.003). Raloxifene was also associated with an increase in hot flushes, particularly in women with new onset menopause. In MORE and CORE trials, 12.6% of women receiving raloxifene had hot

flushes, compared with 6.9% in the placebo group (p<0.0001). (Collins et al., 2009)

with the benzothiophene core substituted by an indole ring. (Gruber & Gruber 2004)

**2.5.1 Pharmacokinetics and pharmacodynamics** 

carefully considered especially due to the high risk of venous thrombosis.

In conclusion, raloxifene offers an alternative in the treatment of osteoporosis in selected patients. Its profile regarding heart disease and breast cancer is good but it should be

Bazedoxifene is a novel, non-steroidal, indole based SERM that was developed using a rigorous preclinical screening process designed to select therapies with favorable effects on bone and lipid profiles while reducing the stimulation of uterus or breast tissue. (Komm et al. 2005; Komm & Lyttle, 2001) It is a third-generation SERM after the first generation tamoxifene, and the second-generation raloxifene. (Bazedoxifene: bazedoxifene acetate, 2008) Significant differences have been shown between the generations in terms of effects especially on the uterus and the breast tissue. (Vogel et al., 2006) It was developed using raloxifene as a template

Bazedoxifene is quickly absorbed with a t-max of approximately 2 hours and displays a linear increase in plasma concentrations after single doses from 0.5 mg up to 120 mg. (Chandrasekaran et al., 2009) It is highly bound (95.8% to 99.3%) to plasma proteins in vitro and it is extensively metabolized in women. Glucuronidation is the most important metabolic pathway. Slight or no cytochrome P450-mediated metabolism is apparent. Bazedoxifene-5-glucuronide is the major circulating metabolite and the concentrations of this glucuronide are approximately 10-fold higher than those of non-metabolized active substance in plasma. Bazedoxifene is excreted principally by feces and has a half-life of approximately 30 hours. Steady-state concentrations are achieved by the second week of once-daily administration. (Biskobing 2007; Shen et al., 2010) To study the bioavailability of bazedoxifene two oral formulations, a 10 mg tablet and two 5 mg capsules, and a 3 mg IV formulation were given to 18 postmenopausal women in a 3-way crossover design. Blood

(Adomaityte et al., 2008)

**2.5 Bazedoxifene** 

was collected for 168 hours after each dose. The bioavailabilty of bazedoxifene was 6.2% for both oral formulations. (Patat et al., 2003) Finally, a study evaluated the longer-term pharmacokinetics of multiple doses of bazedoxifene. In a randomized, crossover study 23 postmenopausal women were given multiple doses of bazedoxifene (5, 20, 40 mg) for 14 days. Maximum concentration was achieved in 1–2 hours and t½ was approximately 28 hours. Protein binding was greater than 99%. Steady state concentrations were achieved by day 7. (Ermer et al., 2003)

#### **2.5.2 Bazedoxifene in humans**

Human studies with bazedoxifene have demonstrated a decreased thickness of the endometrium at doses of 30 to 40 mg/day compared to placebo or conjugated estrogen plus medroxyprogesterone (mean ± standard error of the mean increase after 168 days: 0.04 ± 0.12 mm for 30 mg, 0.12 ± 0.11 mm for 40 mg, 0.58 ± 0.21 mm for placebo, and 1.60 ± 0.23 mm for conjugated estrogen plus medroxyprogesterone acetate). (Ronkin et al., 2005) In a phase 2 study of healthy postmenopausal women, daily oral doses of bazedoxifene 2.5, 5.0, 10, 20, 30, or 40 mg were generally well tolerated and did not stimulate the endometrium. Furthermore, bazedoxifene 30 and 40 mg caused significantly smaller increases in endometrial thickness and significantly reduced the incidence of uterine bleeding compared with placebo. In a 2-year phase 3 study of postmenopausal women at risk of osteoporosis, bazedoxifene 10, 20, and 40 mg showed to prevent bone loss and reduce bone turnover and was associated with a favorable endometrial, ovarian, and breast safety profile. (Ronkin et al., 2005; Pinkerton et al., 2009; Miller et al., 2008; Archer et al., 2009)

A phase III, multicenter, double-blind, randomized, placebo-controlled study was designed exclusively to evaluate the efficacy of bazedoxifene for the prevention of fractures (Silverman et al., 2008). The study comprised 7,492 healthy postmenopausal women with osteoporosis with or without prevalent vertebral fractures. Participants were randomized to 20 or 40 mg per day of bazedoxifene, 60 mg of raloxifene, or placebo plus 1200 mg of calcium and 400 IU of vitamin D. The primary endpoint was the incidence of new vertebral fractures after 36 months. Secondary outcomes included, clinical vertebral fractures, worsening of vertebral fractures, non-vertebral fractures, breast cancer incidence, and changes in height. Both bazedoxifene 20 and 40 mg prevented the incidence of vertebral fractures with a similar efficacy as raloxifene when compared to placebo. The 3-year incidence of new vertebral fractures were 2.3%, 2.5%, 2.3%, and 4.1% in the bazedoxifene 20 mg, bazedoxifene 40 mg, raloxifene 60 mg, and placebo groups, respectively, with a significant reduction in relative risk for new vertebral fracture of 42%, 37%, and 42%, respectively, versus placebo. There was in general no effect on nonvertebral fractures, with incidence rates of 5.7% and 5.6% for the bazedoxifene 20 and 40 mg groups, respectively, compared with 5.9% for the raloxifene treatment group and 6.3% for the placebo group. Though, in a post-hoc analysis of women with higher risk for fractures (low femoral neck T-score and multiple vertebral fractures, n=1,772) bazedoxifene 20 mg demonstrated a 50% and 44% reduction in non-vertebral fracture risk compared with placebo (HR=0.50; 95% CI: 0.28–0.90; p=0.02) or raloxifene 60 mg (HR=0.56; 95% CI: 0.31–1.01; p=0.05), respectively. (Silverman et al., 2008)

#### **2.5.3 Bazedoxifene and conjugated estrogen combination therapy**

The rationale for selecting bazedoxifene as the SERM in this combination is that it may counterbalance estrogen stimulation of endometrial and breast tissue, without the

Pharmacological Treatment of Osteoporosis 565

have estrogens receptors, such as bone, uterus, breast, blood vessels, and liver. Competitive binding experiments demonstrate high affinity of the compound for both ERα and ER. Like other SERMs, lasofoxifene specifically binds to human ERα with high affinity and with a half-inhibitory concentration (IC50) which is similar to that seen with estradiol and consequently at least 10-fold higher than those reported for raloxifene, tamoxifen and droloxifene. Lasofoxifene also shows a high affinity for the human ER similar to the one of

Lasofoxifene has been investigated in postmenopausal women for the prevention and treatment of osteoporosis as well as for the treatment of vaginal atrophy. In a 2-year, randomized, double-blind study comprising 410 postmenopausal women, the mean change in lumbar spine BMD compared to placebo was significantly greater (p<0.05) with lasofoxifene 0.25 and 1.0 mg/day (3.6% and 3.9%, respectively) compared with raloxifene 60 mg (1.7%), although the results were comparable in total hip BMD. Lasofoxifene, as well as raloxifene, significantly reduced bone turnover markers and low-density lipoprotein cholesterol compared with placebo. Results have shown that treatment with lasofoxifene improves signs

Safety and tolerability of lasofoxifene is comparable to that of raloxifene, although discontinuation rates due to adverse events are more common with lasofoxifene. In spite of these findings, evidence proves that lasofoxifene treatment may cause increased endometrial thickness compared with placebo, even though there has been no evidence of an increased risk of endometrial hyperplasia or cancer. Lasofoxifene did not get FDA

The PEARL trial, a 3-year pivotal fracture trial demonstrated that lasofoxifene increased lumbar spine and femoral neck BMD by roughly 3%. Moreover vertebral fractures were reduced by 42%, and non-vertebral fractures by 27%, with reduction in markers of bone turnover. Even though, lasofoxifene did not prevent hip fractures. (Clarke & Khosla 2009)

Bisphosphonates belong to a class of antiresorptive drugs, whose antifracture action is well established in randomized controlled trials. It is important to remember that a direct comparison between them has not been made, which avoids establishing a clear superiority order. There were attempts to compare them through the respective trials and the respective risk reductions, but this approach has limitations that can only be overcome with direct and

Bisphosphonates reduce the risk of fracture due to its inhibitory action of osteoclasts, which allows the osteoblasts to synthesize bone in the resorption spaces and some bone lacunae. This leads to an increase in bone mass. But, in addition, the bisphosphonates improve bone quality, by preserving the bone architecture, as shown in trials, in which the biopsies of the treated patients and controls have been studied. When the treatment with bisphosphonates is indicated, it is essential to administer calcium and vitamin D to assure its maximum

Farnesyl pyrophosphate synthase (FPPS) is an essential regulatory enzyme in the mevalonate pathway. This pathway is important for the production of dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP), which serve as the foundation for the biosynthesis of molecules used in processes as diverse as terpenoid

estradiol. (Gennari et al., 2010; Peterson et al., 2011; Swan et al., 2010)

and symptoms of vaginal atrophy, as well as dyspareunia. (McClung et al., 2006a)

approval for the treatment of vaginal atrophy. (Kulak Junior et al., 2010)

antifracture efficacy. (Olmos-Martinez & Gonzalez-Macias 2008)

**2.7 Bisphosphonates** 

**2.7.1 Overview and mechanism of action** 

randomized trials of the different drugs.

requirement for using a progestin in women with an intact uterus or menopausal vasomotor symptoms, while preserving or increasing BMD. (Gruber & Gruber, 2004; Lewiecki, 2007a) The combination of a SERM with conjugated estrogen has directed to a new class of menopausal therapy called "tissue selective estrogen complex (TSEC)". (Stovall & Pinkerton, 2008)

Preclinical studies have shown that bazedoxifene antagonizes estrogen-induced uterine and mammary gland stimulation more effectively than other SERMs like raloxifene and lasofoxifene. (Peano et al., 2009; Kharode et al., 2008) A randomized, double-blind, placebocontrolled Phase III trial in 3,397 postmenopausal women examined the effect of bazedoxifene 10, 20, or 40 mg combined with conjugated estrogens 0.625 mg or 0.45 mg on bone and endometrium. In this trial, the bazedoxifene plus conjugated estrogen combination therapy showed a statistically significant increase in BMD and a decrease in bone biochemical turnover markers compared with placebo. In addition to the positive effects on bone, bazedoxifene plus conjugated estrogen therapy significantly reduced the incidence and severity of hot flushes and improved vulvo-vaginal atrophy compared with placebo, with a good safety and tolerability profile. (Archer et al., 2009; Lobo et al., 2009; Pickar et al., 2009; Lindsay, 2011)

#### **2.5.4 Safety**

Miller et al., showed that deep venous thromboembolism was rare with bazedoxifene (0% to 0.6% with various doses after 2 years) and similar to placebo (0.3%). Leg cramps were similar to raloxifene and placebo. Hot flushes incidence and severity were comparable to raloxifene, but a little higher than with placebo. (Miller et al., 2008) In the study by Silverman et al, leg cramps (10.9% to 11.7% with various doses after 3 years) and deep venous thromboembolism (0.4% to 0.5% with various doses after 3 years) were significantly more common with bazedoxifene than with placebo (8.2 for leg cramps and 0.2% for deep venous thromboembolism), while breast cyst/fibrocystic breast disease was significantly less frequent. No difference between bazedoxifene and placebo were observed for myocardial infarction, strokes (ischemic or hemorraghic), or retinal vein thrombosis. (Miller et al., 2008; Silverman et al., 2008; Mitwally, 2008)

In conclusion, bazedoxifene seems to have enhanced selectivity compared to other SERMs. Preclinical and clinical studies suggest slight stimulatory effects on uterine tissue and the ability to antagonize estrogen uterine effects. In addition, it does not appear to increase hot flushes. In vitro studies suggest inhibitory effects, at the breast although no long-term clinical data is available on effects on breast cancer rates. The effect of bazedoxifene on the skeleton is similar to raloxifene, and bazedoxifene may be used just as raloxifene. The value of bazedoxifene may reside in a different risk profile than raloxifene, especially in terms of uterine safety, and bazedoxifene may consequently offer an alternative for prevention and treatment of osteoporosis.

#### **2.6 Lasofoxifene**

Lasofoxifene is potent third generation SERM, discovered through a synthetic program intended to isolate innovative molecules with good oral bioavailability and higher potency in vivo. It is a naphthalene derivative, structurally different from the first- and secondgeneration SERMs raloxifene, tamoxifen and clomiphene or idoxifene. Lasofoxifene has potent estrogenic and anti-estrogenic activity in vitro and in vivo, targeting any tissues that

requirement for using a progestin in women with an intact uterus or menopausal vasomotor symptoms, while preserving or increasing BMD. (Gruber & Gruber, 2004; Lewiecki, 2007a) The combination of a SERM with conjugated estrogen has directed to a new class of menopausal therapy called "tissue selective estrogen complex (TSEC)". (Stovall &

Preclinical studies have shown that bazedoxifene antagonizes estrogen-induced uterine and mammary gland stimulation more effectively than other SERMs like raloxifene and lasofoxifene. (Peano et al., 2009; Kharode et al., 2008) A randomized, double-blind, placebocontrolled Phase III trial in 3,397 postmenopausal women examined the effect of bazedoxifene 10, 20, or 40 mg combined with conjugated estrogens 0.625 mg or 0.45 mg on bone and endometrium. In this trial, the bazedoxifene plus conjugated estrogen combination therapy showed a statistically significant increase in BMD and a decrease in bone biochemical turnover markers compared with placebo. In addition to the positive effects on bone, bazedoxifene plus conjugated estrogen therapy significantly reduced the incidence and severity of hot flushes and improved vulvo-vaginal atrophy compared with placebo, with a good safety and tolerability profile. (Archer et al., 2009; Lobo et al., 2009; Pickar et al.,

Miller et al., showed that deep venous thromboembolism was rare with bazedoxifene (0% to 0.6% with various doses after 2 years) and similar to placebo (0.3%). Leg cramps were similar to raloxifene and placebo. Hot flushes incidence and severity were comparable to raloxifene, but a little higher than with placebo. (Miller et al., 2008) In the study by Silverman et al, leg cramps (10.9% to 11.7% with various doses after 3 years) and deep venous thromboembolism (0.4% to 0.5% with various doses after 3 years) were significantly more common with bazedoxifene than with placebo (8.2 for leg cramps and 0.2% for deep venous thromboembolism), while breast cyst/fibrocystic breast disease was significantly less frequent. No difference between bazedoxifene and placebo were observed for myocardial infarction, strokes (ischemic or hemorraghic), or retinal vein thrombosis. (Miller

In conclusion, bazedoxifene seems to have enhanced selectivity compared to other SERMs. Preclinical and clinical studies suggest slight stimulatory effects on uterine tissue and the ability to antagonize estrogen uterine effects. In addition, it does not appear to increase hot flushes. In vitro studies suggest inhibitory effects, at the breast although no long-term clinical data is available on effects on breast cancer rates. The effect of bazedoxifene on the skeleton is similar to raloxifene, and bazedoxifene may be used just as raloxifene. The value of bazedoxifene may reside in a different risk profile than raloxifene, especially in terms of uterine safety, and bazedoxifene may consequently offer an alternative for prevention and

Lasofoxifene is potent third generation SERM, discovered through a synthetic program intended to isolate innovative molecules with good oral bioavailability and higher potency in vivo. It is a naphthalene derivative, structurally different from the first- and secondgeneration SERMs raloxifene, tamoxifen and clomiphene or idoxifene. Lasofoxifene has potent estrogenic and anti-estrogenic activity in vitro and in vivo, targeting any tissues that

Pinkerton, 2008)

2009; Lindsay, 2011)

treatment of osteoporosis.

**2.6 Lasofoxifene** 

et al., 2008; Silverman et al., 2008; Mitwally, 2008)

**2.5.4 Safety** 

have estrogens receptors, such as bone, uterus, breast, blood vessels, and liver. Competitive binding experiments demonstrate high affinity of the compound for both ERα and ER. Like other SERMs, lasofoxifene specifically binds to human ERα with high affinity and with a half-inhibitory concentration (IC50) which is similar to that seen with estradiol and consequently at least 10-fold higher than those reported for raloxifene, tamoxifen and droloxifene. Lasofoxifene also shows a high affinity for the human ER similar to the one of estradiol. (Gennari et al., 2010; Peterson et al., 2011; Swan et al., 2010)

Lasofoxifene has been investigated in postmenopausal women for the prevention and treatment of osteoporosis as well as for the treatment of vaginal atrophy. In a 2-year, randomized, double-blind study comprising 410 postmenopausal women, the mean change in lumbar spine BMD compared to placebo was significantly greater (p<0.05) with lasofoxifene 0.25 and 1.0 mg/day (3.6% and 3.9%, respectively) compared with raloxifene 60 mg (1.7%), although the results were comparable in total hip BMD. Lasofoxifene, as well as raloxifene, significantly reduced bone turnover markers and low-density lipoprotein cholesterol compared with placebo. Results have shown that treatment with lasofoxifene improves signs and symptoms of vaginal atrophy, as well as dyspareunia. (McClung et al., 2006a)

Safety and tolerability of lasofoxifene is comparable to that of raloxifene, although discontinuation rates due to adverse events are more common with lasofoxifene. In spite of these findings, evidence proves that lasofoxifene treatment may cause increased endometrial thickness compared with placebo, even though there has been no evidence of an increased risk of endometrial hyperplasia or cancer. Lasofoxifene did not get FDA approval for the treatment of vaginal atrophy. (Kulak Junior et al., 2010)

The PEARL trial, a 3-year pivotal fracture trial demonstrated that lasofoxifene increased lumbar spine and femoral neck BMD by roughly 3%. Moreover vertebral fractures were reduced by 42%, and non-vertebral fractures by 27%, with reduction in markers of bone turnover. Even though, lasofoxifene did not prevent hip fractures. (Clarke & Khosla 2009)

### **2.7 Bisphosphonates**

### **2.7.1 Overview and mechanism of action**

Bisphosphonates belong to a class of antiresorptive drugs, whose antifracture action is well established in randomized controlled trials. It is important to remember that a direct comparison between them has not been made, which avoids establishing a clear superiority order. There were attempts to compare them through the respective trials and the respective risk reductions, but this approach has limitations that can only be overcome with direct and randomized trials of the different drugs.

Bisphosphonates reduce the risk of fracture due to its inhibitory action of osteoclasts, which allows the osteoblasts to synthesize bone in the resorption spaces and some bone lacunae. This leads to an increase in bone mass. But, in addition, the bisphosphonates improve bone quality, by preserving the bone architecture, as shown in trials, in which the biopsies of the treated patients and controls have been studied. When the treatment with bisphosphonates is indicated, it is essential to administer calcium and vitamin D to assure its maximum antifracture efficacy. (Olmos-Martinez & Gonzalez-Macias 2008)

Farnesyl pyrophosphate synthase (FPPS) is an essential regulatory enzyme in the mevalonate pathway. This pathway is important for the production of dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP), which serve as the foundation for the biosynthesis of molecules used in processes as diverse as terpenoid

Pharmacological Treatment of Osteoporosis 567

associated with a significant increase in the mean lumbar spine and hip BMD. Moreover, it significantly reduced vertebral fracture risk (relative risk, 0.54; 95% CI, 0.37-0.80; p<0.0001). Rovetta et al. have published a study that shows that treating osteoporotic vertebral fractures with 300 mg of intravenous clodronate may have better results than paracetamol in reducing pain. In spite of these results, since the discovery of the potent nitrogen bisphosphonates, the first generation bisphosphonates have been relegated to the last line of

Alendronate is one of the bisphosphonates most widely used. It increases vertebral bone mass around 6-8% and 3-6% at the hip in postmenopausal osteoporotic women treated for 3 years. It shows a decrease of vertebral and non-vertebral fractures of about 50% in this period of time. Ninety five percent of postmenopausal women respond maintaining or increasing bone mass. Alendronate has shown to be able to prevent loss of bone mass of postmenopausal young women with osteopenia and in fragile old women living in retirement homes. In male osteoporosis, it has showed increases of 5% in bone mass at 2 years of treatment. There is reliable security data of the drug at 10 years. Alendronate is approved by the Food and Drug Administration (FDA) of the United States for the

It is administered orally, in weekly doses of 70 mg, fasting with 200 ml of water. The intake of food or drinks has to be avoided in the next 30 minutes and orthostatism has to be kept for this time. There is a preparation of alendronate, which has been available since 2007, that combines the drug with 2,800 U or 5,600 IU of vitamin D. Even though it is commercialized with another name, it is administered in the same way as alendronate alone and it is indicated in patients

The pivotal trial of alendronate, the FIT (Fracture Intervention Trial), showed that the risk of any clinical fracture was lower in the alendronate than in the placebo group (139 (13.6%) vs 183 (18.2%); relative hazard=0.72 (0.58-0.90)). The relative hazards for hip fracture and wrist fracture for alendronate versus placebo were 0.49 (0.23-0.99) and 0.52 (0.31-0.87). (Black et al. 1996) Ensrud et al. published the analysis of a sub group of patients of the FIT. These patients were patients at high risk of fracture. Their results show a 47% significant reduction in risk of new vertebral fractures in the alendronate group compared with the placebo group. The reduction in risk of new vertebral fracture was consistent across fracture risk categories including age (RR=0.49 in women < 75 years compared with 0.62 in those ≥75 years), BMD (RR=0.54 in women with a femoral neck BMD < 0.59 g/cm2 [median] compared with 0.53 in those with a BMD ≥ 0.59 g/cm2), and number of preexisting vertebral fractures (RR=0.58 in women with 1 vertebral fracture compared with 0.52 in those with ≥ 2). The overall significant 28% reduction in risk of incident clinical fractures in the alendronate group compared with the placebo group was also observed within these subgroups. (Ensrud et al., 1997) Several other publications have derived from the FIT population, studying multiple symptomatic fractures, bone mineral density, biochemical markers of formation and resorption, fracture prevention in osteopenic women, effect of alendronate continuation versus discontinuation, and effect in those women who lost bone during treatment. (Levis et al., 2002; Bauer et al., 2004; Chapurlat

In conclusion, alendronate is a well-tolerated, safe and effective drug for the treatment of postmenopausal osteoporosis, osteoporosis in men and glucocorticoid induced osteoporosis.

treatment of osteoporosis in men and glucocorticoid-induced osteoporosis.

that need a supplement of vitamin D, but have an adequate intake of calcium.

treatment. (McCloskey et al., 2004)

et al., 2005; Quandt et al., 2005)

**2.10 Alendronate (Alendronic acid)** 

synthesis, protein prenylation, cell membrane maintenance, hormones, protein anchoring, and N-glycosylation. It is also very important in steroid biosynthesis. Blocking this pathway has a variety of clinical uses, i.e. with statins for the inhibition of hydroxymethylglutaryl-CoA reductase and thus reducing cholesterol biosynthesis, and nitrogenated bisphosphonates used for osteoporosis treatment. (Kavanagh et al., 2006)

Bisphosphonates are pyrophosphate analogs in which the central oxygen has been substituted by a carbon atom and two side chains (R1 and R2). Their intestinal absorption is very low but the affinity for bone is extreme, and once there, they act as very potent antiresorptives. Two phosphate groups are essential so they can bind to bone and for the antiresorptive effect. The long side-chain (R2) determines the chemical properties, the mode of action and the strength of bisphosphonate drugs. The short side-chain (R1), principally influences pharmacokinetics and chemical properties. (Olmos-Martinez & Gonzalez-Macias 2008; Kavanagh et al., 2006)

While some of the first generation bisphosphonates such as etidronate and clodronate act by reversing pyrophosphorylytic reactions catalyzed by aminoacyl-tRNA synthetases, thus producing the corresponding pyrophosphonate analogs of adenosine tri phosphate and osteoclast apoptosis, the action of the nitrogenated bisphosphonates involves a different mechanism, inhibiting the FPPS activity in the mevalonate pathway. Their superior potency results from two main properties: the affinity for bone mineral and the ability to inhibit osteoclast function. (Olmos-Martinez & Gonzalez-Macias 2008)

The difference in potency of the different nitrogenated bisphosphonates depends on their affinity for bone and their capacity of inhibiting FPPS. Their affinity for bone tissue provide bisphosphonates with the capacity of remaining embedded in bone matrix for a long time, thus providing the possibility of weekly, monthly or even yearly regimens. As mentioned earlier, bisphosphonates are poorly absorbed by the intestine (between 1% and 3%) and consequently bioavailability can vary considerably. The new third generation bisphosphonates are administered intravenously, avoiding this difficulty and accordingly increasing the effect of these drugs. (Olmos-Martinez & Gonzalez-Macias 2008)

#### **2.8 Etidronate**

This bisphosphonate was the first one introduced into osteoporosis treatment. At the present time, it is practically not used anymore. Its biggest advantage is probably its price. It increases bone mass in the spine and femur. It reduces the incidence of vertebral fractures; however it has not proven to diminish femoral fractures. Its administration is oral and cyclic, a dose of 400 mg, once a day, during 2 weeks and repeated every 90 days. During the intervals calcium is administrated. There is only one study where its intravenous administration was compared with clodronate and placebo for a short period, and it reduced bone mass loss in the spine.

#### **2.9 Clodronate**

It has been used for postmenopausal osteoporosis treatment in oral and intravenous regimes. The studies show that it prevents bone loss in vertebral spine when comparing with controls, and it has similar effects to estrogens at 2 years. In a 6-year trial, it was observed that it not only increased bone mass, but it also reduced vertebral fractures. McCloskey et al. conducted a 3-year, double blind, placebo controlled trial to study the effect of oral clodronate (800 mg daily) in fracture prevention. In this trial clodronate was

synthesis, protein prenylation, cell membrane maintenance, hormones, protein anchoring, and N-glycosylation. It is also very important in steroid biosynthesis. Blocking this pathway has a variety of clinical uses, i.e. with statins for the inhibition of hydroxymethylglutaryl-CoA reductase and thus reducing cholesterol biosynthesis, and nitrogenated

Bisphosphonates are pyrophosphate analogs in which the central oxygen has been substituted by a carbon atom and two side chains (R1 and R2). Their intestinal absorption is very low but the affinity for bone is extreme, and once there, they act as very potent antiresorptives. Two phosphate groups are essential so they can bind to bone and for the antiresorptive effect. The long side-chain (R2) determines the chemical properties, the mode of action and the strength of bisphosphonate drugs. The short side-chain (R1), principally influences pharmacokinetics and chemical properties. (Olmos-Martinez & Gonzalez-Macias

While some of the first generation bisphosphonates such as etidronate and clodronate act by reversing pyrophosphorylytic reactions catalyzed by aminoacyl-tRNA synthetases, thus producing the corresponding pyrophosphonate analogs of adenosine tri phosphate and osteoclast apoptosis, the action of the nitrogenated bisphosphonates involves a different mechanism, inhibiting the FPPS activity in the mevalonate pathway. Their superior potency results from two main properties: the affinity for bone mineral and the ability to inhibit

The difference in potency of the different nitrogenated bisphosphonates depends on their affinity for bone and their capacity of inhibiting FPPS. Their affinity for bone tissue provide bisphosphonates with the capacity of remaining embedded in bone matrix for a long time, thus providing the possibility of weekly, monthly or even yearly regimens. As mentioned earlier, bisphosphonates are poorly absorbed by the intestine (between 1% and 3%) and consequently bioavailability can vary considerably. The new third generation bisphosphonates are administered intravenously, avoiding this difficulty and accordingly

This bisphosphonate was the first one introduced into osteoporosis treatment. At the present time, it is practically not used anymore. Its biggest advantage is probably its price. It increases bone mass in the spine and femur. It reduces the incidence of vertebral fractures; however it has not proven to diminish femoral fractures. Its administration is oral and cyclic, a dose of 400 mg, once a day, during 2 weeks and repeated every 90 days. During the intervals calcium is administrated. There is only one study where its intravenous administration was compared with clodronate and placebo for a short period, and it

It has been used for postmenopausal osteoporosis treatment in oral and intravenous regimes. The studies show that it prevents bone loss in vertebral spine when comparing with controls, and it has similar effects to estrogens at 2 years. In a 6-year trial, it was observed that it not only increased bone mass, but it also reduced vertebral fractures. McCloskey et al. conducted a 3-year, double blind, placebo controlled trial to study the effect of oral clodronate (800 mg daily) in fracture prevention. In this trial clodronate was

increasing the effect of these drugs. (Olmos-Martinez & Gonzalez-Macias 2008)

bisphosphonates used for osteoporosis treatment. (Kavanagh et al., 2006)

osteoclast function. (Olmos-Martinez & Gonzalez-Macias 2008)

2008; Kavanagh et al., 2006)

**2.8 Etidronate** 

**2.9 Clodronate** 

reduced bone mass loss in the spine.

associated with a significant increase in the mean lumbar spine and hip BMD. Moreover, it significantly reduced vertebral fracture risk (relative risk, 0.54; 95% CI, 0.37-0.80; p<0.0001). Rovetta et al. have published a study that shows that treating osteoporotic vertebral fractures with 300 mg of intravenous clodronate may have better results than paracetamol in reducing pain. In spite of these results, since the discovery of the potent nitrogen bisphosphonates, the first generation bisphosphonates have been relegated to the last line of treatment. (McCloskey et al., 2004)

#### **2.10 Alendronate (Alendronic acid)**

Alendronate is one of the bisphosphonates most widely used. It increases vertebral bone mass around 6-8% and 3-6% at the hip in postmenopausal osteoporotic women treated for 3 years. It shows a decrease of vertebral and non-vertebral fractures of about 50% in this period of time. Ninety five percent of postmenopausal women respond maintaining or increasing bone mass. Alendronate has shown to be able to prevent loss of bone mass of postmenopausal young women with osteopenia and in fragile old women living in retirement homes. In male osteoporosis, it has showed increases of 5% in bone mass at 2 years of treatment. There is reliable security data of the drug at 10 years. Alendronate is approved by the Food and Drug Administration (FDA) of the United States for the treatment of osteoporosis in men and glucocorticoid-induced osteoporosis.

It is administered orally, in weekly doses of 70 mg, fasting with 200 ml of water. The intake of food or drinks has to be avoided in the next 30 minutes and orthostatism has to be kept for this time. There is a preparation of alendronate, which has been available since 2007, that combines the drug with 2,800 U or 5,600 IU of vitamin D. Even though it is commercialized with another name, it is administered in the same way as alendronate alone and it is indicated in patients that need a supplement of vitamin D, but have an adequate intake of calcium.

The pivotal trial of alendronate, the FIT (Fracture Intervention Trial), showed that the risk of any clinical fracture was lower in the alendronate than in the placebo group (139 (13.6%) vs 183 (18.2%); relative hazard=0.72 (0.58-0.90)). The relative hazards for hip fracture and wrist fracture for alendronate versus placebo were 0.49 (0.23-0.99) and 0.52 (0.31-0.87). (Black et al. 1996) Ensrud et al. published the analysis of a sub group of patients of the FIT. These patients were patients at high risk of fracture. Their results show a 47% significant reduction in risk of new vertebral fractures in the alendronate group compared with the placebo group. The reduction in risk of new vertebral fracture was consistent across fracture risk categories including age (RR=0.49 in women < 75 years compared with 0.62 in those ≥75 years), BMD (RR=0.54 in women with a femoral neck BMD < 0.59 g/cm2 [median] compared with 0.53 in those with a BMD ≥ 0.59 g/cm2), and number of preexisting vertebral fractures (RR=0.58 in women with 1 vertebral fracture compared with 0.52 in those with ≥ 2). The overall significant 28% reduction in risk of incident clinical fractures in the alendronate group compared with the placebo group was also observed within these subgroups. (Ensrud et al., 1997) Several other publications have derived from the FIT population, studying multiple symptomatic fractures, bone mineral density, biochemical markers of formation and resorption, fracture prevention in osteopenic women, effect of alendronate continuation versus discontinuation, and effect in those women who lost bone during treatment. (Levis et al., 2002; Bauer et al., 2004; Chapurlat et al., 2005; Quandt et al., 2005)

In conclusion, alendronate is a well-tolerated, safe and effective drug for the treatment of postmenopausal osteoporosis, osteoporosis in men and glucocorticoid induced osteoporosis.

Pharmacological Treatment of Osteoporosis 569

Its absorption is similar to the one of the rest of the oral bisphosphonates since only 0,6% of the administrated dose is absorbed. The administration instructions are also the same as the other oral bisphosphonates, because if it is administered concomitantly with food, the plasmatic concentrations can decrease up to 90%. In studies at 3 years, it has shown to reduce vertebral fractures (52%) and increase vertebral BMD (6.5%) without presenting significant adverse effects or changes in bone histology. It also avoids bone loss in postmenopausal women with osteopenia and it has proven to be very efficient in preventing bone loss in Glucocorticoid-induced osteoporosis. In women with severe osteoporosis (T

It is administered orally in a monthly dose of 150 mg and also intravenously every three months in a dose of 2 mg. Randomized clinical trials like MOPS (Monthly Oral Pilot Study) or MOBILE (Monthly Oral Ibandronate in Ladies) have shown that the ibandronate monthly dose is as effective and secure as the daily dose. In the general population of the pivotal trial (BONE, Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe), the frequency of adverse events of the gastrointestinal tract in the daily dose and the intermittent dose was comparable to the one of placebo. Dyspepsia was the only adverse event with a slight superior frequency in patients in active treatment with ibandronate.

In different chronic therapeutical areas it has been shown that, for oral bisphosphonates, the treatment compliance is poor and, besides, it decreases with time. This has a big impact on the drug's effectiveness, since the early interruption and bad compliance decrease significantly the benefit that these drugs could have. In order to show the importance of the problem, a sub study, with data of the IMPACT study was made. More than 2,300 postmenopausal women were treated for osteoporosis with risedronate. The analysis showed, that, in contrast to the women who did not accomplish the treatment, most of the women, who complied with the treatment, had decreases in the bone resorption markers. In other analysis, that included patients with osteoporosis and osteopenia from a Canadian data base, it was shown that patients with a treatment compliance higher than above 80% had increases in bone mineral density and these were significantly higher than the ones from patients who did not accomplish this requirement. The strict administration requirements that are needed caused some patients to interrupt the treatment with bisphosphonates and it was a reason for some not to start it. In a 6-month study with alendronate, 14.3% of the patients mentioned discomfort as the reason for interrupting the treatment. In prospective trials of crossover treatment it has been shown that the least frequent administration of bisphosphonates increases the treatment compliance. That is why the use of ibandronate with monthly intake could be of benefit. (Delmas et al., 2007) On the other hand, ibandronate has not shown, in randomized controlled trials, reductions in the

Zoledronic acid is a third generation bisphosphonate. Its complete chemical name is 1 hydroxi-2-(1H-imidazol-1-y-1)ethylidene) bisphosphonic acid. The experience with this drug is more extensive in the oncology area. Besides oncology, zoledronic acid has other non-oncological indications like postmenopausal osteoporosis treatment, established osteoporosis treatment, glucocorticoid induced osteoporosis, male osteoporosis and Paget's

score <-3), it reduces non-vertebral fractures up to 69%. (Chesnut, 2006)

**2.12 Ibandronate** 

(Delmas et al., 2004)

incidence of non-vertebral or hip fractures.

**2.13 Zoledronate (Zoledronic acid)** 

#### **2.11 Risedronate**

This drug has showed to increase bone mass in spine and hip and to significantly reduce the risk of fracture in postmenopausal women. Treatment of postmenopausal women with osteoporosis with risedronate during three years has shown to reduce vertebral fractures in approximately 50% and non-vertebral fractures in 39%. At the hip, the fracture reduction is between 40 and 60%. At 5 years, the results are similar. The drug has shown anti fracture efficacy after 6 months of administration. In other studies it has been confirmed that the efficacy still remains after 7 years of treatment with a good security profile. Risedronate has shown to be efficient in the prevention of spinal and femoral bone mass loss in patients with osteopenia. The first available preparation was 5 mg that was administered daily. A couple of years later a preparation of 35 mg became available and had to be taken weekly. Finally, about two years ago, a preparation of 150 mg came out to be taken every month. In Europe, this preparation was split into two 75 mg capsules that have to be taken on consecutive days once a month. Every dosage preparation of risedronate has to be taken following the instructions of oral bisphosphonate administration mentioned earlier.

In one of the main trials of risedronate, McClung et al, studied 5445 women 70 to 79 years old diagnosed with osteoporosis (T score at the femoral neck more than -4 SD below the mean or lower than -3 plus a non-skeletal risk factor for hip fracture, such as poor gait or a tendency to fall) and 3886 women at least 80 years old with at least one non-skeletal risk factor for hip fracture or low bone mineral density at the femoral neck (T score, lower than - 4 or lower than -3 plus a hip-axis length of 11.1 cm or greater). The patients were randomly assigned to receive treatment with oral risedronate (2.5 or 5.0 mg daily) or placebo for three years. The primary end point was the incidence of hip fracture. The results showed that the incidence of hip fracture among the patients assigned to risedronate was 2.8%, as compared with 3.9% among those assigned to placebo (relative risk, 0.7; 95% CI, 0.6 to 0.9; p=0.02). In the group of women with osteoporosis (those 70 to 79 years old), the incidence of hip fracture among those assigned to risedronate was 1.9%, as compared with 3.2% among those assigned to placebo (relative risk, 0.6; 95% CI, 0.4 to 0.9; p=0.009). In the group of women selected primarily on the basis of non-skeletal risk factors (those at least 80 years of age), the incidence of hip fracture was 4.2% among those assigned to risedronate and 5.1% among those assigned to placebo (p=0.35). (McClung et al., 2001)

To evaluate vertebral fracture risk reduction, Reginster et al, completed a randomized, double-blind, placebo-controlled study to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis. The study was conducted at 80 study centers in Europe and Australia. A total of 1226 postmenopausal women with two or more prevalent vertebral fractures received risedronate 2.5 mg or 5 mg daily or placebo. The study lasted 3 years; however, the 2.5 mg group was discontinued by protocol amendment after 2 years. Lateral spinal radiographs were taken annually for evaluation of vertebral fractures, and BMD was measured every 6 months. Risedronate 5 mg reduced the risk of new vertebral fractures by 49% over 3 years compared with control (p<0.001). A significant reduction of 61% was observed within the first year (p = 0.001). The fracture reduction was similar in both groups at 2 years. The nonvertebral fracture risk was reduced by 33% compared with control over 3 years (p = 0.06). Risedronate significantly increased BMD at the spine and hip within 6 months. In conclusion, risedronate 5 mg was an effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving bone density in women with established disease. (Reginster et al., 2000)

#### **2.12 Ibandronate**

568 Osteoporosis

This drug has showed to increase bone mass in spine and hip and to significantly reduce the risk of fracture in postmenopausal women. Treatment of postmenopausal women with osteoporosis with risedronate during three years has shown to reduce vertebral fractures in approximately 50% and non-vertebral fractures in 39%. At the hip, the fracture reduction is between 40 and 60%. At 5 years, the results are similar. The drug has shown anti fracture efficacy after 6 months of administration. In other studies it has been confirmed that the efficacy still remains after 7 years of treatment with a good security profile. Risedronate has shown to be efficient in the prevention of spinal and femoral bone mass loss in patients with osteopenia. The first available preparation was 5 mg that was administered daily. A couple of years later a preparation of 35 mg became available and had to be taken weekly. Finally, about two years ago, a preparation of 150 mg came out to be taken every month. In Europe, this preparation was split into two 75 mg capsules that have to be taken on consecutive days once a month. Every dosage preparation of risedronate has to be taken following the

In one of the main trials of risedronate, McClung et al, studied 5445 women 70 to 79 years old diagnosed with osteoporosis (T score at the femoral neck more than -4 SD below the mean or lower than -3 plus a non-skeletal risk factor for hip fracture, such as poor gait or a tendency to fall) and 3886 women at least 80 years old with at least one non-skeletal risk factor for hip fracture or low bone mineral density at the femoral neck (T score, lower than - 4 or lower than -3 plus a hip-axis length of 11.1 cm or greater). The patients were randomly assigned to receive treatment with oral risedronate (2.5 or 5.0 mg daily) or placebo for three years. The primary end point was the incidence of hip fracture. The results showed that the incidence of hip fracture among the patients assigned to risedronate was 2.8%, as compared with 3.9% among those assigned to placebo (relative risk, 0.7; 95% CI, 0.6 to 0.9; p=0.02). In the group of women with osteoporosis (those 70 to 79 years old), the incidence of hip fracture among those assigned to risedronate was 1.9%, as compared with 3.2% among those assigned to placebo (relative risk, 0.6; 95% CI, 0.4 to 0.9; p=0.009). In the group of women selected primarily on the basis of non-skeletal risk factors (those at least 80 years of age), the incidence of hip fracture was 4.2% among those assigned to risedronate and 5.1% among

To evaluate vertebral fracture risk reduction, Reginster et al, completed a randomized, double-blind, placebo-controlled study to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis. The study was conducted at 80 study centers in Europe and Australia. A total of 1226 postmenopausal women with two or more prevalent vertebral fractures received risedronate 2.5 mg or 5 mg daily or placebo. The study lasted 3 years; however, the 2.5 mg group was discontinued by protocol amendment after 2 years. Lateral spinal radiographs were taken annually for evaluation of vertebral fractures, and BMD was measured every 6 months. Risedronate 5 mg reduced the risk of new vertebral fractures by 49% over 3 years compared with control (p<0.001). A significant reduction of 61% was observed within the first year (p = 0.001). The fracture reduction was similar in both groups at 2 years. The nonvertebral fracture risk was reduced by 33% compared with control over 3 years (p = 0.06). Risedronate significantly increased BMD at the spine and hip within 6 months. In conclusion, risedronate 5 mg was an effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving

instructions of oral bisphosphonate administration mentioned earlier.

those assigned to placebo (p=0.35). (McClung et al., 2001)

bone density in women with established disease. (Reginster et al., 2000)

**2.11 Risedronate** 

Its absorption is similar to the one of the rest of the oral bisphosphonates since only 0,6% of the administrated dose is absorbed. The administration instructions are also the same as the other oral bisphosphonates, because if it is administered concomitantly with food, the plasmatic concentrations can decrease up to 90%. In studies at 3 years, it has shown to reduce vertebral fractures (52%) and increase vertebral BMD (6.5%) without presenting significant adverse effects or changes in bone histology. It also avoids bone loss in postmenopausal women with osteopenia and it has proven to be very efficient in preventing bone loss in Glucocorticoid-induced osteoporosis. In women with severe osteoporosis (T score <-3), it reduces non-vertebral fractures up to 69%. (Chesnut, 2006)

It is administered orally in a monthly dose of 150 mg and also intravenously every three months in a dose of 2 mg. Randomized clinical trials like MOPS (Monthly Oral Pilot Study) or MOBILE (Monthly Oral Ibandronate in Ladies) have shown that the ibandronate monthly dose is as effective and secure as the daily dose. In the general population of the pivotal trial (BONE, Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe), the frequency of adverse events of the gastrointestinal tract in the daily dose and the intermittent dose was comparable to the one of placebo. Dyspepsia was the only adverse event with a slight superior frequency in patients in active treatment with ibandronate. (Delmas et al., 2004)

In different chronic therapeutical areas it has been shown that, for oral bisphosphonates, the treatment compliance is poor and, besides, it decreases with time. This has a big impact on the drug's effectiveness, since the early interruption and bad compliance decrease significantly the benefit that these drugs could have. In order to show the importance of the problem, a sub study, with data of the IMPACT study was made. More than 2,300 postmenopausal women were treated for osteoporosis with risedronate. The analysis showed, that, in contrast to the women who did not accomplish the treatment, most of the women, who complied with the treatment, had decreases in the bone resorption markers. In other analysis, that included patients with osteoporosis and osteopenia from a Canadian data base, it was shown that patients with a treatment compliance higher than above 80% had increases in bone mineral density and these were significantly higher than the ones from patients who did not accomplish this requirement. The strict administration requirements that are needed caused some patients to interrupt the treatment with bisphosphonates and it was a reason for some not to start it. In a 6-month study with alendronate, 14.3% of the patients mentioned discomfort as the reason for interrupting the treatment. In prospective trials of crossover treatment it has been shown that the least frequent administration of bisphosphonates increases the treatment compliance. That is why the use of ibandronate with monthly intake could be of benefit. (Delmas et al., 2007) On the other hand, ibandronate has not shown, in randomized controlled trials, reductions in the incidence of non-vertebral or hip fractures.

