Osteoporosis: A Multifactorial Disease

*Di Wu, Anna Cline-Smith, Elena Shashkova and Rajeev Aurora*

#### **Abstract**

A great achievement of modern medicine is the increased lifespan of the human population. Unfortunately, the comorbidities of aging have created a large economic and health burden on society. Osteoporosis is the most prevalent age-related disease. It is characterized by uncoupled bone resorption that leads to low bone mass, compromised microarchitecture and structural deterioration that increases the likelihood of fracture with minimal trauma, known as fragility fractures. These fractures lead to disproportionally high mortality rate and a drastic decline in quality of life for those affected. While estrogen loss is one known trigger of osteoporosis, a number of recent studies have shown that osteoporosis is a multifactorial condition in both humans and rodent models. The presence or absence of certain factors are likely to determine which subset of the population develop osteoporosis. In this chapter, we review the factors that contribute to osteoporosis with an emphasis on its multifactorial nature and