#### **2.13 Zoledronate (Zoledronic acid)**

Zoledronic acid is a third generation bisphosphonate. Its complete chemical name is 1 hydroxi-2-(1H-imidazol-1-y-1)ethylidene) bisphosphonic acid. The experience with this drug is more extensive in the oncology area. Besides oncology, zoledronic acid has other non-oncological indications like postmenopausal osteoporosis treatment, established osteoporosis treatment, glucocorticoid induced osteoporosis, male osteoporosis and Paget's

Pharmacological Treatment of Osteoporosis 571

Besides, it is a secure treatment that eludes the gastrointestinal adverse events and the bad adherence that are usually seen with other bisfosfonates, but it has to be remembered that, due to its administration route, zoledronate is not for ambulatory use and it has to be administrated very carefully in patients with chronic renal impairment, and those who need

Economical evaluation in medicine includes different types of studies that enable us to give the population better care and attention with resources that are limited. Among the many different types of analysis, we can find cost reduction assays, analysis of cost-effectiveness (mostly used), analysis cost-utility and cost-benefit. The cost-effectiveness analysis is probably the easiest to evaluate, since it expresses the monetary units needed to change the units normally used in clinical practice (viral charge, number of fractures avoided or quality

Internationally a sanitary intervention is considered to be cost-effective if the additional cost for QALY gained, in comparison with another intervention, is below the 50.000.00 US\$ and it is not when it is higher than 100.000.00 US\$. In Spain, the amount used is € 30.000.00 in order to validate the acceptance of interventions. However, there are many authors, who consider this value to be excessively low. (Sacristan et al., 2004a, Sacristan et al., 2004b) In a review of cost-effectiveness analysis, in which 23 studies were included, and some of which included more than 90 clinical trials, it was demonstrated that the available bisfosfonates in Spain show that the cost of risedronate, compared with no treatment in women with previous fracture is of € 43.601.00 and for alendronate € 49,483.00. In women without previous fracture the values increase to € 61,604.00 for risedronate and € 88,634.00 for alendronate, both compared with patients not treated. If we consider only patients over 65 years old, treatment with alendronate as well as with risedronate result cost-effective in patients with previous fracture as well as in patients with no previous fracture. As expected, the bigger the population is, the more cost effective is treatment with bisphosphonates. (Van

It is important to consider that this data is subject to several conditions, such as the comparator and the sample used during the clinical trials, but most importantly the price of the drug. The data used in the Spanish studies presented previously are from 1999, which differ from the actual reality. There are other studies that analyze new bisfosfonates as

These drugs are usually well tolerated, as long as they are taken in a scrupulous way and the intake instructions are followed. Esophageal ulcerations have been known to occur when the drugs are administrated orally and daily. In spite of the good profile that its weekly administration has, it should not be administered to individuals with gastric ulceration or esophageal ulceration, or to those who present pyrosis (heartburn) and require medication. They should not be administrated to pregnant women, or to patients with severe renal function impairment. The intravenous bisphosphonates usually produce acute phase reactions with fever, arthromyalgia and flu like syndrome, that usually disappear by the second administration and that can be relieved with the concomitant use of paracetamol or ibuprofen. Hypocalcaemia can appear more often; therefore it is wise to use calcium and

adjusted life years, QALY). (Sacristan et al., 2004a, Sacristan et al., 2004b)

to get dental extractions.

**2.14 Cost effectiveness** 

Staa et al., 2007; Fleurence et al., 2007)

**2.15 Security of bisphosphonates** 

ibandronate and zoledronate, but not for osteoporosis.

disease of the bone. The difference is not only in the indication, since the administration regime is also different.

Zoledronate is approximately 2-3 times more potent than pamidronate, it is more or less as potent as alendronate, risedronate and ibandronate, but when it is administrated intravenously, the gastrointestinal adverse effects are avoided and the bioavailability increases, while at the same time, it increases the compliance to 100%. The pharmacokinetics of the drug is very similar to that of the other bisphosphonates. The highest plasmatic concentration is reached just after the infusion, with a posterior descent of approximately 10% in 4 h, followed by 1% in the next 24h. The mean urine excretion of the drug is around 44% of the administered dose, which means that the bone tissue absorbs more than 50% from the administered zoledronate.

The HORIZON study (Health Outcomes and Reduced Incidence with Zoledonic Acid Once Yearly Pivotal Fracture Trial) is a multicentric, international, double blind, placebocontrolled trial of postmenopausal women with osteoporosis, whose objective was to show superiority of 5mg of intravenous zoledronic acid against placebo administrated during a period, not shorter than 15 min. In this study, as in most osteoporosis studies, patients received 1.000-1.500 mg of calcium and 400-1.200 U of vitamin D. The patients had densitometric osteoporosis or densitometric osteopenia with at least 2 mild to moderate vertebral fractures. (Lyles et al., 2007) Finally, more than 7.700 patients took part in the study and were followed for 3 years; paying special attention to new fractures, bone remodeling biochemical markers and densitometric changes. At the end of the study, the patients that had received zoledronic acid showed a reduction in the vertebral fracture risk of 70%. The reduction was similar for the first and second year of the study, ranging from 60 to 71%. Besides, patients treated with zoledronate showed a reduction of 41% in hip fracture risk and 25% in non-vertebral fracture risk. The results of bone density and biochemical bone remodeling markers were also significantly better for the group of patients treated with zoledronic acid. Moreover, the increase in bone mineral density was over 6% in the lumbar spine and total hip, and over 5% in the femoral neck. The biochemical markers of bone remodeling, after the first infusion of zoledronic acid, experienced an important decrease, as expected, and they remained stable during the whole study. (Black et al., 2007)

Many patients showed adverse effects during the study, being more frequent in the treatment group. The difference was basically the post-infusion syndrome. This syndrome appeared usually 24-48 hours after the zoledronic acid infusion, just as described by other intravenous bisfosfonates, it happens sometimes, even with the ones administrated orally, and it disappears on the third day post-infusion. The symptoms are light fever, myalgias, flu-like syndrome, headache and/or arthralgias and they disappear with analgesic, nonsteroid anti-inflammatory drugs or paracetamol. The episode appears usually after the first infusion and in seldom cases, after the second one. It shows an incidence with a clear descendent pattern in the later infusions. Some of the patients showed transient renal function deterioration from 9 to 11 days after the infusion, however it did not have any clinical transcendence. (Black et al., 2007)

Probably the most important finding related to the treatment with zoledronate would be the 28% decrease in mortality independent of the cause, showed in a population of over 2.000 patients with femur fracture. (Lyles et al., 2007)

In conclusion, zoledronate treatment is very efficient for the decrease of vertebral, nonvertebral and hip fractures. It decreases mortality for any cause after a femur fracture. Besides, it is a secure treatment that eludes the gastrointestinal adverse events and the bad adherence that are usually seen with other bisfosfonates, but it has to be remembered that, due to its administration route, zoledronate is not for ambulatory use and it has to be administrated very carefully in patients with chronic renal impairment, and those who need to get dental extractions.

#### **2.14 Cost effectiveness**

570 Osteoporosis

disease of the bone. The difference is not only in the indication, since the administration

Zoledronate is approximately 2-3 times more potent than pamidronate, it is more or less as potent as alendronate, risedronate and ibandronate, but when it is administrated intravenously, the gastrointestinal adverse effects are avoided and the bioavailability increases, while at the same time, it increases the compliance to 100%. The pharmacokinetics of the drug is very similar to that of the other bisphosphonates. The highest plasmatic concentration is reached just after the infusion, with a posterior descent of approximately 10% in 4 h, followed by 1% in the next 24h. The mean urine excretion of the drug is around 44% of the administered dose, which means that the bone tissue absorbs more than 50%

The HORIZON study (Health Outcomes and Reduced Incidence with Zoledonic Acid Once Yearly Pivotal Fracture Trial) is a multicentric, international, double blind, placebocontrolled trial of postmenopausal women with osteoporosis, whose objective was to show superiority of 5mg of intravenous zoledronic acid against placebo administrated during a period, not shorter than 15 min. In this study, as in most osteoporosis studies, patients received 1.000-1.500 mg of calcium and 400-1.200 U of vitamin D. The patients had densitometric osteoporosis or densitometric osteopenia with at least 2 mild to moderate vertebral fractures. (Lyles et al., 2007) Finally, more than 7.700 patients took part in the study and were followed for 3 years; paying special attention to new fractures, bone remodeling biochemical markers and densitometric changes. At the end of the study, the patients that had received zoledronic acid showed a reduction in the vertebral fracture risk of 70%. The reduction was similar for the first and second year of the study, ranging from 60 to 71%. Besides, patients treated with zoledronate showed a reduction of 41% in hip fracture risk and 25% in non-vertebral fracture risk. The results of bone density and biochemical bone remodeling markers were also significantly better for the group of patients treated with zoledronic acid. Moreover, the increase in bone mineral density was over 6% in the lumbar spine and total hip, and over 5% in the femoral neck. The biochemical markers of bone remodeling, after the first infusion of zoledronic acid, experienced an important decrease, as expected, and they remained stable

Many patients showed adverse effects during the study, being more frequent in the treatment group. The difference was basically the post-infusion syndrome. This syndrome appeared usually 24-48 hours after the zoledronic acid infusion, just as described by other intravenous bisfosfonates, it happens sometimes, even with the ones administrated orally, and it disappears on the third day post-infusion. The symptoms are light fever, myalgias, flu-like syndrome, headache and/or arthralgias and they disappear with analgesic, nonsteroid anti-inflammatory drugs or paracetamol. The episode appears usually after the first infusion and in seldom cases, after the second one. It shows an incidence with a clear descendent pattern in the later infusions. Some of the patients showed transient renal function deterioration from 9 to 11 days after the infusion, however it did not have any

Probably the most important finding related to the treatment with zoledronate would be the 28% decrease in mortality independent of the cause, showed in a population of over 2.000

In conclusion, zoledronate treatment is very efficient for the decrease of vertebral, nonvertebral and hip fractures. It decreases mortality for any cause after a femur fracture.

regime is also different.

from the administered zoledronate.

during the whole study. (Black et al., 2007)

clinical transcendence. (Black et al., 2007)

patients with femur fracture. (Lyles et al., 2007)

Economical evaluation in medicine includes different types of studies that enable us to give the population better care and attention with resources that are limited. Among the many different types of analysis, we can find cost reduction assays, analysis of cost-effectiveness (mostly used), analysis cost-utility and cost-benefit. The cost-effectiveness analysis is probably the easiest to evaluate, since it expresses the monetary units needed to change the units normally used in clinical practice (viral charge, number of fractures avoided or quality adjusted life years, QALY). (Sacristan et al., 2004a, Sacristan et al., 2004b)

Internationally a sanitary intervention is considered to be cost-effective if the additional cost for QALY gained, in comparison with another intervention, is below the 50.000.00 US\$ and it is not when it is higher than 100.000.00 US\$. In Spain, the amount used is € 30.000.00 in order to validate the acceptance of interventions. However, there are many authors, who consider this value to be excessively low. (Sacristan et al., 2004a, Sacristan et al., 2004b)

In a review of cost-effectiveness analysis, in which 23 studies were included, and some of which included more than 90 clinical trials, it was demonstrated that the available bisfosfonates in Spain show that the cost of risedronate, compared with no treatment in women with previous fracture is of € 43.601.00 and for alendronate € 49,483.00. In women without previous fracture the values increase to € 61,604.00 for risedronate and € 88,634.00 for alendronate, both compared with patients not treated. If we consider only patients over 65 years old, treatment with alendronate as well as with risedronate result cost-effective in patients with previous fracture as well as in patients with no previous fracture. As expected, the bigger the population is, the more cost effective is treatment with bisphosphonates. (Van Staa et al., 2007; Fleurence et al., 2007)

It is important to consider that this data is subject to several conditions, such as the comparator and the sample used during the clinical trials, but most importantly the price of the drug. The data used in the Spanish studies presented previously are from 1999, which differ from the actual reality. There are other studies that analyze new bisfosfonates as ibandronate and zoledronate, but not for osteoporosis.

#### **2.15 Security of bisphosphonates**

These drugs are usually well tolerated, as long as they are taken in a scrupulous way and the intake instructions are followed. Esophageal ulcerations have been known to occur when the drugs are administrated orally and daily. In spite of the good profile that its weekly administration has, it should not be administered to individuals with gastric ulceration or esophageal ulceration, or to those who present pyrosis (heartburn) and require medication. They should not be administrated to pregnant women, or to patients with severe renal function impairment. The intravenous bisphosphonates usually produce acute phase reactions with fever, arthromyalgia and flu like syndrome, that usually disappear by the second administration and that can be relieved with the concomitant use of paracetamol or ibuprofen. Hypocalcaemia can appear more often; therefore it is wise to use calcium and

Pharmacological Treatment of Osteoporosis 573

The illnesses that provoke bone loss, like osteoporosis, derive from the imbalance in the cycles of bone remodeling favoring bone resorption. The receptor activator of the nuclear factor kB (RANK), a member of the tumor necrosis factor (TNF) family proteins, and its ligand (RANKL) are fundamental for differentiation, activation and survival of osteoclasts and, therefore, basic mediators of the regulation of bone remodeling. (Anderson et al., 1997; Burgess et al., 1999; Lacey et al., 1998) It has been demonstrated that the signaling of the RANKL is involved in the pathophysiology of many bone loss illnesses, such as primary and many secondary osteoporoses. RANKL production is increased when estrogen is decreased. (Eghbali-Fatourechi et al., 2003) This condition occurs in menopause and in circumstances of hormonal ablation, and leads to an increase in bone resorption. In animal studies with knockout mice lacking RANKL, an absence of osteoclast can be seen, and

Denosumab, a fully human monoclonal IgG2 antibody to RANKL imitates the effects of osteoprotegerine (OPG), endogenous inhibitor of RANKL blocking bone resorption. Denosumab presents a much longer half-life and it is highly specific since it does not bind to other members of the TNF family, including TNF, TNF-related apoptosis-inducing ligand, or CD40 ligand. (Bone et al., 2008; Kearns et al., 2008; Kostenuik et al., 2009) The binding of denosumab to RANKL prevents rank activation and inhibits the formation, activation and

Comercial denosumab comes as a sterile, colorless solution intended for subcutaneous injection. It comes ready for administration in a 60mg/ml syringe-vial. The prefilled syringe drug product contains denosumab at 60 mg/mL, 17 mM sodium acetate, 4.7% sorbitol, and

The pharmacodynamic profile of denosumab appeared alike across all the subject populations studied. So far it has been studied in healthy postmenopausal women (including a Japanese population), healthy men ≥ 50 years of age, subjects with advanced cancer and bone metastases (breast cancer, other solid tumors [excluding lung], and multiple myeloma), and subjects with rheumatoid arthritis. The results indicate that SC administration of 60 mg denosumab causes a quick reduction in bone resorption within 6 hours, assessed by the marker C-telopeptide of type 1 collagen (CTX1) in serum (approximately 70% reduction), with an approximately 85% reduction occurring by 3 days. Serum CTX1 reductions were maintained for 6 months after the 60-mg dose, with the serum CTX1 reductions partially attenuated from a maximal reduction of ≥ 87% to reductions of approximately 45% or greater (range 45% to 80%), reflecting the reversibility of its effects on bone remodeling. The pharmacokinetics following IV or SC administration of denosumab has been studied at doses up to 3 mg/kg or 210 mg in various populations, including all those described earlier. Following subcutaneous administration, denosumab exhibits dose dependent, nonlinear pharmacokinetics over a wide dose range (as observed for other monoclonal antibodies). Nevertheless, dose-proportional increases in exposure were observed for doses ≥ 60 mg, consistent with saturable and non-saturable mechanisms of elimination. Its bioavailability is approximately 60% after SC injection. No accumulation in

0.01% polysorbate 20, at a pH of 5.2, filled to a target deliverable volume of 1.0 mL.

consequently an increase in bone density. (Kong et al., 1999)

**2.18.1 Pharmacodynamics and pharmacokinetics** 

**2.17 Biological agents** 

**2.18 Denosumab** 

survival of osteoclasts.

vitamin D concomitantly. The renal function has to be controlled before and after the administration of intravenous bisphosphonates.

Avascular necrosis of the jaw, also called osteonecrosis of the jaw is an illness that has worried many physicians, ever since Marx described it for the first time in 2003 and it will be described in detail in another chapter. (Marx, 2003)

#### **2.16 Long-term effects of the treatment with bisphosphonates: Atypical hip fractures**

Reports associating atypical fractures of the femur with long-term use of bisphosphonates led the initiative of the American Society for Bone and Mineral Research (ASBMR) to form a task force to address key questions related to this finding. The task force defined major and minor features of incomplete and complete atypical femoral fractures and recommended that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to appoint a femoral fracture as atypical. Minor features include their relationship with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, co-morbid conditions, and concomitant drug use, including bisphosphonates, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of bisphosphonates on collagen cross-linking and maturation, accumulation of micro-damage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis provide biologic plausibility to a potential association with long-term use of bisphosphonates. Based on published and unpublished data and the extensive use of bisphosphonates, the incidence of atypical femoral fractures associated with bisphosphonate use for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented. Furthermore, a causal association between bisphosphonates and atypical fractures has not been established. However, recent observations imply that the risk rises with increasing treatment duration, and there is concern that lack of knowledge and underreporting may mask the real incidence of the problem. Given the relative infrequency of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to assist studies of the clinical risk factors and optimal surgical and medical management of these fractures. Physicians should be made aware of the possibility of atypical femoral fractures through a change in labeling of bisphosphonates. (Shane et al., 2010)

A study comprising 12,777 Swedish women 55 years of age or older, who sustained a fracture of the femur in 2008 was published recently. Radiographs of 1,234 of the 1,271 women with a subtrochanteric or shaft fracture were reviewed. Fifty-nine patients with atypical fractures were identified. The relative and absolute risk of atypical fractures associated with bisphosphonate use was estimated by means of a nationwide cohort analysis. The 59 case patients were also compared with 263 control patients who had typical subtrochanteric or shaft fractures. The cohort analysis showed an age-adjusted relative risk of atypical fracture of 47.3. The increase in absolute risk was 5 cases per 10,000 patient-years. A total of 78% of the fractured patients and 10% of the controls had received bisphosphonates (multivariable-adjusted odds ratio of 33.3). The risk was independent of coexisting conditions. After drug withdrawal, the risk diminished by 70% per year since the last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38). (Schilcher et al., 2011)

#### **2.17 Biological agents**

572 Osteoporosis

vitamin D concomitantly. The renal function has to be controlled before and after the

Avascular necrosis of the jaw, also called osteonecrosis of the jaw is an illness that has worried many physicians, ever since Marx described it for the first time in 2003 and it will

**2.16 Long-term effects of the treatment with bisphosphonates: Atypical hip fractures**  Reports associating atypical fractures of the femur with long-term use of bisphosphonates led the initiative of the American Society for Bone and Mineral Research (ASBMR) to form a task force to address key questions related to this finding. The task force defined major and minor features of incomplete and complete atypical femoral fractures and recommended that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to appoint a femoral fracture as atypical. Minor features include their relationship with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, co-morbid conditions, and concomitant drug use, including bisphosphonates, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of bisphosphonates on collagen cross-linking and maturation, accumulation of micro-damage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis provide biologic plausibility to a potential association with long-term use of bisphosphonates. Based on published and unpublished data and the extensive use of bisphosphonates, the incidence of atypical femoral fractures associated with bisphosphonate use for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented. Furthermore, a causal association between bisphosphonates and atypical fractures has not been established. However, recent observations imply that the risk rises with increasing treatment duration, and there is concern that lack of knowledge and underreporting may mask the real incidence of the problem. Given the relative infrequency of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to assist studies of the clinical risk factors and optimal surgical and medical management of these fractures. Physicians should be made aware of the possibility of atypical femoral fractures through a change in labeling

A study comprising 12,777 Swedish women 55 years of age or older, who sustained a fracture of the femur in 2008 was published recently. Radiographs of 1,234 of the 1,271 women with a subtrochanteric or shaft fracture were reviewed. Fifty-nine patients with atypical fractures were identified. The relative and absolute risk of atypical fractures associated with bisphosphonate use was estimated by means of a nationwide cohort analysis. The 59 case patients were also compared with 263 control patients who had typical subtrochanteric or shaft fractures. The cohort analysis showed an age-adjusted relative risk of atypical fracture of 47.3. The increase in absolute risk was 5 cases per 10,000 patient-years. A total of 78% of the fractured patients and 10% of the controls had received bisphosphonates (multivariable-adjusted odds ratio of 33.3). The risk was independent of coexisting conditions. After drug withdrawal, the risk diminished by 70% per year since the

last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38). (Schilcher et al., 2011)

administration of intravenous bisphosphonates.

of bisphosphonates. (Shane et al., 2010)

be described in detail in another chapter. (Marx, 2003)

The illnesses that provoke bone loss, like osteoporosis, derive from the imbalance in the cycles of bone remodeling favoring bone resorption. The receptor activator of the nuclear factor kB (RANK), a member of the tumor necrosis factor (TNF) family proteins, and its ligand (RANKL) are fundamental for differentiation, activation and survival of osteoclasts and, therefore, basic mediators of the regulation of bone remodeling. (Anderson et al., 1997; Burgess et al., 1999; Lacey et al., 1998) It has been demonstrated that the signaling of the RANKL is involved in the pathophysiology of many bone loss illnesses, such as primary and many secondary osteoporoses. RANKL production is increased when estrogen is decreased. (Eghbali-Fatourechi et al., 2003) This condition occurs in menopause and in circumstances of hormonal ablation, and leads to an increase in bone resorption. In animal studies with knockout mice lacking RANKL, an absence of osteoclast can be seen, and consequently an increase in bone density. (Kong et al., 1999)

### **2.18 Denosumab**

Denosumab, a fully human monoclonal IgG2 antibody to RANKL imitates the effects of osteoprotegerine (OPG), endogenous inhibitor of RANKL blocking bone resorption. Denosumab presents a much longer half-life and it is highly specific since it does not bind to other members of the TNF family, including TNF, TNF-related apoptosis-inducing ligand, or CD40 ligand. (Bone et al., 2008; Kearns et al., 2008; Kostenuik et al., 2009) The binding of denosumab to RANKL prevents rank activation and inhibits the formation, activation and survival of osteoclasts.

Comercial denosumab comes as a sterile, colorless solution intended for subcutaneous injection. It comes ready for administration in a 60mg/ml syringe-vial. The prefilled syringe drug product contains denosumab at 60 mg/mL, 17 mM sodium acetate, 4.7% sorbitol, and 0.01% polysorbate 20, at a pH of 5.2, filled to a target deliverable volume of 1.0 mL.

#### **2.18.1 Pharmacodynamics and pharmacokinetics**

The pharmacodynamic profile of denosumab appeared alike across all the subject populations studied. So far it has been studied in healthy postmenopausal women (including a Japanese population), healthy men ≥ 50 years of age, subjects with advanced cancer and bone metastases (breast cancer, other solid tumors [excluding lung], and multiple myeloma), and subjects with rheumatoid arthritis. The results indicate that SC administration of 60 mg denosumab causes a quick reduction in bone resorption within 6 hours, assessed by the marker C-telopeptide of type 1 collagen (CTX1) in serum (approximately 70% reduction), with an approximately 85% reduction occurring by 3 days.

Serum CTX1 reductions were maintained for 6 months after the 60-mg dose, with the serum CTX1 reductions partially attenuated from a maximal reduction of ≥ 87% to reductions of approximately 45% or greater (range 45% to 80%), reflecting the reversibility of its effects on bone remodeling. The pharmacokinetics following IV or SC administration of denosumab has been studied at doses up to 3 mg/kg or 210 mg in various populations, including all those described earlier. Following subcutaneous administration, denosumab exhibits dose dependent, nonlinear pharmacokinetics over a wide dose range (as observed for other monoclonal antibodies). Nevertheless, dose-proportional increases in exposure were observed for doses ≥ 60 mg, consistent with saturable and non-saturable mechanisms of elimination. Its bioavailability is approximately 60% after SC injection. No accumulation in

Pharmacological Treatment of Osteoporosis 575

fracture reduction of denosumab. The patients received 60 mg subcutaneous denosumab or placebo every 6 months for 36 months. Around 23% of the patients had a previous vertebral fracture. The patients' retention rate in the study was 83%. The new fracture relative risk reduction was 68% (2.3% vs. 7.2%; p<0.0001) for vertebral fractures, 20% (6.5% vs. 8.0%) for non-vertebral fractures and 40% (0.7% vs. 1.2%) for hip fractures. As compared with subjects in the placebo group, subjects in the denosumab group had a relative increase of 9.2% in bone mineral density at the lumbar spine and 6.0% at the total hip at 36 months. There were no significant differences between subjects who received denosumab and those who received placebo in the total incidence of adverse events, serious adverse events, or discontinuation of study treatment because of adverse events. No cases of osteonecrosis of

In conclusion, denosumab offers a highly effective alternative to the treatment of osteoporosis by decreasing bone resorption and increasing bone mineral density through

One of the clear advantages of denosumab is its administration route and dosage. A subcutaneous injection every 6 months is very comfortable and increases the adherence to treatment. This finding is very important when establishing the cost-effectiveness advantages of any treatment since fracture prevention is improved when adherence is optimal. In order to establish the cost-effectiveness of denosumab compared to generic alendronate, branded risedronate, strontium ranelate and no treatment in a Swedish setting, Jönsson et al, designed a Markov cohort model and followed them for 5 years. The mean age of the Typical Swedish patient population is 71 years old, with a mean BMD T-score of ≤ 2.5 SD and a prevalence of morphometric vertebral fractures of 34%. Treatment persistence and residual effect after discontinuation was assumed to be equal to the time on treatment. Persistence with the comparators and with denosumab was derived from prescription data and a persistence study, respectively. The base-case incremental cost-effectiveness ratios were anticipated at €27,000, €12,000, €5,000, and €14,000, for denosumab compared with generic alendronate, risedronate, strontium ranelate, and no treatment, respectively. Fracture and unit costs, as well as mortality rates for the general population were based on data from 2008. Suboptimal persistence had the greatest impact in the comparison with generic alendronate, where the difference in drug cost was larger. They concluded that persistence improvement impacts positively on cost-effectiveness increasing the number of fractures prevented in the population targeted for osteoporosis treatment. (Jonsson et al., 2011) In another similar study, denosumab was cost effective compared with all other therapies. In particular, denosumab was found to be cost effective compared with branded alendronate and risedronate at a threshold value of €30,000 per QALY and denosumab was dominant (lower cost and greater effectiveness) compared with risedronate from the age of 70 years in women with a T-score of -

Fluoride is the anion F-, a monovalent ion (-1 charge). At high doses it can be lethal to humans. At low doses, 1 to 2 mg per day, it prevents dental caries. At intermediate doses,

the jaw were observed in either group. (Cummings et al. 2009)

2.5 or less and no prior fractures. (Hiligsmann & Reginster, 2011)

**2.18.3 Cost effectiveness studies of the treatment with denosumab** 

the inhibition of RANKL.

**3. Anabolic agents** 

**3.1 Fluoride** 

serum denosumab concentrations was observed with repeated doses of 60 mg every 6 months. There is no evidence that the rare (approximately 0.5% of treated subjects) and transient development of binding antibodies to denosumab influences its pharmacokinetics or pharmacodynamics. Changes in serum calcium levels following administration of denosumab are not related to the extent of exposure. (Yonemori et al., 2008; Perez-Edo, 2011)

#### **2.18.2 Denosumab in human clinical trials**

Information is available from 44 clinical trials in healthy adults and patients with osteoporosis (approximately 13,500 subjects), bone loss associated with hormone-ablation therapy (approximately 1,900 subjects), rheumatoid arthritis (approximately 200 subjects), advanced cancer (multiple myeloma and advanced malignancies involving bone [approximately 7,800 subjects]) and giant cell tumor of the bone (approximately 260 subjects) collected between June 2001 to November 2010.

In the *Denosumab Fortifies Bone Density* (DEFEND) trial, a phase III randomized, placebo controlled study, of 332 postmenopausal women with osteopenia and stratified according to the beginning of menopause (<5 years, >5 years), denosumab demonstrated a significant increase in lumbar BMD (6.5%) at 24 months, compared with placebo (-0.6%). It also increased BMD in other locations as total hip, distal third of the radius, and whole body (p> 0.001) in the two patients' strata. The incidence of adverse effects was similar between the placebo group and the denosumab group. (Bone et al., 2008)

In a comparative clinical trial, the DECIDE (*Determining Efficacy: Comparison of Initiating Denosumab vs. Alendronate*) trial, comprising 1,189 postmenopausal women with low BMD (T-score: ≤-2 SD), patients were randomized 1:1 to receive subcutaneous denosumab (60 mg every 6 months) plus oral alendronate placebo weekly or oral alendronate weekly (70 mg) plus a subcutaneous denosumab placebo injection every 6 months. Denosumab increased total hip BMD when compared to alendronate (3.5 % vs. 2.5 %, p <0.00001). A greater increase in BMD could be seen with denosumab than with alendronate in other locations, as in the trochanter (4.5 % vs. 3.5 %), distal radius (1.1 % vs. 0.6 %), lumbar spine (5.3 % vs. 4.2 %) and femoral neck (2.2 % vs. 1.6 %); p <0.0003. The safety profile was similar for the two groups. No patient included in the study developed antibodies against denosumab. (Brown et al., 2009)

Another phase III, multicenter, double blind study, called STAND (*Study of transitioning from Alendronate to Denosumab*) was performed to evaluate the effect of denosumab in patients who were receiving alendronate. Five hundred four postmenopausal women ≥ 55 years of age with a BMD T-score of <-2.0 and >-4 SD, who were receiving weekly oral alendronate for at least 6 months, were randomized and treated for 44±33 months. Changes in BMD and bone biochemical markers were evaluated. At 12 months the group receiving denosumab (but previously treated with alendronate) showed a significantly higher increase in total hip BMD compared to those still receiving alendronate (1.9% vs. 1.05%; p<0.00012). Significantly higher BMD increases with denosumab compared with alendronate were also seen at 12 months at the lumbar spine, femoral neck, and distal radius (all p<0.0125). The adverse events and serious adverse events were similar in both groups of treatment. (Kendler et al., 2010)

Finally, the main phase III trial, the FREEDOM (*Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months*) trial, comprised 7,868 postmenopausal women with osteoporosis with a BMD T-score between <-2.0 and >-4 SD and evaluated the efficacy in

serum denosumab concentrations was observed with repeated doses of 60 mg every 6 months. There is no evidence that the rare (approximately 0.5% of treated subjects) and transient development of binding antibodies to denosumab influences its pharmacokinetics or pharmacodynamics. Changes in serum calcium levels following administration of denosumab are not related to the extent of exposure. (Yonemori et al., 2008; Perez-Edo, 2011)

Information is available from 44 clinical trials in healthy adults and patients with osteoporosis (approximately 13,500 subjects), bone loss associated with hormone-ablation therapy (approximately 1,900 subjects), rheumatoid arthritis (approximately 200 subjects), advanced cancer (multiple myeloma and advanced malignancies involving bone [approximately 7,800 subjects]) and giant cell tumor of the bone (approximately 260

In the *Denosumab Fortifies Bone Density* (DEFEND) trial, a phase III randomized, placebo controlled study, of 332 postmenopausal women with osteopenia and stratified according to the beginning of menopause (<5 years, >5 years), denosumab demonstrated a significant increase in lumbar BMD (6.5%) at 24 months, compared with placebo (-0.6%). It also increased BMD in other locations as total hip, distal third of the radius, and whole body (p> 0.001) in the two patients' strata. The incidence of adverse effects was similar between the

In a comparative clinical trial, the DECIDE (*Determining Efficacy: Comparison of Initiating Denosumab vs. Alendronate*) trial, comprising 1,189 postmenopausal women with low BMD (T-score: ≤-2 SD), patients were randomized 1:1 to receive subcutaneous denosumab (60 mg every 6 months) plus oral alendronate placebo weekly or oral alendronate weekly (70 mg) plus a subcutaneous denosumab placebo injection every 6 months. Denosumab increased total hip BMD when compared to alendronate (3.5 % vs. 2.5 %, p <0.00001). A greater increase in BMD could be seen with denosumab than with alendronate in other locations, as in the trochanter (4.5 % vs. 3.5 %), distal radius (1.1 % vs. 0.6 %), lumbar spine (5.3 % vs. 4.2 %) and femoral neck (2.2 % vs. 1.6 %); p <0.0003. The safety profile was similar for the two groups. No patient included in the study developed antibodies against denosumab. (Brown

Another phase III, multicenter, double blind study, called STAND (*Study of transitioning from Alendronate to Denosumab*) was performed to evaluate the effect of denosumab in patients who were receiving alendronate. Five hundred four postmenopausal women ≥ 55 years of age with a BMD T-score of <-2.0 and >-4 SD, who were receiving weekly oral alendronate for at least 6 months, were randomized and treated for 44±33 months. Changes in BMD and bone biochemical markers were evaluated. At 12 months the group receiving denosumab (but previously treated with alendronate) showed a significantly higher increase in total hip BMD compared to those still receiving alendronate (1.9% vs. 1.05%; p<0.00012). Significantly higher BMD increases with denosumab compared with alendronate were also seen at 12 months at the lumbar spine, femoral neck, and distal radius (all p<0.0125). The adverse events and serious adverse events were similar in both groups of treatment. (Kendler et al.,

Finally, the main phase III trial, the FREEDOM (*Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months*) trial, comprised 7,868 postmenopausal women with osteoporosis with a BMD T-score between <-2.0 and >-4 SD and evaluated the efficacy in

**2.18.2 Denosumab in human clinical trials** 

et al., 2009)

2010)

subjects) collected between June 2001 to November 2010.

placebo group and the denosumab group. (Bone et al., 2008)

fracture reduction of denosumab. The patients received 60 mg subcutaneous denosumab or placebo every 6 months for 36 months. Around 23% of the patients had a previous vertebral fracture. The patients' retention rate in the study was 83%. The new fracture relative risk reduction was 68% (2.3% vs. 7.2%; p<0.0001) for vertebral fractures, 20% (6.5% vs. 8.0%) for non-vertebral fractures and 40% (0.7% vs. 1.2%) for hip fractures. As compared with subjects in the placebo group, subjects in the denosumab group had a relative increase of 9.2% in bone mineral density at the lumbar spine and 6.0% at the total hip at 36 months. There were no significant differences between subjects who received denosumab and those who received placebo in the total incidence of adverse events, serious adverse events, or discontinuation of study treatment because of adverse events. No cases of osteonecrosis of the jaw were observed in either group. (Cummings et al. 2009)

In conclusion, denosumab offers a highly effective alternative to the treatment of osteoporosis by decreasing bone resorption and increasing bone mineral density through the inhibition of RANKL.

#### **2.18.3 Cost effectiveness studies of the treatment with denosumab**

One of the clear advantages of denosumab is its administration route and dosage. A subcutaneous injection every 6 months is very comfortable and increases the adherence to treatment. This finding is very important when establishing the cost-effectiveness advantages of any treatment since fracture prevention is improved when adherence is optimal. In order to establish the cost-effectiveness of denosumab compared to generic alendronate, branded risedronate, strontium ranelate and no treatment in a Swedish setting, Jönsson et al, designed a Markov cohort model and followed them for 5 years. The mean age of the Typical Swedish patient population is 71 years old, with a mean BMD T-score of ≤ 2.5 SD and a prevalence of morphometric vertebral fractures of 34%. Treatment persistence and residual effect after discontinuation was assumed to be equal to the time on treatment. Persistence with the comparators and with denosumab was derived from prescription data and a persistence study, respectively. The base-case incremental cost-effectiveness ratios were anticipated at €27,000, €12,000, €5,000, and €14,000, for denosumab compared with generic alendronate, risedronate, strontium ranelate, and no treatment, respectively. Fracture and unit costs, as well as mortality rates for the general population were based on data from 2008. Suboptimal persistence had the greatest impact in the comparison with generic alendronate, where the difference in drug cost was larger. They concluded that persistence improvement impacts positively on cost-effectiveness increasing the number of fractures prevented in the population targeted for osteoporosis treatment. (Jonsson et al., 2011) In another similar study, denosumab was cost effective compared with all other therapies. In particular, denosumab was found to be cost effective compared with branded alendronate and risedronate at a threshold value of €30,000 per QALY and denosumab was dominant (lower cost and greater effectiveness) compared with risedronate from the age of 70 years in women with a T-score of - 2.5 or less and no prior fractures. (Hiligsmann & Reginster, 2011)

#### **3. Anabolic agents**

#### **3.1 Fluoride**

Fluoride is the anion F-, a monovalent ion (-1 charge). At high doses it can be lethal to humans. At low doses, 1 to 2 mg per day, it prevents dental caries. At intermediate doses,

al., 2000b)

**3.1.4 Toxicity** 

fractures. (O'Duffy et al., 1986)

defect. (Lundy et al., 1995)

administered injections.

(Hodsman et al., 2005)

increasing renal 1- hydroxylase.

**3.2 Parathyroid hormone and analogs** 

Pharmacological Treatment of Osteoporosis 577

fractures with monofluorophosphate, (Reginster et al., 1998) or sodium fluoride treatment,(Farrerons et al., 1997) while other studies, using the same preparations and doses, failed in doing so. Vestergaard et al, in 2008 published a meta-analysis including 25 different studies and concluding that in spite of the BMD increase in spine and femur, fluoride treatment did not reduce significantly vertebral risk of fracture. (Vestergaard et al., 2008) Moreover, another meta-analysis goes even further and establishes the increase in fracture risk with increasing doses at four years. (Haguenauer et al., 2000a; Haguenauer et

The adverse events seen with fluoride treatment are varied. The most frequent ones are gastrointestinal symptoms and acute lower extremities pain. The frequency and intensity of these effects is dose and preparation dependant. Gastrointestinal symptoms include dyspepsia, epigastralgia, nausea and vomiting, and they appear in 10% to 40% of patients. Lower extremity pain is quite common also, appearing in around 15% of patients, especially in those patients receiving high doses of sodium fluoride or monofluorophosphate. Some authors have established a relationship between these pains and development of stress

Finally, bone biopsies have demonstrated that patients treated with fluoride develop an abnormal bone, consistent with an increase of trabecular width, volume and trabecular surface covered with osteoid material which can be seen inside mineralized bone. When analyzing dynamic histomorphometric indices, a reduction in tetracycline labeling and an extension in the mineralization interval can be seen. Both findings indicate a mineralization

Among the many therapeutic options teriparatide or recombinant human PTH (1-34), occupies an important place. It is classified into a group of anabolic bone-forming drugs as opposed to the anti-resorptive or catabolic. Teriparatide is given as daily subcutaneous self-

It induces *de novo* bone formation by increasing the rate of bone turnover in favor of formation. The treatment with teriparatide increases trabecular connectivity and cortical bone thickness. (Dempster et al., 2001) Teriparatide improves bone mechanical properties resulting in a significant decrease in vertebral and non-vertebral fractures in postmenopausal women with osteoporosis, male osteoporosis and corticosteroid-induced osteoporosis. (Keaveny et al., 2007) That is why its use is considered appropriate mainly in patients at high risk of fracture and in those who have failed previous treatments.

The fundamental physiological action of parathyroid hormone (PTH) is the maintenance of calcium homeostasis to maintain nearly constant concentrations through the tubular resorption of calcium by stimulating calcium absorption in the bowel by vitamin D,

The effect exerted by PTH on the skeleton is complex. High levels of PTH observed in primary and secondary hyperparathyroidism, leading to increased bone resorption by its action on osteoclasts, produce secondary osteoporosis. In contrast, low levels increase the osteoblastic activity of bone formation. This would contrast with the desired effect by

ranging from 8 to 80 mg daily, skeletal fluorosis can develop. These doses are not so rare, they can be found in some regions with high fluoride levels in well waters or in some industrial settings. It was thought to be a therapeutical agent after observing the osteosclerosis effect at high doses. (Heaney, 1994)

Many years ago, endemic fluorosis was described in patients living in regions with high fluoride water levels or grounds where vegetables and tea were cultivated, like some places in India. Moreover some observations were published describing a low fracture incidence in patients living in areas with high fluoride levels. It was used for the treatment of osteoporosis for the first time in 1961. It was approved for the use of osteoporosis prevention in several countries in Europe, but it never got the approval from the American Federal Drug Administration (FDA). (Pandey & Pandey 2011; Turner, 1996)

#### **3.1.1 Pharmacokinetics**

Two different types of compounds have been used for the treatment of osteoporosis: sodium fluoride and monofluorophosphate. Sodium fluoride could be found as capsules or tablets with an enteric protection. A more recent preparation is the sustained release formulation. The ion equivalences usually used were: monofluorophosphate 200 mg containing 16,4 mg of fluoride and sodium fluoride 50 mg containing 22,6 mg if the ion. (Watts, 1999)

Absorption and bioavailability of fluoride preparations depend on their formulation. Thus sodium fluoride is quickly absorbed in the stomach with maximum plasma fluoride levels 30 minutes after ingestion with almost a 100% bioavailability, while sodium monofluorophosphate absorption is slower with a bioavailability around 65%. It is cleared by the kidney and about 50% of absorbed fluoride is deposited in the skeleton. Its distribution is not homogeneous since higher amounts are deposited in areas with high bone remodeling rate, such as trabecular bone. (Ekstrand & Spak, 1990)

#### **3.1.2 Mechanism of action**

Fluoride increases bone formation increasing osteoblasts proliferation, without altering their differentiation. The molecular basis of this mitogenic action is not known, but there are several hypotheses. The most popular one indicates that fluoride induces an increase in tyrosine phosphorilation of signaling proteins of the mitogenic process. Besides this effect over the osteoblastic cells, fluoride modifies the crystallization of the bone tissue. Thus replacing hydroxylic radicals of hydroxyapatite, forming fluoroapatite, a compound with a lesser structural stability and more resistance to osteoclastic resorption. (Marie et al., 1992)

#### **3.1.3 Effect of fluoride in bone mineral density and fracture risk reduction**

Results from studies evaluating the effect of fluoride compounds on BMD agree that this agent increases lumbar spine BMD in a consistent and linear manner. The increases in spinal BMD vary between 2.3 and 9% annually. A recent meta-analysis establishes the mean increase of spinal BMD in 8.1% at two years and 16.1% at four years, when comparing it to placebo. The increase in BMD depends on the doses, formulation and fluoride compound used. An interesting finding among all the trials is that there are 25% of patients considered as non-responders, since they did not experience any change in BMD during the fluoride treatment. (Heaney, 1994; Haguenauer et al., 2000a)

The results of the trials that have studied the effect of fluoride in fracture risk reduction are inconclusive. Some studies have demonstrated the decrease in the incidence of vertebral fractures with monofluorophosphate, (Reginster et al., 1998) or sodium fluoride treatment,(Farrerons et al., 1997) while other studies, using the same preparations and doses, failed in doing so. Vestergaard et al, in 2008 published a meta-analysis including 25 different studies and concluding that in spite of the BMD increase in spine and femur, fluoride treatment did not reduce significantly vertebral risk of fracture. (Vestergaard et al., 2008) Moreover, another meta-analysis goes even further and establishes the increase in fracture risk with increasing doses at four years. (Haguenauer et al., 2000a; Haguenauer et al., 2000b)

### **3.1.4 Toxicity**

576 Osteoporosis

ranging from 8 to 80 mg daily, skeletal fluorosis can develop. These doses are not so rare, they can be found in some regions with high fluoride levels in well waters or in some industrial settings. It was thought to be a therapeutical agent after observing the

Many years ago, endemic fluorosis was described in patients living in regions with high fluoride water levels or grounds where vegetables and tea were cultivated, like some places in India. Moreover some observations were published describing a low fracture incidence in patients living in areas with high fluoride levels. It was used for the treatment of osteoporosis for the first time in 1961. It was approved for the use of osteoporosis prevention in several countries in Europe, but it never got the approval from the American

Two different types of compounds have been used for the treatment of osteoporosis: sodium fluoride and monofluorophosphate. Sodium fluoride could be found as capsules or tablets with an enteric protection. A more recent preparation is the sustained release formulation. The ion equivalences usually used were: monofluorophosphate 200 mg containing 16,4 mg

Absorption and bioavailability of fluoride preparations depend on their formulation. Thus sodium fluoride is quickly absorbed in the stomach with maximum plasma fluoride levels 30 minutes after ingestion with almost a 100% bioavailability, while sodium monofluorophosphate absorption is slower with a bioavailability around 65%. It is cleared by the kidney and about 50% of absorbed fluoride is deposited in the skeleton. Its distribution is not homogeneous since higher amounts are deposited in areas with high

Fluoride increases bone formation increasing osteoblasts proliferation, without altering their differentiation. The molecular basis of this mitogenic action is not known, but there are several hypotheses. The most popular one indicates that fluoride induces an increase in tyrosine phosphorilation of signaling proteins of the mitogenic process. Besides this effect over the osteoblastic cells, fluoride modifies the crystallization of the bone tissue. Thus replacing hydroxylic radicals of hydroxyapatite, forming fluoroapatite, a compound with a lesser structural stability and more resistance to osteoclastic resorption. (Marie et al., 1992)

Results from studies evaluating the effect of fluoride compounds on BMD agree that this agent increases lumbar spine BMD in a consistent and linear manner. The increases in spinal BMD vary between 2.3 and 9% annually. A recent meta-analysis establishes the mean increase of spinal BMD in 8.1% at two years and 16.1% at four years, when comparing it to placebo. The increase in BMD depends on the doses, formulation and fluoride compound used. An interesting finding among all the trials is that there are 25% of patients considered as non-responders, since they did not experience any change in BMD during the fluoride

The results of the trials that have studied the effect of fluoride in fracture risk reduction are inconclusive. Some studies have demonstrated the decrease in the incidence of vertebral

Federal Drug Administration (FDA). (Pandey & Pandey 2011; Turner, 1996)

of fluoride and sodium fluoride 50 mg containing 22,6 mg if the ion. (Watts, 1999)

bone remodeling rate, such as trabecular bone. (Ekstrand & Spak, 1990)

**3.1.3 Effect of fluoride in bone mineral density and fracture risk reduction** 

treatment. (Heaney, 1994; Haguenauer et al., 2000a)

osteosclerosis effect at high doses. (Heaney, 1994)

**3.1.1 Pharmacokinetics** 

**3.1.2 Mechanism of action** 

The adverse events seen with fluoride treatment are varied. The most frequent ones are gastrointestinal symptoms and acute lower extremities pain. The frequency and intensity of these effects is dose and preparation dependant. Gastrointestinal symptoms include dyspepsia, epigastralgia, nausea and vomiting, and they appear in 10% to 40% of patients. Lower extremity pain is quite common also, appearing in around 15% of patients, especially in those patients receiving high doses of sodium fluoride or monofluorophosphate. Some authors have established a relationship between these pains and development of stress fractures. (O'Duffy et al., 1986)

Finally, bone biopsies have demonstrated that patients treated with fluoride develop an abnormal bone, consistent with an increase of trabecular width, volume and trabecular surface covered with osteoid material which can be seen inside mineralized bone. When analyzing dynamic histomorphometric indices, a reduction in tetracycline labeling and an extension in the mineralization interval can be seen. Both findings indicate a mineralization defect. (Lundy et al., 1995)

### **3.2 Parathyroid hormone and analogs**

Among the many therapeutic options teriparatide or recombinant human PTH (1-34), occupies an important place. It is classified into a group of anabolic bone-forming drugs as opposed to the anti-resorptive or catabolic. Teriparatide is given as daily subcutaneous selfadministered injections.

It induces *de novo* bone formation by increasing the rate of bone turnover in favor of formation. The treatment with teriparatide increases trabecular connectivity and cortical bone thickness. (Dempster et al., 2001) Teriparatide improves bone mechanical properties resulting in a significant decrease in vertebral and non-vertebral fractures in postmenopausal women with osteoporosis, male osteoporosis and corticosteroid-induced osteoporosis. (Keaveny et al., 2007) That is why its use is considered appropriate mainly in patients at high risk of fracture and in those who have failed previous treatments. (Hodsman et al., 2005)

The fundamental physiological action of parathyroid hormone (PTH) is the maintenance of calcium homeostasis to maintain nearly constant concentrations through the tubular resorption of calcium by stimulating calcium absorption in the bowel by vitamin D, increasing renal 1- hydroxylase.

The effect exerted by PTH on the skeleton is complex. High levels of PTH observed in primary and secondary hyperparathyroidism, leading to increased bone resorption by its action on osteoclasts, produce secondary osteoporosis. In contrast, low levels increase the osteoblastic activity of bone formation. This would contrast with the desired effect by

Pharmacological Treatment of Osteoporosis 579

antiresorptives. The EUROFORS study was a prospective, open-label, randomized trial of 865 postmenopausal women with established osteoporosis and was designed to investigate various sequential treatments of teriparatide over 24 months. Patients were classified into various groups depending on their previous treatments. The results of the BMD changes and biochemical markers of bone formation showed that treatment with teriparatide induces positive effects on bone mass and osteoblast function regardless of previous longterm exposure to antiresorptive therapies in postmenopausal women with established

Duration of antiresorptive therapy and elapsed time between stopping previous therapy and starting teriparatide did not affect the BMD response at any skeletal site. The skeletal responses at the lumbar spine were similar among previous antiresorptive therapy groups at each time point during the study, although previous users of etidronate showed a higher increase, probably reflecting its weaker anti-remodeling activity. At month 6, total hip and femoral neck BMD significantly decreased in the previous alendronate subgroup, and total hip BMD significantly decreased in the previous risedronate subgroup. Total hip and femoral neck BMD was numerically decreased from baseline in all other subgroups at 6 months. However, this transient decrease was reversed with longer teriparatide treatment. All subgroups showed a statistically significant increase in BMD compared with baseline after 18 and 24 months of treatment, and without differences between the groups at any

In another non-randomized study, 59 postmenopausal women with osteoporosis previously treated with raloxifene or alendronate for 18-36 months, were given 18-month treatment with teriparatide. Changes in BMD and bone-turnover markers were assessed. Women who had previously been treated with alendronate had a late increase in bone-turnover markers with values lower than one third those of patients who had previously received raloxifene. During the first 6 months there were significant differences in the increase in BMD at the lumbar spine and hip. Women previously treated with raloxifene had a greater increase in BMD at the two locations. At 18 months of treatment in the lumbar spine significant differences remained in favor of prior treatment with raloxifene, but in the hip differences were not significant. This demonstrates that treatment with teriparatide increases bone turnover in patients previously treated with raloxifene or alendronate, but this increase is

There are also trials showing efficacy of teriparatide in the treatment of glucocorticoidinduced osteoporosis. In a randomized, double blind trial, 428 patients of both sexes aged between 22 and 89 years who had received corticosteroids for at least 3 months were randomized to receive alendronate 10mg/day or 20 g/day of teriparatide for 18 months. After 12 months the total femur BMD was higher in the teriparatide group and at the end of

Teriparatide has also been used in men with osteoporosis. The study compared men with idiopathic or secondary osteoporosis receiving teriparatide vs. placebo. The study showed increases independently of gonadal status and other factors in the teriparatide group.

study there were less vertebral fractures in the teriparatide group. (Saag et al., 2009)

greater and earlier in raloxifene pretreatment group. (Ettinger et al., 2004)

**3.3.4 Corticosteroid-induced osteoporosis and male osteoporosis** 

time point in the study. (Obermayer-Pietsch et al., 2008)

osteoporosis.

**3.3.3 Sequential therapy** 

(Orwoll et al., 2003)

administering PTH as a treatment for osteoporosis. However, it was observed that the action of the hormone on bone varies if administration is continuous (emulating persistently high levels of hyperparathyroidism) that induce catabolic effects on bone, or intermittent (as given in treatment) which also increases resorption as well as formation of bone.

#### **3.3 Teriparatide (1-34 parathohormone)**

The first available indication for teriparatide was the treatment of established osteoporosis in postmenopausal women. Of the various existing studies on this drug, the FPT (Fracture Prevention Trial) is the most important. It compared teriparatide at doses of 20 or 40 g/day versus placebo in 1637 postmenopausal women with vertebral fractures. Patients receiving teriparatide achieved significant reductions in the rate of new vertebral and non-vertebral fractures. They also produced an increase in lumbar and femoral neck bone density. Although 40 g/day achieved greater effects on BMD, fracture risk was not significantly different between the two doses, while the higher dose was less tolerated (11% of withdrawals due to adverse effects with 40 g/day versus 6% with 20 g/day or placebo). The dose of 20 g/day showed a reduction in vertebral fracture risk of 65% and a non-hip non-vertebral fracture risk reduction of 35%. This study was initially planned to last for 36 months, but it was stopped when patients had completed an average of 21 months for security measures due to osteosarcomas observed in drug toxicity studies in rats. (Neer et al., 2001) However, in other studies it became clear that this finding occurred only in young rats treated with high doses of PTH. (Vahle et al., 2004) Moreover, no cases have been reported in humans.

A subgroup of patients were followed for up to 18 months after cessation of treatment. The subgroup of women who had received teriparatide showed a persistent 40% reduction in vertebral fracture risk at 18 months compared with placebo. These results suggest that the benefit on the incidence of non-vertebral fractures persist once it has been stopped. (Lindsay et al. 2004)

#### **3.3.1 Combination therapy: Teriparatide plus antiresorptives**

Although currently bisphosphonates are the gold standard in the treatment of osteoporosis, there are several trials that have evaluated if the association of teriparatide and BP has any beneficial effect. The studies suggest that if both drugs are administered simultaneously, bisphosphonates do not enhance, but on the contrary, seem to blunt the anabolic effect of teriparatide.

Finkelstein et al. also carried out a study in men with three groups, receiving PTH (1-34), alendronate or the combination of both. In this last group, PTH (1-34) was started at month six. All three groups were followed for 30 months. Spine BMD as measured by DXA and quantitative computed tomography. BMD was increased to a greater extent in the PTH group than in the alendronate or the combination group. Thus, these studies show no evidence of synergy between PTH and alendronate. Furthermore, alendronate may impair the anabolic activity of PTH. It is hypothesized that PTH is less effective when bone turnover is suppressed. (Finkelstein et al. 2003)

#### **3.3.2 Teriparatide in patients previously treated with antiresorptives**

Once the antagonistic effect of antiresorptives and teriparatide was observed a study was conducted to evaluate the response of teriparatide in patients previously treated with

administering PTH as a treatment for osteoporosis. However, it was observed that the action of the hormone on bone varies if administration is continuous (emulating persistently high levels of hyperparathyroidism) that induce catabolic effects on bone, or intermittent (as

The first available indication for teriparatide was the treatment of established osteoporosis in postmenopausal women. Of the various existing studies on this drug, the FPT (Fracture Prevention Trial) is the most important. It compared teriparatide at doses of 20 or 40 g/day versus placebo in 1637 postmenopausal women with vertebral fractures. Patients receiving teriparatide achieved significant reductions in the rate of new vertebral and non-vertebral fractures. They also produced an increase in lumbar and femoral neck bone density. Although 40 g/day achieved greater effects on BMD, fracture risk was not significantly different between the two doses, while the higher dose was less tolerated (11% of withdrawals due to adverse effects with 40 g/day versus 6% with 20 g/day or placebo). The dose of 20 g/day showed a reduction in vertebral fracture risk of 65% and a non-hip non-vertebral fracture risk reduction of 35%. This study was initially planned to last for 36 months, but it was stopped when patients had completed an average of 21 months for security measures due to osteosarcomas observed in drug toxicity studies in rats. (Neer et al., 2001) However, in other studies it became clear that this finding occurred only in young rats treated with high doses of PTH. (Vahle et al., 2004) Moreover, no cases have been

A subgroup of patients were followed for up to 18 months after cessation of treatment. The subgroup of women who had received teriparatide showed a persistent 40% reduction in vertebral fracture risk at 18 months compared with placebo. These results suggest that the benefit on the incidence of non-vertebral fractures persist once it has been stopped. (Lindsay

Although currently bisphosphonates are the gold standard in the treatment of osteoporosis, there are several trials that have evaluated if the association of teriparatide and BP has any beneficial effect. The studies suggest that if both drugs are administered simultaneously, bisphosphonates do not enhance, but on the contrary, seem to blunt the anabolic effect of

Finkelstein et al. also carried out a study in men with three groups, receiving PTH (1-34), alendronate or the combination of both. In this last group, PTH (1-34) was started at month six. All three groups were followed for 30 months. Spine BMD as measured by DXA and quantitative computed tomography. BMD was increased to a greater extent in the PTH group than in the alendronate or the combination group. Thus, these studies show no evidence of synergy between PTH and alendronate. Furthermore, alendronate may impair the anabolic activity of PTH. It is hypothesized that PTH is less effective when bone

Once the antagonistic effect of antiresorptives and teriparatide was observed a study was conducted to evaluate the response of teriparatide in patients previously treated with

**3.3.1 Combination therapy: Teriparatide plus antiresorptives** 

**3.3.2 Teriparatide in patients previously treated with antiresorptives** 

turnover is suppressed. (Finkelstein et al. 2003)

given in treatment) which also increases resorption as well as formation of bone.

**3.3 Teriparatide (1-34 parathohormone)** 

reported in humans.

et al. 2004)

teriparatide.

antiresorptives. The EUROFORS study was a prospective, open-label, randomized trial of 865 postmenopausal women with established osteoporosis and was designed to investigate various sequential treatments of teriparatide over 24 months. Patients were classified into various groups depending on their previous treatments. The results of the BMD changes and biochemical markers of bone formation showed that treatment with teriparatide induces positive effects on bone mass and osteoblast function regardless of previous longterm exposure to antiresorptive therapies in postmenopausal women with established osteoporosis.

Duration of antiresorptive therapy and elapsed time between stopping previous therapy and starting teriparatide did not affect the BMD response at any skeletal site. The skeletal responses at the lumbar spine were similar among previous antiresorptive therapy groups at each time point during the study, although previous users of etidronate showed a higher increase, probably reflecting its weaker anti-remodeling activity. At month 6, total hip and femoral neck BMD significantly decreased in the previous alendronate subgroup, and total hip BMD significantly decreased in the previous risedronate subgroup. Total hip and femoral neck BMD was numerically decreased from baseline in all other subgroups at 6 months. However, this transient decrease was reversed with longer teriparatide treatment. All subgroups showed a statistically significant increase in BMD compared with baseline after 18 and 24 months of treatment, and without differences between the groups at any time point in the study. (Obermayer-Pietsch et al., 2008)

#### **3.3.3 Sequential therapy**

In another non-randomized study, 59 postmenopausal women with osteoporosis previously treated with raloxifene or alendronate for 18-36 months, were given 18-month treatment with teriparatide. Changes in BMD and bone-turnover markers were assessed. Women who had previously been treated with alendronate had a late increase in bone-turnover markers with values lower than one third those of patients who had previously received raloxifene. During the first 6 months there were significant differences in the increase in BMD at the lumbar spine and hip. Women previously treated with raloxifene had a greater increase in BMD at the two locations. At 18 months of treatment in the lumbar spine significant differences remained in favor of prior treatment with raloxifene, but in the hip differences were not significant. This demonstrates that treatment with teriparatide increases bone turnover in patients previously treated with raloxifene or alendronate, but this increase is greater and earlier in raloxifene pretreatment group. (Ettinger et al., 2004)

#### **3.3.4 Corticosteroid-induced osteoporosis and male osteoporosis**

There are also trials showing efficacy of teriparatide in the treatment of glucocorticoidinduced osteoporosis. In a randomized, double blind trial, 428 patients of both sexes aged between 22 and 89 years who had received corticosteroids for at least 3 months were randomized to receive alendronate 10mg/day or 20 g/day of teriparatide for 18 months. After 12 months the total femur BMD was higher in the teriparatide group and at the end of study there were less vertebral fractures in the teriparatide group. (Saag et al., 2009)

Teriparatide has also been used in men with osteoporosis. The study compared men with idiopathic or secondary osteoporosis receiving teriparatide vs. placebo. The study showed increases independently of gonadal status and other factors in the teriparatide group. (Orwoll et al., 2003)

Pharmacological Treatment of Osteoporosis 581

risk. Mean age of patients in the study was 64 years, and of them, 19% had at least one vertebral fracture. After 18 months, the increase in BMD at the lumbar spine in women treated with PTH (1-84) was 7% compared with the placebo group. The risk of new vertebral fractures decreased by 66% in the group treated with PTH. Hypercalcemia was observed in 28.3% of treated women, compared to 4.7% in the control group. (Greenspan et al., 2007)

The effects of concurrent or sequential therapy with PTH and antiresorptive agents have been studied. Black et al. compared the effects of PTH (1-84), alendronate, or both in combination in postmenopausal women in the study PaTH. In this study, 238 postmenopausal women were randomized with ages comprised 55-85 years with a T-score <-2.5 or a T-score <- 2 and with at least one risk factor or additional fracture. Initially there were 3 groups receiving: PTH (1-84) 100 mcg/day + placebo (n=119), alendronate (ALN) 10mg/day + placebo (n=60) and PTH (1-84) 100 mcg/day + ALN 10 mg / day (n=59). All participants received daily calcium 500mg

At one year, spine DXA had increased in all three groups. There was no difference in spine DXA between the PTH group and the combination group. However, the PTH group had a significantly greater increase in volumetric BMD of the spine on quantitative CT than the alendronate and combination groups. Volumetric trabecular lumbar BMD increased with respect to baseline by 26%, 13% and 11% in the PTH alone, PTH and alendronate and alendronate group respectively at 12 months. Similarly, volumetric trabecular BMD of the

In spite of the facts of all these studies previously published, data about what was happening in bone was lacking. Recker et al. studied bone biopsies from iliac crest from postmenopausal osteoporotic women who received placebo (n=8) or 100 mcg PTH(1-84) for 18 (n=8) or 24 (n=7) months to assess cancellous and cortical bone formation and structure. Using micro CT and histomorphometry at 18 months, cancellous bone volume (BV/TV) measured was 45-48% higher in subjects treated with PTH(1-84) versus placebo, and also resulted in a higher trabecular number (Tb.N) and thickness. The higher Tb.N appeared to result from intra-trabecular tunneling. Connectivity density was higher and structure model index was lower, indicating a better connected and more plate-like trabecular architecture. Cancellous bone formation rate (BFR) was 2-fold higher in PTH (1-84)-treated subjects,

The physical effects produced by PTH 1-84 are in most cases mild. The most common is hypercalcemia, present in 28% of women treated vs. 4.6% in the placebo group and hypercalciuria, 46% versus 23% respectively. However, the number of withdrawals of treatment due to this cause was rare in published clinical trials (two patients in the PaTH study and six patients in the TOP study) and generally the effect was controlled by removing the supplements of calcium and vitamin D. Although it is believed that hypercalcemia could slightly modify electrocardiographic studies decreasing the QT interval without significant changes or minimal changes in heart rate, PR interval or QRS duration and axis, no differences between groups were observed. Other reported side

**3.4.2 Combination and sequential therapy** 

+ vitamin D (400UI) supplements. (Black et al., 2003)

**3.4.3 Effects on bone architecture** 

**3.4.4 Adverse effects** 

total hip increased by 9%, 6% and 2% respectively in the 3 groups.

primarily because of greater mineralizing surface. (Recker et al.,2009)

#### **3.3.5 Side effects**

In general, teriparatide, recombinant human PTH (1-34), injections are well tolerated. It is cleared from the circulation within four hours of subcutaneous administration. A daily injection is necessary and transient redness at the injection site has been noted. Headache and nausea occur in less than 10% of subjects receiving a daily dose of 20 µg Mild, early, and transient hypercalcemia can occur, but severe hypercalcemia is rare. Increases in urinary calcium (by 30 µg per day) and serum uric acid concentrations (by 13%) are seen but do not appear to have clinical consequences.

In conclusion, teriparatide is a suitable and efficient treatment option for osteoporosis. It is effective in several clinical problems, such as male osteoporosis or corticosteroids induced osteoporosis.

#### **3.4 1-84 Parathormone**

Intact PTH (PTH 1-84) has been described as having a positive effect on bone micro architecture and a reduction in the risk of new fractures due to a bone-forming mechanism. (Rosen & Bilezikian, 2001)

1-84 PTH (as well as 1-34 PTH) acts through its receptor, exerts its action in bone through osteoblasts by modulating the levels of cAMP by activating secondary messengers it acts on the osteoclast bone resorptive process. In collagen tissue, PTH in high and sustained doses inhibits its synthesis, but at low doses and used intermittently, through the action of IGF-1, it stimulates its synthesis.

PTH also increases the local synthesis of IGF-1, which may explain its anabolic effect in bone tissue. Other actions of PTH include modulation of TGF B1 and the production of prostaglandins that may contribute to bone formation, acting on the pre-osteoblast differentiation stage. And it is through the IGF-1 that it inhibits apoptosis.

This mechanism distinguishes the effect of treatment with PTH of other treatments that inhibit the resorption stage of bone remodeling acting on osteoclast (like bisphosphonates). The ability of PTH to act directly on the osteoblast, the cell that directly produces new bone, drives in the enhancement of production of new bone with consequent gain in bone mineral density and fracture risk reduction.

#### **3.4.1 Clinical use of 1-84 PTH**

Hodsman et al. conducted a study in 217 postmenopausal women with osteoporosis, with a mean age of 64.5 years, who were randomly classified into different groups receiving placebo or PTH 1-84 at doses of 50, 75, or 100 mcg. The primary endpoint was change in BMD at the lumbar spine after 1 year of treatment. The results showed a mean increase in BMD of 3.0%, 5.1% and 7.8% in the group receiving 50, 75 and 100mcg/day of 1-84 PTH respectively, compared with placebo, with all increases clearly statistically significant, whereas in the control group receiving calcium and vitamin D, there was an increase of 0.9% that did not reach statistical significance. The increase in BMD obtained by the group that received 100 mcg was statistically significant with respect to the other two groups receiving PTH, passing from a T-score of -3.2 at baseline to -2.8 at the end of treatment. In contrast there were no statistically significant differences in BMD at the hip. (Hodsman et al., 2003) The pivotal clinical trial with 1-84 PTH is the TOP (Treatment of Osteoporosis) study. It comprised 2,532 postmenopausal women with osteoporosis receiving PTH (1-84) or placebo. The follow up was up to 18 months. The main goal was the reduction in vertebral fracture

In general, teriparatide, recombinant human PTH (1-34), injections are well tolerated. It is cleared from the circulation within four hours of subcutaneous administration. A daily injection is necessary and transient redness at the injection site has been noted. Headache and nausea occur in less than 10% of subjects receiving a daily dose of 20 µg Mild, early, and transient hypercalcemia can occur, but severe hypercalcemia is rare. Increases in urinary calcium (by 30 µg per day) and serum uric acid concentrations (by 13%) are seen but do not

In conclusion, teriparatide is a suitable and efficient treatment option for osteoporosis. It is effective in several clinical problems, such as male osteoporosis or corticosteroids induced

Intact PTH (PTH 1-84) has been described as having a positive effect on bone micro architecture and a reduction in the risk of new fractures due to a bone-forming mechanism.

1-84 PTH (as well as 1-34 PTH) acts through its receptor, exerts its action in bone through osteoblasts by modulating the levels of cAMP by activating secondary messengers it acts on the osteoclast bone resorptive process. In collagen tissue, PTH in high and sustained doses inhibits its synthesis, but at low doses and used intermittently, through the action of IGF-1,

PTH also increases the local synthesis of IGF-1, which may explain its anabolic effect in bone tissue. Other actions of PTH include modulation of TGF B1 and the production of prostaglandins that may contribute to bone formation, acting on the pre-osteoblast

This mechanism distinguishes the effect of treatment with PTH of other treatments that inhibit the resorption stage of bone remodeling acting on osteoclast (like bisphosphonates). The ability of PTH to act directly on the osteoblast, the cell that directly produces new bone, drives in the enhancement of production of new bone with consequent gain in bone mineral

Hodsman et al. conducted a study in 217 postmenopausal women with osteoporosis, with a mean age of 64.5 years, who were randomly classified into different groups receiving placebo or PTH 1-84 at doses of 50, 75, or 100 mcg. The primary endpoint was change in BMD at the lumbar spine after 1 year of treatment. The results showed a mean increase in BMD of 3.0%, 5.1% and 7.8% in the group receiving 50, 75 and 100mcg/day of 1-84 PTH respectively, compared with placebo, with all increases clearly statistically significant, whereas in the control group receiving calcium and vitamin D, there was an increase of 0.9% that did not reach statistical significance. The increase in BMD obtained by the group that received 100 mcg was statistically significant with respect to the other two groups receiving PTH, passing from a T-score of -3.2 at baseline to -2.8 at the end of treatment. In contrast there were no statistically significant differences in BMD at the hip. (Hodsman et al., 2003) The pivotal clinical trial with 1-84 PTH is the TOP (Treatment of Osteoporosis) study. It comprised 2,532 postmenopausal women with osteoporosis receiving PTH (1-84) or placebo. The follow up was up to 18 months. The main goal was the reduction in vertebral fracture

differentiation stage. And it is through the IGF-1 that it inhibits apoptosis.

**3.3.5 Side effects** 

osteoporosis.

**3.4 1-84 Parathormone** 

(Rosen & Bilezikian, 2001)

it stimulates its synthesis.

density and fracture risk reduction.

**3.4.1 Clinical use of 1-84 PTH** 

appear to have clinical consequences.

risk. Mean age of patients in the study was 64 years, and of them, 19% had at least one vertebral fracture. After 18 months, the increase in BMD at the lumbar spine in women treated with PTH (1-84) was 7% compared with the placebo group. The risk of new vertebral fractures decreased by 66% in the group treated with PTH. Hypercalcemia was observed in 28.3% of treated women, compared to 4.7% in the control group. (Greenspan et al., 2007)

### **3.4.2 Combination and sequential therapy**

The effects of concurrent or sequential therapy with PTH and antiresorptive agents have been studied. Black et al. compared the effects of PTH (1-84), alendronate, or both in combination in postmenopausal women in the study PaTH. In this study, 238 postmenopausal women were randomized with ages comprised 55-85 years with a T-score <-2.5 or a T-score <- 2 and with at least one risk factor or additional fracture. Initially there were 3 groups receiving: PTH (1-84) 100 mcg/day + placebo (n=119), alendronate (ALN) 10mg/day + placebo (n=60) and PTH (1-84) 100 mcg/day + ALN 10 mg / day (n=59). All participants received daily calcium 500mg + vitamin D (400UI) supplements. (Black et al., 2003)

At one year, spine DXA had increased in all three groups. There was no difference in spine DXA between the PTH group and the combination group. However, the PTH group had a significantly greater increase in volumetric BMD of the spine on quantitative CT than the alendronate and combination groups. Volumetric trabecular lumbar BMD increased with respect to baseline by 26%, 13% and 11% in the PTH alone, PTH and alendronate and alendronate group respectively at 12 months. Similarly, volumetric trabecular BMD of the total hip increased by 9%, 6% and 2% respectively in the 3 groups.

#### **3.4.3 Effects on bone architecture**

In spite of the facts of all these studies previously published, data about what was happening in bone was lacking. Recker et al. studied bone biopsies from iliac crest from postmenopausal osteoporotic women who received placebo (n=8) or 100 mcg PTH(1-84) for 18 (n=8) or 24 (n=7) months to assess cancellous and cortical bone formation and structure. Using micro CT and histomorphometry at 18 months, cancellous bone volume (BV/TV) measured was 45-48% higher in subjects treated with PTH(1-84) versus placebo, and also resulted in a higher trabecular number (Tb.N) and thickness. The higher Tb.N appeared to result from intra-trabecular tunneling. Connectivity density was higher and structure model index was lower, indicating a better connected and more plate-like trabecular architecture. Cancellous bone formation rate (BFR) was 2-fold higher in PTH (1-84)-treated subjects, primarily because of greater mineralizing surface. (Recker et al.,2009)

#### **3.4.4 Adverse effects**

The physical effects produced by PTH 1-84 are in most cases mild. The most common is hypercalcemia, present in 28% of women treated vs. 4.6% in the placebo group and hypercalciuria, 46% versus 23% respectively. However, the number of withdrawals of treatment due to this cause was rare in published clinical trials (two patients in the PaTH study and six patients in the TOP study) and generally the effect was controlled by removing the supplements of calcium and vitamin D. Although it is believed that hypercalcemia could slightly modify electrocardiographic studies decreasing the QT interval without significant changes or minimal changes in heart rate, PR interval or QRS duration and axis, no differences between groups were observed. Other reported side

Pharmacological Treatment of Osteoporosis 583

Serum concentration of strontium can be affected by the administration together with calcium and with meals. When administered together with 0,5 grams of calcium, strontium relative bioavailability decreased 57%, 63% when administered with meals and 71% when administered with calcium and meals. Due to these absorption difficulties, several studies were conducted in order to determine the best mode of administration. Comparing strontium administration one hour before breakfast and three hours after breakfast to every 12 hours resulted in a decrease of bioavailability of 46 and 55% respectively. In phase 2 studies no difference was observed between giving strontium 1 gram every 12 hours or 2 grams before bedtime. Thus, to guarantee the best absorption and bioavailability, it is recommended to administer strontium ranelate two hours after dinner. (Leeuwenkamp et al., 1990; Reginster & Meunier 2003) Vitamin D seems to increase the medications' absorption, though in phase 3 studies it was observed that the influence of vitamin D did not change strontium availability in more than 10%, which is clinically insignificant.

Strontium excretion is mainly through renal clearance, and to a lesser extent through feces and sweat. In healthy adults, strontium plasma clearance varies between 9.4 and 11.7 ml/min, meanwhile the urinary clearance is between 4.0 and 5.4 ml/min. (Papworth & Vennart, 1984; Leeuwenkamp et al., 1989) In animal studies, the bone tissue strontium content decreased to approximately 50% at week 6 to 10 after stopping treatment. Renelic acid, given its high polarity, is poorly absorbed and its half-life in animals is about 1 hour, though it varies according to its absorption. In humans, renelic acid excretion is approximately 78 ml/min and therefore it has a half-life of 2.6 hours. (Li et al., 2006;

Due to its chemical properties, strontium can form complexes with oral tetracyclines and quinolones, and therefore its administration with these medications is not recommended. Strontium administration together with diuretics could increase its serum concentration around 20%. This effect is greater with thiazide diuretics, furosemide and indapamide, and could be explained by the increase in the strontium tubular re-absorption, together with calcium, which would rise in parallel. Even though this increase in strontium levels is not clinically significant and no dose adjustment is needed. Magnesium and aluminum hydroxide can significantly decrease strontium bioavailability, therefore it is not recommended to take these medications at night, when strontium should be administered.

In-vitro, strontium ranelate increases collagen and non-collagen protein synthesis thru mature osteoblasts. The bone forming effects were confirmed with the increase in the replication of pre-osteoblastic cells. This stimulus of the replication of the pre-osteoblastic cells and the increase of collagen and non-collagen proteins are the reason why strontium ranelate is considered as a dual effect bone agent, since it does not only decrease resorption. (Bonnelye et al., 2008) In an in-vitro assay of isolated rat osteoclasts, the pre-incubation of bone slices pre-treated with strontium ranelate, demonstrated a dose dependant decrease in bone resorption activity. In another assay, using chicken bone marrow, a dose dependant decrease in the expression of carbonic anhydrase II and the alpha subunit of the vitronectin receptor could be observed. (Takahashi et al., 2003; Caverzasio, 2008; Bonnelye et al., 2008;

(Ardissino et al., 2000; Leeuwenkamp et al., 1990; Marie, 2003)

Leeuwenkamp et al., 1990)

(Leeuwenkamp et al., 1990; Marie, 2003)

**4.1.2 Mechanism of action** 

Reginster et al., 2003)

effects, although often not as important as the ones mentioned above, were nausea and vomiting. Fisher et al, reported a study with 344 rats treated with nearly life-long daily teriparatide, and found an increased risk of osteosarcoma. Nevertheless, to date there is no reported increase in prevalence of osteosarcoma in humans treated with neither teriparatide nor PTH 1-84, and no association has been found between primary hyperparathyroidism and osteosarcoma. Recently, Tashjian et al. reported that they had not collected a single case of osteosarcoma in humans, following the prescription of more than 250,000 treatments with PTH, 1-34 and 1-84 after follow-up of patients who participated in the studies with PTH 1-84 in the 80's. (Tashjian & Goltzman, 2008)

### **4. Dual action agents**

#### **4.1 Strontium ranelate**

Strontium (Sr) is a chemical element with an atomic number 38. It is an alkaline earth metal and was isolated for the first time, as an impure substance, in 1808 in a Scottish city named "Strontain" from which this element received its name. It is in this city where strontium is found in higher concentrations than usual (73g/kg). The earth cortex contains 0.042% of strontium and is as abundant as chloride and sulfur. It can also be found in rocks, dust, carbon and oil, as well as in some foods as cereals, green vegetables and milk. In marine water, strontium is the most abundant trace element, reaching values of 8 mg/L. (Cabrera et al., 1999) In its natural state, called stable strontium, this element is not radioactive and it is harmless. The only compound harmful for the human being is strontium chromate, and due to chrome not to strontium. (Levy et al., 1986) The therapeutic potential of strontium was discovered around 1940, when strontium-89 was used as an analgesic agent in bone metastases from prostate cancer. (Giammarile et al., 1999; Saarto et al., 2002) Afterwards this isotope, together with strontium-88, have been used as markers for calcium absorption. (Cabrera et al., 1999)

#### **4.1.1 Pharmacological characteristics**

The main entrance of strontium into the body is through the gastrointestinal system. The skin and the lungs can also absorb it. Its gastrointestinal absorption varies with age and has a very high variability in infants. In the elderly, the fluctuation is about 10%. A number of absorption mechanisms have been proposed, beginning with the passive mechanisms and diffusion, to transporter mediated absorption, as proposed by Papworth et al. Strontium absorption augments with fasting and it is seriously affected by calcium, phosphorus and other chelating agents in the bowel and its absorption rate is about half of calcium. Other experimental studies have demonstrated that during pregnancy and breast-feeding strontium absorption is increased, reaching a maximum during breast-feeding. (Papworth & Patrick 1970; Papworth & Vennart, 1984)

Absorption of strontium is dose dependant. Its bioavailability decreases with a lower dose, confirming that, just like calcium, absorption involves passive diffusion, independent of vitamin D levels, as well as saturable active transport, regulated by vitamin D and a facilitated diffusion. (Ardissino et al., 2000) Studies in a variety of animals (i.e. rats or monkeys) demonstrate that the pharmacokinetic data of renelic acid have a high variability. It is estimated that its oral absorption is poor and slow, probably due to a deficient intestinal permeability. (Li et al., 2006)

effects, although often not as important as the ones mentioned above, were nausea and vomiting. Fisher et al, reported a study with 344 rats treated with nearly life-long daily teriparatide, and found an increased risk of osteosarcoma. Nevertheless, to date there is no reported increase in prevalence of osteosarcoma in humans treated with neither teriparatide nor PTH 1-84, and no association has been found between primary hyperparathyroidism and osteosarcoma. Recently, Tashjian et al. reported that they had not collected a single case of osteosarcoma in humans, following the prescription of more than 250,000 treatments with PTH, 1-34 and 1-84 after follow-up of patients who participated in the studies with PTH 1-84

Strontium (Sr) is a chemical element with an atomic number 38. It is an alkaline earth metal and was isolated for the first time, as an impure substance, in 1808 in a Scottish city named "Strontain" from which this element received its name. It is in this city where strontium is found in higher concentrations than usual (73g/kg). The earth cortex contains 0.042% of strontium and is as abundant as chloride and sulfur. It can also be found in rocks, dust, carbon and oil, as well as in some foods as cereals, green vegetables and milk. In marine water, strontium is the most abundant trace element, reaching values of 8 mg/L. (Cabrera et al., 1999) In its natural state, called stable strontium, this element is not radioactive and it is harmless. The only compound harmful for the human being is strontium chromate, and due to chrome not to strontium. (Levy et al., 1986) The therapeutic potential of strontium was discovered around 1940, when strontium-89 was used as an analgesic agent in bone metastases from prostate cancer. (Giammarile et al., 1999; Saarto et al., 2002) Afterwards this isotope, together with strontium-88, have been used as markers for calcium absorption.

The main entrance of strontium into the body is through the gastrointestinal system. The skin and the lungs can also absorb it. Its gastrointestinal absorption varies with age and has a very high variability in infants. In the elderly, the fluctuation is about 10%. A number of absorption mechanisms have been proposed, beginning with the passive mechanisms and diffusion, to transporter mediated absorption, as proposed by Papworth et al. Strontium absorption augments with fasting and it is seriously affected by calcium, phosphorus and other chelating agents in the bowel and its absorption rate is about half of calcium. Other experimental studies have demonstrated that during pregnancy and breast-feeding strontium absorption is increased, reaching a maximum during breast-feeding. (Papworth &

Absorption of strontium is dose dependant. Its bioavailability decreases with a lower dose, confirming that, just like calcium, absorption involves passive diffusion, independent of vitamin D levels, as well as saturable active transport, regulated by vitamin D and a facilitated diffusion. (Ardissino et al., 2000) Studies in a variety of animals (i.e. rats or monkeys) demonstrate that the pharmacokinetic data of renelic acid have a high variability. It is estimated that its oral absorption is poor and slow, probably due to a deficient intestinal

in the 80's. (Tashjian & Goltzman, 2008)

**4. Dual action agents 4.1 Strontium ranelate** 

(Cabrera et al., 1999)

**4.1.1 Pharmacological characteristics** 

Patrick 1970; Papworth & Vennart, 1984)

permeability. (Li et al., 2006)

Serum concentration of strontium can be affected by the administration together with calcium and with meals. When administered together with 0,5 grams of calcium, strontium relative bioavailability decreased 57%, 63% when administered with meals and 71% when administered with calcium and meals. Due to these absorption difficulties, several studies were conducted in order to determine the best mode of administration. Comparing strontium administration one hour before breakfast and three hours after breakfast to every 12 hours resulted in a decrease of bioavailability of 46 and 55% respectively. In phase 2 studies no difference was observed between giving strontium 1 gram every 12 hours or 2 grams before bedtime. Thus, to guarantee the best absorption and bioavailability, it is recommended to administer strontium ranelate two hours after dinner. (Leeuwenkamp et al., 1990; Reginster & Meunier 2003) Vitamin D seems to increase the medications' absorption, though in phase 3 studies it was observed that the influence of vitamin D did not change strontium availability in more than 10%, which is clinically insignificant. (Ardissino et al., 2000; Leeuwenkamp et al., 1990; Marie, 2003)

Strontium excretion is mainly through renal clearance, and to a lesser extent through feces and sweat. In healthy adults, strontium plasma clearance varies between 9.4 and 11.7 ml/min, meanwhile the urinary clearance is between 4.0 and 5.4 ml/min. (Papworth & Vennart, 1984; Leeuwenkamp et al., 1989) In animal studies, the bone tissue strontium content decreased to approximately 50% at week 6 to 10 after stopping treatment. Renelic acid, given its high polarity, is poorly absorbed and its half-life in animals is about 1 hour, though it varies according to its absorption. In humans, renelic acid excretion is approximately 78 ml/min and therefore it has a half-life of 2.6 hours. (Li et al., 2006; Leeuwenkamp et al., 1990)

Due to its chemical properties, strontium can form complexes with oral tetracyclines and quinolones, and therefore its administration with these medications is not recommended. Strontium administration together with diuretics could increase its serum concentration around 20%. This effect is greater with thiazide diuretics, furosemide and indapamide, and could be explained by the increase in the strontium tubular re-absorption, together with calcium, which would rise in parallel. Even though this increase in strontium levels is not clinically significant and no dose adjustment is needed. Magnesium and aluminum hydroxide can significantly decrease strontium bioavailability, therefore it is not recommended to take these medications at night, when strontium should be administered. (Leeuwenkamp et al., 1990; Marie, 2003)

### **4.1.2 Mechanism of action**

In-vitro, strontium ranelate increases collagen and non-collagen protein synthesis thru mature osteoblasts. The bone forming effects were confirmed with the increase in the replication of pre-osteoblastic cells. This stimulus of the replication of the pre-osteoblastic cells and the increase of collagen and non-collagen proteins are the reason why strontium ranelate is considered as a dual effect bone agent, since it does not only decrease resorption. (Bonnelye et al., 2008) In an in-vitro assay of isolated rat osteoclasts, the pre-incubation of bone slices pre-treated with strontium ranelate, demonstrated a dose dependant decrease in bone resorption activity. In another assay, using chicken bone marrow, a dose dependant decrease in the expression of carbonic anhydrase II and the alpha subunit of the vitronectin receptor could be observed. (Takahashi et al., 2003; Caverzasio, 2008; Bonnelye et al., 2008; Reginster et al., 2003)

Pharmacological Treatment of Osteoporosis 585

therefore the utility of these formulas is restricted to almost only research. It is easier and almost accurate to calculate that half of the DMO gained in the first year of treatment with strontium ranelate is due to an increase on BMD and the rest is due to the higher molecular

Currently we have data from clinical studies comparing strontium ranelate to placebo for fracture prevention for up to five years. Moreover we have data of fracture incidence in patients treated with strontium ranelate for up to 10 years. The phase III pivotal trial was performed in 75 centers distributed through 12 countries worldwide. It was structured in three different clinical trials. The FIRST (Fracture International run-in for Strontium Ranelate) trial mean duration was 101 days (SD 52) and was performed with the objective of normalizing calcium and vitamin D levels of all subjects. From this trial the other two were derived, the SOTI (Spinal Osteoporosis Therapeutic Intervention) trial and the TROPOS (Treatment of Peripheral Osteoporosis) trial. (Reginster & Meunier, 2003; Reginster et al., 2005) The main propose of these trials was to evaluate the effect of strontium ranelate in axial and appendicular skeleton as well as the tolerability in postmenopausal osteoporotic women. Their main objective was to calculate the reduction in the incidence of new vertebral fractures (SOTI trial) as well as non-vertebral fractures (TROPOS trial). (Reginster et al., 2008) The analysis included 1649 postmenopausal women in the SOTI trial and 5091 patients in the TROPOS trial. In the SOTI trial women were randomized into two groups, a placebo (control) group and another one receiving 2 g daily of strontium ranelate for a period of four years. In the fifth year, the patients taking placebo switched to strontium ranelate and 50% of the ones taking strontium ranelate switched to placebo. In the TROPOS trial, all patients remained in their original treatment group during the whole 5 years. The preliminary three-year results showed a vertebral fracture reduction of 41% with a NNT of 9. Furthermore an increase in BMD of 12.7% was observed. The vertebral fracture reduction at the end of the forth and fifth year was of 33% and 24%, respectively. Similar results were obtained from the TROPOS trial where the vertebral reduction rate was 39% at the end of the third year and 24% at the end of the fifth year. Regarding the non-vertebral fractures the decrease in the relative risk of fracture with strontium ranelate was 16% at the end of the third year and 15% at the end of the fifth. A post-hoc analysis of these data in a subgroup of 1,977 patients with high fracture risk (74 years old and a T-score of -2.4) showed a vertebral fracture risk reduction of 36% at the end of the third year and 43% at the end of the fifth. (Blake & Fogelman, 2005; Reginster et al., 2007; Moro-Alvarez & Diaz-Curiel, 2007) Since there is no data showing the fracture reduction risk of strontium ranelate in placebo controlled patients, Reginster et al, compared the fracture incidence between the original strontium ranelate group at the end of the fifth year to the strontium ranelate group followed for ten years. The results are shown in table 2. (Reginster et al., 2010) These results show no statistically significant differences between the incidence of fractures at the end of year 5 or 10. An important fact to bear in mind is that the sample was significantly reduced

since at the end of the tenth year, just 233 patients continued in the follow up study.

the fifth. (Seeman et al., 2010; Seeman et al., 2006)

Another sub study performed by Seeman et al, with patients over 80 years of age showed a reduction in the vertebral fracture risk of 32% in the third year and 31% in the fifth year. For peripheral fractures, the reduction in fracture risk was of 31% in the third year and 27% in the fifth year, and for hip fractures the risk reduction was 32% in the third year and 24% in

weight on strontium measured by the DXA. (Blake & Fogelman, 2006b)

The main mechanism of action that rules bone resorption at a molecular level is the RANK/RNAKL/OPG system described earlier. Concentrations of 0.1 mM to 2 nM of strontium ranelate, decrease the ability of human osteoblasts of inducing osteoclast differentiation, by decreasing expression of mRNA of RANK-L and increasing mRNA expression of OPG, according to the studies done by Brennan et al in 2006. (Close et al., 2006; Chapurlat & Delmas, 2004)

The human body has a very strict extracellular calcium control mechanism. This control is performed by varied body tissues with the aim of keeping extracellular calcium levels within a narrow range, which is essential for the normal cellular function including muscular contraction, nerve impulse transmission or platelet aggregation, for example. The tissues involved in this task, like the chief cells of parathyroid glands, C cells of the thyroid glands, renal tubules, the cortical ascending limb of the nephron, the intestinal epithelium and the bone cells like osteoclasts and osteoblasts, express a receptor capable of detecting changes in the extracellular calcium levels and act according to the requirements, these receptors are called calcium receptors or calcium sensing receptors (CaR). (Brown 2003)

Several studies with cell cultures have been able to demonstrate that this receptor can be activated by other divalent cations, including strontium, which just as calcium but with a lower potency can activate the CaR. This means that in the presence of strontium, chief cells of the parathyroid glands will decrease its secretion and that osteoclasts will decrease bone resorption, for example. Numerous assays demonstrate that 0.13 nM strontium plasma levels, like the ones seen in patients treated with 2 g of strontium ranelate daily, won't affect the CaR in soft tissues. The effect on osteoclast apoptosis could be related to the activation of the transmembrane receptor attached to phopholipase C (CaR) and mediated by an independent signaling pathway of IP3-protein kinase C. Some other authors suggest that besides CaR, there are other receptors that can also influence these actions. These receptors could be related to the stimulating effect of strontium on osteoblasts replication in CaR knockout rats. (Arlot et al., 2008; Brown, 2003)

#### **4.1.3 Effects on other tissues**

Some studies have demonstrated that strontium ranelate has beneficial effects in tissues other than bone. Taking cartilage for example, strontium ranelate increased basal production of proteoglycans stimulated by insulin growth factor 1 by chondrocytes of young subjects, old subjects and subjects with osteoarthritis. On the contrary, it showed no effect on the proteoglycans production induced by interleukin 1 (IL-1), the stromelycin production stimulated by IL-1 or chondrocytes activity. These findings suggest that strontium ranelate stimulates human cartilage matrix formation in vitro without activating the chondroresorption process. (Henrotin et al., 2001)

#### **4.1.4 Effect of strontium ranelate in fracture reduction**

It is known that due to the chemical properties of the compound (a higher molecular weight), densitometric values of patients treated with strontium ranelate will be higher than the true values. There are many studies that have measured the influence of the chemical characteristics of strontium on densitometry and have developed some mathematical formulas to remove this influence from the DMO value. These formulas are a little bit complicated and require too much time to put them into practice in the daily practice,

The main mechanism of action that rules bone resorption at a molecular level is the RANK/RNAKL/OPG system described earlier. Concentrations of 0.1 mM to 2 nM of strontium ranelate, decrease the ability of human osteoblasts of inducing osteoclast differentiation, by decreasing expression of mRNA of RANK-L and increasing mRNA expression of OPG, according to the studies done by Brennan et al in 2006. (Close et al.,

The human body has a very strict extracellular calcium control mechanism. This control is performed by varied body tissues with the aim of keeping extracellular calcium levels within a narrow range, which is essential for the normal cellular function including muscular contraction, nerve impulse transmission or platelet aggregation, for example. The tissues involved in this task, like the chief cells of parathyroid glands, C cells of the thyroid glands, renal tubules, the cortical ascending limb of the nephron, the intestinal epithelium and the bone cells like osteoclasts and osteoblasts, express a receptor capable of detecting changes in the extracellular calcium levels and act according to the requirements, these receptors are called calcium receptors or calcium sensing receptors

Several studies with cell cultures have been able to demonstrate that this receptor can be activated by other divalent cations, including strontium, which just as calcium but with a lower potency can activate the CaR. This means that in the presence of strontium, chief cells of the parathyroid glands will decrease its secretion and that osteoclasts will decrease bone resorption, for example. Numerous assays demonstrate that 0.13 nM strontium plasma levels, like the ones seen in patients treated with 2 g of strontium ranelate daily, won't affect the CaR in soft tissues. The effect on osteoclast apoptosis could be related to the activation of the transmembrane receptor attached to phopholipase C (CaR) and mediated by an independent signaling pathway of IP3-protein kinase C. Some other authors suggest that besides CaR, there are other receptors that can also influence these actions. These receptors could be related to the stimulating effect of strontium on osteoblasts replication in CaR

Some studies have demonstrated that strontium ranelate has beneficial effects in tissues other than bone. Taking cartilage for example, strontium ranelate increased basal production of proteoglycans stimulated by insulin growth factor 1 by chondrocytes of young subjects, old subjects and subjects with osteoarthritis. On the contrary, it showed no effect on the proteoglycans production induced by interleukin 1 (IL-1), the stromelycin production stimulated by IL-1 or chondrocytes activity. These findings suggest that strontium ranelate stimulates human cartilage matrix formation in vitro without activating

It is known that due to the chemical properties of the compound (a higher molecular weight), densitometric values of patients treated with strontium ranelate will be higher than the true values. There are many studies that have measured the influence of the chemical characteristics of strontium on densitometry and have developed some mathematical formulas to remove this influence from the DMO value. These formulas are a little bit complicated and require too much time to put them into practice in the daily practice,

2006; Chapurlat & Delmas, 2004)

knockout rats. (Arlot et al., 2008; Brown, 2003)

the chondroresorption process. (Henrotin et al., 2001)

**4.1.4 Effect of strontium ranelate in fracture reduction** 

**4.1.3 Effects on other tissues** 

(CaR). (Brown 2003)

therefore the utility of these formulas is restricted to almost only research. It is easier and almost accurate to calculate that half of the DMO gained in the first year of treatment with strontium ranelate is due to an increase on BMD and the rest is due to the higher molecular weight on strontium measured by the DXA. (Blake & Fogelman, 2006b)

Currently we have data from clinical studies comparing strontium ranelate to placebo for fracture prevention for up to five years. Moreover we have data of fracture incidence in patients treated with strontium ranelate for up to 10 years. The phase III pivotal trial was performed in 75 centers distributed through 12 countries worldwide. It was structured in three different clinical trials. The FIRST (Fracture International run-in for Strontium Ranelate) trial mean duration was 101 days (SD 52) and was performed with the objective of normalizing calcium and vitamin D levels of all subjects. From this trial the other two were derived, the SOTI (Spinal Osteoporosis Therapeutic Intervention) trial and the TROPOS (Treatment of Peripheral Osteoporosis) trial. (Reginster & Meunier, 2003; Reginster et al., 2005) The main propose of these trials was to evaluate the effect of strontium ranelate in axial and appendicular skeleton as well as the tolerability in postmenopausal osteoporotic women. Their main objective was to calculate the reduction in the incidence of new vertebral fractures (SOTI trial) as well as non-vertebral fractures (TROPOS trial). (Reginster et al., 2008) The analysis included 1649 postmenopausal women in the SOTI trial and 5091 patients in the TROPOS trial. In the SOTI trial women were randomized into two groups, a placebo (control) group and another one receiving 2 g daily of strontium ranelate for a period of four years. In the fifth year, the patients taking placebo switched to strontium ranelate and 50% of the ones taking strontium ranelate switched to placebo. In the TROPOS trial, all patients remained in their original treatment group during the whole 5 years. The preliminary three-year results showed a vertebral fracture reduction of 41% with a NNT of 9. Furthermore an increase in BMD of 12.7% was observed. The vertebral fracture reduction at the end of the forth and fifth year was of 33% and 24%, respectively. Similar results were obtained from the TROPOS trial where the vertebral reduction rate was 39% at the end of the third year and 24% at the end of the fifth year. Regarding the non-vertebral fractures the decrease in the relative risk of fracture with strontium ranelate was 16% at the end of the third year and 15% at the end of the fifth. A post-hoc analysis of these data in a subgroup of 1,977 patients with high fracture risk (74 years old and a T-score of -2.4) showed a vertebral fracture risk reduction of 36% at the end of the third year and 43% at the end of the fifth. (Blake & Fogelman, 2005; Reginster et al., 2007; Moro-Alvarez & Diaz-Curiel, 2007)

Since there is no data showing the fracture reduction risk of strontium ranelate in placebo controlled patients, Reginster et al, compared the fracture incidence between the original strontium ranelate group at the end of the fifth year to the strontium ranelate group followed for ten years. The results are shown in table 2. (Reginster et al., 2010) These results show no statistically significant differences between the incidence of fractures at the end of year 5 or 10. An important fact to bear in mind is that the sample was significantly reduced since at the end of the tenth year, just 233 patients continued in the follow up study.

Another sub study performed by Seeman et al, with patients over 80 years of age showed a reduction in the vertebral fracture risk of 32% in the third year and 31% in the fifth year. For peripheral fractures, the reduction in fracture risk was of 31% in the third year and 27% in the fifth year, and for hip fractures the risk reduction was 32% in the third year and 24% in the fifth. (Seeman et al., 2010; Seeman et al., 2006)

Pharmacological Treatment of Osteoporosis 587

osteoclast–osteoblast interaction, resulting in less inhibition of bone formation, than available bisphosphonate antiresorptive agents. Human cathepsin K inhibitors have been shown to prevent bone loss in ovariectomized mice without blunting the anabolic action of

Although no CatK inhibitor is currently marketed for osteoporosis treatment or prevention, studies of three CatK inhibitors for the treatment of osteoporosis have been reported:

The most commonly used drugs for the treatment of osteoporosis inhibit osteoclastmediated bone resorption. Osteoclasts are hematopoietically derived multinucleated giant cells that resorb bone by focal attachment and demineralization, followed by the enzymatic degradation of organic bone matrix. The demineralization is achieved by the secretion of acid onto the bone surface. The organic matrix (mainly type 1 collagen, the principal bone matrix protein) is degraded primarily by the enzymatic action of cysteine proteases, particularly cathepsin K (CatK). CatK is the most abundantly expressed cysteine protease in osteoclasts and exhibits collagenolytic activity under acidic conditions. Currently treatment of osteoporosis, like bisphosphonates prevent acid secretion by disruption of the ruffled

The collagenases of the matrix metalloproteinase family have been considered as the main proteases for the degradation of collagen as they were thought to be the main ones capable of cleaving triple helical collagen. However, matrix metalloproteinase are active at neutral to slightly alkaline pH values whereas at the site of bone resorption, within the resorption lacuna, acidic pH conditions prevail. Thus, acidic lysosomal hydrolases were proposed to operate as the main collagen degrading proteases. Previously, only Cathepsins B and L were known. Cathepsins B and L were thought to be the key factors, as both enzymes were known to cleave in the telopeptide region of triple helical collagens. However in the early 1990's a new cathepsine was identified thanks to DNA clonation techniques. Initially this new cathepsine was identified only in osteoclasts and was called cathepsine O, later its name changed to cathepsine K. This protease exhibited a potent collagenase activity towards the main connective tissue collagens type I and II, and immunohistochemical analyses revealed a predominant but not exclusive expression in osteoclasts. After that, pycnodysostosis, a hereditary form of osteopretosis was related to a low level of Cathepsine

Balicatib is highly selective for CatK in enzyme assays but has lesser selectivity in living cells. In vitro studies have shown that a basic moiety in its chemical structure results in its accumulation in the acidic environment of the lysosomes at concentrations sufficient to inhibit cathepsins B and L and possibly others. Clinical studies of balicatib have demonstrated BMD increases in postmenopausal women, but treatment was associated with cutaneous adverse events. The first demonstration of the effect of cathepsin K inhibitors on bone density in humans was seen with balicatib. This trial, published by Adami et al., in an ASBMR meeting in 2009 (Denver, CO, USA) was a multicenter, randomized, placebocontrolled, 12-month, dose-range finding study of 675 postmenopausal women with lumbar spine T-score less than 2.0. In the group that received 50mg of balicatib daily, markers of bone resorption declined by more than 55% with no decline in markers of bone formation (osteocalcin, bone-specific alkaline phosphatase and N-terminal propeptide of type I

parathyroid hormone (PTH).

balicatib, relacatib, and odanacatib.

K due to a complete deficiency.

**5.1.1 Balicatib** 

border and proton pump required for hydrogen ion secretion.


Table 2. Fracture incidence at 10 years. (Reginster et al., 2010)

### **4.1.5 Adverse events**

At the end of the third year, in the phase III studies, the only adverse event that showed statistically significant differences compared to placebo was diarrhea, found in 6% of the patients taking the drug and 3.6% of the placebo group. Other adverse events found to be more frequent with strontium ranelate, but with no statistically significant difference compared to placebo, were nausea, headache, dermatitis, eczema, and thrombo-embolic events. The latter was studied thoroughly, but no relation to the drug was found. Other studies with high doses of strontium ranelate have been performed in order to investigate thrombo-embolism, but no alteration in coagulation parameters have been found to support the finding in the phase III trial. (Blake & Fogelman, 2006a; Halil et al., 2007; Liu et al., 2009; Ulger et al., 2010)

At the end of the fifth year some other events were found to be more frequent (with no statistically significant differences compared to placebo) such as memory loss, cognitive impairment and seizures. The rest of the adverse events had the same incidence in the study drug and the placebo group. (Blake & Fogelman, 2006a; Liu et al., 2009)

Strontium ranelate has been used widely in Europe and there is a rare adverse event reported to be due to treatment with this compound. Reports state that 0% to 8% of patients suffer a drug rash with eosinophilia and systemic symptoms (DRESS), which is an allergic reaction to the medication that usually appears between 3 and 6 weeks after starting treatment. This syndrome can be fatal if the medication is not stopped and treatment with glucocorticoids started. (Musette et al., 2010)

### **5. Future therapies**

#### **5.1 Cathepsine K (CatK) inhibitors**

Human cathepsin K is a 329 amino acid long protein consisting of an N-terminal 15 amino acid long signal sequence, a 99 amino acid long propeptide, and a 215 amino acid long catalytic unit. It shares about 60% protein sequence identity with cathepsins L, S, V and less than 35% with cathepsins F, O, B, H, and W. Cathepsin K is expressed predominantly in osteoclasts and various other multinucleated cells such as giant foreign body cells and Langhans cells. To a lesser degree it is found in macrophages, synovial fibroblasts, and fibroblasts at locations of wound healing or inflammation, chondrocytes, various epithelial cells of the human fetus, adult lung airway epithelium, thyroid epithelium, and possibly at low concentrations in smooth muscle cells. Once the enzyme is synthesized, it is sequestered into lysosomes and can be secreted into the extracellular environment. It is specifically secreted into the resorption lacuna underneath actively resorbing osteclasts where it is responsible for the degradation of the collagen type I dominated organic bone matrix. Thus, similarly to pycnoidisostosis, elimination of cathepsin K in osteoclasts results in inhibition of bone resorption. Inhibitors of cathepsin K are suggested to have less of an effect on

incidence 20.9% 12.9% 13.7%

At the end of the third year, in the phase III studies, the only adverse event that showed statistically significant differences compared to placebo was diarrhea, found in 6% of the patients taking the drug and 3.6% of the placebo group. Other adverse events found to be more frequent with strontium ranelate, but with no statistically significant difference compared to placebo, were nausea, headache, dermatitis, eczema, and thrombo-embolic events. The latter was studied thoroughly, but no relation to the drug was found. Other studies with high doses of strontium ranelate have been performed in order to investigate thrombo-embolism, but no alteration in coagulation parameters have been found to support the finding in the phase III trial. (Blake & Fogelman, 2006a; Halil et al., 2007; Liu et al., 2009;

At the end of the fifth year some other events were found to be more frequent (with no statistically significant differences compared to placebo) such as memory loss, cognitive impairment and seizures. The rest of the adverse events had the same incidence in the study

Strontium ranelate has been used widely in Europe and there is a rare adverse event reported to be due to treatment with this compound. Reports state that 0% to 8% of patients suffer a drug rash with eosinophilia and systemic symptoms (DRESS), which is an allergic reaction to the medication that usually appears between 3 and 6 weeks after starting treatment. This syndrome can be fatal if the medication is not stopped and treatment with

Human cathepsin K is a 329 amino acid long protein consisting of an N-terminal 15 amino acid long signal sequence, a 99 amino acid long propeptide, and a 215 amino acid long catalytic unit. It shares about 60% protein sequence identity with cathepsins L, S, V and less than 35% with cathepsins F, O, B, H, and W. Cathepsin K is expressed predominantly in osteoclasts and various other multinucleated cells such as giant foreign body cells and Langhans cells. To a lesser degree it is found in macrophages, synovial fibroblasts, and fibroblasts at locations of wound healing or inflammation, chondrocytes, various epithelial cells of the human fetus, adult lung airway epithelium, thyroid epithelium, and possibly at low concentrations in smooth muscle cells. Once the enzyme is synthesized, it is sequestered into lysosomes and can be secreted into the extracellular environment. It is specifically secreted into the resorption lacuna underneath actively resorbing osteclasts where it is responsible for the degradation of the collagen type I dominated organic bone matrix. Thus, similarly to pycnoidisostosis, elimination of cathepsin K in osteoclasts results in inhibition of bone resorption. Inhibitors of cathepsin K are suggested to have less of an effect on

drug and the placebo group. (Blake & Fogelman, 2006a; Liu et al., 2009)

glucocorticoids started. (Musette et al., 2010)

**5.1 Cathepsine K (CatK) inhibitors** 

5 years with Strontium ranelate

10 years with strontium ranelate

5 years with placebo

Table 2. Fracture incidence at 10 years. (Reginster et al., 2010)

Non-vertebral fracture

**4.1.5 Adverse events** 

Ulger et al., 2010)

**5. Future therapies** 

Vertebral fracture incidence 24.9% 18.5% 20.6

osteoclast–osteoblast interaction, resulting in less inhibition of bone formation, than available bisphosphonate antiresorptive agents. Human cathepsin K inhibitors have been shown to prevent bone loss in ovariectomized mice without blunting the anabolic action of parathyroid hormone (PTH).

Although no CatK inhibitor is currently marketed for osteoporosis treatment or prevention, studies of three CatK inhibitors for the treatment of osteoporosis have been reported: balicatib, relacatib, and odanacatib.

The most commonly used drugs for the treatment of osteoporosis inhibit osteoclastmediated bone resorption. Osteoclasts are hematopoietically derived multinucleated giant cells that resorb bone by focal attachment and demineralization, followed by the enzymatic degradation of organic bone matrix. The demineralization is achieved by the secretion of acid onto the bone surface. The organic matrix (mainly type 1 collagen, the principal bone matrix protein) is degraded primarily by the enzymatic action of cysteine proteases, particularly cathepsin K (CatK). CatK is the most abundantly expressed cysteine protease in osteoclasts and exhibits collagenolytic activity under acidic conditions. Currently treatment of osteoporosis, like bisphosphonates prevent acid secretion by disruption of the ruffled border and proton pump required for hydrogen ion secretion.

The collagenases of the matrix metalloproteinase family have been considered as the main proteases for the degradation of collagen as they were thought to be the main ones capable of cleaving triple helical collagen. However, matrix metalloproteinase are active at neutral to slightly alkaline pH values whereas at the site of bone resorption, within the resorption lacuna, acidic pH conditions prevail. Thus, acidic lysosomal hydrolases were proposed to operate as the main collagen degrading proteases. Previously, only Cathepsins B and L were known. Cathepsins B and L were thought to be the key factors, as both enzymes were known to cleave in the telopeptide region of triple helical collagens. However in the early 1990's a new cathepsine was identified thanks to DNA clonation techniques. Initially this new cathepsine was identified only in osteoclasts and was called cathepsine O, later its name changed to cathepsine K. This protease exhibited a potent collagenase activity towards the main connective tissue collagens type I and II, and immunohistochemical analyses revealed a predominant but not exclusive expression in osteoclasts. After that, pycnodysostosis, a hereditary form of osteopretosis was related to a low level of Cathepsine K due to a complete deficiency.

#### **5.1.1 Balicatib**

Balicatib is highly selective for CatK in enzyme assays but has lesser selectivity in living cells. In vitro studies have shown that a basic moiety in its chemical structure results in its accumulation in the acidic environment of the lysosomes at concentrations sufficient to inhibit cathepsins B and L and possibly others. Clinical studies of balicatib have demonstrated BMD increases in postmenopausal women, but treatment was associated with cutaneous adverse events. The first demonstration of the effect of cathepsin K inhibitors on bone density in humans was seen with balicatib. This trial, published by Adami et al., in an ASBMR meeting in 2009 (Denver, CO, USA) was a multicenter, randomized, placebocontrolled, 12-month, dose-range finding study of 675 postmenopausal women with lumbar spine T-score less than 2.0. In the group that received 50mg of balicatib daily, markers of bone resorption declined by more than 55% with no decline in markers of bone formation (osteocalcin, bone-specific alkaline phosphatase and N-terminal propeptide of type I

Pharmacological Treatment of Osteoporosis 589

The results of the extension of the phase II study to 36 months (published by Eisman et al at the ASBMR meeting 2009 in Denver, included 169 women who were randomized to odanacatib 50 mg and placebo weekly. In the odanacatib group, BMD continued to increase (lumbar spine 7.5%, total hip 5.5%, femoral neck 5.5% and trochanter 7.4%). The urine NTX resorption marker was 50% lower compared with placebo, whereas there were no differences in the BSAP (bone specific alkaline phosphatase) formation marker. At three years, formation markers were not only not reduced, but in fact increased by 18% over

ONO-5334 is a new cathepsin K inhibitor. There has been a first study to investigate the efficacy and safety of ONO-5334 in postmenopausal osteoporosis. This was a 12-month, randomized, double blind, placebo and active-controlled parallel-group study conducted in 13 centers in 6 European countries. Investigators included 285 postmenopausal women aged 55 to 75 years with osteoporosis. Subjects were randomized into one of five treatment groups: placebo; 50 mg twice daily, 100 mg once daily, or 300 mg once daily of ONO-5334; or alendronate 70mg once weekly. After a year of follow up all ONO-5334 doses and alendronate showed a significant increase in BMD at the lumbar spine, total hip (except 100 mg once daily), and femoral neck. There was little or no suppression of ONO-5334 on boneformation markers compared with alendronate, although the suppressive effects on boneresorption markers were similar. There were no clinically relevant safety concerns. With a significant increase in BMD, ONO-5334 also demonstrated a new mode of action as a potential agent for treating osteoporosis. This new drug increases the armamentarium not only in cathepsin K inhibitors (the second that seems to be available) but also in osteoporosis

In conclusion, Cathepsine K inhibitors are a new family of drugs that increase the armamentarium in the fight against fractures, as the most dangerous effect of osteoporosis. Having the possibility to treat this disease in different points of the resorption pathway is positive and it gives us the possibility to reach a better and easier way to decrease the

Sclerostosis is a rare autosomal-recessive disorder. Patients with this disease characterize for having a high bone mass. (Hamersma et al., 2003; Beighton, 1988; Barnard et al., 1980) The study of its etiopatogenesis led to the discovery of sclerostin, a protein that in humans is encoded by the SOST gene. (Balemans et al. 2001; Brunkow et al., 2001) It is classified as a key inhibitor of osteoblast-mediated bone formation. (Poole et al., 2005; Wergedal et al., 2003) Loss-of-function mutations in this gene are associated with sclerosteosis, which causes

Another similar disease is van Buchem disease, which is a milder form of sclerostosis and is caused by a deletion downstream of this gene, with a consequent reduced sclerostin expression. SOST gene knock out mice don't produce sclerostin and have a high bone mass, confirming the effect of this protein on bone mass and BMD. Besides the increase in bone mass and BMD taking place from sclerostin deficiency, there have been no reports of fractures in individuals with sclerosteosis or van Buchem disease. (Hamersma et al., 2003;

progressive bone overgrowth and increases in bone mass and BMD.

baseline values.

**5.1.4 ONO 5334** 

treatment. (Eastell et al., 2011)

**5.2 Anti-sclerostin monoclonal antibody** 

incidence of fractures.

Wergedal et al., 2003)

collagen). The BMD in the lumbar spine increased 4.46% and 2.25% in the total hip. Skin reactions, including pruritus and morphea-like changes, were noted in a small number of patients. In a small Japanese trial, intact PTH levels were shown to increase by 50% with balicatib treatment.

#### **5.1.2 Relacatib**

Relacatib is a potent but nonselective inhibitor of cathepsins K, L, V, and S for which no clinical information has been published. Administration of relacatib to ovariectomized and control monkeys resulted in an acute and rapid reduction of bone markers, and this effect lasted for up to 2 days depending on the dose delivered.

Due to side effects, especially skin reactions, drug development of all cathepsin K inhibitors has been suspended or slowed down except for odanacatib and currently ONO 5334.

#### **5.1.3 Odanacatib**

Odanacatib is a powerful, reversible nonpeptidic biaryl inhibitor of cathepsin K that inactivates the proteolytic activity of cathepsin k. It is synthesized by replacing the P2-P3 amide bond of an aminoacetronintrile dipeptide 1 with a phenyl ring. This results in a powerful, selective inhibitor with the capacity to inhibit cathepsin K in osteoclasts. (Bromme & Lecaille, 2009)

Two studies have been carried out to evaluate the efficacy and safety of odanacatib, a phase I study to determine the dose and a phase II study to evaluate the safety and efficacy. In the Phase I study a group of 49 women was used to evaluate a weekly dose. Doses of 5mg, 25 mg, 50mg, and 100 mg were used and 12 women were assigned to the placebo group. A group of 30 women was used to evaluate the daily dose. Doses of 0.5, 2.5, and 10mg were used, with 6 women assigned to the placebo group. All doses were administered in fasting conditions. Odanacatib had a long half-life of between 66 and 93 hours for all the regimes and doses used. The efficacy of weekly, and daily doses in modifying the markers was evaluated. The effect was dose-dependant although not dose proportional. Reductions in resorption markers were greatest for doses *>*50 mg weekly and doses *≥*2.5mg daily. Maximum suppression was achieved between day 3 and day 5 with the weekly dose and was maintained until the following dose. (Stoch et al., 2009)

The Phase II trial published by Cusick et al in the ASBMR meeting in 2009 (Denver, Co, USA), was a double-blind, randomized, placebo-controlled trial of 12 months duration with an anticipated extension period of 24 months. It included 399 post-menopausal women (postmenopausal (5yr) or bilateral oophorectomy) between 45 and 85 years,with a T-score *<- 2* but not less than -3.5 at any site. Patients were divided into five groups according to the dose: placebo, 3 mg/weekly, 10 mg/weekly, 25mg/weekly and 50 mg/weekly. The changes in BMD at the lumbar spine were assessed and considered a primary objective. Also changes in bone remodeling, changes in BMD in other sites and adverse effects were evaluated. The results showed a dose-dependant increase in BMD in all sites. The greatest increase was obtained with the highest dose. Weekly administration of 50mg of odanacatib increased bone mass by 5.7% in the lumbar spine, 4.1% in the total hip, 4.7% in the femoral neck, 5.2% in the trochanter and 2.9% in the distal third of the radius at 24 months. Resorption markers fell in a dose-dependant manner from the beginning of treatment and remained reduced during the first six months, after which they increased and the differences with placebo disappeared.

The results of the extension of the phase II study to 36 months (published by Eisman et al at the ASBMR meeting 2009 in Denver, included 169 women who were randomized to odanacatib 50 mg and placebo weekly. In the odanacatib group, BMD continued to increase (lumbar spine 7.5%, total hip 5.5%, femoral neck 5.5% and trochanter 7.4%). The urine NTX resorption marker was 50% lower compared with placebo, whereas there were no differences in the BSAP (bone specific alkaline phosphatase) formation marker. At three years, formation markers were not only not reduced, but in fact increased by 18% over baseline values.

#### **5.1.4 ONO 5334**

588 Osteoporosis

collagen). The BMD in the lumbar spine increased 4.46% and 2.25% in the total hip. Skin reactions, including pruritus and morphea-like changes, were noted in a small number of patients. In a small Japanese trial, intact PTH levels were shown to increase by 50% with

Relacatib is a potent but nonselective inhibitor of cathepsins K, L, V, and S for which no clinical information has been published. Administration of relacatib to ovariectomized and control monkeys resulted in an acute and rapid reduction of bone markers, and this effect

Due to side effects, especially skin reactions, drug development of all cathepsin K inhibitors

Odanacatib is a powerful, reversible nonpeptidic biaryl inhibitor of cathepsin K that inactivates the proteolytic activity of cathepsin k. It is synthesized by replacing the P2-P3 amide bond of an aminoacetronintrile dipeptide 1 with a phenyl ring. This results in a powerful, selective inhibitor with the capacity to inhibit cathepsin K in osteoclasts. (Bromme

Two studies have been carried out to evaluate the efficacy and safety of odanacatib, a phase I study to determine the dose and a phase II study to evaluate the safety and efficacy. In the Phase I study a group of 49 women was used to evaluate a weekly dose. Doses of 5mg, 25 mg, 50mg, and 100 mg were used and 12 women were assigned to the placebo group. A group of 30 women was used to evaluate the daily dose. Doses of 0.5, 2.5, and 10mg were used, with 6 women assigned to the placebo group. All doses were administered in fasting conditions. Odanacatib had a long half-life of between 66 and 93 hours for all the regimes and doses used. The efficacy of weekly, and daily doses in modifying the markers was evaluated. The effect was dose-dependant although not dose proportional. Reductions in resorption markers were greatest for doses *>*50 mg weekly and doses *≥*2.5mg daily. Maximum suppression was achieved between day 3 and day 5 with the weekly dose and

The Phase II trial published by Cusick et al in the ASBMR meeting in 2009 (Denver, Co, USA), was a double-blind, randomized, placebo-controlled trial of 12 months duration with an anticipated extension period of 24 months. It included 399 post-menopausal women (postmenopausal (5yr) or bilateral oophorectomy) between 45 and 85 years,with a T-score *<- 2* but not less than -3.5 at any site. Patients were divided into five groups according to the dose: placebo, 3 mg/weekly, 10 mg/weekly, 25mg/weekly and 50 mg/weekly. The changes in BMD at the lumbar spine were assessed and considered a primary objective. Also changes in bone remodeling, changes in BMD in other sites and adverse effects were evaluated. The results showed a dose-dependant increase in BMD in all sites. The greatest increase was obtained with the highest dose. Weekly administration of 50mg of odanacatib increased bone mass by 5.7% in the lumbar spine, 4.1% in the total hip, 4.7% in the femoral neck, 5.2% in the trochanter and 2.9% in the distal third of the radius at 24 months. Resorption markers fell in a dose-dependant manner from the beginning of treatment and remained reduced during the first six months, after which they increased and the differences with placebo

has been suspended or slowed down except for odanacatib and currently ONO 5334.

lasted for up to 2 days depending on the dose delivered.

was maintained until the following dose. (Stoch et al., 2009)

balicatib treatment.

**5.1.2 Relacatib** 

**5.1.3 Odanacatib** 

& Lecaille, 2009)

disappeared.

ONO-5334 is a new cathepsin K inhibitor. There has been a first study to investigate the efficacy and safety of ONO-5334 in postmenopausal osteoporosis. This was a 12-month, randomized, double blind, placebo and active-controlled parallel-group study conducted in 13 centers in 6 European countries. Investigators included 285 postmenopausal women aged 55 to 75 years with osteoporosis. Subjects were randomized into one of five treatment groups: placebo; 50 mg twice daily, 100 mg once daily, or 300 mg once daily of ONO-5334; or alendronate 70mg once weekly. After a year of follow up all ONO-5334 doses and alendronate showed a significant increase in BMD at the lumbar spine, total hip (except 100 mg once daily), and femoral neck. There was little or no suppression of ONO-5334 on boneformation markers compared with alendronate, although the suppressive effects on boneresorption markers were similar. There were no clinically relevant safety concerns. With a significant increase in BMD, ONO-5334 also demonstrated a new mode of action as a potential agent for treating osteoporosis. This new drug increases the armamentarium not only in cathepsin K inhibitors (the second that seems to be available) but also in osteoporosis treatment. (Eastell et al., 2011)

In conclusion, Cathepsine K inhibitors are a new family of drugs that increase the armamentarium in the fight against fractures, as the most dangerous effect of osteoporosis. Having the possibility to treat this disease in different points of the resorption pathway is positive and it gives us the possibility to reach a better and easier way to decrease the incidence of fractures.

### **5.2 Anti-sclerostin monoclonal antibody**

Sclerostosis is a rare autosomal-recessive disorder. Patients with this disease characterize for having a high bone mass. (Hamersma et al., 2003; Beighton, 1988; Barnard et al., 1980) The study of its etiopatogenesis led to the discovery of sclerostin, a protein that in humans is encoded by the SOST gene. (Balemans et al. 2001; Brunkow et al., 2001) It is classified as a key inhibitor of osteoblast-mediated bone formation. (Poole et al., 2005; Wergedal et al., 2003) Loss-of-function mutations in this gene are associated with sclerosteosis, which causes progressive bone overgrowth and increases in bone mass and BMD.

Another similar disease is van Buchem disease, which is a milder form of sclerostosis and is caused by a deletion downstream of this gene, with a consequent reduced sclerostin expression. SOST gene knock out mice don't produce sclerostin and have a high bone mass, confirming the effect of this protein on bone mass and BMD. Besides the increase in bone mass and BMD taking place from sclerostin deficiency, there have been no reports of fractures in individuals with sclerosteosis or van Buchem disease. (Hamersma et al., 2003; Wergedal et al., 2003)

Pharmacological Treatment of Osteoporosis 591

Bazedoxifene: bazedoxifene acetate, TSE 424, TSE-424, WAY 140424. 2008. Drugs in R&D,

Adomaityte, J., Farooq, M. and Qayyum, R., 2008. Effect of raloxifene therapy on venous

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Arlot, M.E., Jiang, Y., Genant, H.K., Zhao, J., Burt-Pichat, B., Roux, J.P., Delmas, P.D. and

Balemans, W., Ebeling, M., Patel, N., Van Hul, E., Olson, P., Dioszegi, M., Lacza, C., Wuyts,

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2000. No difference in intestinal strontium absorption after oral or IV calcitriol in children with secondary hyperparathyroidism. The European Study Group on Vitamin D in Children with Renal Failure. Kidney international, 58(3), pp. 981-988.

Meunier, P.J., 2008. Histomorphometric and microCT analysis of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate. Journal of bone and mineral research : the official journal of the American Society for Bone

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**7. References** 

*9(3), pp. 191-196.* 

haemostasis, 99(2), pp. 338-342.

Nature, 390(6656), pp. 175-179.

Sclerostin binds to low-density lipoprotein receptor-related protein (LRP) 5/6 and blocks Wnt-signaling, negatively regulating bone formation and in that way, inhibiting osteoblast differentiation, proliferation, and activity. (Baron & Rawadi 2007) Thus, the inhibition of sclerostin was thought to have therapeutic potential in treating human bone metabolism defects such as systemic bone loss, focal bone loss, fracture healing, and orthopedic procedures where increases in bone formation, bone mass, bone mineral density (BMD), and consequently bone strength, are sought-after. (Ott, 2005)

#### **5.2.1 Sclerostin inhibition**

Rats treated with a sclerostin antibody experience a reversal of estrogen deficiency induced bone loss at several skeletal sites. Additionally, an increase in bone mass and strength is observed in treated rats compared with controls. Similar results were observed in treated monkeys. In models of fracture healing in mice and rats, treatment with a sclerostin antibody increased bridging and bone strength at sites of fracture, resulting in enhanced bone healing compared with controls. (Padhi et al., 2011)

AMG 785 is a high affinity immunoglobulin G2 (IgG2) monoclonal antibody generated by humanizing a mouse sclerostin monoclonal antibody that neutralizes sclerostin. The first-inhuman single-dose study in healthy men and postmenopausal women was performed to evaluate pharmacokinetics, pharmacodynamics, tolerability and safety of doses of 0.1, 0.3, 1, 3, 5 or 10 mg/kg sub-cutaneus and 1 or 10 mg/kg intravenous of AMG 785. A total of 72 subjects participated in the study and were followed for up to 85 days. Study product pharmacokinetics was nonlinear with dose. Dose-related increases in bone formation markers and decreases in bone resorption markers were observed. A small percentage of the patients developed anti-investigational product bodies but most of them were nonneutralizing antibodies. The medication was well tolerated. (Padhi et al., 2011) A phase II study of 419 postmenopausal women with low BMD has been started to compare the efficacy of sclerostin neutralization with alendronate and teriparatide. (Rachner et al., 2011) Finally, a multicenter, phase IIa, randomized double-blind, placebo controlled, multi-dose study is ongoing to evaluate safety, tolerability, pharmacokinetics, and phamacodynamics of AMG 785 in postmenopausal women with low bone mass. In conclusion, anti sclerostin antibody treatment could be the most effective treatment for osteoporosis and bone defect related diseases. Even though, we will have to wait until all the ongoing and planned trials are over to analyze the data and have access to this kind of treatment.

### **6. Conclusion**

During the last 10 years, new therapeutic agents have emerged among the pharmacological treatment options for osteoporosis. The newer options belong to new families with optimized mechanisms of action, allowing us to restore the lost bone mass quicker and more effectively than with the old medications. Nevertheless, one has to be conscious that all treatment options have specific indications and a wide range of adverse events, that have to be taken into consideration before making any decision. Moreover, it has to be remembered that most treatments for osteoporosis have to be given concomitantly with changes in lifestyle and/or calcium and vitamin D supplementation. New therapies are in development that probably will allow us to treat for a shorter time obtaining better results for our patients.

### **7. References**

590 Osteoporosis

Sclerostin binds to low-density lipoprotein receptor-related protein (LRP) 5/6 and blocks Wnt-signaling, negatively regulating bone formation and in that way, inhibiting osteoblast differentiation, proliferation, and activity. (Baron & Rawadi 2007) Thus, the inhibition of sclerostin was thought to have therapeutic potential in treating human bone metabolism defects such as systemic bone loss, focal bone loss, fracture healing, and orthopedic procedures where increases in bone formation, bone mass, bone mineral density (BMD), and

Rats treated with a sclerostin antibody experience a reversal of estrogen deficiency induced bone loss at several skeletal sites. Additionally, an increase in bone mass and strength is observed in treated rats compared with controls. Similar results were observed in treated monkeys. In models of fracture healing in mice and rats, treatment with a sclerostin antibody increased bridging and bone strength at sites of fracture, resulting in enhanced

AMG 785 is a high affinity immunoglobulin G2 (IgG2) monoclonal antibody generated by humanizing a mouse sclerostin monoclonal antibody that neutralizes sclerostin. The first-inhuman single-dose study in healthy men and postmenopausal women was performed to evaluate pharmacokinetics, pharmacodynamics, tolerability and safety of doses of 0.1, 0.3, 1, 3, 5 or 10 mg/kg sub-cutaneus and 1 or 10 mg/kg intravenous of AMG 785. A total of 72 subjects participated in the study and were followed for up to 85 days. Study product pharmacokinetics was nonlinear with dose. Dose-related increases in bone formation markers and decreases in bone resorption markers were observed. A small percentage of the patients developed anti-investigational product bodies but most of them were nonneutralizing antibodies. The medication was well tolerated. (Padhi et al., 2011) A phase II study of 419 postmenopausal women with low BMD has been started to compare the efficacy of sclerostin neutralization with alendronate and teriparatide. (Rachner et al., 2011) Finally, a multicenter, phase IIa, randomized double-blind, placebo controlled, multi-dose study is ongoing to evaluate safety, tolerability, pharmacokinetics, and phamacodynamics of AMG 785 in postmenopausal women with low bone mass. In conclusion, anti sclerostin antibody treatment could be the most effective treatment for osteoporosis and bone defect related diseases. Even though, we will have to wait until all the ongoing and planned trials

During the last 10 years, new therapeutic agents have emerged among the pharmacological treatment options for osteoporosis. The newer options belong to new families with optimized mechanisms of action, allowing us to restore the lost bone mass quicker and more effectively than with the old medications. Nevertheless, one has to be conscious that all treatment options have specific indications and a wide range of adverse events, that have to be taken into consideration before making any decision. Moreover, it has to be remembered that most treatments for osteoporosis have to be given concomitantly with changes in lifestyle and/or calcium and vitamin D supplementation. New therapies are in development that probably will allow us to treat for a shorter time obtaining better results for our

consequently bone strength, are sought-after. (Ott, 2005)

bone healing compared with controls. (Padhi et al., 2011)

are over to analyze the data and have access to this kind of treatment.

**5.2.1 Sclerostin inhibition** 

**6. Conclusion** 

patients.


Pharmacological Treatment of Osteoporosis 593

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years of age and older. J Bone Miner Res, 21(7), pp. 1113-20.

1038-1042.

Research, 25(11), pp. 2267-2294.

chemicals, 38(9), pp. 1471-1479.

Mineral Research, 23(12), pp. 1923-1934.

journal of medicine, 325(11), pp. 756-762.

therapeutics, 86(2), pp. 175-182.

and quality of remaining life-years in women over 80 years of age. Bone, 46(4), pp.

Varela, A.R., Fiore, C., Brixen, K., Reginster, J.Y. and Boonen, S., 2006. Strontium ranelate reduces the risk of vertebral and nonvertebral fractures in women eighty

Cosman, F., Curtis, J.R., Dell, R., Dempster, D., Einhorn, T.A., Genant, H.K., Geusens, P., Klaushofer, K., Koval, K., Lane, J.M., Mckiernan, F., Mckinney, R., Ng, A., Nieves, J., O'keefe, R., Papapoulos, S., Sen, H.T., Van Der Meulen, M.C., Weinstein, R.S., Whyte, M. And American Society For Bone and Mineral Research, 2010. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral


**29** 

*Spain* 

Marta Lamarca

*Department of Gynecology,* 

*Miguel Servet University Hospital, Zaragoza,* 

**The Role of Hormone Replacement Therapy** 

**Treatment of Postmenopausal Osteoporosis** 

Life expectancy has increased considerably in recent decades thanks to the improvement of measures for health protection and disease prevention as well as improvements in the quality of health systems. While in the middle of last century the average life expectancy of a woman was about 50 years, today there are over 350 million women older than 60. Furthermore, from the perspective of developed countries, postmenopause is a stage that spans more than one third of the life of a woman. That is why the research on the

The decrease in sex steroid production by the ovary that occurs in perimenopause and menopause is associated with a rapid loss of bone mass due to increased resorption. In the past two decades, multiple observational studies have noted the beneficial effect of hormone replacement therapy (HRT) in postmenopausal women's health, based mainly on the relief of symptoms associated with estrogen deprivation such as vasomotor and genitourinary symptoms. These studies also indicated a preventive effect on aging-related diseases such as osteoporosis. Estrogens have been shown to be effective in increasing bone mineral density (BMD) and prevent fractures, but information on side effects from long use has reduced

Tibolone is a synthetic steroid used in the treatment of postmenopausal symptoms and

Although the intimate mechanisms of control of bone remodelling are not still completely known, we do have enough information to say that estrogens have a role in the homeostasis of the skeleton, which is why their decline is associated with reduced bone mass, impaired

The following chapter discusses the role of estrogen therapy and tibolone in the prevention

Studies with English language abstracts identified in MEDLINE, HealthSTAR, and Cochrane Library databases from 1990 to 2010 are reviewed. Reference lists of key articles

pathophysiology and treatment of menopause has become necessary and important.

their use for the treatment of osteoporosis (Tamborini & Ruiz, 2004).

decreased libido that has an estrogen agonist effect on bone.

in the microarchitecture and increased risk of fracture.

and treatment of postmenopausal osteoporosis.

**2. Literature search** 

**1. Introduction** 

**(HRT) and Tibolone in the Prevention and** 

Yonemori, K., Fujiwara, Y., Minami, H., Kitagawa, K., Fujii, H., Arai, T., Sohn, W., Ohkura, M. and Ohtsu, T., 2008. Phase 1 trial of denosumab safety, pharmacokinetics, and pharmacodynamics in Japanese women with breast cancer-related bone metastases. Cancer science, 99(6), pp. 1237-1242.

## **The Role of Hormone Replacement Therapy (HRT) and Tibolone in the Prevention and Treatment of Postmenopausal Osteoporosis**

Marta Lamarca *Department of Gynecology, Miguel Servet University Hospital, Zaragoza, Spain* 

### **1. Introduction**

608 Osteoporosis

Yonemori, K., Fujiwara, Y., Minami, H., Kitagawa, K., Fujii, H., Arai, T., Sohn, W., Ohkura,

Cancer science, 99(6), pp. 1237-1242.

M. and Ohtsu, T., 2008. Phase 1 trial of denosumab safety, pharmacokinetics, and pharmacodynamics in Japanese women with breast cancer-related bone metastases.

> Life expectancy has increased considerably in recent decades thanks to the improvement of measures for health protection and disease prevention as well as improvements in the quality of health systems. While in the middle of last century the average life expectancy of a woman was about 50 years, today there are over 350 million women older than 60. Furthermore, from the perspective of developed countries, postmenopause is a stage that spans more than one third of the life of a woman. That is why the research on the pathophysiology and treatment of menopause has become necessary and important.

> The decrease in sex steroid production by the ovary that occurs in perimenopause and menopause is associated with a rapid loss of bone mass due to increased resorption. In the past two decades, multiple observational studies have noted the beneficial effect of hormone replacement therapy (HRT) in postmenopausal women's health, based mainly on the relief of symptoms associated with estrogen deprivation such as vasomotor and genitourinary symptoms. These studies also indicated a preventive effect on aging-related diseases such as osteoporosis. Estrogens have been shown to be effective in increasing bone mineral density (BMD) and prevent fractures, but information on side effects from long use has reduced their use for the treatment of osteoporosis (Tamborini & Ruiz, 2004).

> Tibolone is a synthetic steroid used in the treatment of postmenopausal symptoms and decreased libido that has an estrogen agonist effect on bone.

> Although the intimate mechanisms of control of bone remodelling are not still completely known, we do have enough information to say that estrogens have a role in the homeostasis of the skeleton, which is why their decline is associated with reduced bone mass, impaired in the microarchitecture and increased risk of fracture.

> The following chapter discusses the role of estrogen therapy and tibolone in the prevention and treatment of postmenopausal osteoporosis.

#### **2. Literature search**

Studies with English language abstracts identified in MEDLINE, HealthSTAR, and Cochrane Library databases from 1990 to 2010 are reviewed. Reference lists of key articles

The Role of Hormone Replacement Therapy (HRT) and

JNK signal (Srivastava et al., 2001).

secretion of PTH and calcitonin.

**3.1.2 Androgens and bone** 

Tibolone in the Prevention and Treatment of Postmenopausal Osteoporosis 611

have also shown the ability to inhibit TRAP expression or inhibit certain steps in the RANK-

The current idea of the action of estrogen is that it is through different pathways. There is, first, an antiapoptotic effect of estradiol on osteoblasts and osteocytes due to rapid nongenomic action (Kousteni et al., 2001). It has succeeded in synthesizing a ligand called ESTREN that act exclusively through this channel, and theoretically could have the same effect as estrogens on bone without the genomic consequences of these. This model has been named to a new class of pharmacological agents called ANGELS (Activators of NonGenotropics Estrogens Like Signalins), and there would be another apoptotic action on osteoclasts (Manolagas et al., 1995). The actions of estrogen on bone cells, are inhibition of bone resorption by decreasing the synthesis or response to interleukins such as IL-6, IL-1 and TNF-α with less differentiation of precursor cells into osteoclasts by increasing IL-4. Among other effects, estrogens decrease lytic enzyme activity of osteoclasts and produce changes in growth factors insulin-like IGF-I, IGF-II and interferon types α, β and γ. The effect of estrogen is mediated in part by growth factors and interleukins such as IL-6, which is a potent stimulator of bone resorption by blocking estrogen synthesis by osteoblasts. Estrogen may also antagonize the interleukin receptors. The apoptosis of osteoclasts is also regulated by estrogens. Faced with reduced levels of estrogen, osteoclasts live longer and have greater capacity of absorption. Estrogens regulate tumor growth factor system associated with the RANK/RANK-L resulting in a decrease in the activity of osteoclasts. They also stimulate the production of osteoprotegerin (OPG) by osteoblasts. Thus, the presence of estrogen prevents binding of RANK-L to RANK resulting in inhibition of the formation, differentiation and survival of osteoclasts (Eghbali-Fatourechi et al., 2003). In response to increased bone resorption, it exists an increase in bone formation, creating a high turnover that leads to bone loss and deterioration in the microarchitecture. In the first 5 years since menopause, a substantial disruption of the trabecular architecture can be observed, demonstrated by the analysis of iliac crest biopsies using computed microtomography techniques (Issever et al., 2002). Once broken the continuity of a

trabecula, we can increase thickness, but will not get a new connectivity.

We could conclude that steroid hormones are involved with a complex action system clearly influencing the bone marrow regulation. They are part of the mechanism regulating RANK-RANKL-osteoprotegerin, whose predominant action is bone resorption, and it is performed through genomic and nongenomic actions. In addition, estrogens also act through indirect mechanisms of action such as reducing the sensitivity of the bone to resorptive effects of parathyroid hormone (PTH), acting as antiresorptive agents. They produce an initial decrease in serum calcium and, therefore, a transient increase in PTH and calcitonin secondary modifications. Due to the increase in α 1-hydroxylase activity and phosphorus decreased, they produce an increase in hydroxyvitamin D3. Estrogens also increase the intestinal absorption and decrease renal excretion of calcium, and have direct effects on the

Androgens have a profound effect on bone and muscle physiology in women. Both for their intrinsic activity as for their conversion to estrogens, androgens have a modulatory effect on bone remodelling cycle. The androgen deficiency, like estrogen, may facilitate the development of osteoporosis. Androgenic anabolic steroids are sometimes used in the

and meta-analyses have also been reviewed. We used all published studies of HRT and tibolone if they contained a comparison group of HRT nonusers and reported data relating to HRT use and clinical outcomes of interest. Studies have been excluded if the population was selected according to prior events or presence of conditions associated with higher risks for targeted outcomes.

### **3. Hormone replacement therapy (HRT)**

### **3.1 Effect of sex steroids on bone**

The possible adverse effects of estrogen deficiency on the bone metabolism are known since the 40 decade (Albright, 1940, 1947). The first studies confirmed a higher rate of oophorectomies among osteoporotic women than in general population, and that the surgical treatment had place earlier than the age for natural menopause. These studies also showed that the negative balance of osteoporosis was normalized with the administration of estrogen. Thus it was postulated that estrogen somehow stimulated the action of osteoblasts, which is now accepted as one of the potential mechanisms of action of estrogen on bone mass (Lindsay, 1995).

Oophorectomized and postmenopausal women have decreased circulating levels of other steroids in addition to estrogens (Lindsay, 1995). In women, circulating androgen concentrations are in the order of nanomoles or micromoles while estrogens do so at concentrations on the order of picomoles. The concept of androgen deficiency syndrome is relatively old, but in recent years there has been a renewed interest in the subject.

The premenopausal ovary produces significant amounts of progesterone during the luteal phase of each cycle. Progesterone appears to act directly on bone turnover and may play a role in the relationship between bone resorption and new bone formation (Prior, 1990).

Although we do not yet fully understand the bone turnover process or control, there is sufficient information to conclude that sex steroids play an important role in skeletal homeostasis. The lack of secretion of ovarian sex steroids results in a net loss of bone tissue. When given to women with deficiency of sex steroids, these hormones reverse many of the effects related to loss of ovarian function. Therefore, it has been suggested that postmenopausal women should take HRT long term to prevent these negative effects, including osteoporosis and fractures.

#### **3.1.1 Estrogens and bone**

With the decrease in estrogen levels that occurs at menopause, there is an increase of bone remodelling with a loss of balance between formation/resorption, predominantly the latter. HRT decreases the elevated levels of resorption to those before menopause. Bone cells have estrogen receptors (Vidal et al., 1999). The most important action of estrogen on bone is to inhibit bone resorption. This action indirectly regulates the production of cytokines and growth factors in osteoblasts. Since there are estrogen receptors in osteoclasts, may also be logical to think that there is a direct action. Inhibition of bone resorption by estrogen is probably the conclusion of inducing apoptosis in osteoclasts (Kameda et al., 1997), this action being probably due to increased TGF-β. Estrogens have shown to increase the proliferation of osteoblasts and the expression of different genes that encode enzymes, bone matrix proteins, transcription factors, hormone receptors, growth factors and cytokines. However, these results have varied depending on crop models (Manolagas, 2000). Estrogens

and meta-analyses have also been reviewed. We used all published studies of HRT and tibolone if they contained a comparison group of HRT nonusers and reported data relating to HRT use and clinical outcomes of interest. Studies have been excluded if the population was selected according to prior events or presence of conditions associated with higher risks

The possible adverse effects of estrogen deficiency on the bone metabolism are known since the 40 decade (Albright, 1940, 1947). The first studies confirmed a higher rate of oophorectomies among osteoporotic women than in general population, and that the surgical treatment had place earlier than the age for natural menopause. These studies also showed that the negative balance of osteoporosis was normalized with the administration of estrogen. Thus it was postulated that estrogen somehow stimulated the action of osteoblasts, which is now accepted as one of the potential mechanisms of action of estrogen on bone

Oophorectomized and postmenopausal women have decreased circulating levels of other steroids in addition to estrogens (Lindsay, 1995). In women, circulating androgen concentrations are in the order of nanomoles or micromoles while estrogens do so at concentrations on the order of picomoles. The concept of androgen deficiency syndrome is

The premenopausal ovary produces significant amounts of progesterone during the luteal phase of each cycle. Progesterone appears to act directly on bone turnover and may play a role in the relationship between bone resorption and new bone formation (Prior, 1990). Although we do not yet fully understand the bone turnover process or control, there is sufficient information to conclude that sex steroids play an important role in skeletal homeostasis. The lack of secretion of ovarian sex steroids results in a net loss of bone tissue. When given to women with deficiency of sex steroids, these hormones reverse many of the effects related to loss of ovarian function. Therefore, it has been suggested that postmenopausal women should take HRT long term to prevent these negative effects,

With the decrease in estrogen levels that occurs at menopause, there is an increase of bone remodelling with a loss of balance between formation/resorption, predominantly the latter. HRT decreases the elevated levels of resorption to those before menopause. Bone cells have estrogen receptors (Vidal et al., 1999). The most important action of estrogen on bone is to inhibit bone resorption. This action indirectly regulates the production of cytokines and growth factors in osteoblasts. Since there are estrogen receptors in osteoclasts, may also be logical to think that there is a direct action. Inhibition of bone resorption by estrogen is probably the conclusion of inducing apoptosis in osteoclasts (Kameda et al., 1997), this action being probably due to increased TGF-β. Estrogens have shown to increase the proliferation of osteoblasts and the expression of different genes that encode enzymes, bone matrix proteins, transcription factors, hormone receptors, growth factors and cytokines. However, these results have varied depending on crop models (Manolagas, 2000). Estrogens

relatively old, but in recent years there has been a renewed interest in the subject.

for targeted outcomes.

mass (Lindsay, 1995).

**3. Hormone replacement therapy (HRT)** 

**3.1 Effect of sex steroids on bone** 

including osteoporosis and fractures.

**3.1.1 Estrogens and bone** 

have also shown the ability to inhibit TRAP expression or inhibit certain steps in the RANK-JNK signal (Srivastava et al., 2001).

The current idea of the action of estrogen is that it is through different pathways. There is, first, an antiapoptotic effect of estradiol on osteoblasts and osteocytes due to rapid nongenomic action (Kousteni et al., 2001). It has succeeded in synthesizing a ligand called ESTREN that act exclusively through this channel, and theoretically could have the same effect as estrogens on bone without the genomic consequences of these. This model has been named to a new class of pharmacological agents called ANGELS (Activators of NonGenotropics Estrogens Like Signalins), and there would be another apoptotic action on osteoclasts (Manolagas et al., 1995). The actions of estrogen on bone cells, are inhibition of bone resorption by decreasing the synthesis or response to interleukins such as IL-6, IL-1 and TNF-α with less differentiation of precursor cells into osteoclasts by increasing IL-4. Among other effects, estrogens decrease lytic enzyme activity of osteoclasts and produce changes in growth factors insulin-like IGF-I, IGF-II and interferon types α, β and γ. The effect of estrogen is mediated in part by growth factors and interleukins such as IL-6, which is a potent stimulator of bone resorption by blocking estrogen synthesis by osteoblasts. Estrogen may also antagonize the interleukin receptors. The apoptosis of osteoclasts is also regulated by estrogens. Faced with reduced levels of estrogen, osteoclasts live longer and have greater capacity of absorption. Estrogens regulate tumor growth factor system associated with the RANK/RANK-L resulting in a decrease in the activity of osteoclasts. They also stimulate the production of osteoprotegerin (OPG) by osteoblasts. Thus, the presence of estrogen prevents binding of RANK-L to RANK resulting in inhibition of the formation, differentiation and survival of osteoclasts (Eghbali-Fatourechi et al., 2003). In response to increased bone resorption, it exists an increase in bone formation, creating a high turnover that leads to bone loss and deterioration in the microarchitecture. In the first 5 years since menopause, a substantial disruption of the trabecular architecture can be observed, demonstrated by the analysis of iliac crest biopsies using computed microtomography techniques (Issever et al., 2002). Once broken the continuity of a trabecula, we can increase thickness, but will not get a new connectivity.

We could conclude that steroid hormones are involved with a complex action system clearly influencing the bone marrow regulation. They are part of the mechanism regulating RANK-RANKL-osteoprotegerin, whose predominant action is bone resorption, and it is performed through genomic and nongenomic actions. In addition, estrogens also act through indirect mechanisms of action such as reducing the sensitivity of the bone to resorptive effects of parathyroid hormone (PTH), acting as antiresorptive agents. They produce an initial decrease in serum calcium and, therefore, a transient increase in PTH and calcitonin secondary modifications. Due to the increase in α 1-hydroxylase activity and phosphorus decreased, they produce an increase in hydroxyvitamin D3. Estrogens also increase the intestinal absorption and decrease renal excretion of calcium, and have direct effects on the secretion of PTH and calcitonin.

### **3.1.2 Androgens and bone**

Androgens have a profound effect on bone and muscle physiology in women. Both for their intrinsic activity as for their conversion to estrogens, androgens have a modulatory effect on bone remodelling cycle. The androgen deficiency, like estrogen, may facilitate the development of osteoporosis. Androgenic anabolic steroids are sometimes used in the

The Role of Hormone Replacement Therapy (HRT) and

1993).

**3.2 HRT - Type, dose** 

postmenopausal women.

Tibolone in the Prevention and Treatment of Postmenopausal Osteoporosis 613

osteoclasts. However, the effects of progestagens on bone are not clear. A study about the activity of a "pure progestogen" on human osteogenic osteosarcoma cells did not observe any effect on cell proliferation when progestins were added alone to culture, but after the combined administration with 17β-estradiol, a strong action synergistically was confirmed on the proliferation of osteosarcoma cells. Moreover, other studies show that some synthetic progestins produce their effects through the activation of the estrogen receptor (Jordan et al.,

Almost all information about the effects of estrogens on the bone come from the use of estradiol and conjugated equine estrogens (CEE). Isolated estrone also has a beneficial effect on bone, and it seems that estriol does not have an obvious role in skeletal production in

The route of administration, oral or transdermal, does not imply differences in the beneficial effect on bone (Hillard et al., 1994). The estrogenic pulsotherapy has also shown a normalization of the markers of resorption and formation to premenopausal values after 3 months of treatment at doses of 300 mcg/day. The increase in BMD at this dose is similar to that found with 50 mcg/day of transdermal 17-beta-estradiol, providing significant differences in the measurement of BMD over baseline in spine and hip in the evaluation performed after 56 weeks treatment (Palacios et al., 2002). In women with uterus is necessary to administer a progestin to counteract endometrial proliferation induced by estrogen. The dosing regimen of progestin does not influence the beneficial effect of

Significant BMD improvements have also been noted with systemic estrogen doses delivered via a vaginal ring. In an randomized controlled trial of 174 postmenopausal women younger than age 65, daily doses of 0.05 and 0.1 mg of estradiol acetate delivered via the ring significantly increased hip BMD (1.7% and 1.8%, respectively) and lumbar spine

It has been established that a dose range of estradiol between 40 and 50 pg/ml is enough to increase BMD, although a safe level is 60 pg/ml. A dose-response study indicated that daily doses would have more generalizable effect: 0.625 mg of conjugated equine estrogens (CEE), or their equivalents: 0.05 mg of transdermal 17-beta-estradiol or 15 mcg of oral ethinyl estradiol (EE). The standard dose preserves bone mass in at least 80% of postmenopausal women (Table 1). These doses of estrogen and progestogen can induce side effects in both regimes (continuous and sequential), being the most frequent irregular bleeding and breast tenderness. To minimize these undesirable effects, the use of low doses has shown to be also effective in improving menopausal symptoms and quality of life and prevent or reverse

The loss of bone mass and the incidence of vertebral and hip fractures are inversely related to circulating estrogen levels. It has been confirmed that in elderly women estrogen circulating levels of 10 pg/ml improves both BMD and fracture rate. Any increase in estrogen levels has a beneficial effect especially in older women, even when the ultra-low dose is given (25% of the standard dose) (Simon & Snabe, 2007). Neither age nor initial BMD do seem to affect the effectiveness of patterns of low-dose. The effect of low doses of estrogen in women with low BMD has been analized in a randomized, double-blind, placebo-controlled trial, using CEE 0.3 mg/day and 2.5 mg/day of progesterone in women over 65 years and low BMD, in which after 3.5 years of follow up, an increase in vertebral

estrogen on the bone so the choice is given by the characteristics of women.

BMD (2.7% and 3.3%) compared with baseline (Al-Azzawi et al., 2005).

bone loss in postmenopausal women (Delmas et al., 2000).

treatment of osteoporosis but their use is limited by side effects of virilizing type. Evidence of the effects of androgens on bone mass comes from women with polycystic ovary syndrome or steroid-secreting ovarian tumors in which there is an increase in bone mineral density (Gregoriou et al., 2000). On the other hand, we know that the combination of androgens and estrogens for hormone replacement therapy in menopausal women is associated with increased bone mass above that observed with estrogen alone (Castelo-Branco et al., 2000). A cohort study developed to assess BMD in postmenopausal women using estradiol and testosterone hormonal implants comparing to that of patients without hormonal therapy, confirmed that BMD variance between the groups in the period of 1 year was significantly different, and concluded that the combination of estradiol and testosterone promoted bone protection in postmenopausal women (Britto et al., 2011).

Androgen receptors have been identified in osteoblasts, osteoclasts and osteocytes. Androgens stimulate the proliferation and differentiation of osteoblasts, stimulate the synthesis of extracellular matrix proteins, and stimulate mineralization. These steroids affect the functionality of bone cells through their effects on local factors that control bone cell microenvironment, have proapoptotic effects on osteoblasts and osteocytes, and increase strength and muscle. This ultimately leads to increased physical activity and this in turn to activation of bone formation by stimulation of the osteocytes (Notelovitz, 2002).

#### **3.1.3 Progestins and bone**

The role of progestins in preventing bone loss is less studied. However, there is general consensus that 19-norderived progestins with androgenic properties, such as norethindrone and norethindrone acetate, at higher doses than necessary for hormone replacement therapy, have beneficial effects on bone density.

Thus, for example, progestins can increase bone density in women with postmenopausal osteoporosis and alleviate the effects of estrogen deficiency in young women treated with GnRH agonists. However, data on the effects of progestins C21 derivatives such as medroxyprogesterone acetate are mixed. It has been reported that, in premenopausal women with luteal defects, medroxyprogesterone acetate (10mg/day, 10 days/cycle) can significantly increase vertebral bone density (Prior et al., 1994). In contrast, administration of 20 mg/day of this progestin could not stop the loss of vertebral bone density in postmenopausal women (Gallagher et al., 1991). In addition, premenopausal women using depot medroxyprogesterone acetate as a contraceptive or taking oral doses (50mg/day) of this progestin on gynecologic pathology have varying significantly decreased bone density (Cundy et al., 1996). The different findings in these studies clearly indicate that the effects of medroxyprogesterone acetate on bone may vary according to the dose administered and the estrogen status of the user. When administered in doses sufficient to induce hypogonadism, medroxyprogesterone acetate is associated with a rapid and significant loss of bone mineral density at the lumbar level. This bone loss is the result of estrogen deficiency and occurs despite an increase in body weight, although it seems partially reversible.

Clinical trials have shown that postmenopausal women receiving norethindrone acetate associated with estrogen show a significant increase in bone mineral density compared with patients treated only with estrogen (Speroff et al., 1996). In contrast, neither the micronized progesterone nor medroxyprogesterone acetate contributed significantly to the positive effects of estrogen on bone (PEPI Trial, 1996).

Progestins influence the bone formation within the bone remodelling process (Sootweg et al., 1992). Receptors for progesterone have been identified in human osteoblasts and osteoclasts. However, the effects of progestagens on bone are not clear. A study about the activity of a "pure progestogen" on human osteogenic osteosarcoma cells did not observe any effect on cell proliferation when progestins were added alone to culture, but after the combined administration with 17β-estradiol, a strong action synergistically was confirmed on the proliferation of osteosarcoma cells. Moreover, other studies show that some synthetic progestins produce their effects through the activation of the estrogen receptor (Jordan et al., 1993).

### **3.2 HRT - Type, dose**

612 Osteoporosis

treatment of osteoporosis but their use is limited by side effects of virilizing type. Evidence of the effects of androgens on bone mass comes from women with polycystic ovary syndrome or steroid-secreting ovarian tumors in which there is an increase in bone mineral density (Gregoriou et al., 2000). On the other hand, we know that the combination of androgens and estrogens for hormone replacement therapy in menopausal women is associated with increased bone mass above that observed with estrogen alone (Castelo-Branco et al., 2000). A cohort study developed to assess BMD in postmenopausal women using estradiol and testosterone hormonal implants comparing to that of patients without hormonal therapy, confirmed that BMD variance between the groups in the period of 1 year was significantly different, and concluded that the combination of estradiol and testosterone

Androgen receptors have been identified in osteoblasts, osteoclasts and osteocytes. Androgens stimulate the proliferation and differentiation of osteoblasts, stimulate the synthesis of extracellular matrix proteins, and stimulate mineralization. These steroids affect the functionality of bone cells through their effects on local factors that control bone cell microenvironment, have proapoptotic effects on osteoblasts and osteocytes, and increase strength and muscle. This ultimately leads to increased physical activity and this in turn to

The role of progestins in preventing bone loss is less studied. However, there is general consensus that 19-norderived progestins with androgenic properties, such as norethindrone and norethindrone acetate, at higher doses than necessary for hormone replacement

Thus, for example, progestins can increase bone density in women with postmenopausal osteoporosis and alleviate the effects of estrogen deficiency in young women treated with GnRH agonists. However, data on the effects of progestins C21 derivatives such as medroxyprogesterone acetate are mixed. It has been reported that, in premenopausal women with luteal defects, medroxyprogesterone acetate (10mg/day, 10 days/cycle) can significantly increase vertebral bone density (Prior et al., 1994). In contrast, administration of 20 mg/day of this progestin could not stop the loss of vertebral bone density in postmenopausal women (Gallagher et al., 1991). In addition, premenopausal women using depot medroxyprogesterone acetate as a contraceptive or taking oral doses (50mg/day) of this progestin on gynecologic pathology have varying significantly decreased bone density (Cundy et al., 1996). The different findings in these studies clearly indicate that the effects of medroxyprogesterone acetate on bone may vary according to the dose administered and the estrogen status of the user. When administered in doses sufficient to induce hypogonadism, medroxyprogesterone acetate is associated with a rapid and significant loss of bone mineral density at the lumbar level. This bone loss is the result of estrogen deficiency and occurs

Clinical trials have shown that postmenopausal women receiving norethindrone acetate associated with estrogen show a significant increase in bone mineral density compared with patients treated only with estrogen (Speroff et al., 1996). In contrast, neither the micronized progesterone nor medroxyprogesterone acetate contributed significantly to the positive

Progestins influence the bone formation within the bone remodelling process (Sootweg et al., 1992). Receptors for progesterone have been identified in human osteoblasts and

promoted bone protection in postmenopausal women (Britto et al., 2011).

activation of bone formation by stimulation of the osteocytes (Notelovitz, 2002).

despite an increase in body weight, although it seems partially reversible.

**3.1.3 Progestins and bone** 

therapy, have beneficial effects on bone density.

effects of estrogen on bone (PEPI Trial, 1996).

Almost all information about the effects of estrogens on the bone come from the use of estradiol and conjugated equine estrogens (CEE). Isolated estrone also has a beneficial effect on bone, and it seems that estriol does not have an obvious role in skeletal production in postmenopausal women.

The route of administration, oral or transdermal, does not imply differences in the beneficial effect on bone (Hillard et al., 1994). The estrogenic pulsotherapy has also shown a normalization of the markers of resorption and formation to premenopausal values after 3 months of treatment at doses of 300 mcg/day. The increase in BMD at this dose is similar to that found with 50 mcg/day of transdermal 17-beta-estradiol, providing significant differences in the measurement of BMD over baseline in spine and hip in the evaluation performed after 56 weeks treatment (Palacios et al., 2002). In women with uterus is necessary to administer a progestin to counteract endometrial proliferation induced by estrogen. The dosing regimen of progestin does not influence the beneficial effect of estrogen on the bone so the choice is given by the characteristics of women.

Significant BMD improvements have also been noted with systemic estrogen doses delivered via a vaginal ring. In an randomized controlled trial of 174 postmenopausal women younger than age 65, daily doses of 0.05 and 0.1 mg of estradiol acetate delivered via the ring significantly increased hip BMD (1.7% and 1.8%, respectively) and lumbar spine BMD (2.7% and 3.3%) compared with baseline (Al-Azzawi et al., 2005).

It has been established that a dose range of estradiol between 40 and 50 pg/ml is enough to increase BMD, although a safe level is 60 pg/ml. A dose-response study indicated that daily doses would have more generalizable effect: 0.625 mg of conjugated equine estrogens (CEE), or their equivalents: 0.05 mg of transdermal 17-beta-estradiol or 15 mcg of oral ethinyl estradiol (EE). The standard dose preserves bone mass in at least 80% of postmenopausal women (Table 1). These doses of estrogen and progestogen can induce side effects in both regimes (continuous and sequential), being the most frequent irregular bleeding and breast tenderness. To minimize these undesirable effects, the use of low doses has shown to be also effective in improving menopausal symptoms and quality of life and prevent or reverse bone loss in postmenopausal women (Delmas et al., 2000).

The loss of bone mass and the incidence of vertebral and hip fractures are inversely related to circulating estrogen levels. It has been confirmed that in elderly women estrogen circulating levels of 10 pg/ml improves both BMD and fracture rate. Any increase in estrogen levels has a beneficial effect especially in older women, even when the ultra-low dose is given (25% of the standard dose) (Simon & Snabe, 2007). Neither age nor initial BMD do seem to affect the effectiveness of patterns of low-dose. The effect of low doses of estrogen in women with low BMD has been analized in a randomized, double-blind, placebo-controlled trial, using CEE 0.3 mg/day and 2.5 mg/day of progesterone in women over 65 years and low BMD, in which after 3.5 years of follow up, an increase in vertebral

The Role of Hormone Replacement Therapy (HRT) and

developing osteoporosis and hence on the quality of life.

**3.5 Estrogen and progestogen combined treatment** 

Group of the PEPI Trial, 1996).

(established osteoporosis) (Adachi et al., 1997).

women (50-59 years) a very low absolute risk (Farquhar et al., 2005).

the effect was less marked in women over 75 years (Felson et al., 1993).

even when associated with low estrogen dose (Christiansen & Riis, 1990).

**3.4 Duration of HRT** 

affect bone mass.

Tibolone in the Prevention and Treatment of Postmenopausal Osteoporosis 615

The reduction of bone loss will last as long as you keep the estrogen therapy. When you cease treatment, bone loss returns to pretreatment rate, therefore, to obtain maximum benefit, treatment should begin as early after menopause and stay as long as possible. The optimal duration of treatment has not been fully established, but the results from the Women's Health Inititative (WHI) suggest that estrogen therapy should take the lowest dose for the shortest possible time but then we know that short treatment will not positively

Analyzing the evolution of bone mass in climacteric women, it has been shown that during the 5 years after the time of onset of menopause the bone loss is equivalent to 60% of what is lost along the climacteric stage; it is at this time when occur the disruption of the trabecular architecture. Once the trabeculae are broken, they will not reconnect again, which would lose bone strength despite getting increases in BMD. Thus, estrogen therapy, at least theoretically, should start as early and stay at least that long in women with natural menopause and up to 55 years in women with early menopause. This would ensure that the loss of bone mass will be delayed, and it will have a positive impact on the possibility of

The use of combined HRT has been associated with an increased risk of venous thromboembolism or coronary artery disease (after a year of use), acute stroke (after 3 years of use), breast cancer (after 5 years of use) and gallbladder disease. Long use of estrogen alone was associated with increased stroke and gallbladder disease. According to recent reanalysis, age is a determining factor in establishing the risks, resulting in very young

However, even if treatment is started long after menopause, there are substantial gains in bone mass. In the Framingham study, elderly women with a mean age of 76 years and 7 years since menopause had a significant increase in BMD compared to nonusers, although

The association of progestin does not counteract the beneficial effect of estrogen on bone. It has been reported that derivatives of 19-norethisterone are effective in preventing bone loss

Some studies suggest a greater benefit by associating progestin, while others have failed to show this superiority to estrogen alone. It is possible that the effect has to do with the type of progestin used and it seems that this superior effect is limited exclusively to the administration of compounds of the family of 19-norethisterone. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, multicenter randomized controlled trial of 875 postmenopausal women with an average age of 56 years, which after 3 years of followup BMD increases are seen in lumbar spine (3-5%) and hip (1.7%) with no differences between groups treated with estrogen alone or combined with progestin (The Writing

The BMD status before the start of hormonal treatment will not influence the effect of it. It has been shown that estrogen administered with and without progestin increases bone mass in healthy women as well and even in osteopenic women with osteoporosis and fractures


BMD of 5% and 1.6% in hip has been confirmed, with significant increase in total skeletal and forearm (Recker et al., 1999).

Table 1. Estrogen dose used in HRT

The HOPE study (Women's Health Osteoporosis Progestin Estrogen) (Lindsay et al., 2005), evaluates the effectiveness of low and moderate doses, 0.45 mg/day and 0.30 mg/day alone or combined CEE on vasomotor symptoms, genital atrophy, metabolism, endometrial response and bone density in 2805 women aged 40-65 years treated for 2 years. The results confirmed an improvement in vasomotor symptoms and genital atrophy with low doses comparable to improvement obtained with standard doses, with less bleeding and the beneficial effect on lipid profile. Bone turnover markers such as osteocalcin and Ntelopeptide of type I collagen were significantly reduced compared to baseline in the treatment group while no changes were found in the placebo group. BMD increased in both vertebral and hip evaluation. Another study showed similar results (Gambacciani et al., 2001), suggesting that low doses of HRT were able to reduce climacteric symptoms resulting in a decrease in bone turnover and protect against bone loss. The same study showed significant increases in BMD of 2.72 ± 0.3% in women treated while not receiving estrogen therapy had a loss in BMD of 7.9 ± 0.8%.

In an open trial healthy postmenopausal women received for 2 years a low-dose continuous combined HRT containing 1mg estradiol plus 0.5 mg norethisterone acetate, or 0.5 mg of 17 estradiol and 0.25 mg of norethisterone acetate (ultra low dose) along with 1000 mg of calcium per day. The study confirmed that low-dose-HRT and Ultra-low-dose-HRT can alleviate subjective symptoms providing an effective protection against the postmenopausal decrease of BMD (Gambacciani et al., 2008).

Despite the large amount of literature about the beneficial effect of low doses in the bone, there are no studies linking low doses of HRT to the prevention of fractures.

#### **3.3 HRT limitations**

Women who may benefit from HRT are those showing climacteric symptoms and also osteoporosis risk. There is general consensus with regard to women with premature menopause should be treated until at least the theoretical age of menopause.

At present there are few absolute contraindications to HRT, being as such pregnancy, vaginal bleeding not studied, active hepatitis, active venous thromboembolism and hormone-specific cancer history.

However, there are circumstances that require careful consideration and consensus with the patient and the presence of pathological conditions such as lupus or endometriosis. Women treated with thyroid hormones or coumarin may need a dose adjustment.

### **3.4 Duration of HRT**

614 Osteoporosis

BMD of 5% and 1.6% in hip has been confirmed, with significant increase in total skeletal

The HOPE study (Women's Health Osteoporosis Progestin Estrogen) (Lindsay et al., 2005), evaluates the effectiveness of low and moderate doses, 0.45 mg/day and 0.30 mg/day alone or combined CEE on vasomotor symptoms, genital atrophy, metabolism, endometrial response and bone density in 2805 women aged 40-65 years treated for 2 years. The results confirmed an improvement in vasomotor symptoms and genital atrophy with low doses comparable to improvement obtained with standard doses, with less bleeding and the beneficial effect on lipid profile. Bone turnover markers such as osteocalcin and Ntelopeptide of type I collagen were significantly reduced compared to baseline in the treatment group while no changes were found in the placebo group. BMD increased in both vertebral and hip evaluation. Another study showed similar results (Gambacciani et al., 2001), suggesting that low doses of HRT were able to reduce climacteric symptoms resulting in a decrease in bone turnover and protect against bone loss. The same study showed significant increases in BMD of 2.72 ± 0.3% in women treated while not receiving estrogen

In an open trial healthy postmenopausal women received for 2 years a low-dose continuous combined HRT containing 1mg estradiol plus 0.5 mg norethisterone acetate, or 0.5 mg of 17 estradiol and 0.25 mg of norethisterone acetate (ultra low dose) along with 1000 mg of calcium per day. The study confirmed that low-dose-HRT and Ultra-low-dose-HRT can alleviate subjective symptoms providing an effective protection against the postmenopausal

Despite the large amount of literature about the beneficial effect of low doses in the bone,

Women who may benefit from HRT are those showing climacteric symptoms and also osteoporosis risk. There is general consensus with regard to women with premature

At present there are few absolute contraindications to HRT, being as such pregnancy, vaginal bleeding not studied, active hepatitis, active venous thromboembolism and

However, there are circumstances that require careful consideration and consensus with the patient and the presence of pathological conditions such as lupus or endometriosis. Women

there are no studies linking low doses of HRT to the prevention of fractures.

menopause should be treated until at least the theoretical age of menopause.

treated with thyroid hormones or coumarin may need a dose adjustment.

Estradiol valerate 1 mg 2 mg 3 mg

CEE 0,3 mg 0,625 mg 1,25 mg

Tibolone 1,25 mg 2,5 mg

Low dose Standard dose High dose

25-37,5 mcg 50 mcg 75-100 mcg

300 mcg

and forearm (Recker et al., 1999).

Table 1. Estrogen dose used in HRT

therapy had a loss in BMD of 7.9 ± 0.8%.

decrease of BMD (Gambacciani et al., 2008).

**3.3 HRT limitations** 

hormone-specific cancer history.

Transdermal Estradiol

Estrogen pulsotherapy The reduction of bone loss will last as long as you keep the estrogen therapy. When you cease treatment, bone loss returns to pretreatment rate, therefore, to obtain maximum benefit, treatment should begin as early after menopause and stay as long as possible. The optimal duration of treatment has not been fully established, but the results from the Women's Health Inititative (WHI) suggest that estrogen therapy should take the lowest dose for the shortest possible time but then we know that short treatment will not positively affect bone mass.

Analyzing the evolution of bone mass in climacteric women, it has been shown that during the 5 years after the time of onset of menopause the bone loss is equivalent to 60% of what is lost along the climacteric stage; it is at this time when occur the disruption of the trabecular architecture. Once the trabeculae are broken, they will not reconnect again, which would lose bone strength despite getting increases in BMD. Thus, estrogen therapy, at least theoretically, should start as early and stay at least that long in women with natural menopause and up to 55 years in women with early menopause. This would ensure that the loss of bone mass will be delayed, and it will have a positive impact on the possibility of developing osteoporosis and hence on the quality of life.

The use of combined HRT has been associated with an increased risk of venous thromboembolism or coronary artery disease (after a year of use), acute stroke (after 3 years of use), breast cancer (after 5 years of use) and gallbladder disease. Long use of estrogen alone was associated with increased stroke and gallbladder disease. According to recent reanalysis, age is a determining factor in establishing the risks, resulting in very young women (50-59 years) a very low absolute risk (Farquhar et al., 2005).

However, even if treatment is started long after menopause, there are substantial gains in bone mass. In the Framingham study, elderly women with a mean age of 76 years and 7 years since menopause had a significant increase in BMD compared to nonusers, although the effect was less marked in women over 75 years (Felson et al., 1993).

### **3.5 Estrogen and progestogen combined treatment**

The association of progestin does not counteract the beneficial effect of estrogen on bone. It has been reported that derivatives of 19-norethisterone are effective in preventing bone loss even when associated with low estrogen dose (Christiansen & Riis, 1990).

Some studies suggest a greater benefit by associating progestin, while others have failed to show this superiority to estrogen alone. It is possible that the effect has to do with the type of progestin used and it seems that this superior effect is limited exclusively to the administration of compounds of the family of 19-norethisterone. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, multicenter randomized controlled trial of 875 postmenopausal women with an average age of 56 years, which after 3 years of followup BMD increases are seen in lumbar spine (3-5%) and hip (1.7%) with no differences between groups treated with estrogen alone or combined with progestin (The Writing Group of the PEPI Trial, 1996).

The BMD status before the start of hormonal treatment will not influence the effect of it. It has been shown that estrogen administered with and without progestin increases bone mass in healthy women as well and even in osteopenic women with osteoporosis and fractures (established osteoporosis) (Adachi et al., 1997).

The Role of Hormone Replacement Therapy (HRT) and

in older women, 60-69 years.

fractures were also statistically significant.

(RR = 0.62, 95% CI = 0.58-0.66).

affect the dose effect on BMD.

Tibolone in the Prevention and Treatment of Postmenopausal Osteoporosis 617

treatment with 0.1 mg of 17-beta-estradiol transdermal and oral medroxyprogesterone acetate, 11 days per month, analyzing the BMD, markers of bone turnover and histomorphometric study of iliac crest biopsy, demonstrated a positive effect of estrogen on the parameters analyzed resulting in a reduction given the frequency of vertebral fracture in the treated group versus placebo (RR = 0.39, 95% CI = 0.16-0.95). It can be infered that the

However, other studies have shown no differences between the treatment groups and placebo. The Heart and Estrogen/Progestin Replacement Study (HERS) included 584 women with coronary disease, with an age range of 44-79 years who were treated with 0.625 mg/day CEE and 2.5 mg/day medroxyprogesterone acetate were compared with a placebo group in a follow-up period of 45 months. In this study, there was no beneficial effect of treatment compared with placebo in hip fracture rates or overall rates of fracture in such women not selected for risk factors for osteoporosis and had a low risk of osteoporosis. After 3 years, they published another analysis of these data, reaching the same results (Cauley et al., 2001).

A review of 57 prospective cohort and retrospective case-control studies noted the limited evidence to confirm the anti-fracture efficacy in women who are on hormone replacement therapy (Reginster et al., 2000). Another review (Beral et al., 2002) of 4 randomized studies that included 20,000 women followed an average of 4.9 years, estimated a reduction of fractured neck of femur in 17/1000 users aged 50-59 years, this reduction rising to 5.5/1000

The highest level of evidence on the effect of HRT on fracture was obtained from the Women's Health Initiative (WHI) (Rossouw et al., 2002), This study was carried out in order to assess the main risks and benefits of the combined hormone preparation most commonly used in the United States, 0.625 mg CEE plus 2.5 mg of medroxyprogesterone acetate to health of postmenopausal women. The study included 8506 women in the treatment group and 8102 in the placebo group, with a follow-up time of 5.2 years. This study (The WHI Steering Committee, 2004) shows unequivocally that estrogen with or without progesterone reduce the risk of hip fracture, vertebral and other fractures, the only treatment that has

demonstrated this effect in osteoporotic woman, regardless personal risk for fracture.

The reduction observed was similar to that reported in previous observational studies and meta-analysis. The results in terms of fractures indicated that estrogen alone or in combination with progestin reduces the rate of hip fractures and clinical vertebral fractures by one third compared with placebo. Reductions in other osteoporotic fractures and total

All types of therapy, route of application and guidelines-beneficial as indicated in the results of a prospective cohort study with more than one million women (Million Women Study Collaborators, 2003), HRT users had significantly more low risk of fracture than nonusers

A meta-analysis (Wells et al., 2002) indicates that BMD measurements are similar when comparing studies of prevention or treatment, estrogen alone or estrogen plus progestin, transdermal or oral, and different types of progestins. The duration and doses of treatment

HRT has a tendency to reduce the risk of vertebral (RR = 0.66, 95% CI = 0.411 to 0.7) and non-vertebral fracture (RR = 0.87, 95% CI = 0.711 to 0.8). The protection against fractures require longer use of HRT. Cross-sectional studies indicate that for hip fracture prevention. Treatment duration should be between 5 and 10 years (Kiel et al., 1987). Swedish Hip

number needed to treat (NNT) is 7 women/year to reduce vertebral fracture.

#### **3.6 Estrogen effect on BMD**

Estrogen administration, associated or not with progestin, has been shown highly effective in the prevention of bone loss in both natural and surgical menopause. It has been shown how treatment with estrogen and progestin can not only maintain but also increase BMD in postmenopausal women, compared to the decline experienced by the placebo group (Christiansen et al., 1981). More than 50 randomized, placebo-controlled studies have shown that estrogen alone or combined with progestin increases BMD, with values ranging from 4- 6% in spine and 2-3% in hip, justifying the difference by the different rate of remodelling of these places (Wells et al., 2002).

Estrogen therapy also appears to be effective in patients with established osteoporosis. Women with low bone mass generally have higher turnover and this turnover increases with age. So the best response to estrogen observed in older women or in women with low BMD might result from the suppression of increased bone turnover associated with improvement in the bioavailability of calcium due to improved intestinal absorption of vitamin D. Using CEE double dose (1.2 mg/day) for one year, a double-blind, placebocontrolled study in 21 osteoporotic women showed an improvement in BMD, more marked in the lumbar spine than in femoral neck and an increase in intestinal absorption of calcium (Citivelli et al., 1988). The authors suggest that the beneficial effect is due to inhibition of bone resorption associated with an increased secretion of calcitonin.

A trial of 50 women aged over 75 years and "physical frailty", of which 90% were osteopenic or osteoporotic, who received 9 months of CEE 0.625 mg/day, showed an increase in lumbar spine BMD of 4, 3% (Villareal et al., 2001). The increase was 1.7% in total hip and 2.3% in trochanter 2.3%, these results being similar to those observed in previous studies.

### **4. Fracture prevention and HRT**

Randomized, case control and cohort studies indicate a potential effect of HRT in the prevention of vertebral, hip and forearm fractures in osteoporotic populations.

A cohort study (Cauley et al., 1995) conducted in 9706 women aged over 65 years, and whose main objective was the evaluation of appendicular bone fractures in women treated with HRT, showed that current users who started treatment within 5 years after menopause decreased the risk of wrist fractures (RR = 0.39, 95% CI = 0.24 to 0.64), hip fractures (RR = 0.60, 95% CI = 0.36 to 1.02) and other nonvertebral fractures (RR = 0.66, 95% CI = 0.54 to 0.80) when compared with nonusers of estrogen. HRT is more effective in reducing fracture risk if you start the five years following menopause, and if their use continues for more than 10 years.

A randomized controlled trial of 4 years of follow up in 464 recently menopausal women (Komulainen et al., 1998), treated with 2 mg estradiol valerate and 1 mg cyproterone acetate daily, demonstrated a reduction in risk with RR 0.29 (0.10 to 0.90 CI).

A meta-analysis (Grady et al., 1992) concluded that there is a 25% reduction in risk of hip fracture in postmenopausal women who used HRT. Subsequently, other published metaanalysis (Torgerson & Bell-Syer, 2001) finds that the use of estrogen alone or combined with progestin for at least one year reduces the risk of nonvertebral fracture (RR 0.73, 95% CI: 0.56 -0.94, P = 0.02). In women over 60 years, the effect was less marked (RR 0.88, 95% CI 0.71 to 1.08, p = 0.22).

In women with established osteoporosis (one or more prior vertebral fractures) has also shown a positive effect of HRT in preventing fractures. In a randomized study (Gonnelli et al., 1997), double-blind, placebo-controlled trial conducted in 75 women who were given

Estrogen administration, associated or not with progestin, has been shown highly effective in the prevention of bone loss in both natural and surgical menopause. It has been shown how treatment with estrogen and progestin can not only maintain but also increase BMD in postmenopausal women, compared to the decline experienced by the placebo group (Christiansen et al., 1981). More than 50 randomized, placebo-controlled studies have shown that estrogen alone or combined with progestin increases BMD, with values ranging from 4- 6% in spine and 2-3% in hip, justifying the difference by the different rate of remodelling of

Estrogen therapy also appears to be effective in patients with established osteoporosis. Women with low bone mass generally have higher turnover and this turnover increases with age. So the best response to estrogen observed in older women or in women with low BMD might result from the suppression of increased bone turnover associated with improvement in the bioavailability of calcium due to improved intestinal absorption of vitamin D. Using CEE double dose (1.2 mg/day) for one year, a double-blind, placebocontrolled study in 21 osteoporotic women showed an improvement in BMD, more marked in the lumbar spine than in femoral neck and an increase in intestinal absorption of calcium (Citivelli et al., 1988). The authors suggest that the beneficial effect is due to inhibition of

A trial of 50 women aged over 75 years and "physical frailty", of which 90% were osteopenic or osteoporotic, who received 9 months of CEE 0.625 mg/day, showed an increase in lumbar spine BMD of 4, 3% (Villareal et al., 2001). The increase was 1.7% in total hip and 2.3% in trochanter 2.3%, these results being similar to those observed in previous studies.

Randomized, case control and cohort studies indicate a potential effect of HRT in the

A cohort study (Cauley et al., 1995) conducted in 9706 women aged over 65 years, and whose main objective was the evaluation of appendicular bone fractures in women treated with HRT, showed that current users who started treatment within 5 years after menopause decreased the risk of wrist fractures (RR = 0.39, 95% CI = 0.24 to 0.64), hip fractures (RR = 0.60, 95% CI = 0.36 to 1.02) and other nonvertebral fractures (RR = 0.66, 95% CI = 0.54 to 0.80) when compared with nonusers of estrogen. HRT is more effective in reducing fracture risk if you start the five

A randomized controlled trial of 4 years of follow up in 464 recently menopausal women (Komulainen et al., 1998), treated with 2 mg estradiol valerate and 1 mg cyproterone acetate

A meta-analysis (Grady et al., 1992) concluded that there is a 25% reduction in risk of hip fracture in postmenopausal women who used HRT. Subsequently, other published metaanalysis (Torgerson & Bell-Syer, 2001) finds that the use of estrogen alone or combined with progestin for at least one year reduces the risk of nonvertebral fracture (RR 0.73, 95% CI: 0.56 -0.94, P = 0.02). In women over 60 years, the effect was less marked (RR 0.88, 95% CI 0.71 to

In women with established osteoporosis (one or more prior vertebral fractures) has also shown a positive effect of HRT in preventing fractures. In a randomized study (Gonnelli et al., 1997), double-blind, placebo-controlled trial conducted in 75 women who were given

prevention of vertebral, hip and forearm fractures in osteoporotic populations.

years following menopause, and if their use continues for more than 10 years.

daily, demonstrated a reduction in risk with RR 0.29 (0.10 to 0.90 CI).

bone resorption associated with an increased secretion of calcitonin.

**3.6 Estrogen effect on BMD** 

these places (Wells et al., 2002).

**4. Fracture prevention and HRT** 

1.08, p = 0.22).

treatment with 0.1 mg of 17-beta-estradiol transdermal and oral medroxyprogesterone acetate, 11 days per month, analyzing the BMD, markers of bone turnover and histomorphometric study of iliac crest biopsy, demonstrated a positive effect of estrogen on the parameters analyzed resulting in a reduction given the frequency of vertebral fracture in the treated group versus placebo (RR = 0.39, 95% CI = 0.16-0.95). It can be infered that the number needed to treat (NNT) is 7 women/year to reduce vertebral fracture.

However, other studies have shown no differences between the treatment groups and placebo. The Heart and Estrogen/Progestin Replacement Study (HERS) included 584 women with coronary disease, with an age range of 44-79 years who were treated with 0.625 mg/day CEE and 2.5 mg/day medroxyprogesterone acetate were compared with a placebo group in a follow-up period of 45 months. In this study, there was no beneficial effect of treatment compared with placebo in hip fracture rates or overall rates of fracture in such women not selected for risk factors for osteoporosis and had a low risk of osteoporosis. After 3 years, they published another analysis of these data, reaching the same results (Cauley et al., 2001).

A review of 57 prospective cohort and retrospective case-control studies noted the limited evidence to confirm the anti-fracture efficacy in women who are on hormone replacement therapy (Reginster et al., 2000). Another review (Beral et al., 2002) of 4 randomized studies that included 20,000 women followed an average of 4.9 years, estimated a reduction of fractured neck of femur in 17/1000 users aged 50-59 years, this reduction rising to 5.5/1000 in older women, 60-69 years.

The highest level of evidence on the effect of HRT on fracture was obtained from the Women's Health Initiative (WHI) (Rossouw et al., 2002), This study was carried out in order to assess the main risks and benefits of the combined hormone preparation most commonly used in the United States, 0.625 mg CEE plus 2.5 mg of medroxyprogesterone acetate to health of postmenopausal women. The study included 8506 women in the treatment group and 8102 in the placebo group, with a follow-up time of 5.2 years. This study (The WHI Steering Committee, 2004) shows unequivocally that estrogen with or without progesterone reduce the risk of hip fracture, vertebral and other fractures, the only treatment that has demonstrated this effect in osteoporotic woman, regardless personal risk for fracture.

The reduction observed was similar to that reported in previous observational studies and meta-analysis. The results in terms of fractures indicated that estrogen alone or in combination with progestin reduces the rate of hip fractures and clinical vertebral fractures by one third compared with placebo. Reductions in other osteoporotic fractures and total fractures were also statistically significant.

All types of therapy, route of application and guidelines-beneficial as indicated in the results of a prospective cohort study with more than one million women (Million Women Study Collaborators, 2003), HRT users had significantly more low risk of fracture than nonusers (RR = 0.62, 95% CI = 0.58-0.66).

A meta-analysis (Wells et al., 2002) indicates that BMD measurements are similar when comparing studies of prevention or treatment, estrogen alone or estrogen plus progestin, transdermal or oral, and different types of progestins. The duration and doses of treatment affect the dose effect on BMD.

HRT has a tendency to reduce the risk of vertebral (RR = 0.66, 95% CI = 0.411 to 0.7) and non-vertebral fracture (RR = 0.87, 95% CI = 0.711 to 0.8). The protection against fractures require longer use of HRT. Cross-sectional studies indicate that for hip fracture prevention. Treatment duration should be between 5 and 10 years (Kiel et al., 1987). Swedish Hip

The Role of Hormone Replacement Therapy (HRT) and

**5.3 Tibolone and prevention of fractures** 

**5.4 Adverse effects of tibolone** 

**6. Conclusions** 

increases the risk.

Tibolone in the Prevention and Treatment of Postmenopausal Osteoporosis 619

Tibolone (1.25 and 2.5 mg, respectively) increased lumbar and hip bone mineral density to a significantly greater extent than placebo in women with and without osteoporosis (Kenemans et al., 2009), as it was shown with a dose of 1.25 mg/day compared with raloxifene in a study of older osteopenic women (mean age 66 years) (Delmas et al., 2008). The lower dose also reduced the risk of vertebral and non-vertebral fractures in older osteoporotic women (mean age 68.3 years) in the LIFT study (Cummings et al., 2008). The data described about tibolone, in both experimental and clinical studies about the turnover markers and BMD, tibolone is similar to estrogen, and considering its relationship

To understand the effects of tibolone on the incidence rate of new vertebral fractures in postmenopausal osteoporotic women began the Long-term Intervention on Fractures with Tibolone (LIFT) (Cummings, 2006), a multinational, double-blind trial, including 4000 women with tibolone versus placebo with calcium and a duration of 3-5 years. This study indicates the beneficial effect of tibolone on vertebral fractures (RR = 0.59) but has been discontinued by the

In a randomized, double-blind, placebo-controlled clinical trial (Cummings et al., 2008), they examined the effect of 1.25 mg of tibolone daily on the risk of vertebral and clinical fractures after 3 years and planned to assess the risks of breast cancer, cardiovascular disease, and endometrial cancer after 5 years. During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% CI, 0.41 to 0.74; p < 0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per

The results of the LIFT study (Cummings et al., 2008) showed that the tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; p = 0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; p = 0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; p = 0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either

HRT produce increases in BMD at all skeletal sites. The reduction in fracture risk has been

Estrogen is a therapeutic option for the prevention and treatment of osteoporosis especially in women with postmenopausal symptoms, with consideration of their long-term use

Therefore, treatment should be individualized by assessing the potential personal risks associated with therapy against the expected benefits. In this way, the patient will maintain

Tibolone is as effective as hormone replacement therapy (HRT) in treating symptoms and preventing bone loss, and it improves sexuality. It reduces bone turnover and improves

to fractures, it is conceivable that tibolone may have a similar effect on them.

increased risk of ischemic and hemorrhagic stroke (RR = 2.3 after 2.75 years).

1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; p = 0.01).

coronary heart disease or venous thromboembolism between the two groups.

documented by data from a meta-analysis, cohort studies and the WHI study.

continuity in the treatment, and will get the benefit sought in the bone.

Fracture In Study, a case-control study (Michaëlsson, 1998) on 1327 women aged 50-81 years who had suffered a hip fracture and 3262 controls, current users of HRT have a substantial decrease in fracture risk compared to older users. The RR of hip fracture was 0.35 (95% CI = 0.24 to 0.53) versus 0.76 (95% CI = 0.57 to 1.01). These data indicate that HRT is effective after menopause to maintain protection against fracture but only recent use was associated with optimal protection, since after 5 years without the protective effect of HRT use drops significantly. The beneficial effect is displayed even when treatment is started long after menopause. Thus, in current users, the initiation of therapy nine or more years after menopause provides a reduced risk of hip fracture are equivalent to those women who started early after menopause but who discontinued treatment.

### **5. Tibolone**

Tibolone is a synthetic steroid derived from 19-nortestosterone, structurally similar to norestinone and noretinodrel, first generation nor-derived progestagens. It is described as a selective tissue estrogenic activity regulator (STEAR) because it has specific effects in different tissues after conversion to three active metabolites following oral ingestion (Kenemans, 2004). It has estrogenic, progestogenic and androgenic effects. Estrogenic metabolites act centrally, on the vagina and other tissues and, together with androgenic metabolites, relieve hot flushes and improve energy and sexual well-being (Nathorst-Booszz, & Hammar, 1997; Nijland et al., 2008). On bone, tibolone has estrogenic effect acting on the estrogenic receptor (Modelska & Cummings, 2002).

#### **5.1 Effects on bone**

Preclinical studies indicate that tibolone prevents bone loss (axial and appendicular), caused by oophorectomy or low calcium intake in both young and mature rats and in rats with established osteopenia (Yoshitake et al, 1999). Experimental data conclude that tibolone is as effective as estrogen to prevent bone loss secondary to the decline of ovarian function, observed even in osteopenic rats an increase in BMD and femoral and vertebral bone strength, similar to estrogen (Berning et al., 2001).

In humans, the action of tibolone on the skeletal system is also largely mediated by estrogen receptor binding and stimulation of it by some of its metabolites.

### **5.2 Tibolone and bone turnover markers**

In general, studies show that tibolone decreases bone turnover (decrease in the formation and resorption) similar to that obtained with both estrogen in postmenopausal women with normal BMD and in the osteoporotic patient and, returning the process of turnover the existing levels in premenopausal women (Moore, 1999).

Analyzing the effect of tibolone on BMD, it is shown to be capable of inhibiting the decrease and increase BMD compared with placebo or untreated control in both spontaneous and surgical menopause. Like estrogen, we analyzed the results of the use of low doses of tibolone. Low doses of 1.25 mg/day have an effect on the spine and hip similar to that found with standard doses of 2.5 mg/day, in elderly women and women younger postmenopausal (Gallagher et al., 2001). It has proven effective in maintaining BMD in menopausal women at standard doses.

### **5.3 Tibolone and prevention of fractures**

618 Osteoporosis

Fracture In Study, a case-control study (Michaëlsson, 1998) on 1327 women aged 50-81 years who had suffered a hip fracture and 3262 controls, current users of HRT have a substantial decrease in fracture risk compared to older users. The RR of hip fracture was 0.35 (95% CI = 0.24 to 0.53) versus 0.76 (95% CI = 0.57 to 1.01). These data indicate that HRT is effective after menopause to maintain protection against fracture but only recent use was associated with optimal protection, since after 5 years without the protective effect of HRT use drops significantly. The beneficial effect is displayed even when treatment is started long after menopause. Thus, in current users, the initiation of therapy nine or more years after menopause provides a reduced risk of hip fracture are equivalent to those women who

Tibolone is a synthetic steroid derived from 19-nortestosterone, structurally similar to norestinone and noretinodrel, first generation nor-derived progestagens. It is described as a selective tissue estrogenic activity regulator (STEAR) because it has specific effects in different tissues after conversion to three active metabolites following oral ingestion (Kenemans, 2004). It has estrogenic, progestogenic and androgenic effects. Estrogenic metabolites act centrally, on the vagina and other tissues and, together with androgenic metabolites, relieve hot flushes and improve energy and sexual well-being (Nathorst-Booszz, & Hammar, 1997; Nijland et al., 2008). On bone, tibolone has estrogenic effect acting

Preclinical studies indicate that tibolone prevents bone loss (axial and appendicular), caused by oophorectomy or low calcium intake in both young and mature rats and in rats with established osteopenia (Yoshitake et al, 1999). Experimental data conclude that tibolone is as effective as estrogen to prevent bone loss secondary to the decline of ovarian function, observed even in osteopenic rats an increase in BMD and femoral and vertebral bone

In humans, the action of tibolone on the skeletal system is also largely mediated by estrogen

In general, studies show that tibolone decreases bone turnover (decrease in the formation and resorption) similar to that obtained with both estrogen in postmenopausal women with normal BMD and in the osteoporotic patient and, returning the process of turnover the

Analyzing the effect of tibolone on BMD, it is shown to be capable of inhibiting the decrease and increase BMD compared with placebo or untreated control in both spontaneous and surgical menopause. Like estrogen, we analyzed the results of the use of low doses of tibolone. Low doses of 1.25 mg/day have an effect on the spine and hip similar to that found with standard doses of 2.5 mg/day, in elderly women and women younger postmenopausal (Gallagher et al., 2001). It has proven effective in maintaining BMD in menopausal women

started early after menopause but who discontinued treatment.

on the estrogenic receptor (Modelska & Cummings, 2002).

strength, similar to estrogen (Berning et al., 2001).

existing levels in premenopausal women (Moore, 1999).

**5.2 Tibolone and bone turnover markers** 

receptor binding and stimulation of it by some of its metabolites.

**5. Tibolone** 

**5.1 Effects on bone** 

at standard doses.

Tibolone (1.25 and 2.5 mg, respectively) increased lumbar and hip bone mineral density to a significantly greater extent than placebo in women with and without osteoporosis (Kenemans et al., 2009), as it was shown with a dose of 1.25 mg/day compared with raloxifene in a study of older osteopenic women (mean age 66 years) (Delmas et al., 2008). The lower dose also reduced the risk of vertebral and non-vertebral fractures in older osteoporotic women (mean age 68.3 years) in the LIFT study (Cummings et al., 2008).

The data described about tibolone, in both experimental and clinical studies about the turnover markers and BMD, tibolone is similar to estrogen, and considering its relationship to fractures, it is conceivable that tibolone may have a similar effect on them.

To understand the effects of tibolone on the incidence rate of new vertebral fractures in postmenopausal osteoporotic women began the Long-term Intervention on Fractures with Tibolone (LIFT) (Cummings, 2006), a multinational, double-blind trial, including 4000 women with tibolone versus placebo with calcium and a duration of 3-5 years. This study indicates the beneficial effect of tibolone on vertebral fractures (RR = 0.59) but has been discontinued by the increased risk of ischemic and hemorrhagic stroke (RR = 2.3 after 2.75 years).

In a randomized, double-blind, placebo-controlled clinical trial (Cummings et al., 2008), they examined the effect of 1.25 mg of tibolone daily on the risk of vertebral and clinical fractures after 3 years and planned to assess the risks of breast cancer, cardiovascular disease, and endometrial cancer after 5 years. During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% CI, 0.41 to 0.74; p < 0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; p = 0.01).

### **5.4 Adverse effects of tibolone**

The results of the LIFT study (Cummings et al., 2008) showed that the tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; p = 0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; p = 0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; p = 0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups.

### **6. Conclusions**

HRT produce increases in BMD at all skeletal sites. The reduction in fracture risk has been documented by data from a meta-analysis, cohort studies and the WHI study.

Estrogen is a therapeutic option for the prevention and treatment of osteoporosis especially in women with postmenopausal symptoms, with consideration of their long-term use increases the risk.

Therefore, treatment should be individualized by assessing the potential personal risks associated with therapy against the expected benefits. In this way, the patient will maintain continuity in the treatment, and will get the benefit sought in the bone.

Tibolone is as effective as hormone replacement therapy (HRT) in treating symptoms and preventing bone loss, and it improves sexuality. It reduces bone turnover and improves

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**30** 

*Poland* 

*Department of Oral Surgery,* 

**Osteonecrosis of the Jaw Involving** 

*Medical College of the Jagiellonian University Kraków,* 

Maria Panaś, Małgorzata Zaleska and Tomasz Kaczmarzyk

**Bisphosphonate Treatment for Osteoporosis** 

Bisphosphonates (BPs) play a key role in the treatment of both primary and secondary osteoporosis on account of their effect on the calcium metabolism in the human body. The administering of BPs reduces the frequency of fractures of the spine, the neck of the femur and the wrist. They also promote bone mass growth in the whole skeleton. In addition, they improve the quality of life of treated patients significantly (Almazrooa & Woo, 2009; Watts

However, during the course of treatment with bisphosphonates it is of importance to bear in mind the possible development of a specific complication, namely osteonecrosis of the jaw. It should be noted that no bisphosphonate-related necrosis is observed in other bones. Since 2003 when the first cases of osteonecrosis of the jaw following BP administration were described (Marx, 2003), more references to BPs Bisphosphonate–Related Osteonecrosis of the Jaw, i.e. BRONJ, have appeared in the literature, encompassing new and more numerous groups of patients (Durie et al., 2005; Kos et al., 2010; Otto et al., 2011; Ruggiero et al., 2004). BRONJ was initially observed in patients receiving BPs for malignant tumours, bone metastases (most frequently from breast, prostate or lung cancer), and in cases of multiple myeloma (Wang et al., 2007). BPs such as pamidronate and zoledronate were applied intravenously and doses of the medication exceeded many times over the dose used in osteoporosis. Recently, BRONJ has likewise been confirmed in patients with osteoporosis who had received oral alendronate, and in earlier years - etidronate (Magremanne, 2008;

BRONJ manifests itself as a necrotically changed, exposed bone with a depleted mucous membrane and often accompanying by inflammation (Peters et al., 1993). It frequently follows a tooth extraction. It occurs more commonly in the mandible than in the maxilla

Osteonecrosis of the jaw can also be triggered by other factors than the administering of BPs (Almazrooa & Woo, 2009). It occurs after: radiation therapy of the facial area, trauma (osteotomy of the jaw bone or during intubation), viral infection (Herpes zoster or HIV), fungal infection with Aspergillus, circulatory insufficiency, local application of chemical agents in dental treatment, inhaling cocaine, and osteomyelitis. Also described is the idiopathic exposure of the lingual surface of the mandibular base in its posterior section in the area of the protruding mylohyoid ridge covered with thin mucous membrane and

**1. Introduction** 

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## **Osteonecrosis of the Jaw Involving Bisphosphonate Treatment for Osteoporosis**

Maria Panaś, Małgorzata Zaleska and Tomasz Kaczmarzyk *Department of Oral Surgery, Medical College of the Jagiellonian University Kraków, Poland* 

### **1. Introduction**

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Estrogen decreases osteoclast formation by down-regulating receptor activator of NK-kappa B ligand (RANKL)-induced JNK activation. *J Biol Chem*, Vol. 276, No.12,

prevention of postmenopausal osteoporosis: gynecologic point of view. *Rev Med* 

estrogen in postmenopausal women with hysterectomy. *JAMA*, Vol. 291, No. 14,

density. Results from the post-menopausal estrogen/progesterone interventions

vertebral fractures: a meta-analysis of randomised trials. *BMC Musculoskelet Disord*,

receptor-beta in murine and human bone. *J Bone Miner Res*, Vol. 14, No. 6, June

(2001). Bone mineral density response to estrogen replacement in frail elderly women: a randomized controlled trial. *JAMA*, Vol. 286, No. 7, (2001), pp. (815-20).

Methodology Group and the Osteoporosis Research Advisory Group. (2002). Metaanalysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. *Endocr Rev*, Vol. 23, No. 4, (2002), pp. (529-

Effects of 16 weeks of treatment with tibolone on bone mass and bone mechanical and histomorphometric indices in mature ovariectomized rats with established osteopenia on a low-calcium diet. *Bone*, Vol. 25, No. 3, (September 1999), pp. (311Bisphosphonates (BPs) play a key role in the treatment of both primary and secondary osteoporosis on account of their effect on the calcium metabolism in the human body. The administering of BPs reduces the frequency of fractures of the spine, the neck of the femur and the wrist. They also promote bone mass growth in the whole skeleton. In addition, they improve the quality of life of treated patients significantly (Almazrooa & Woo, 2009; Watts & Diab, 2010).

However, during the course of treatment with bisphosphonates it is of importance to bear in mind the possible development of a specific complication, namely osteonecrosis of the jaw. It should be noted that no bisphosphonate-related necrosis is observed in other bones.

Since 2003 when the first cases of osteonecrosis of the jaw following BP administration were described (Marx, 2003), more references to BPs Bisphosphonate–Related Osteonecrosis of the Jaw, i.e. BRONJ, have appeared in the literature, encompassing new and more numerous groups of patients (Durie et al., 2005; Kos et al., 2010; Otto et al., 2011; Ruggiero et al., 2004). BRONJ was initially observed in patients receiving BPs for malignant tumours, bone metastases (most frequently from breast, prostate or lung cancer), and in cases of multiple myeloma (Wang et al., 2007). BPs such as pamidronate and zoledronate were applied intravenously and doses of the medication exceeded many times over the dose used in osteoporosis. Recently, BRONJ has likewise been confirmed in patients with osteoporosis who had received oral alendronate, and in earlier years - etidronate (Magremanne, 2008; Palaska et al., 2009; Watts & Diab, 2010).

BRONJ manifests itself as a necrotically changed, exposed bone with a depleted mucous membrane and often accompanying by inflammation (Peters et al., 1993). It frequently follows a tooth extraction. It occurs more commonly in the mandible than in the maxilla (Kos et al., 2010; Ruggiero et al., 2004).

Osteonecrosis of the jaw can also be triggered by other factors than the administering of BPs (Almazrooa & Woo, 2009). It occurs after: radiation therapy of the facial area, trauma (osteotomy of the jaw bone or during intubation), viral infection (Herpes zoster or HIV), fungal infection with Aspergillus, circulatory insufficiency, local application of chemical agents in dental treatment, inhaling cocaine, and osteomyelitis. Also described is the idiopathic exposure of the lingual surface of the mandibular base in its posterior section in the area of the protruding mylohyoid ridge covered with thin mucous membrane and

Osteonecrosis of the Jaw Involving Bisphosphonate Treatment for Osteoporosis 627

in the case of bone inflammation, as well as loss of bone structure. Later, bone sequestra may develop, leading to pathological fractures (Figure 4) (Almazrooa & Woo, 2009;

Fig. 3. Unobtrusive marginal osteolysis during the initial phase of BRONJ (arrow)

(Migliorati et al., 2005; Ruggiero et al., 2006; Panaś et al., 2010).

teeth (Figure 10), widening of the periodontal space.

Histopathological examination demonstrates typical images of chronic inflammation of the bone with fibrous granulation tissue with abundant, chronic partially purulent inflammatory infiltration and necrotically changed osseous trabeculae (Figures 5, 6 & 7)

Ruggiero et al. (2006) suggested a division of BRONJ into three degrees depending on the

Degree 1: Exposure of bone without swelling or redness of the surrounding soft tissue (Figure 1). No change in the radiological image. The exposure of the bone may be preceded by pain. Degree 2: Exposure of bone with inflammatory swelling of the soft tissue or with a secondary infection, the presence of pain and teeth mobility. Radiological images show necrotic changes in the bone that may resemble rarefaction of bone around the apices of the

Ruggiero et al., 2006).

Fig. 2. Skin fistula in course of BRONJ

progress in the pathology:

poorly vascularised as a physiological result of trauma of the mucosa membrane in generally healthy individuals. BRONJ most frequently appears in this region. Osteonecrosis is also encountered in cases of long-term steroid use, but usually it affects the femur (Almazrooa & Woo, 2009).

Diagnosis of BRONJ can be made in case of bone exposure lasting longer than eight weeks, with no previous history of radiation therapy of the facial region (Almazrooa & Woo, 2009; Ruggiero et al., 2006).

### **2. Clinical and radiologic profile**

Necrosis of the jaw bone in patients treated with BPs can remain asymptomatic for many months or even years.

Fig. 1. Redness of the oral mucosa and purulent fistulas of the lower gingiva

The bone becomes exposed, and is sometimes accompanied by pain. The first symptoms before the emergence of a clinically developed image of necrosis include pain, tooth mobility, swelling and redness of the mucosa membrane, and ulceration (Figure 1). These symptoms can appear independently, but much more commonly they do occur after surgery on the alveolar ridge, mostly after tooth extraction. Since the post-extraction socket does not heal, subsequently pain sensation occurs, followed by inflammation of the surrounding tissue and bone necrosis. This leads to pathological fractures of the mandible, the appearance of skin (Figure 2) and gingival (Figure 1) fistulas or secondary inflammation of the maxillary sinus and oro-antral fistulas in the area of necrosis. Numbness of the skin of the lips and face may also be observed. In the initial period the exposed bone is smooth before later becoming rough and coarse. The sharp border of the bone can cause subsequent ulceration of the surrounding tissue exposed to the injury. The most frequent site of traumatic ulceration is the posterior-lateral part of the tongue adjacent to the sequestrum on the lingual surface of the mandibular body (Migliorati et al., 2005; Ruggiero et al., 2006).

Initially radiological images show no significant changes (Figure 3). There may be a widening of the periodontal space around existing teeth, and later rarefaction of the bone as in the case of bone inflammation, as well as loss of bone structure. Later, bone sequestra may develop, leading to pathological fractures (Figure 4) (Almazrooa & Woo, 2009; Ruggiero et al., 2006).

Fig. 2. Skin fistula in course of BRONJ

626 Osteoporosis

poorly vascularised as a physiological result of trauma of the mucosa membrane in generally healthy individuals. BRONJ most frequently appears in this region. Osteonecrosis is also encountered in cases of long-term steroid use, but usually it affects the femur

Diagnosis of BRONJ can be made in case of bone exposure lasting longer than eight weeks, with no previous history of radiation therapy of the facial region (Almazrooa & Woo, 2009;

Necrosis of the jaw bone in patients treated with BPs can remain asymptomatic for many

Fig. 1. Redness of the oral mucosa and purulent fistulas of the lower gingiva

The bone becomes exposed, and is sometimes accompanied by pain. The first symptoms before the emergence of a clinically developed image of necrosis include pain, tooth mobility, swelling and redness of the mucosa membrane, and ulceration (Figure 1). These symptoms can appear independently, but much more commonly they do occur after surgery on the alveolar ridge, mostly after tooth extraction. Since the post-extraction socket does not heal, subsequently pain sensation occurs, followed by inflammation of the surrounding tissue and bone necrosis. This leads to pathological fractures of the mandible, the appearance of skin (Figure 2) and gingival (Figure 1) fistulas or secondary inflammation of the maxillary sinus and oro-antral fistulas in the area of necrosis. Numbness of the skin of the lips and face may also be observed. In the initial period the exposed bone is smooth before later becoming rough and coarse. The sharp border of the bone can cause subsequent ulceration of the surrounding tissue exposed to the injury. The most frequent site of traumatic ulceration is the posterior-lateral part of the tongue adjacent to the sequestrum on the lingual surface of the mandibular body (Migliorati et al., 2005; Ruggiero et al., 2006). Initially radiological images show no significant changes (Figure 3). There may be a widening of the periodontal space around existing teeth, and later rarefaction of the bone as

(Almazrooa & Woo, 2009).

**2. Clinical and radiologic profile** 

Ruggiero et al., 2006).

months or even years.

Fig. 3. Unobtrusive marginal osteolysis during the initial phase of BRONJ (arrow)

Histopathological examination demonstrates typical images of chronic inflammation of the bone with fibrous granulation tissue with abundant, chronic partially purulent inflammatory infiltration and necrotically changed osseous trabeculae (Figures 5, 6 & 7) (Migliorati et al., 2005; Ruggiero et al., 2006; Panaś et al., 2010).

Ruggiero et al. (2006) suggested a division of BRONJ into three degrees depending on the progress in the pathology:

Degree 1: Exposure of bone without swelling or redness of the surrounding soft tissue (Figure 1). No change in the radiological image. The exposure of the bone may be preceded by pain.

Degree 2: Exposure of bone with inflammatory swelling of the soft tissue or with a secondary infection, the presence of pain and teeth mobility. Radiological images show necrotic changes in the bone that may resemble rarefaction of bone around the apices of the teeth (Figure 10), widening of the periodontal space.

Osteonecrosis of the Jaw Involving Bisphosphonate Treatment for Osteoporosis 629

Fig. 6. Histopathological examination of BRONJ (H&E, x120)

Fig. 7. Histopathological examination of BRONJ (H&E, x140)

The pathogenesis of BRONJ is connected with the fact that BPs have a significant influence on the physiological process of bone tissue remodelling by hampering the effect of osteoclasts function, leading to their apoptosis and the inhibition of the differentiation of osteoclast precursor cells. BPs also inhibit angiogenesis by reducing the level of VEGF

**3. Pathogenesis** 

Degree 3: Exposure of bone with accompanying pain, inflammatory swelling of the surrounding soft tissue or secondary infection that is difficult to control with antibiotic treatments. Appearance of gingival and skin fistulas in the region of bone sequestra or pathological fractures of the mandible, hypoesthesia of the lower lip, as well as secondary inflammation of the maxillary sinus, and oro-nasal fistula in the necrosis of the jaw. Radiograms show bone rarefaction, sequestra, and sometimes pathological fractures (Figure 4).

Fig. 4. Pathological fracture in course of BRONJ of the right mandible body

Fig. 5. Histopathological examination of BRONJ (H&E, x60)

Fig. 6. Histopathological examination of BRONJ (H&E, x120)

Fig. 7. Histopathological examination of BRONJ (H&E, x140)

### **3. Pathogenesis**

628 Osteoporosis

Degree 3: Exposure of bone with accompanying pain, inflammatory swelling of the surrounding soft tissue or secondary infection that is difficult to control with antibiotic treatments. Appearance of gingival and skin fistulas in the region of bone sequestra or pathological fractures of the mandible, hypoesthesia of the lower lip, as well as secondary inflammation of the maxillary sinus, and oro-nasal fistula in the necrosis of the jaw. Radiograms show bone rarefaction, sequestra, and sometimes pathological fractures

Fig. 4. Pathological fracture in course of BRONJ of the right mandible body

Fig. 5. Histopathological examination of BRONJ (H&E, x60)

(Figure 4).

The pathogenesis of BRONJ is connected with the fact that BPs have a significant influence on the physiological process of bone tissue remodelling by hampering the effect of osteoclasts function, leading to their apoptosis and the inhibition of the differentiation of osteoclast precursor cells. BPs also inhibit angiogenesis by reducing the level of VEGF

Osteonecrosis of the Jaw Involving Bisphosphonate Treatment for Osteoporosis 631

inflammation. Aerobic bacteria strains predominate in bacteriological tests, including Streptococci sensitive to penicillin and clindamycin, but Actinomyces species and Eikenella corrodens are also quite often cultured (Block Veras et al., 2008; Panaś et al., 2010). In addition, bacterial products increase bone resorption and decrease rate of bone remodelling, when there is an increased need for remodelling of the bone after surgery performed on the alveolar ridge.

Treatment of patients with BRONJ is difficult and challenging. The recommended therapy for first degree BRONJ cases is frequent rinsing of the oral cavity with an antiseptic solution,

In case of a second degree BRONJ one shall undergo antibacterial therapy involving a

During the third degree BRONJ the surgical removal of necrotic bone is necessary. Targeted antibiotic therapy administered orally or intravenously is also advisable (Rizzoli et al., 2008), as is intensive rinsing of the oral cavity. In addition to the removal of bone sequestra, it is also often necessary to perform a partial resection of the mandible or maxilla (Kunchur et al., 2009; Ruggiero et al., 2006; Williamson, 2009). Moreover, some authors propose the

Discontinuation of BPs therapy remains an issue of contention on account of their long halflife time, i.e. approximately 10 years, after they become concentrated within the body skeleton (Dello Russo, 2007). Any decision to withdraw BPs due to the development of

Due to the long half life times of BPs in the bone, osteonecrosis recurs despite the

Because of the difficulties in treating BRONJ and the specificity of this chronic disease,

Before BPs treatment is implemented, all patients should be referred for dental examination (Shane et al., 2006). It is important to achieve oral cavity assanation, so that no surgical procedures on the alveolar ridge will be necessary during the course of BPs treatment, which significantly increases the risk of the development of BRONJ. It will be necessary to extract those teeth that are not suitable for conservative or endodontic treatment, carry out conservative therapy on other teeth and also perform periodontal treatment. Teeth for which the prognosis for restoration is poor should be extracted. Other essential hygienic procedures and elective dento–alveolar surgery should be performed during this period. The introduction of bisphosphonates should take place 4 - 6 weeks after the dento–alveolar surgery, after suitable healing of the bone wound (Kunchur et al, 2009; Malden et al., 2009;

Prophylactic procedures in the oral cavity, consisting in the maintenance of good oral hygiene, control of caries, and conservative therapy, must continue for the entire period of BPs treatment. Patients using removable partial or complete dentures must be examined to identify any possible pressure of the denture base on the mucosa membrane of the oral cavity as well as the emergence of decubitus ulcers, especially in the lingual region of the lower prosthesis. Patients must be taught the necessity of regular dentist check-ups and maintaining perfect oral hygiene as well as the importance of refraining from smoking and alcohol drinking. Patients

BRONJ should be made by consensus with the attending physician and dentist.

e.g. chlorhexidine, together with regular clinical check-ups of the oral cavity.

targeted antibiotic, together with analgesics and rinsing of the oral cavity.

application of hyperbaric oxygen therapy (Migliorati et al., 2005).

introduction of the appropriate treatment (Watts & Diab, 2010).

**4. Treatment** 

**5. Prevention** 

Ruggiero et al., 2006).

prevention is of vital importance.

(vascular endothelial growth factor) in the blood (Almazrooa et al., 2009; Marx, 2003; Ruggiero et al., 2004). Certain bisphosphonates (i.e. pamidronate) significantly reduce blood flow through the diploe, as shown by experimental research, and this may be the reason for the occurrence of ischaemic osteonecrosis (Choi et al., 2007). BPs tend to be deposited in the jaw bones because of their high metabolic rate. The greater metabolic rate is caused by the constant pressure on the bone, especially during chewing. Micro-cracking of the maxillary bone resulting from the physiological force of chewing requires repair, and the need for bone repair and remodelling increases in the case of surgical procedures, i.e. after tooth extraction, which in patients receiving BPs is hampered by the inhibition of key elements in this process (Migliorati et al., 2005). Reduced blood supply in the mandibular body in its posterior section on the lingual side explains the frequent appearance of BRONJ in this area. Risk factors for the development of BRONJ (Table 1) include radiotherapy of the facial region, chemotherapy, the use of corticosteriods, diabetes and coagulopathies (Palaska et al., 2009; Ruggiero et al., 2006). The duration, type and method of BP treatment are also significant factors that determine the appearance of osteonecrosis. The longer the bisphosphonate is administered the greater the risk of BRONJ appearing. When administered intravenously, necrosis occurs 4.4 times more frequently compared to oral route of administration, and among intravenous medications it is most common with zoledronic acid (Almazrooa & Woo, 2009) . The average time for BRONJ to appear is 2 years for BPs administered intravenously among patients with neoplastic diseases, as compared with 4.6 years for oral therapy in cases of osteoporosis, with the minimum time being 3 years (Palaska et al., 2009). Tobacco smoking and excessive alcohol intake also favour the development of BRONJ.


Table 1. Risk factors for developing BRONJ according to Malden et al. (2009)

A particularly high risk factors for BRONJ development are the extraction of a tooth or any other surgery on the alveolar ridge as well as injury to the mucosa membrane by a denture plate and the occurrence of ulceration (Marx, 2007; Ruggiero et al., 2006). The bacterial environment of the oral cavity favours secondary superinfection with subsequent inflammation. Aerobic bacteria strains predominate in bacteriological tests, including Streptococci sensitive to penicillin and clindamycin, but Actinomyces species and Eikenella corrodens are also quite often cultured (Block Veras et al., 2008; Panaś et al., 2010). In addition, bacterial products increase bone resorption and decrease rate of bone remodelling, when there is an increased need for remodelling of the bone after surgery performed on the alveolar ridge.

### **4. Treatment**

630 Osteoporosis

(vascular endothelial growth factor) in the blood (Almazrooa et al., 2009; Marx, 2003; Ruggiero et al., 2004). Certain bisphosphonates (i.e. pamidronate) significantly reduce blood flow through the diploe, as shown by experimental research, and this may be the reason for the occurrence of ischaemic osteonecrosis (Choi et al., 2007). BPs tend to be deposited in the jaw bones because of their high metabolic rate. The greater metabolic rate is caused by the constant pressure on the bone, especially during chewing. Micro-cracking of the maxillary bone resulting from the physiological force of chewing requires repair, and the need for bone repair and remodelling increases in the case of surgical procedures, i.e. after tooth extraction, which in patients receiving BPs is hampered by the inhibition of key elements in this process (Migliorati et al., 2005). Reduced blood supply in the mandibular body in its posterior section on the lingual side explains the frequent appearance of BRONJ in this area. Risk factors for the development of BRONJ (Table 1) include radiotherapy of the facial region, chemotherapy, the use of corticosteriods, diabetes and coagulopathies (Palaska et al., 2009; Ruggiero et al., 2006). The duration, type and method of BP treatment are also significant factors that determine the appearance of osteonecrosis. The longer the bisphosphonate is administered the greater the risk of BRONJ appearing. When administered intravenously, necrosis occurs 4.4 times more frequently compared to oral route of administration, and among intravenous medications it is most common with zoledronic acid (Almazrooa & Woo, 2009) . The average time for BRONJ to appear is 2 years for BPs administered intravenously among patients with neoplastic diseases, as compared with 4.6 years for oral therapy in cases of osteoporosis, with the minimum time being 3 years (Palaska et al., 2009). Tobacco smoking and excessive alcohol intake also favour the development of BRONJ.

General risk factors Local risk factors

Table 1. Risk factors for developing BRONJ according to Malden et al. (2009)

A particularly high risk factors for BRONJ development are the extraction of a tooth or any other surgery on the alveolar ridge as well as injury to the mucosa membrane by a denture plate and the occurrence of ulceration (Marx, 2007; Ruggiero et al., 2006). The bacterial environment of the oral cavity favours secondary superinfection with subsequent

Mandibular molar extractions (two thirds of BRONJ cases have been reported in the mandible)

All dentoalveolar surgery

Periodontitis/poor oral hygiene (the bacterial biofil present in periodontal disease is responsible for gingival inlammation and alveolar bone resorption; this pathology, together with the interactions between bacteria themselves and BPs can increase the possibility of BRONJ)

Trauma related to dentures

Thin mucosal coverage, lingual to lower molars and bony tori

Concomitant therapies: corticosteroids, other immunosuppressants (eg methotrexate, thalidomide), chemotherapeutic agents (eg hormone antagonists)

Systemic conditions affecting bone turover: immunocompromised patients, rheumatoid arthritis, poorly controlled diabetes

Smoking

Sociodemographic characteristics: extreme of age (over 6th decade), gender (females)

Treatment of patients with BRONJ is difficult and challenging. The recommended therapy for first degree BRONJ cases is frequent rinsing of the oral cavity with an antiseptic solution, e.g. chlorhexidine, together with regular clinical check-ups of the oral cavity.

In case of a second degree BRONJ one shall undergo antibacterial therapy involving a targeted antibiotic, together with analgesics and rinsing of the oral cavity.

During the third degree BRONJ the surgical removal of necrotic bone is necessary. Targeted antibiotic therapy administered orally or intravenously is also advisable (Rizzoli et al., 2008), as is intensive rinsing of the oral cavity. In addition to the removal of bone sequestra, it is also often necessary to perform a partial resection of the mandible or maxilla (Kunchur et al., 2009; Ruggiero et al., 2006; Williamson, 2009). Moreover, some authors propose the application of hyperbaric oxygen therapy (Migliorati et al., 2005).

Discontinuation of BPs therapy remains an issue of contention on account of their long halflife time, i.e. approximately 10 years, after they become concentrated within the body skeleton (Dello Russo, 2007). Any decision to withdraw BPs due to the development of BRONJ should be made by consensus with the attending physician and dentist.

Due to the long half life times of BPs in the bone, osteonecrosis recurs despite the introduction of the appropriate treatment (Watts & Diab, 2010).

## **5. Prevention**

Because of the difficulties in treating BRONJ and the specificity of this chronic disease, prevention is of vital importance.

Before BPs treatment is implemented, all patients should be referred for dental examination (Shane et al., 2006). It is important to achieve oral cavity assanation, so that no surgical procedures on the alveolar ridge will be necessary during the course of BPs treatment, which significantly increases the risk of the development of BRONJ. It will be necessary to extract those teeth that are not suitable for conservative or endodontic treatment, carry out conservative therapy on other teeth and also perform periodontal treatment. Teeth for which the prognosis for restoration is poor should be extracted. Other essential hygienic procedures and elective dento–alveolar surgery should be performed during this period. The introduction of bisphosphonates should take place 4 - 6 weeks after the dento–alveolar surgery, after suitable healing of the bone wound (Kunchur et al, 2009; Malden et al., 2009; Ruggiero et al., 2006).

Prophylactic procedures in the oral cavity, consisting in the maintenance of good oral hygiene, control of caries, and conservative therapy, must continue for the entire period of BPs treatment. Patients using removable partial or complete dentures must be examined to identify any possible pressure of the denture base on the mucosa membrane of the oral cavity as well as the emergence of decubitus ulcers, especially in the lingual region of the lower prosthesis.

Patients must be taught the necessity of regular dentist check-ups and maintaining perfect oral hygiene as well as the importance of refraining from smoking and alcohol drinking. Patients

Osteonecrosis of the Jaw Involving Bisphosphonate Treatment for Osteoporosis 633

together with redness of the mucosa membrane. A pantomographic X-ray revealed rarefaction of the bone of the mandibular body on the left side with a diameter of 3 centimetres (Figure 8). Actinomyces naeslundi were cultured in the bacteriological test. With a targeted antibiotic prophylaxis (clindamycin) curettage was performed on inflamed granulation tissue with minor bone sequestra from the area of the bone rarefaction. Histopathological tests showed fibrous-granulation tissue with extensive partially purulent inflammatory infiltration and necrotically changed osseous trabeculae with adjacent colonies of Actinomyces. Two months before, BP was withdrawn and a preparation of calcium and vitamin D3 was prescribed instead. The pain resumed 8 months after the surgery and an X-ray showed an increase in rarefaction of the bone structure (Figure 9). An antibiotic was used once again and the bone was curetted. Nine months later pain and a purulent fistula appeared in the region of the endodontically treated upper premolar tooth 25, together with a focus of the rarefaction of the bone structure on the X-ray (Figure 10), which was subsequently curetted. Histopathological test: osteomyelitis. The patient is currently in the course of another seven month follow-up without complications. CT does

not show any new osteolytic lesions in the jaws (Figure 11).

Fig. 8. Focal osteolysis of the left mandible body

Fig. 9. Follow-up X-ray examination reveals progression of the bone resorption

should also be made aware of early manifestations of developing osteonecrosis, which should be reported immediately to a dentist; any pain sensations in the oral cavity, oedema or bone exposure, should be reported to the attending physician (Haumschild & Haumschild, 2010).

During the course of BPs treatment surgical procedures involving teeth extractions should be avoided. If a tooth is not suitable for restoration crown of the tooth should be removed, but its roots should be left in place after endodontic treatment. However, significantly mobile teeth with periodontal abscess should be extracted. The timing and conditions of this procedure should be determined by the dental surgeon in consultation with the attending physician. Certain authors suggest that to minimise the risk of BRONJ, BPs treatment should be interrupted ("drug holidays") prior to the planned surgical procedure and, if the need arises, BPs should be replaced with a different medication used for osteoporosis. Recently it has been postulated that the CTX test (the C–terminal Cross–Linking Telopeptide test) should be carried out beforehand. This test can identify a risk group of patients treated with BPs as a measure of the total rate of bone remodelling. A safe CTX value prior to the procedure is 150 pg/ml. The surgery should be carried out with an antibiotic prophylaxis, the most recommended being penicillin derivatives or metronidazole (Bahlous et al., 2009; Kunchur et al., 2009; Malden et al., 2009; Marx et al., 2007).

Placement of dental implants in patients receiving intravenous BPs should be avoided (Ruggiero et al., 2006). However, some authors claim that oral route of BPs administration does not conflict with dental implant placement (Dello Russo et al., 2007). Nevertheless, in these cases, prophylactic antibiotic administration is obligatory and informed consent about an increased risk of implant failure should be provided.

In view of the possible development of BRONJ with prolonged BPs treatment for osteoporosis, the option of BP withdrawal after 5 years should be considered, a fact which shall be decided by the attending physician. Prolonged BPs therapy of more than 5 years should be carefully considered for patients with a high risk of spinal fracture, e.g. those with very low BMD (bone mineral density) (Watts & Diab, 2010).

Some authors claim that bone healing in patients who have been taking oral BPs for less than 3 years is expected to be uncomplicated (Marx et al., 2007). In this period, the accumulation of an oral BP in bone is slowed by its minimal gastrointestinal absorption (Dello Russo et al., 2007). Therefore, a serum CTX is not required prior to oral surgical procedures. However, if the patient relates a history of greater than 3 years of oral BP use or fewer than 3 years but with concomitant corticosteroid or chemotherapy use, a CTX test is highly recommended (Marx et al., 2007).

### **6. Conclusion**

BRONJ complications during BPs treatment appear far more commonly among cancer patients who have received high doses of BPs intravenously. However, until now 200 cases of BRONJ have been observed in patients with osteoporosis (Rondon, 2009). Owing to an ageing population and the growing number of patients with osteoporosis, for whom BPs play a key role in their treatment, more attention should be paid to this problem as well as to learning the risk factors for the development of BRONJ. An important factor affecting the outcome of osteoporosis treatment is co-operation between the attending physician and the dentist.

One example of the development of BRONJ following BP administration is the case of a 70 year old female patient with osteoporosis who was treated with oral bisphosphonate (alendronate group) for 8 years. She reported periodic pain and bleeding in the posterior part of the lower gingiva under the denture base, where a small fistula was identified

should also be made aware of early manifestations of developing osteonecrosis, which should be reported immediately to a dentist; any pain sensations in the oral cavity, oedema or bone exposure, should be reported to the attending physician (Haumschild & Haumschild, 2010). During the course of BPs treatment surgical procedures involving teeth extractions should be avoided. If a tooth is not suitable for restoration crown of the tooth should be removed, but its roots should be left in place after endodontic treatment. However, significantly mobile teeth with periodontal abscess should be extracted. The timing and conditions of this procedure should be determined by the dental surgeon in consultation with the attending physician. Certain authors suggest that to minimise the risk of BRONJ, BPs treatment should be interrupted ("drug holidays") prior to the planned surgical procedure and, if the need arises, BPs should be replaced with a different medication used for osteoporosis. Recently it has been postulated that the CTX test (the C–terminal Cross–Linking Telopeptide test) should be carried out beforehand. This test can identify a risk group of patients treated with BPs as a measure of the total rate of bone remodelling. A safe CTX value prior to the procedure is 150 pg/ml. The surgery should be carried out with an antibiotic prophylaxis, the most recommended being penicillin derivatives or metronidazole (Bahlous et al., 2009;

Placement of dental implants in patients receiving intravenous BPs should be avoided (Ruggiero et al., 2006). However, some authors claim that oral route of BPs administration does not conflict with dental implant placement (Dello Russo et al., 2007). Nevertheless, in these cases, prophylactic antibiotic administration is obligatory and informed consent about

In view of the possible development of BRONJ with prolonged BPs treatment for osteoporosis, the option of BP withdrawal after 5 years should be considered, a fact which shall be decided by the attending physician. Prolonged BPs therapy of more than 5 years should be carefully considered for patients with a high risk of spinal fracture, e.g. those with

Some authors claim that bone healing in patients who have been taking oral BPs for less than 3 years is expected to be uncomplicated (Marx et al., 2007). In this period, the accumulation of an oral BP in bone is slowed by its minimal gastrointestinal absorption (Dello Russo et al., 2007). Therefore, a serum CTX is not required prior to oral surgical procedures. However, if the patient relates a history of greater than 3 years of oral BP use or fewer than 3 years but with concomitant corticosteroid or chemotherapy use, a CTX test is

BRONJ complications during BPs treatment appear far more commonly among cancer patients who have received high doses of BPs intravenously. However, until now 200 cases of BRONJ have been observed in patients with osteoporosis (Rondon, 2009). Owing to an ageing population and the growing number of patients with osteoporosis, for whom BPs play a key role in their treatment, more attention should be paid to this problem as well as to learning the risk factors for the development of BRONJ. An important factor affecting the outcome of osteoporosis treatment is co-operation between the attending physician and the dentist. One example of the development of BRONJ following BP administration is the case of a 70 year old female patient with osteoporosis who was treated with oral bisphosphonate (alendronate group) for 8 years. She reported periodic pain and bleeding in the posterior part of the lower gingiva under the denture base, where a small fistula was identified

Kunchur et al., 2009; Malden et al., 2009; Marx et al., 2007).

an increased risk of implant failure should be provided.

very low BMD (bone mineral density) (Watts & Diab, 2010).

highly recommended (Marx et al., 2007).

**6. Conclusion** 

together with redness of the mucosa membrane. A pantomographic X-ray revealed rarefaction of the bone of the mandibular body on the left side with a diameter of 3 centimetres (Figure 8). Actinomyces naeslundi were cultured in the bacteriological test. With a targeted antibiotic prophylaxis (clindamycin) curettage was performed on inflamed granulation tissue with minor bone sequestra from the area of the bone rarefaction. Histopathological tests showed fibrous-granulation tissue with extensive partially purulent inflammatory infiltration and necrotically changed osseous trabeculae with adjacent colonies of Actinomyces. Two months before, BP was withdrawn and a preparation of calcium and vitamin D3 was prescribed instead. The pain resumed 8 months after the surgery and an X-ray showed an increase in rarefaction of the bone structure (Figure 9). An antibiotic was used once again and the bone was curetted. Nine months later pain and a purulent fistula appeared in the region of the endodontically treated upper premolar tooth 25, together with a focus of the rarefaction of the bone structure on the X-ray (Figure 10), which was subsequently curetted. Histopathological test: osteomyelitis. The patient is currently in the course of another seven month follow-up without complications. CT does not show any new osteolytic lesions in the jaws (Figure 11).

Fig. 8. Focal osteolysis of the left mandible body

Fig. 9. Follow-up X-ray examination reveals progression of the bone resorption

Osteonecrosis of the Jaw Involving Bisphosphonate Treatment for Osteoporosis 635

Bahlous, A., Bonzid, K., Sahli, H., Sallami, S., & Abdelmoula, J. (2009). Effects of risedronate

Block Veras, R., Kriwalsky, M.S., Wilhelms, D., & Schubert, J. (2008). Osteochemonecrosis:

Choi, J.Y., Kim, H.J., Lee, Y.C., Cho, B.O., Seong, H.S., Cho, M., & Kim S.G. (2007). Inhibition

Dello Russo, N.M., Jeffcoat, M.K., Marx, R.E., & Fugazzotto, P. (2007). Osteonecrosis in the

Durie, B.G., Katz, M., & Crowley, J. (2005). Osteonecrosis of the jaw and bisphosphonates. *N* 

Haumschild, M.S., & Haumschild R.J. (2010). Postmenopausal females and the link between

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Kunchur, R., Need, A., Hughes, T., & Goss A. (2009). Clinical investigation of C–terminal

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Marx, R.E., Cillo, J.E. Jr., & Ulloa J.J. (2007). Oral bisphosphonate – induced osteonecrosis:

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Fig. 10. Osteolytic lesion in the periapical area of the tooth 25

Fig. 11. Follow-up CT-scan confirming the existence of osteolytic lesions in the left mandible body and in the left maxilla. However, it does not reveal any new lesion

### **7. References**

Almazrooa, S.A., & Woo, S.B. (2009). Bisphosphonate and non bisphosphonate – associated osteonecrosis of the jaw. A review. *J Am Dent Assoc*, Vol. 140, No. 7, pp. 864-875

Fig. 11. Follow-up CT-scan confirming the existence of osteolytic lesions in the left mandible

Almazrooa, S.A., & Woo, S.B. (2009). Bisphosphonate and non bisphosphonate – associated osteonecrosis of the jaw. A review. *J Am Dent Assoc*, Vol. 140, No. 7, pp. 864-875

body and in the left maxilla. However, it does not reveal any new lesion

**7. References** 

Fig. 10. Osteolytic lesion in the periapical area of the tooth 25


**1. Introduction** 

costs (Becker, S. 2008).

fracture (Garfin SR. 2002)

(Deramond, H . et. Al. 1998).

Wardlaw D. et. al (2009)).

**2. Rational** 

mortality (Johnell, O.1996; Edidin AA, et.al. 2011).

**31** 

*Lebanon* 

**Balloon Kyphoplasty for** 

Sami Salem and Moussa Alaywan

**Osteoporosis: Technical Notes** 

Vertebral fractures are the most common fractures in osteoporosis and have significant impact on quality of life and survival rates, as well as carrying increased socioeconomic

Kyphotic deformity results from those fractures are associated with increased morbidity and

Balloon kyphoplasty is a minimally invasive procedure designed to restore vertebral body height, decreasing kyphosis, and also aims to achieve pain relief by stabilization of the

In 1987, Galibert et.al described percutaneous vertebroplasty as an alternative of conventional treatment of vertebral fracture (Galibert P et.al. 1987). The technique and the products used were developed until the description of balloon kyphoplasty in 1998

Balloon Kyphoplasty is performed nowadays by spine surgeons as well as by interventional radiologist. This is certainly an effective treatment of osteoporotic compression fracture, but it's more and more used in traumatic and metastatic fractures (Voggenreiter, G (2005);

Our experience is based on 176 cases of Balloon Kyphoplasty performed between 2004 and 2010. 136 cases were managed by transpedicular and 40 cases via extrapedicular approach. 82 cases were treated unilaterally and 94 cases were treated bilaterally. Decision for procedure

> Levels No. of cases 1 146 2 20 3 6 4 4

was based on accessibility, extent of collapse and form of the pathological vertebra.

Table 1. The number of vertebral levels treated in a single procedure

Antoine Nachanakian, Antonios El Helou,

*Saint George Hospital University Medical Center, Division of Neurosurgery, Balamand University* 

coincidence – a multi–centre study. *J Craniomaxillofac Surg*, Vol. 39, No. 4, pp. 272- 277.


## **Balloon Kyphoplasty for Osteoporosis: Technical Notes**

Antoine Nachanakian, Antonios El Helou, Sami Salem and Moussa Alaywan *Saint George Hospital University Medical Center, Division of Neurosurgery, Balamand University Lebanon* 

## **1. Introduction**

636 Osteoporosis

Palaska, P.K., Cartsos, V., & Zavras, A.I. (2009). Bisphosphonates and time to osteonecrosis

Panaś, M., Zaleska, M., & Pełka, P. (2010). Bisphosphonate–related osteonecrosis of the jaws.

Peters, E., Lovas, G.L., & Wysocki, G.P. (1993). Lingual mandibular sequestration and

Rizzoli, R., Burlet, N., Cahall, D., Delmas, P.D., Eriksen, E.F., Felsenberg, D., Grbic, J., Jontell,

Rondon, N. (2009). Osteonecrosis of the jaw (ONJ), In: *yourdentistryguide.com*, Available

Ruggiero, S.L., Mebrotra, B., Rosenberg, T.J., & Engroff, S.J. (2004). Osteonecrosis of the jaws

Ruggiero, S.L., Fantasia, J., & Carlson E. (2006). Bisphosphonate – related osteonecrosis of

Wang, E.P., Kaban, L.B., Strewler, G.J., Raje, N. & Troulis M.J. (2007). Incidence of

Watts, N.B., & Diab, D.L. (2010). Long – term use of bisphosphonates in osteoporosis. *J Clin* 

Williamson, R.A. (2009). Surgical management of bisphosphonates and time to osteonecrosis

Wao, S.B., Hellstein, J.W., & Kalmar J.R. (2006). Systematic review: bisphosphonates and osteonecrosis of the jaws. *Ann Intern Med*, Vol. 144, No.10, pp. 753-761

*Surg Oral Med Oral Pathol Oral Radiol Endod*, Vol. 102, No. 4, pp. 433-441 Shane, E., Goldring, S., Christakos, S., Drezner, M., Eisman, J., Silverman, S., & Pendrys, D.

from: <http://www.yourdentistryguide.com/osteonecrosis>

development. *Oncologist*, Vol. 14, No. 11, pp. 1154-1166

*Reumatologia*, Vol. 48, No. 3, pp. 198-203

of osteoporosis. *Bone*, Vol. 42, No.5, pp. 841-847

*Endocrinol Metab*, Vol. 95, No. 4, pp. 1555-1556

development. *Oncologist*, Vol. 14, No. 11, pp. 1154-1166

*Surg*, Vol. 62, No. 5, pp. 527-534

No. 10, pp. 1503-1505

7, pp. 1328-1331

277.

743

coincidence – a multi–centre study. *J Craniomaxillofac Surg*, Vol. 39, No. 4, pp. 272-

ulceration. *Oral Surg Oral Med Oral Pathol Oral Radiol Endod*, Vol. 75, No. 6, pp. 739-

M., Landesberg, R., Laslop, A., Wollenhaupt, M., Papapoulos, S., Sezer, O., Sprafka, M., & Reginster, J.Y. (2008). Osteonecrosis of the jaw and bisphosphonate treatment

associated with the use of bisphosphonates: a review of 63 cases. *J Oral Maxillofac* 

the jaw: background and guidelines for diagnosis, staging and management. *Oral* 

(2006). Osteonecrosis of the jaw: more research needed. *J Bone Miner Res*, Vol. 21,

osteonecrosis of the jaw in patients with multiple myelona and breast or prostate cancer on intravenous bisphosphonate therapy. *J Oral Maxillofac Surg*, Vol. 65, No. Vertebral fractures are the most common fractures in osteoporosis and have significant impact on quality of life and survival rates, as well as carrying increased socioeconomic costs (Becker, S. 2008).

Kyphotic deformity results from those fractures are associated with increased morbidity and mortality (Johnell, O.1996; Edidin AA, et.al. 2011).

Balloon kyphoplasty is a minimally invasive procedure designed to restore vertebral body height, decreasing kyphosis, and also aims to achieve pain relief by stabilization of the fracture (Garfin SR. 2002)

In 1987, Galibert et.al described percutaneous vertebroplasty as an alternative of conventional treatment of vertebral fracture (Galibert P et.al. 1987). The technique and the products used were developed until the description of balloon kyphoplasty in 1998 (Deramond, H . et. Al. 1998).

## **2. Rational**

Balloon Kyphoplasty is performed nowadays by spine surgeons as well as by interventional radiologist. This is certainly an effective treatment of osteoporotic compression fracture, but it's more and more used in traumatic and metastatic fractures (Voggenreiter, G (2005); Wardlaw D. et. al (2009)).

Our experience is based on 176 cases of Balloon Kyphoplasty performed between 2004 and 2010. 136 cases were managed by transpedicular and 40 cases via extrapedicular approach. 82 cases were treated unilaterally and 94 cases were treated bilaterally. Decision for procedure was based on accessibility, extent of collapse and form of the pathological vertebra.


Table 1. The number of vertebral levels treated in a single procedure

Balloon Kyphoplasty for Osteoporosis: Technical Notes 639


Indications for balloon kyphoplasty are (Lieberman IH, et. al (2001); Taylor RS, et.al (2007)) : - Primary or secondary osteoporosis, multiple myeloma, or osteolytic metastatic tumors. - Painful fractures with a back pain score of 4 points or more on a 0–10 scale. And, not




In our institution, patients are admitted for 24 hours the same day of the procedure. In preop, the patient is asked to hold anti-platelets and other anti-coagulation for 5 days. Only

Post op, spinal cord X-ray of the operated region is done. The patient is ambulated with

Injection pressure and cement viscosity are the most important factors for injection. Studies show that the use of more viscous cement in association to lower injection pressure is

For this purpose, a geometrically modified cannulas and high viscosity cement were developed to decrease injection pressure and reduce the risk of insufficient filling of

vertebral body (Berlemann,U (2008); Phillips, FM (2003); Vaccaro, A (2003)).

Patients are excluded if they (Theodorou DJ, et. al (2002); Berlemann, U (2008)):




LMWH can be tolerated up to 12 hours before the procedure.

Usually, the patients had regular follow up at 1, 3 and 12 months.

deficit, radicular pain, spinal cord compression, or canal narrowing


responding to conservative treatment for 6 weeks.


more in Lumbar level

**3.2 Indication** 

vice versa.

**3.3 Contra indication** 


energy trauma.

abdominal belt for 1 month.

**3.4 Hospitalization and follow up** 

**3.5 Biomechanics of cement injection** 

advantageous for the regular spreading.


Most patients were treated for vertebral fracture involving a single level (Table 1). Fracture types are divided into four groups: Primary and secondary Osteoporosis, trauma and tumor (Table 2).

For secondary osteoporosis, chronic steroid use is the main etiology.


Table 2. Etiology and number of patients with chronology of treatment

Vertebral fracture is confirmed through careful correlation of the patient's history, clinical examination, and radiological findings on X-ray's, CT scan and MRI.

The majority of vertebral osteoporotic compression fracture occurs at the thoracolumbar junction: 30 cases at Th12 level and 108 at L1 level (Table 3).

The duration between diagnosis of the fracture and the intervention was between 1 day and 90 days with a mean of 10 to 30 days (Table 4).


Table 3. Number of compression fractures cases at each vertebral level


Table 4. Period of symptoms prior to the treatment of vertebral compression fractures

### **3. Decision making**

#### **3.1 Diagnostic criteria**

Patients are eligible for enrolment if they have:



### **3.2 Indication**

638 Osteoporosis

Fracture types are divided into four groups: Primary and secondary Osteoporosis, trauma

Etiology No. of cases % of cases Cases Time of the treatment

130 12 4

> 2 2 2

> 2 2

> 2

156 88.6 10

4 2.3 2

Vertebral fracture is confirmed through careful correlation of the patient's history, clinical

The majority of vertebral osteoporotic compression fracture occurs at the thoracolumbar

The duration between diagnosis of the fracture and the intervention was between 1 day and

Level Th7 Th8 Th11 Th12 L1 L2 L3 L4 No. of cases 2 4 10 30 108 6 10 6

treatment in Days 1-3 3-10 10-20 20-30 30-40 40-50 50-60 60-90 >90 No. of cases 6 10 52 30 44 10 6 14 4

Table 4. Period of symptoms prior to the treatment of vertebral compression fractures

Days

<10 10-60 60-90 > 90

> 3 50 65

> 48 72

Most patients were treated for vertebral fracture involving a single level (Table 1).

For secondary osteoporosis, chronic steroid use is the main etiology.

Trauma 10 5.7 4

Tumors 6 3.4 2

Total Number 176 100 176

Table 2. Etiology and number of patients with chronology of treatment

examination, and radiological findings on X-ray's, CT scan and MRI.

Table 3. Number of compression fractures cases at each vertebral level

junction: 30 cases at Th12 level and 108 at L1 level (Table 3).

90 days with a mean of 10 to 30 days (Table 4).

Patients are eligible for enrolment if they have:


and tumor (Table 2).

Primary Osteoporosis

Secondary Osteoporosis

Duration before

**3. Decision making 3.1 Diagnostic criteria**  Indications for balloon kyphoplasty are (Lieberman IH, et. al (2001); Taylor RS, et.al (2007)) :


### **3.3 Contra indication**

Patients are excluded if they (Theodorou DJ, et. al (2002); Berlemann, U (2008)):


### **3.4 Hospitalization and follow up**

In our institution, patients are admitted for 24 hours the same day of the procedure. In preop, the patient is asked to hold anti-platelets and other anti-coagulation for 5 days. Only LMWH can be tolerated up to 12 hours before the procedure.

Post op, spinal cord X-ray of the operated region is done. The patient is ambulated with abdominal belt for 1 month.

Usually, the patients had regular follow up at 1, 3 and 12 months.

### **3.5 Biomechanics of cement injection**

Injection pressure and cement viscosity are the most important factors for injection. Studies show that the use of more viscous cement in association to lower injection pressure is advantageous for the regular spreading.

For this purpose, a geometrically modified cannulas and high viscosity cement were developed to decrease injection pressure and reduce the risk of insufficient filling of vertebral body (Berlemann,U (2008); Phillips, FM (2003); Vaccaro, A (2003)).

Balloon Kyphoplasty for Osteoporosis: Technical Notes 641

A basic instrument set with bone access tools is used in the procedure. The set contains the


pressure manometer

**3.6.2 Operative procedure** 

configuration and patient's anatomy.

Fig. 2. Above: Jamshidi needle and 2 cement cannulas. Below: Kyphoplasty Balloon with

The level of the pedicle of the fractured vertebrae is localized under fluoroscopy. A 3 mm incision is made at this level. An 11 gauge biopsy needle is advanced into the fractured vertebral body via Trans or extra-pedicular approach depending on the fracture

**3.6.1.3 The instrument used** 

following (Figure 2):



### **3.6 Surgery 3.6.1 Operative technique**

### **3.6.1.1 Preparation**

The procedure is done under local-assisted anesthesia. The patient is in prone position on a radiolucent table in the operating room.

Double C-arm fluoroscopies are positioned. One is for AP view and the other is for lateral view. (Figure 1)

Fig. 1. Position of the patient with Antero-posterior and lateral C-arm.

### **3.6.1.2 Product used**

Polymethylmethacrylate (PMMA) bone cement was the first used in balloon kyphoplasty. It consists of several ingredients that all have their importance. To site, PMMA is composed by methyl methacrylate, PMMA powder ,radio-opacifier, dibenzoyl peroxide, and other additives such as stabilizers, inhibitors, radical catchers, coloring agents and antibiotics (Berlemann,U (2008); Baroud G, Steffen T (2005); Bohner M, et.al (2003)).

PMMA is an easy handled product. It has an adequate balance between high viscosity, which reduces extravasation risks, and low viscosity, which enables low injection forces (Baroud G, et.al (2004); Weißkopf, M, et.al (2008)).

PMMA is allowed to cure for 3 to 5 minutes before injection to achieve a tooth paste viscosity. It needs 8 to 12 minutes in vivo to harden before removing injecting cannulas

### **3.6.1.3 The instrument used**

A basic instrument set with bone access tools is used in the procedure. The set contains the following (Figure 2):


640 Osteoporosis

The procedure is done under local-assisted anesthesia. The patient is in prone position on a

Double C-arm fluoroscopies are positioned. One is for AP view and the other is for lateral

Fig. 1. Position of the patient with Antero-posterior and lateral C-arm.

(Berlemann,U (2008); Baroud G, Steffen T (2005); Bohner M, et.al (2003)).

(Baroud G, et.al (2004); Weißkopf, M, et.al (2008)).

Polymethylmethacrylate (PMMA) bone cement was the first used in balloon kyphoplasty. It consists of several ingredients that all have their importance. To site, PMMA is composed by methyl methacrylate, PMMA powder ,radio-opacifier, dibenzoyl peroxide, and other additives such as stabilizers, inhibitors, radical catchers, coloring agents and antibiotics

PMMA is an easy handled product. It has an adequate balance between high viscosity, which reduces extravasation risks, and low viscosity, which enables low injection forces

PMMA is allowed to cure for 3 to 5 minutes before injection to achieve a tooth paste viscosity. It needs 8 to 12 minutes in vivo to harden before removing injecting cannulas

**3.6 Surgery** 

**3.6.1.1 Preparation** 

view. (Figure 1)

**3.6.1.2 Product used** 

**3.6.1 Operative technique** 

radiolucent table in the operating room.


Fig. 2. Above: Jamshidi needle and 2 cement cannulas. Below: Kyphoplasty Balloon with pressure manometer

### **3.6.2 Operative procedure**

The level of the pedicle of the fractured vertebrae is localized under fluoroscopy. A 3 mm incision is made at this level. An 11 gauge biopsy needle is advanced into the fractured vertebral body via Trans or extra-pedicular approach depending on the fracture configuration and patient's anatomy.

Balloon Kyphoplasty for Osteoporosis: Technical Notes 643

The balloon is slowly deployed under fluoroscopic guidance until maximum fracture

The inflation is stopped when the balloons reaches the cortical wall; Or, when we have

The cement is polymethylmetacrelate that needs 5 minutes to reach its semi-solid

Balloon is deflated and subsequently removed when the cement is ready to be used.

reduction is accomplished. (Figure 5)

Fig. 5. Maximum fracture reduction under fluoroscopy.

"balloon kissing" position in the bi-pedicular approach (Figure 6).

Fig. 6. Bipedicular Balloon tamps inflation, "Kissing Balloons". During inflation, an assistant prepares the cement to be injected.

constitution. It's loaded in 5 injection cannulas

A working cannula is inserted over the needle's trajectory. Once it's positioned, the needle is removed. (Figure 3)

Fig. 3. Insertion of a working cannula.

An inflatable balloon tamp is advanced under the collapsed end plate.

Once inserted through the cannula into the vertebral body, the inflatable balloon tamps are expanded using fluoroscopic control. The volume and pressure are usually managed using the built in digital manometer.(Figure 4)

Fig. 4. Right: Insertion of Inflatable Balloon tamps. Left: Inflation of the Balloon tamps.

A working cannula is inserted over the needle's trajectory. Once it's positioned, the needle is

removed. (Figure 3)

Fig. 3. Insertion of a working cannula.

the built in digital manometer.(Figure 4)

An inflatable balloon tamp is advanced under the collapsed end plate.

Once inserted through the cannula into the vertebral body, the inflatable balloon tamps are expanded using fluoroscopic control. The volume and pressure are usually managed using

 Fig. 4. Right: Insertion of Inflatable Balloon tamps. Left: Inflation of the Balloon tamps. The balloon is slowly deployed under fluoroscopic guidance until maximum fracture reduction is accomplished. (Figure 5)

Fig. 5. Maximum fracture reduction under fluoroscopy.

The inflation is stopped when the balloons reaches the cortical wall; Or, when we have "balloon kissing" position in the bi-pedicular approach (Figure 6).

Balloon is deflated and subsequently removed when the cement is ready to be used.

Fig. 6. Bipedicular Balloon tamps inflation, "Kissing Balloons".

During inflation, an assistant prepares the cement to be injected.

The cement is polymethylmetacrelate that needs 5 minutes to reach its semi-solid constitution. It's loaded in 5 injection cannulas

Balloon Kyphoplasty for Osteoporosis: Technical Notes 645

Fig. 8. Above: MRI of the lumbo-sacral spine showing L2-L3-L4 vertebral compression fractures. Below : Per-operative fluoroscopy after balloon inflation and reduction of

During balloon kyphoplasty, untoward effect is minimal (3 – 10) %. Minor complications, as cardiopulmonary toxicity defined by transient bradycardia and desaturation, were the most

vertebral height.

common.

**3.8 Complications** 

The cement is then injected into the vertebral body's created cavity meticulously under fluoroscopy.

From our observation, the cement fills the entire fracture tract first then it fills the created cavity.

Once packed and hardened, the cannula is removed.

The incision is closed by single cutaneous layer suture.

Fig. 7. Antero-posterior and lateral views of a case of 2 levels Kyphoplasty.

### **3.7 Long term results**

As far as the inclusion criteria were respected and for osteoporotic fracture mainly, pain relief was achieved with 24 hours in more than 60% of cases.

The difference of pain relief and kyphotic deformity restoration are highly correlated to the time since the onset of the fracture. And though, patients presenting within 45 days showed optimal results. Whereas, patient presenting after 60 days necessitated moderate potency analgesics to achieve complete pain relief.

Long term follow up, after 3, 6 and 12 months shows an increase in number of cases relieved by the treatment to (70 - 82) % of the population that doesn't necessitate any analgesic use. (6 – 8)%, who already has radicular pain before the procedure, necessitated 3-6 months of Gabapentin treatment.

1% necessitated another surgical procedure and, 9% achieved partial relieve of their pain.

The cement is then injected into the vertebral body's created cavity meticulously under

From our observation, the cement fills the entire fracture tract first then it fills the created

As far as the inclusion criteria were respected and for osteoporotic fracture mainly, pain

The difference of pain relief and kyphotic deformity restoration are highly correlated to the time since the onset of the fracture. And though, patients presenting within 45 days showed optimal results. Whereas, patient presenting after 60 days necessitated moderate potency

Long term follow up, after 3, 6 and 12 months shows an increase in number of cases relieved by the treatment to (70 - 82) % of the population that doesn't necessitate any analgesic use. (6 – 8)%, who already has radicular pain before the procedure, necessitated 3-6 months of

1% necessitated another surgical procedure and, 9% achieved partial relieve of their pain.

Fig. 7. Antero-posterior and lateral views of a case of 2 levels Kyphoplasty.

relief was achieved with 24 hours in more than 60% of cases.

analgesics to achieve complete pain relief.

Once packed and hardened, the cannula is removed. The incision is closed by single cutaneous layer suture.

fluoroscopy.

**3.7 Long term results** 

Gabapentin treatment.

cavity.

Fig. 8. Above: MRI of the lumbo-sacral spine showing L2-L3-L4 vertebral compression fractures. Below : Per-operative fluoroscopy after balloon inflation and reduction of vertebral height.

### **3.8 Complications**

During balloon kyphoplasty, untoward effect is minimal (3 – 10) %. Minor complications, as cardiopulmonary toxicity defined by transient bradycardia and desaturation, were the most common.

Balloon Kyphoplasty for Osteoporosis: Technical Notes 647

Despite being relatively a new technique, balloon kyphoplasty becomes popular. It showed, in all studies conducted, that it's an effective method for treating pain and kyphosis induced

With the increase in indications and use of this technique, advancement in injection kits

In experienced, well trained hands in the field, balloon kyphoplasty is safe and efficient

Baroud G, Bohner M, Heini P, et al (2004) Injection biomechanics of bone cements used in

Baroud G, Steffen T (2005) A new cannula to ease cement injection during vertebroplasty.

Becker, S. (2008). Balloon Kyphoplasty(Ogon, Micheal), Springer Wien New York, 978-3-211-

Berlemann,U (2008). Results in kyphoplasty, risks and complications in: Balloon

Bohner M, Gasser B, Baroud G, et al (2003) Theoretical and experimental model to describe

Kyphoplasty(Ogon, Micheal), Springer Wien New York, 978-3-211-74220-4, Austria

the injection of a polymethylmethacrylate cement into a porous structure.

Fig. 10. Extravasation of the cement to the Epidural Space.

vertebroplasty. Biomed Mater Eng 14: 487–504

**4. Conclusion** 

**5. References** 

by osteoporotic vertebral fractures.

decreased the rate of complications.

technique for several types of fractures.

Eur Spine J 14(5): 474–9

Biomaterials 24: 2731–8

74220-4, Austria

Severe complications as cement pulmonary embolus (Perrin C et.al (1999)), extravasation to the epidural space or to the foraminae are rare (Moreland DB et.al (2001)). The risk of pulmonary embolism is 0.01 – 1%. The rate of extrusions is 8.5%. Nevertheless, most of these extrusions are clinically asymptomatic and the rate of serious problems remains low. In the literature, the overall clinically significant rate of complication is described as 1%.

Fig. 9. A case of single level Kyphoplasty.

### **3.8.1 How to avoid complications**

### **3.8.1.1 Cement embolus**

Cement pulmonary embolus are due to hazardous extravasation of the cement to the venous system. The latter is avoided by ascertaining the position of the injector in the middle of the cavity created by the inflated balloon. Clinically, cement pulmonary embolism presents by desaturation with heart rate changes. Thus monitoring is mandatory during the procedure. The procedure should be stopped and management of expected cement pulmonary embolism should be started.

#### **3.8.1.2 Extravasation to the epidural space or foramina**

It's the most common complication (Figure 10). Two third of those patients will necessitate open surgical decompression. This complication can be avoided if cement is left to become thick for 5 minutes after injection and the removal of the cannula should be done slowly in rotating manner.

Fig. 10. Extravasation of the cement to the Epidural Space.

### **4. Conclusion**

646 Osteoporosis

Severe complications as cement pulmonary embolus (Perrin C et.al (1999)), extravasation to the epidural space or to the foraminae are rare (Moreland DB et.al (2001)). The risk of pulmonary embolism is 0.01 – 1%. The rate of extrusions is 8.5%. Nevertheless, most of these

Cement pulmonary embolus are due to hazardous extravasation of the cement to the venous system. The latter is avoided by ascertaining the position of the injector in the middle of the cavity created by the inflated balloon. Clinically, cement pulmonary embolism presents by desaturation with heart rate changes. Thus monitoring is mandatory during the procedure. The procedure should be stopped and management of expected cement pulmonary

It's the most common complication (Figure 10). Two third of those patients will necessitate open surgical decompression. This complication can be avoided if cement is left to become thick for 5 minutes after injection and the removal of the cannula should be done slowly in

Fig. 9. A case of single level Kyphoplasty.

**3.8.1.2 Extravasation to the epidural space or foramina** 

**3.8.1 How to avoid complications** 

**3.8.1.1 Cement embolus** 

embolism should be started.

rotating manner.

extrusions are clinically asymptomatic and the rate of serious problems remains low. In the literature, the overall clinically significant rate of complication is described as 1%.

> Despite being relatively a new technique, balloon kyphoplasty becomes popular. It showed, in all studies conducted, that it's an effective method for treating pain and kyphosis induced by osteoporotic vertebral fractures.

> With the increase in indications and use of this technique, advancement in injection kits decreased the rate of complications.

> In experienced, well trained hands in the field, balloon kyphoplasty is safe and efficient technique for several types of fractures.

### **5. References**


**32** 

*Italy* 

**Minimally Invasive Treatment** 

**of Vertebral Body Fractures** 

*Department of Surgical Oncology and Pain Medicine,* 

*IRCCS Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture,* 

Gestures rather harmless at first sight like weight-lifting , a sudden movement, sometimes only remaking the bed in the morning could cause, in susceptible individuals, the failure and collapse of the vertebral body. Painful fractures, which cause changes in appearance and posture, persistent back pain, limited mobility and a general decay in the affected individuals, most often even unaware of the cause of their evil ( Eastell et al., 1991). One of the most frequent causes of fractures of the vertebral body is osteoporosis (Dempster, 2011; Haczynski, 2001), relentless and "silent" disease spread rapidly, due to an aging world population. Vertebral fractures can also be the result of a traumatic event, of hematologic malignancies(multiple myeloma, leukemia), solid tumor metastases to the spine (Bouvard et al., 2011) or long-term steroid therapy(treatment of rheumatoid arthritis, post-transplant patients)(Naganathan et al., 2000). Despite the persistent pain and a more accentuated thoracic and lumbar deformities, those affected often find it hard to realize it , confusing the symptoms with a simple back pain. A compression fracture of the vertebral body not properly treated, increases by 5 times the risk of further fractures, with all that entails in terms of quality of life of the patient and health and social costs (Oleksik et al., 2000). Usually, in case of spinal pain from vertebral fracture, the patient underwent conservative treatment, covering the prescription of a rigid bust, prolonged immobilization and antiinflammatory medication and painkillers (Prather et al.,2007). A similar solution, however, may not always be sufficient to solve the problem, because the pain can persist for several months and, above all, the patient does not recover the correct posture with increased comorbidity (Cauley et al., 2000) Currently there are minimally invasive methods, such as balloon kyphoplasty, vertebroplasty, and other percutaneous techniques for stabilization, inherently safe for characteristics and dynamics of action, allowing an immediate relief of

the pain, and ensuring a good recovery of the statics of the spine (Frank, 2003).

The spine consists of 33 vertebrae, including 7 cervical, 12 thoracic, 5 lumbar, 5 sacral segments often fused together, and finally 4 coccygeal segments (Gray, 1973). These segments are spaced by the intervertebral discs and structurally connected by ligaments and muscles. Observed in the lateral projection, a normal spine shows lordosis at the cervical

**1. Introduction** 

**2. Spine anatomy** 

Pasquale De Negri and Tiziana Tirri


## **Minimally Invasive Treatment of Vertebral Body Fractures**

Pasquale De Negri and Tiziana Tirri *Department of Surgical Oncology and Pain Medicine, IRCCS Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy* 

### **1. Introduction**

648 Osteoporosis

Deramond, H Depriester C, Galibert P, Le Gars D (1998) . Percutaneous vertebroplasty with

Edidin AA, Ong KL, Lau E, Kurtz SM (2011). Mortality Risk for Operated and Non-

Garfin SR, Yuan HA, Reiley MA (2002). New technologies in spine: Kyphoplasty and

Galibert P, Deramond H, Rosat P, Le Gars D (1987). Preliminary note on the treatment of

Johnell, O (1996). Advances in osteoporosis: better identification of risk factors can reduce

Lieberman IH, Dudeney S, Reinhardt MK, Bell G (2001) Initial outcome and efficacy of

Moreland DB, Landi MK, Grand W (2001). Vertebroplasty, techniques to avoid

Perrin C, Jullien V, Padovani B, Blaive B (1999). Percutaneous vertebroplasty complicated by

Phillips, FM (2003). Minimally invasive treatements of osteoporotic vertebral compression

Taylor RS, Fritzell P, Taylor RJ (2007) Balloon kyphoplasty in the management of vertebral compression fractures: an updated systematic review and meta-analysis. Eur Spine J Theodorou DJ, Theodorou SJ, Duncan TD, Garfin SR, Wong WH (2002). Percutaneous

Vaccaro, A (2003). Spine surgery tricks of the trade (Thieme), Thieme New York Stuttgart, 1-

Voggenreiter, G (2005). Balloon Kyphoplasty is Effective in Deformity Correction of Osteoporotic Vertebral Compression Fractures. Spine, 30, 24, 2806–2812 Wardlaw D, Cummings SR, Van Meirhaeghe J, Bastian L, Tillman JB, Ranstam J, Eastell R,

Weißkopf, M. Weisskopf M, Ohnsorge JA, Niethard FU (2008). Intravertebral Pressure During Vertebroplasty and Balloon Kyphoplasty. Spine, 33, 2, 178-182

balloon kyphoplasty for the correction of spinal deformity in painful vertebral

Shabe P, Talmadge K, Boonen S (2009). Efficacy and safety of balloon kyphoplasty compared with non-surgical care for vertebral compression fracture (FREE): a

pulmonary embolus of acrylic cement. Rev Mal Respir, 16: 215-217

Am, 36, 533–546

14, 1511-1515

33,2,166-168

fractures. Spine 26(14): 1631–8

complications. Spine J ,1: 66-71

fratures. Spine,28(15 suppl): S45-53

58890-038-X, USA

and Mineral Research, 2011 Jul;26(7):1617-26

morbidity and mortality. J Intern Med, 239, 299-304

body compression fractures. Clin Imaging, 239:299-304

randomized controlled trial. Lancet, 373, 1016 – 1024

polymethylmethacrylate: technique, indications, and results. Radiol Clin North

Operated Vertebral Fracture Patients in the Medicare Population. Journal of Bone

vertebroplasty for treatment of painful osteoportic compression fracture. Spine, 26,

vertebral angioma by percutaneous acrylic vertebroplasty. Neurochirurgie,

kyphoplasty in the treatment of painful osteoporotic vertebral compression

Gestures rather harmless at first sight like weight-lifting , a sudden movement, sometimes only remaking the bed in the morning could cause, in susceptible individuals, the failure and collapse of the vertebral body. Painful fractures, which cause changes in appearance and posture, persistent back pain, limited mobility and a general decay in the affected individuals, most often even unaware of the cause of their evil ( Eastell et al., 1991). One of the most frequent causes of fractures of the vertebral body is osteoporosis (Dempster, 2011; Haczynski, 2001), relentless and "silent" disease spread rapidly, due to an aging world population. Vertebral fractures can also be the result of a traumatic event, of hematologic malignancies(multiple myeloma, leukemia), solid tumor metastases to the spine (Bouvard et al., 2011) or long-term steroid therapy(treatment of rheumatoid arthritis, post-transplant patients)(Naganathan et al., 2000). Despite the persistent pain and a more accentuated thoracic and lumbar deformities, those affected often find it hard to realize it , confusing the symptoms with a simple back pain. A compression fracture of the vertebral body not properly treated, increases by 5 times the risk of further fractures, with all that entails in terms of quality of life of the patient and health and social costs (Oleksik et al., 2000). Usually, in case of spinal pain from vertebral fracture, the patient underwent conservative treatment, covering the prescription of a rigid bust, prolonged immobilization and antiinflammatory medication and painkillers (Prather et al.,2007). A similar solution, however, may not always be sufficient to solve the problem, because the pain can persist for several months and, above all, the patient does not recover the correct posture with increased comorbidity (Cauley et al., 2000) Currently there are minimally invasive methods, such as balloon kyphoplasty, vertebroplasty, and other percutaneous techniques for stabilization, inherently safe for characteristics and dynamics of action, allowing an immediate relief of the pain, and ensuring a good recovery of the statics of the spine (Frank, 2003).

### **2. Spine anatomy**

The spine consists of 33 vertebrae, including 7 cervical, 12 thoracic, 5 lumbar, 5 sacral segments often fused together, and finally 4 coccygeal segments (Gray, 1973). These segments are spaced by the intervertebral discs and structurally connected by ligaments and muscles. Observed in the lateral projection, a normal spine shows lordosis at the cervical

Minimally Invasive Treatment of Vertebral Body Fractures 651

vertebral venous system, instead, consists of three interconnected systems venous valve diameter (interosseous, epidural and paravertebral). These systems are in close communication with the intertrabecular and intraosseous space. The most important venous system, responsible for the drainage of blood from the vertebral venous system, is the basivertebral that connects with the epidural venous system which surrounds the nerve roots and dural sac. The lateral drainage of the vertebral veins communicate with the paravertebral veins forming a system that runs on both sides of the vertebrae vertically and horizontally and interconnects with epidural anterior and posterior venous system . The central veins are major tributaries of the vena cava and azygos carrying the effluent venous

The vertebral body is made by an extremely thin cortical shell filled with a porous cancellous centrum, the latter carrying about 90% of the load (Duan et al., 2001). During a vertebral compression fracture, the cortex buckles and cracks while the cancellous part collapses and become compacted, reducing the height and volume of vertebra. A vertebral compression fracture (VCF) is defined as a fracture ( fig. n. 2) in which there is a partial collapse of the vertebral body with a reduction of at least 20% of the height of the vertebra (Eastell et al., 1991). Vertebral compression fractures may be related to primary osteoporosis, to drugs (prolonged use of steroids as observed in patients with COPD, rheumatoid arthritis, patients with lymphoma or myeloma, transplant patients, androgen deprivation therapy in patients with prostate cancer) or to primary or secondary neoplastic disease. It has been found an incidence of approximately 700,000 spinal fractures annually in the U.S., which represents a large problem for the health care system (US Department of Health and Human Services, 2004), while in Europe every 30 seconds a patient reports a fracture as a result of osteoporosis (EPOS Group, 2002; O'Neill et al., 2009). In Italy each year we observe at least 30 - 40.000 vertebral fractures osteoporosis-related ( Johnell et al., 2006) . The disability has been associated with an increase in fee costs for home care and treatment of concurrent medical problems; pain treatment can be difficult: often the pain is not adequately controlled with oral medication alone. It has been calculated that 40% of women of average age (8 out 20) and 15% of middle-aged men (3 out 20) will present one or more osteoporotic fractures during their lifetime (Silverman, 1992). Vertebral compression fractures and the fractures of sacrum have inherent characteristics that are influenced by the biomechanics of each spinal element. VCFs are clearly caused by a number of different force vectors. The intrinsic alignment of the column, the presence or absence of kyphosis or lordosis, has a direct influence on the type of fracture. VCFs in the lumbar and cervical areas are typically determined by a bending mechanism. Since the 3/4 of body weight are distributed in 2/3 of the anterior part of spine, it is common to observe the compression of the anterior part of the vertebral body without involvement of the posterior vertebral wall and the connected elements ( Denis, 1983). Vertebral fractures can occur with many simple variants: there may be compression of the posterior wall with or without protrusion of fragments into the spinal canal, whose presence always results in compressive spinal cord or nerve disease; some fractures may lead to the creation of air-filled cavities or liquid in the vertebral body; vertebral compression can be extreme with a loss of vertebral body height more than 70%, ("vertebra plana"). Less frequently, VCFs are caused by trauma, the so-

blood to the lungs ( Groen et al., 2004).

**3. Features of vertebral fractures** 

and lumbar regions and a mild kyphosis at the thoracic and sacral regions. These variations in the curvature are important because they are responsible for the orientation of the single vertebra and important components such as the vertebral pedicles, which are the main access route of percutaneous stabilization techniques which will be discussed later( Ortiz & Deramond, 2001). The size of the vertebrae gradually increase from cervical to lumbar tract with variability dependent on the size of the individual. Theoretically there is an increase in volume ranging from 7.2 ml of the cervical area to 22.4 ml of the lumbar spine. In the thoracic area vertebrae are connected bilaterally with the ribs by ligaments that go from the head of the rib to the vertebral body and then from the rib to the vertebral transverse process. The pedicles of the lower thoracic are relatively large and oriented in an anteriorposterior direction. Heading toward the upper tract, we observe a progressive reduction in the size of the pedicles whose orientation becomes more oblique. In the lumbar tract, we observe larger vertebrae and the orientation of the pedicles is different as we go from L1 to L5. The pedicles of the lumbar spine than have a straight anterior-posterior direction similar to that of the lower thoracic. The pedicles tend therefore to be more oblique in the lower lumbar vertebrae reaching their maximum inclination at L5 ( fig. n. 1).

Fig. 1. Vertebral anatomy

The sacrum is then connected to the pelvis through the sacroiliac joints. The sacrum forms the keystone of the pelvis thus counteracting slipping down determined by the higher load . This situation is then responsible for sacral insufficiency fractures secondary to osteo porosis and trauma ( De Smet et al., 1985). The blood supply for vertebral bodies derives from arterial branches leaving the aorta , running along the lateral margins of the vertebrae and then sending collaterals to the vertebral bodies, the epidural space and nerve roots. These branches are connected above and below the vertebrae in the paraspinous regions . The

and lumbar regions and a mild kyphosis at the thoracic and sacral regions. These variations in the curvature are important because they are responsible for the orientation of the single vertebra and important components such as the vertebral pedicles, which are the main access route of percutaneous stabilization techniques which will be discussed later( Ortiz & Deramond, 2001). The size of the vertebrae gradually increase from cervical to lumbar tract with variability dependent on the size of the individual. Theoretically there is an increase in volume ranging from 7.2 ml of the cervical area to 22.4 ml of the lumbar spine. In the thoracic area vertebrae are connected bilaterally with the ribs by ligaments that go from the head of the rib to the vertebral body and then from the rib to the vertebral transverse process. The pedicles of the lower thoracic are relatively large and oriented in an anteriorposterior direction. Heading toward the upper tract, we observe a progressive reduction in the size of the pedicles whose orientation becomes more oblique. In the lumbar tract, we observe larger vertebrae and the orientation of the pedicles is different as we go from L1 to L5. The pedicles of the lumbar spine than have a straight anterior-posterior direction similar to that of the lower thoracic. The pedicles tend therefore to be more oblique in the lower

The sacrum is then connected to the pelvis through the sacroiliac joints. The sacrum forms the keystone of the pelvis thus counteracting slipping down determined by the higher load . This situation is then responsible for sacral insufficiency fractures secondary to osteo porosis and trauma ( De Smet et al., 1985). The blood supply for vertebral bodies derives from arterial branches leaving the aorta , running along the lateral margins of the vertebrae and then sending collaterals to the vertebral bodies, the epidural space and nerve roots. These branches are connected above and below the vertebrae in the paraspinous regions . The

lumbar vertebrae reaching their maximum inclination at L5 ( fig. n. 1).

Fig. 1. Vertebral anatomy

vertebral venous system, instead, consists of three interconnected systems venous valve diameter (interosseous, epidural and paravertebral). These systems are in close communication with the intertrabecular and intraosseous space. The most important venous system, responsible for the drainage of blood from the vertebral venous system, is the basivertebral that connects with the epidural venous system which surrounds the nerve roots and dural sac. The lateral drainage of the vertebral veins communicate with the paravertebral veins forming a system that runs on both sides of the vertebrae vertically and horizontally and interconnects with epidural anterior and posterior venous system . The central veins are major tributaries of the vena cava and azygos carrying the effluent venous blood to the lungs ( Groen et al., 2004).

### **3. Features of vertebral fractures**

The vertebral body is made by an extremely thin cortical shell filled with a porous cancellous centrum, the latter carrying about 90% of the load (Duan et al., 2001). During a vertebral compression fracture, the cortex buckles and cracks while the cancellous part collapses and become compacted, reducing the height and volume of vertebra. A vertebral compression fracture (VCF) is defined as a fracture ( fig. n. 2) in which there is a partial collapse of the vertebral body with a reduction of at least 20% of the height of the vertebra (Eastell et al., 1991). Vertebral compression fractures may be related to primary osteoporosis, to drugs (prolonged use of steroids as observed in patients with COPD, rheumatoid arthritis, patients with lymphoma or myeloma, transplant patients, androgen deprivation therapy in patients with prostate cancer) or to primary or secondary neoplastic disease. It has been found an incidence of approximately 700,000 spinal fractures annually in the U.S., which represents a large problem for the health care system (US Department of Health and Human Services, 2004), while in Europe every 30 seconds a patient reports a fracture as a result of osteoporosis (EPOS Group, 2002; O'Neill et al., 2009). In Italy each year we observe at least 30 - 40.000 vertebral fractures osteoporosis-related ( Johnell et al., 2006) . The disability has been associated with an increase in fee costs for home care and treatment of concurrent medical problems; pain treatment can be difficult: often the pain is not adequately controlled with oral medication alone. It has been calculated that 40% of women of average age (8 out 20) and 15% of middle-aged men (3 out 20) will present one or more osteoporotic fractures during their lifetime (Silverman, 1992). Vertebral compression fractures and the fractures of sacrum have inherent characteristics that are influenced by the biomechanics of each spinal element. VCFs are clearly caused by a number of different force vectors. The intrinsic alignment of the column, the presence or absence of kyphosis or lordosis, has a direct influence on the type of fracture. VCFs in the lumbar and cervical areas are typically determined by a bending mechanism. Since the 3/4 of body weight are distributed in 2/3 of the anterior part of spine, it is common to observe the compression of the anterior part of the vertebral body without involvement of the posterior vertebral wall and the connected elements ( Denis, 1983). Vertebral fractures can occur with many simple variants: there may be compression of the posterior wall with or without protrusion of fragments into the spinal canal, whose presence always results in compressive spinal cord or nerve disease; some fractures may lead to the creation of air-filled cavities or liquid in the vertebral body; vertebral compression can be extreme with a loss of vertebral body height more than 70%, ("vertebra plana"). Less frequently, VCFs are caused by trauma, the so-

Minimally Invasive Treatment of Vertebral Body Fractures 653

the involved vertebral body, with no radicular pain. In the chronic phase we observe a deformity of the spine, due to loss of height of the vertebral body and the gradual emergence of a protuberant abdomen. The residual back pain in patients with healed vertebral fracture is typically of muscular origin and derives from the now permanent spinal deformity caused by the fracture. In patients with vertebral fracture, in fact, the center of gravity moves forward, creating a wide anterior flexor movement, while muscles of the back and ligaments must offset the increase in flexion. In the presence of contributory causes of back pain (i.e. arthritis and stenosis), treatment of vertebral fracture is not able to offer

In order to correctly diagnose a vertebral fracture, we need a thorough neurological examination to rule out concomitant causes and an accurate X-ray imaging ( fig. n. 3) . The X-ray imaging includes: preferably a plain radiograph in lateral position as very often the vertebral fracture can be difficult to diagnose if the examination is performed in the anteroposterior position as the direction of the beams is not parallel to the endplates; MRI sequences with T1, T2 and STIR weighted sequences; a CT scan of the affected vertebra; in alternative a bone scan. When the patient with suspected vertebral fracture undergoes an MRI examination, the aim is to look for the edematous reactive component. The finding of bone marrow edema during an MRI is very useful in predicting which patients will benefit most from treatment. Fractures of recent onset, thus with the presence of edema, are those that best respond to the treatment . On sagittal T1-weighted sequences, edema associated with compression appears dark, compared with the high (bright) signal normally seen in the marrow fat. Heavily T2-weighted sequences are the most sensitive, with fluid representing marrow edema; standard T2-weighted fast spin-echo sequences without fat saturation pulse are often insensitive to marrow edema because of the relatively high signal intensity from

Finally MRI with short tau inversion recovery (STIR) sequences can eliminate all the fatty component to show only the reactive fluid component. In the event that it is impossible to perform an MRI, the patient may undergo a bone scan that identifies osteoblast activity;

complete relief from pain.

fatty marrow.

Fig. 3. AP and LL images of dorsal column with a VCF

called burst fractures, characterized by multiple interruptions along the perimeter of the body; less common are those in which there is a separation of the front and the back of the vertebral body (Magerl et al., 1994). It is important to note that the percentage loss of vertebral body height is not related to the amount of pain experienced by the patient nor the duration of pain. The upper endplate is most frequently affected by fractures than the lower one. Most fractures related to osteoporosis are located in the midthoracic (T7–T8), thoracolumbar (T11–T12), and lumbar regions. At the sacrum, rather than vertebral compression fractures, we observe fracture lines that give rise to the so-called sacral insufficiency (Schindler et al., 2007). Fractures can affect one or both wings of the sacrum with or without involvement of the central part. VCFs are associated with significant morbidity with difficulty to perform common activities of daily living and increased mortality directly related to the number of fractures and deformities secondary to changes in the kyphotic spine . These deformities cause respiratory and gastrointestinal disorders. VCFs reduce lung function: a thoracic VCF causes a loss of 9% of forced vital capacity, and lung function (FVC, FEV 1) decreased significantly in patients with thoracic and lumbar fractures (Sclaich et al., 1998). In addition, once an osteoporotic vertebral fracture occurred, the risk of subsequent fracture is increased by 5 to 10 times. In patients with VCF the risk of mortality increases of 23-34%; it has been also observed that in case of hip or vertebral fracture, there is an increased risk of mortality, respectively, from 7 to 9 times (Lindsay et al., 2001).

Fig. 2. Vertebral body fracture

### **4. Evaluation and selection of the patient**

Due to the complex etiology of back pain, sometimes the diagnosis of vertebral fracture is delayed despite the persistence of severe back pain and the initial defects of posture not attributable to other causes (Nolla et al., 2001). It has been observed that in most cases the fracture has been recognized during a routine examination. The pain ranges from mild to intense, it can become chronic, but it can also disappear after a few weeks, that is, once the fracture has consolidated. The persistence of pain is higher in people in whom the bone repair is slower. In the acute phase there may be a sudden back pain after a slight injury or no history of trauma; painful is elicitated with local palpation over the posterior elements of

called burst fractures, characterized by multiple interruptions along the perimeter of the body; less common are those in which there is a separation of the front and the back of the vertebral body (Magerl et al., 1994). It is important to note that the percentage loss of vertebral body height is not related to the amount of pain experienced by the patient nor the duration of pain. The upper endplate is most frequently affected by fractures than the lower one. Most fractures related to osteoporosis are located in the midthoracic (T7–T8), thoracolumbar (T11–T12), and lumbar regions. At the sacrum, rather than vertebral compression fractures, we observe fracture lines that give rise to the so-called sacral insufficiency (Schindler et al., 2007). Fractures can affect one or both wings of the sacrum with or without involvement of the central part. VCFs are associated with significant morbidity with difficulty to perform common activities of daily living and increased mortality directly related to the number of fractures and deformities secondary to changes in the kyphotic spine . These deformities cause respiratory and gastrointestinal disorders. VCFs reduce lung function: a thoracic VCF causes a loss of 9% of forced vital capacity, and lung function (FVC, FEV 1) decreased significantly in patients with thoracic and lumbar fractures (Sclaich et al., 1998). In addition, once an osteoporotic vertebral fracture occurred, the risk of subsequent fracture is increased by 5 to 10 times. In patients with VCF the risk of mortality increases of 23-34%; it has been also observed that in case of hip or vertebral fracture, there is an increased risk of mortality, respectively, from 7 to 9 times (Lindsay et al.,

Due to the complex etiology of back pain, sometimes the diagnosis of vertebral fracture is delayed despite the persistence of severe back pain and the initial defects of posture not attributable to other causes (Nolla et al., 2001). It has been observed that in most cases the fracture has been recognized during a routine examination. The pain ranges from mild to intense, it can become chronic, but it can also disappear after a few weeks, that is, once the fracture has consolidated. The persistence of pain is higher in people in whom the bone repair is slower. In the acute phase there may be a sudden back pain after a slight injury or no history of trauma; painful is elicitated with local palpation over the posterior elements of

2001).

Fig. 2. Vertebral body fracture

**4. Evaluation and selection of the patient** 

the involved vertebral body, with no radicular pain. In the chronic phase we observe a deformity of the spine, due to loss of height of the vertebral body and the gradual emergence of a protuberant abdomen. The residual back pain in patients with healed vertebral fracture is typically of muscular origin and derives from the now permanent spinal deformity caused by the fracture. In patients with vertebral fracture, in fact, the center of gravity moves forward, creating a wide anterior flexor movement, while muscles of the back and ligaments must offset the increase in flexion. In the presence of contributory causes of back pain (i.e. arthritis and stenosis), treatment of vertebral fracture is not able to offer complete relief from pain.

Fig. 3. AP and LL images of dorsal column with a VCF

In order to correctly diagnose a vertebral fracture, we need a thorough neurological examination to rule out concomitant causes and an accurate X-ray imaging ( fig. n. 3) . The X-ray imaging includes: preferably a plain radiograph in lateral position as very often the vertebral fracture can be difficult to diagnose if the examination is performed in the anteroposterior position as the direction of the beams is not parallel to the endplates; MRI sequences with T1, T2 and STIR weighted sequences; a CT scan of the affected vertebra; in alternative a bone scan. When the patient with suspected vertebral fracture undergoes an MRI examination, the aim is to look for the edematous reactive component. The finding of bone marrow edema during an MRI is very useful in predicting which patients will benefit most from treatment. Fractures of recent onset, thus with the presence of edema, are those that best respond to the treatment . On sagittal T1-weighted sequences, edema associated with compression appears dark, compared with the high (bright) signal normally seen in the marrow fat. Heavily T2-weighted sequences are the most sensitive, with fluid representing marrow edema; standard T2-weighted fast spin-echo sequences without fat saturation pulse are often insensitive to marrow edema because of the relatively high signal intensity from fatty marrow.

Finally MRI with short tau inversion recovery (STIR) sequences can eliminate all the fatty component to show only the reactive fluid component. In the event that it is impossible to perform an MRI, the patient may undergo a bone scan that identifies osteoblast activity;

Minimally Invasive Treatment of Vertebral Body Fractures 655

needle placement. Once the needle has been inserted into vertebral body, the cement (polymethylmetacrylate-PMMA ) is prepared and mixed until it becomes like toothpaste and then injected trough the needle ( between 3 – 6 ml) under continuous lateral fluoroscopic control in order to observe and prevent any cement leakage. The cement diffuses into space and tends to solidify in 1 hour, stabilizing the vertebral body. After procedure, in fact, the patient must remain lying down for several hours, to prevent movement of cement that is not yet consolidated. The approach to the cervical vertebrae is anterior; needle introduction should preferably be done on the right side (opposite the esophagus) and avoiding carotid

Vertebroplasty is a treatment used to get relief from pain, but has little or no effect on the recovery of the height of the vertebral body fractured. The mechanisms, by which we obtain adequate analgesia, are two: the first mechanism is based on the ability of PMMA to combine the individual bone fragments in a single block, avoiding the painful micro shiftings of individual fragments between them. The second mechanism may be related to the exothermic process that accompanies the polymerization of PMMA and that would result in a "thermal neurolysis" of the nerve within the vertebral body. In addition, the PMMA results in a significant strengthening of osteoporotic bone, reducing the risk of subsequent fractures. The incidence of complications ranges from 1 to 3% in osteoporotic

artery, internal jugular vein, vertebral artery and esophagus.

Fig. 4. AP X-ray image of vertebroplasty

vertebrae.

unfortunately osteoblast activity has been active for about two years after the fracture and the level of the vertebra with fracture is difficult to identify. CT scan however is mandatory to assess the integrity of the posterior wall of the vertebral body and to assess eventual posterior displacement of bone fragments and eventually to assess the adjacent vertebrae (Wehrli et al., 1995).

### **5. Techniques of pain relief in vertebral compression fractures**

Purpose of the augmentation / stabilization techniques, in case of vertebral fracture, is to obtain adequate pain relief, to ensure the healing of vertebral body so to allow the rapid resumption of activities related to daily life, possibly to restore the height of the vertebral body and thus to counteract spinal kyphosis and the consequences related to it. The spinal augmentation / stabilization techniques are indicated in patients in whom conservative treatment represents another cause of morbidity due to bed rest, immobility and untolerable side effects related to analgesics prescribed, or when an "open" surgical procedure is not advisable on the basis of the patient's clinical condition. The techniques that we will describe are: vertebroplasty(Mathis et al., 2001), balloon kyphoplasty (Taylor et al., 2007) and vertebral stabilization by percutaneous pedicular screws (Foley et al., 2001) . Biplane fluoroscopy allows the procedures to be performed more rapidly, but they can also be accomplished safely with a single-plane C-arm; CT has been described as an aid to fluoroscopy, but it adds considerable complexity and cost to the procedure without corresponding benefit to the routine treatment of a VCF (Gangi et al., 1994).

#### **5.1 Vertebroplasty**

Vertebroplasty (VP) was performed as an open procedure to improve the grip of pedicle screws in spinal surgery or during filling of the continuous solutions in the vertebral body after resections for cancer. Percutaneous VP was performed for the first time by Galibert and Deramond (Galibert et al., 1987) for the treatment of severe neck pain secondary to a hemangioma that affected the entire body of C2; after an intervention of laminectomy and resection of the neoplastic component invading the epidural space, they decided to strengthen the structure of the vertebra by the injection of polymethylmethacrylate (PMMA) by anterolateral percutaneous approach. The amount of PMMA injected was 3 ml, with a complete pain relief .The technique was then introduced in the U.S., where it was used primarily to treat pain from osteoporotic vertebral fracture (Deramond et al., 1998). After other experiences, the same authors established key points for the execution of this technique (Mathis et al., 2001). They decided to use large- bore needle (10-13 gauge) for the thoracic and lumbar levels and a smaller needle (13-15 gauge) for the cervical level; the PMMA was made opaque by the addition of contrast to make it visible when injected and to evaluate the distribution during the injection. After a small skin incision, the disposable bone needle is advanced, under fluoroscopic guidance, using an unilateral or bilateral transpedicular/extrapedicular approach ( at lumbar and thoracic spine level respectively) through the centre of the pedicle ( fig. n. 4) , and then into the vertebral body with the expectation that the central portion of the vertebra can be filled. Fluoroscopy, with frequent switching between the frontal and lateral projections, ensures that the needle is correctly positioned. The tip of the needle should be placed within the anterior one-third of the vertebral body, close to the midline; biopsy, if indicated, can be performed before final

unfortunately osteoblast activity has been active for about two years after the fracture and the level of the vertebra with fracture is difficult to identify. CT scan however is mandatory to assess the integrity of the posterior wall of the vertebral body and to assess eventual posterior displacement of bone fragments and eventually to assess the adjacent vertebrae

Purpose of the augmentation / stabilization techniques, in case of vertebral fracture, is to obtain adequate pain relief, to ensure the healing of vertebral body so to allow the rapid resumption of activities related to daily life, possibly to restore the height of the vertebral body and thus to counteract spinal kyphosis and the consequences related to it. The spinal augmentation / stabilization techniques are indicated in patients in whom conservative treatment represents another cause of morbidity due to bed rest, immobility and untolerable side effects related to analgesics prescribed, or when an "open" surgical procedure is not advisable on the basis of the patient's clinical condition. The techniques that we will describe are: vertebroplasty(Mathis et al., 2001), balloon kyphoplasty (Taylor et al., 2007) and vertebral stabilization by percutaneous pedicular screws (Foley et al., 2001) . Biplane fluoroscopy allows the procedures to be performed more rapidly, but they can also be accomplished safely with a single-plane C-arm; CT has been described as an aid to fluoroscopy, but it adds considerable complexity and cost to the procedure without

Vertebroplasty (VP) was performed as an open procedure to improve the grip of pedicle screws in spinal surgery or during filling of the continuous solutions in the vertebral body after resections for cancer. Percutaneous VP was performed for the first time by Galibert and Deramond (Galibert et al., 1987) for the treatment of severe neck pain secondary to a hemangioma that affected the entire body of C2; after an intervention of laminectomy and resection of the neoplastic component invading the epidural space, they decided to strengthen the structure of the vertebra by the injection of polymethylmethacrylate (PMMA) by anterolateral percutaneous approach. The amount of PMMA injected was 3 ml, with a complete pain relief .The technique was then introduced in the U.S., where it was used primarily to treat pain from osteoporotic vertebral fracture (Deramond et al., 1998). After other experiences, the same authors established key points for the execution of this technique (Mathis et al., 2001). They decided to use large- bore needle (10-13 gauge) for the thoracic and lumbar levels and a smaller needle (13-15 gauge) for the cervical level; the PMMA was made opaque by the addition of contrast to make it visible when injected and to evaluate the distribution during the injection. After a small skin incision, the disposable bone needle is advanced, under fluoroscopic guidance, using an unilateral or bilateral transpedicular/extrapedicular approach ( at lumbar and thoracic spine level respectively) through the centre of the pedicle ( fig. n. 4) , and then into the vertebral body with the expectation that the central portion of the vertebra can be filled. Fluoroscopy, with frequent switching between the frontal and lateral projections, ensures that the needle is correctly positioned. The tip of the needle should be placed within the anterior one-third of the vertebral body, close to the midline; biopsy, if indicated, can be performed before final

**5. Techniques of pain relief in vertebral compression fractures** 

corresponding benefit to the routine treatment of a VCF (Gangi et al., 1994).

(Wehrli et al., 1995).

**5.1 Vertebroplasty** 

needle placement. Once the needle has been inserted into vertebral body, the cement (polymethylmetacrylate-PMMA ) is prepared and mixed until it becomes like toothpaste and then injected trough the needle ( between 3 – 6 ml) under continuous lateral fluoroscopic control in order to observe and prevent any cement leakage. The cement diffuses into space and tends to solidify in 1 hour, stabilizing the vertebral body. After procedure, in fact, the patient must remain lying down for several hours, to prevent movement of cement that is not yet consolidated. The approach to the cervical vertebrae is anterior; needle introduction should preferably be done on the right side (opposite the esophagus) and avoiding carotid artery, internal jugular vein, vertebral artery and esophagus.

Fig. 4. AP X-ray image of vertebroplasty

Vertebroplasty is a treatment used to get relief from pain, but has little or no effect on the recovery of the height of the vertebral body fractured. The mechanisms, by which we obtain adequate analgesia, are two: the first mechanism is based on the ability of PMMA to combine the individual bone fragments in a single block, avoiding the painful micro shiftings of individual fragments between them. The second mechanism may be related to the exothermic process that accompanies the polymerization of PMMA and that would result in a "thermal neurolysis" of the nerve within the vertebral body. In addition, the PMMA results in a significant strengthening of osteoporotic bone, reducing the risk of subsequent fractures. The incidence of complications ranges from 1 to 3% in osteoporotic vertebrae.

Minimally Invasive Treatment of Vertebral Body Fractures 657

vertebral body; the balloon restores the vertebral body height in addition to creating the cavity. Into the cavity created by the balloon, a preparation of PMMA thicker than that used in vertebroplasty is then injected under relatively low pressure; because this PMMA is more viscous that used for vertebroplasty and it is injected under lower pressure that in vertebroplasty, the risk of intravascular extrusion is thought to be lower. The risk of cement extravasation is reduced due to containment produced by the newly created vertebral cavity. The entity of the vertebral body reduction varies from case to case, depending by the maximum volume of the balloon inflated and the pressure required to .Although associated with a finite level of cement leakage, serious adverse events appear to be rare. Osteoporotic vertebral compression fractures appear to be associated with a higher level of cement leakage following BKP than non-osteoporotic vertebral compression fractures ( Taylor et al., 2007).

In 2009 it has been conducted a study in which 300 patients have been randomly assigned to receive kyphoplasty treatment or non-surgical care. The primary outcome has been the difference in change from baseline to 1 month in the short-form (SF)-36 physical component summary (PCS) score between the kyphoplasty and control groups. Quality of life and other efficacy measurements and safety have been assessed up to 12 months. Serious adverse events (such as myocardial infarction and pulmonary embolism) did not occur perioperatively and were not related to procedure. Authors concluded that balloon kyphoplasty was an effective and safe procedure for patients with acute vertebral fractures

and could be used as an early treatment option ( Wardlaw et al, 2009).

Fig. 5. AP X-ray image of kyphoplasty

The majority of complications could be divided into:

	- bleeding of the site of needle insertion,
	- rib fracture ,
	- transient fever
	- transient worsening of pain symptoms secondary to the heat produced by the polymerization of the cement,
	- cement leaks into the disk or in paravertebral soft tissues
	- new fractures in adjacent vertebrae (Lindsay et al., 2001)
	- irritation of the nerve trunks,
	- cement leak in epidural space
	- needle displacement
	- infection
	- cement leaks into paravertebral veins, leading to pulmonary embolism, cardiac perforation, cerebral embolism and even death. ( less than 1% when treating osteoporotic compression fractures, increasing to 2–5% when treating osteolytic metastatic disease) (Scroop et al., 2002).

The possible extrusion of cement in the spinal canal (which occurs with an incidence of 3%) is a feared complication, requiring immediate surgical decompression in an attempt to limit the damage from spinal cord compression (Mathis, 2003). Cement can also leak into the disk space. We do not know actually if a cement leak into the disk may be responsible for fracture of an adjacent vertebra as adjacent-level fractures after VP are known to occur also without leak.

After vertebroplasty, it has been reported a marked improvement in pain symptoms in 90% of cases, but residual pain may persist in the early days, in the area of needle insertion or for muscle distraction. The complete disappearance of pain, accompanied by the discontinuation of analgesic drugs has been observed after 3 to 6 weeks. Despite the disappearance of pain, the patient must pay attention to physical activity as the possibility of subsequent vertebral fracture is always present.

#### **5.2 Kyphoplasty**

Kyphoplasty ( KP) has been introduced as an alternative approach in US (Garfin et al., 2001). It can be performed in thoracic vertebrae from T5 to T12 and on all lumbar vertebrae. It is similar to vertebroplasty and has been referred to as "balloon-assisted vertebroplasty" (BKP). Kyphoplasty is a technological advancement of vertebroplasty (fig. n. 5); beside the relief of pain secondary to the VCF, it is possible to obtain a partial recovery of the height of the vertebral body (Lieberman et al., 2001). To restore vertebral anatomy after a fracture, the vertebral endplates must be reduced to their correct anatomic position. This action requires the volume of vertebral body to be increased ( creation of a void) and requires sufficient separing force to move the endplates (reduction). The reduction of the fractured vertebra reduces the kyphosis of the spine; this effect determines an esthetic improvement (posture) and could reduce the risk of fracture of the adjacent vertebra as a result of abnormal load bearing. Kyphoplasty entails the inflation of a percutaneously delivered balloon in the

transient worsening of pain symptoms secondary to the heat produced by the

 cement leaks into paravertebral veins, leading to pulmonary embolism, cardiac perforation, cerebral embolism and even death. ( less than 1% when treating osteoporotic compression fractures, increasing to 2–5% when treating osteolytic

The possible extrusion of cement in the spinal canal (which occurs with an incidence of 3%) is a feared complication, requiring immediate surgical decompression in an attempt to limit the damage from spinal cord compression (Mathis, 2003). Cement can also leak into the disk space. We do not know actually if a cement leak into the disk may be responsible for fracture of an adjacent vertebra as adjacent-level fractures after VP are known to occur also

After vertebroplasty, it has been reported a marked improvement in pain symptoms in 90% of cases, but residual pain may persist in the early days, in the area of needle insertion or for muscle distraction. The complete disappearance of pain, accompanied by the discontinuation of analgesic drugs has been observed after 3 to 6 weeks. Despite the disappearance of pain, the patient must pay attention to physical activity as the possibility

Kyphoplasty ( KP) has been introduced as an alternative approach in US (Garfin et al., 2001). It can be performed in thoracic vertebrae from T5 to T12 and on all lumbar vertebrae. It is similar to vertebroplasty and has been referred to as "balloon-assisted vertebroplasty" (BKP). Kyphoplasty is a technological advancement of vertebroplasty (fig. n. 5); beside the relief of pain secondary to the VCF, it is possible to obtain a partial recovery of the height of the vertebral body (Lieberman et al., 2001). To restore vertebral anatomy after a fracture, the vertebral endplates must be reduced to their correct anatomic position. This action requires the volume of vertebral body to be increased ( creation of a void) and requires sufficient separing force to move the endplates (reduction). The reduction of the fractured vertebra reduces the kyphosis of the spine; this effect determines an esthetic improvement (posture) and could reduce the risk of fracture of the adjacent vertebra as a result of abnormal load bearing. Kyphoplasty entails the inflation of a percutaneously delivered balloon in the

The majority of complications could be divided into:

bleeding of the site of needle insertion,

polymerization of the cement,

metastatic disease) (Scroop et al., 2002).

of subsequent vertebral fracture is always present.

 irritation of the nerve trunks, cement leak in epidural space

needle displacement

infection

 cement leaks into the disk or in paravertebral soft tissues new fractures in adjacent vertebrae (Lindsay et al., 2001)

minor:

moderate

severe

without leak.

**5.2 Kyphoplasty** 

 rib fracture , transient fever vertebral body; the balloon restores the vertebral body height in addition to creating the cavity. Into the cavity created by the balloon, a preparation of PMMA thicker than that used in vertebroplasty is then injected under relatively low pressure; because this PMMA is more viscous that used for vertebroplasty and it is injected under lower pressure that in vertebroplasty, the risk of intravascular extrusion is thought to be lower. The risk of cement extravasation is reduced due to containment produced by the newly created vertebral cavity. The entity of the vertebral body reduction varies from case to case, depending by the maximum volume of the balloon inflated and the pressure required to .Although associated with a finite level of cement leakage, serious adverse events appear to be rare. Osteoporotic vertebral compression fractures appear to be associated with a higher level of cement leakage following BKP than non-osteoporotic vertebral compression fractures ( Taylor et al., 2007).

Fig. 5. AP X-ray image of kyphoplasty

In 2009 it has been conducted a study in which 300 patients have been randomly assigned to receive kyphoplasty treatment or non-surgical care. The primary outcome has been the difference in change from baseline to 1 month in the short-form (SF)-36 physical component summary (PCS) score between the kyphoplasty and control groups. Quality of life and other efficacy measurements and safety have been assessed up to 12 months. Serious adverse events (such as myocardial infarction and pulmonary embolism) did not occur perioperatively and were not related to procedure. Authors concluded that balloon kyphoplasty was an effective and safe procedure for patients with acute vertebral fractures and could be used as an early treatment option ( Wardlaw et al, 2009).

Minimally Invasive Treatment of Vertebral Body Fractures 659

marrow from the vertebrae using a suction device and injection of the CPC. CPCs are justified in the treatment of recent burst fractures of thoracolumbar vertebral bodies in

The use of pedicle screw-assisted spinal stabilization( Foley et al., 2001; Fuentes et al., 2010) has become popular worldwide; pedicle screw fixation is a safe and effective treatment for many spinal disorders, including vertebral fractures not suitable to be treated by vertebro /kyphoplasty. Standard "open " techniques for pedicle screw placement have been associated with a wide median incision of the back and the disconnection of large muscle areas, to allow adequate visualization of the spine and bone, for easy access, with extensive blood loss , lengthy period of hospitalization and costs. Recently it has been introduced into the market a minimally invasive posterior fixation of the lumbar spine in which percutaneous screws and rods are used,minimizing paraspinous tissue trauma without

Fig. 6. Live insertion of percutaneous screw assisted spinal stabilization device

In fact the minimally invasive techniques with the aid of new fluoroscopy generation allows to place percutaneous spinal instrumentation accurately , through small skin incisions and with minimal radiation exposure. The vertebral pedicles represent a very strong connecting structure in the spine, so the placement of a screw inside the pedicle allows for a significant strengthening of the vertebra. The length of screws varies according to different dimensions of the pedicles. The most common screws are made of titanium and are equipped with a head (poliassial screws) that can rotate so as to adapt to different conditions and anatomical locations. Once placed, the rods can be percutaneously inserted into the screws, contributing to the stabilization of the spine ( fig. n. 7) . The benefit of percutaneous intervention is evident because the surgical incisions are less painful, blunt dissection and the muscle dilation do not alter the normal anatomy, blood loss is minimal, the scars are esthetically irrelevant and hospital stay is significantly reduced. Although there are still not many prospective randomized studies comparing conservative treatment versus mini-invasive methods of

young patients ( Bohner et al., 2005).

**5.4 Pedicle screw-assisted spinal stabilization** 

sacrificing the quality of spinal fixation (fig. n. 6).

#### **5.3 Cement selection**

The introduction of an external component in the human body brings up the general problem of biocompatibility. Several types of cement are actually available: the recent development of polymethyl metacrylate cement ( **PMMAs)** and the market introduction of new cements like **composite cements** and **calcium phosphate cements,** allow physicians to choose the best material for the treatment of different lesions causing vertebral pain.

#### **5.3.1 Polymethyl methacrylate (PMMA)**

The most commonly used cement is poly-methyl methacrylate (PMMA) and its function is to immobilize the fracture and increase the strength of the vertebra. PMMA cements fall into two general categories: rapid set or slow set types. Most inexperienced operators initially feel more comfortable by using the slow-set varieties, because these materials allow more working time of the cement at room temperature; however, the rapid-set materials offer definite advantages that quickly surface. A new acrylic osseous cement, with 10% hydroxyapatite wellknown for its osteo-conductive properties, possesses better biocompatibility than traditional cements. The hydroxyapatite particles on the surface of the cement improve the response from the osteoblasts, consequently reducing inflammatory reactions . The high viscosity properties of Confidence Spinal Cement System ©( DePuy Spine, Inc 2011) allows for interdigitation, preserving the trabecular structure of bone; this cement shows immediate post-mixing high viscosity, so reducing the potential leakage within vertebral body. *N*-methyl-pyrrolidone (NMP) has been added to a PMMA bone cement (Boger et al., 2009) making the PMMA cement more compliant for the use in cancellous bone augmentation in osteoporotic patients due to modification of its mechanical properties similar to those of cancellous bone, a lower polymerization temperature, and an extended handling time.

#### **5.3.2 Composite cements**

They have been used since the late 1970's in orthopedic applications, like pedicle screws augmentation. Those cements offset the disadvantages of PMMA like the exothermic reaction, the release of unreacted monomer in the circulatory system and the modification of the initial composition of the PMMA (changes in the monomer-to-polymer-ratio and addition of contrast materials).Moreover they appear to be more biocompatible, easy-tohandle with sufficient radiopacity and with good biomechanical properties. One of these composite cements is Cortoss® ( Sun et al., 2008) developed by Orthovita-Malvern, USA, a glass-ceramic reinforced cement based on the Bowen molecule diluted with triethylene glycol dimethacrylate (TEGDMA ) (Smit et al., 2008). The optimal temperature of Cortoss® to be used is as close as possible to 20°C. Higher temperature will reduce the setting time; to obtain a good fluoroscopic visualisation, there is no need to modify Cortoss, as it contains over 65% of radiopaque fillers.

#### **5.3.3 Calcium phosphate cements (CPCs)**

Calcium phosphate cements (CPCs) are made of different calcium phosphate (CaP) powders and an aqueous solution belonging to the category of the low-temperature cements. CaPs are very similar to the mineral part of bone. They are less injectable if compared with to other PMMA cements, which are hydrophobic and tend to stay compact within the vertebral bodies. In order to prevent this problem, we could create a cavity in the vertebral body with an expandable balloon and filling the new cavity with CPC or removal of bone

The introduction of an external component in the human body brings up the general problem of biocompatibility. Several types of cement are actually available: the recent development of polymethyl metacrylate cement ( **PMMAs)** and the market introduction of new cements like **composite cements** and **calcium phosphate cements,** allow physicians to

The most commonly used cement is poly-methyl methacrylate (PMMA) and its function is to immobilize the fracture and increase the strength of the vertebra. PMMA cements fall into two general categories: rapid set or slow set types. Most inexperienced operators initially feel more comfortable by using the slow-set varieties, because these materials allow more working time of the cement at room temperature; however, the rapid-set materials offer definite advantages that quickly surface. A new acrylic osseous cement, with 10% hydroxyapatite wellknown for its osteo-conductive properties, possesses better biocompatibility than traditional cements. The hydroxyapatite particles on the surface of the cement improve the response from the osteoblasts, consequently reducing inflammatory reactions . The high viscosity properties of Confidence Spinal Cement System ©( DePuy Spine, Inc 2011) allows for interdigitation, preserving the trabecular structure of bone; this cement shows immediate post-mixing high viscosity, so reducing the potential leakage within vertebral body. *N*-methyl-pyrrolidone (NMP) has been added to a PMMA bone cement (Boger et al., 2009) making the PMMA cement more compliant for the use in cancellous bone augmentation in osteoporotic patients due to modification of its mechanical properties similar to those of cancellous bone, a lower

They have been used since the late 1970's in orthopedic applications, like pedicle screws augmentation. Those cements offset the disadvantages of PMMA like the exothermic reaction, the release of unreacted monomer in the circulatory system and the modification of the initial composition of the PMMA (changes in the monomer-to-polymer-ratio and addition of contrast materials).Moreover they appear to be more biocompatible, easy-tohandle with sufficient radiopacity and with good biomechanical properties. One of these composite cements is Cortoss® ( Sun et al., 2008) developed by Orthovita-Malvern, USA, a glass-ceramic reinforced cement based on the Bowen molecule diluted with triethylene glycol dimethacrylate (TEGDMA ) (Smit et al., 2008). The optimal temperature of Cortoss® to be used is as close as possible to 20°C. Higher temperature will reduce the setting time; to obtain a good fluoroscopic visualisation, there is no need to modify Cortoss, as it contains

Calcium phosphate cements (CPCs) are made of different calcium phosphate (CaP) powders and an aqueous solution belonging to the category of the low-temperature cements. CaPs are very similar to the mineral part of bone. They are less injectable if compared with to other PMMA cements, which are hydrophobic and tend to stay compact within the vertebral bodies. In order to prevent this problem, we could create a cavity in the vertebral body with an expandable balloon and filling the new cavity with CPC or removal of bone

choose the best material for the treatment of different lesions causing vertebral pain.

**5.3 Cement selection** 

**5.3.2 Composite cements** 

over 65% of radiopaque fillers.

**5.3.3 Calcium phosphate cements (CPCs)** 

**5.3.1 Polymethyl methacrylate (PMMA)** 

polymerization temperature, and an extended handling time.

marrow from the vertebrae using a suction device and injection of the CPC. CPCs are justified in the treatment of recent burst fractures of thoracolumbar vertebral bodies in young patients ( Bohner et al., 2005).

### **5.4 Pedicle screw-assisted spinal stabilization**

The use of pedicle screw-assisted spinal stabilization( Foley et al., 2001; Fuentes et al., 2010) has become popular worldwide; pedicle screw fixation is a safe and effective treatment for many spinal disorders, including vertebral fractures not suitable to be treated by vertebro /kyphoplasty. Standard "open " techniques for pedicle screw placement have been associated with a wide median incision of the back and the disconnection of large muscle areas, to allow adequate visualization of the spine and bone, for easy access, with extensive blood loss , lengthy period of hospitalization and costs. Recently it has been introduced into the market a minimally invasive posterior fixation of the lumbar spine in which percutaneous screws and rods are used,minimizing paraspinous tissue trauma without sacrificing the quality of spinal fixation (fig. n. 6).

Fig. 6. Live insertion of percutaneous screw assisted spinal stabilization device

In fact the minimally invasive techniques with the aid of new fluoroscopy generation allows to place percutaneous spinal instrumentation accurately , through small skin incisions and with minimal radiation exposure. The vertebral pedicles represent a very strong connecting structure in the spine, so the placement of a screw inside the pedicle allows for a significant strengthening of the vertebra. The length of screws varies according to different dimensions of the pedicles. The most common screws are made of titanium and are equipped with a head (poliassial screws) that can rotate so as to adapt to different conditions and anatomical locations. Once placed, the rods can be percutaneously inserted into the screws, contributing to the stabilization of the spine ( fig. n. 7) . The benefit of percutaneous intervention is evident because the surgical incisions are less painful, blunt dissection and the muscle dilation do not alter the normal anatomy, blood loss is minimal, the scars are esthetically irrelevant and hospital stay is significantly reduced. Although there are still not many prospective randomized studies comparing conservative treatment versus mini-invasive methods of

Minimally Invasive Treatment of Vertebral Body Fractures 661

Kallmes et al. in 2009 in a multicenter trial, randomly assigned 131 patients with painful osteoporotic vertebral compression fractures to undergo either vertebroplasty or a simulated procedure without cement; patients were allowed to cross over to the other study group after 1 month. For those receiving the sham procedure, 42% opted to receive VP at three months, compared with 12% for the other arm. The two groups did not differ significantly on Roland– Morris Disability Questionnaire (RDQ) or average pain intensity at 1 month, but there was a trend toward a higher rate of clinically meaningful improvement in pain in the vertebroplasty group . The authors found that improvements in pain and pain-related disability associated with vertebral fractures in patients treated with vertebroplasty were similar to the improvements of control group. Anyway the higher rate of cross-over could reflect dissatisfaction with the sham procedure compared with PV, or possibly flaws in the blinding of the sham procedure such that patients were able to "guess" which intervention underwent. Clark et al. and Baerlocher et al. in 2009 criticized the previous study underlying that a more appropriate selection criterion would have included patients with uncontrolled pain for less than 6 weeks as the number of patients with pain for less than 6 weeks was too small for a subgroup analysis. Moreover the study of Buchbinder had a target enrollment of 200 patients, but only 78 were enrolled over 4 years, substantially limiting statistical power. More criticism evidenced that in the study, described as multicenter trial, two of the four hospitals withdrew early from the study, after enrolling five patients each; 68% of the procedures were performed in one hospital by one radiologist; respectively 64% and 70% of eligible patients declined to participate in trials reported by Buchbinder and Kallmes raising further concerns regarding patient selection. Both trials did not examine the role of VP in non osteoporotic vertebral fractures or in the inpatient setting (Weinstein, 2009) Recently a multicenter study, the so called VERTOS II, randomized over 200 patients with a vertebral compression fracture and pain of less than 6 weeks duration to conservative treatment or VP; participants and physicians as well as outcome assessors were not blinded. Sham procedure was not performed. Authors found a statistically significant reduction in pain in the VP arm after one month and one year (Clazen et al., 2010). Rousing et al. reported a 12-month follow-up from an open-label, randomized study including 50 patients with a vertebral fracture less than 8 weeks comparing VP with conservative management. They observed an immediate and significant pain relief following VP. One month after hospital discharge, patients undergone VP, had a statistically significantly reduction in pain compared with the ones in conservative therapy arm. However, no difference in pain scores have been observed between groups after 3 and 12 months. They suggested that the role of VP may therefore be considered as a short-term method of pain control in those who fail conservative treatment or for those whom conservative treatment and the accompanying

immobilization carry serious risks (Rousing et al., 2010).

Long-term effectiveness and complication data from VP or KP are currently lacking. Performing a true blinded randomized-controlled trial between conservative therapy and invasive techniques is impossible. It is the authors' opinion that for patients who are failing conservative treatment or are at increased risk from prolonged bed rest, ( i.e. older patients or patients with COPD), augmentation techniques could offer a good pain relief in comparison to conservative treatment, even if no durable long-term benefit has been yet demonstrated. On the other side patients with pain of greater than three months duration

**7. Conclusions** 

vertebral stabilization (Kallmes et al., 2009; Buchbinder et al., 2006; Clazen et al., 2010; Clark et al., 2011), pain relief is often achieved in 80% of cases with the latter within a few hours , stopping the progression of the deformity of the spine, even in long-term studies.

Fig. 7. LL X-ray image of percutaneous screw assisted spinal stabilization device

The immediate analgesic effect is due to cement injection into the fracture, while the longterm effect is guaranteed by stabilization or correction of spinal deformity, which guarantees not only the restoration of proper biomechanics but also the reduction in fracture risk of other vertebrae. The improvement of quality of life is significant, allowing more motor activity of the patient, which in turn leads to better preservation of bone mass and thus fracture risk containment, not only of the spine.

### **6. Controversies**

Buchbinder et al. in 2009 performed a multicenter, randomized, double-blind, placebocontrolled trial in which participants with painful osteoporotic vertebral fractures not older than one year and unhealed, were randomly assigned to undergo vertebroplasty or a sham procedure. Outcomes were assessed at 1 week and at 1, 3, and 6 months; the primary outcome was pain evaluation at 3 months. They found no beneficial effect of vertebroplasty as compared with a sham procedure in patients at 1 week or at 1, 3, or 6 months after treatment.

vertebral stabilization (Kallmes et al., 2009; Buchbinder et al., 2006; Clazen et al., 2010; Clark et al., 2011), pain relief is often achieved in 80% of cases with the latter within a few hours ,

stopping the progression of the deformity of the spine, even in long-term studies.

Fig. 7. LL X-ray image of percutaneous screw assisted spinal stabilization device

thus fracture risk containment, not only of the spine.

**6. Controversies** 

treatment.

The immediate analgesic effect is due to cement injection into the fracture, while the longterm effect is guaranteed by stabilization or correction of spinal deformity, which guarantees not only the restoration of proper biomechanics but also the reduction in fracture risk of other vertebrae. The improvement of quality of life is significant, allowing more motor activity of the patient, which in turn leads to better preservation of bone mass and

Buchbinder et al. in 2009 performed a multicenter, randomized, double-blind, placebocontrolled trial in which participants with painful osteoporotic vertebral fractures not older than one year and unhealed, were randomly assigned to undergo vertebroplasty or a sham procedure. Outcomes were assessed at 1 week and at 1, 3, and 6 months; the primary outcome was pain evaluation at 3 months. They found no beneficial effect of vertebroplasty as compared with a sham procedure in patients at 1 week or at 1, 3, or 6 months after Kallmes et al. in 2009 in a multicenter trial, randomly assigned 131 patients with painful osteoporotic vertebral compression fractures to undergo either vertebroplasty or a simulated procedure without cement; patients were allowed to cross over to the other study group after 1 month. For those receiving the sham procedure, 42% opted to receive VP at three months, compared with 12% for the other arm. The two groups did not differ significantly on Roland– Morris Disability Questionnaire (RDQ) or average pain intensity at 1 month, but there was a trend toward a higher rate of clinically meaningful improvement in pain in the vertebroplasty group . The authors found that improvements in pain and pain-related disability associated with vertebral fractures in patients treated with vertebroplasty were similar to the improvements of control group. Anyway the higher rate of cross-over could reflect dissatisfaction with the sham procedure compared with PV, or possibly flaws in the blinding of the sham procedure such that patients were able to "guess" which intervention underwent. Clark et al. and Baerlocher et al. in 2009 criticized the previous study underlying that a more appropriate selection criterion would have included patients with uncontrolled pain for less than 6 weeks as the number of patients with pain for less than 6 weeks was too small for a subgroup analysis. Moreover the study of Buchbinder had a target enrollment of 200 patients, but only 78 were enrolled over 4 years, substantially limiting statistical power. More criticism evidenced that in the study, described as multicenter trial, two of the four hospitals withdrew early from the study, after enrolling five patients each; 68% of the procedures were performed in one hospital by one radiologist; respectively 64% and 70% of eligible patients declined to participate in trials reported by Buchbinder and Kallmes raising further concerns regarding patient selection. Both trials did not examine the role of VP in non osteoporotic vertebral fractures or in the inpatient setting (Weinstein, 2009) Recently a multicenter study, the so called VERTOS II, randomized over 200 patients with a vertebral compression fracture and pain of less than 6 weeks duration to conservative treatment or VP; participants and physicians as well as outcome assessors were not blinded. Sham procedure was not performed. Authors found a statistically significant reduction in pain in the VP arm after one month and one year (Clazen et al., 2010). Rousing et al. reported a 12-month follow-up from an open-label, randomized study including 50 patients with a vertebral fracture less than 8 weeks comparing VP with conservative management. They observed an immediate and significant pain relief following VP. One month after hospital discharge, patients undergone VP, had a statistically significantly reduction in pain compared with the ones in conservative therapy arm. However, no difference in pain scores have been observed between groups after 3 and 12 months. They suggested that the role of VP may therefore be considered as a short-term method of pain control in those who fail conservative treatment or for those whom conservative treatment and the accompanying

### **7. Conclusions**

immobilization carry serious risks (Rousing et al., 2010).

Long-term effectiveness and complication data from VP or KP are currently lacking. Performing a true blinded randomized-controlled trial between conservative therapy and invasive techniques is impossible. It is the authors' opinion that for patients who are failing conservative treatment or are at increased risk from prolonged bed rest, ( i.e. older patients or patients with COPD), augmentation techniques could offer a good pain relief in comparison to conservative treatment, even if no durable long-term benefit has been yet demonstrated. On the other side patients with pain of greater than three months duration

Minimally Invasive Treatment of Vertebral Body Fractures 663

Foley KT, Gupta SK, Justis JR & Sherman MC. Percutaneous pedicle screw fixation of the

Frank PM. Minimally Invasive Treatments of Osteoporotic Vertebral Compression

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**Part 7** 

**Research and New Challenges in Osteoporosis** 

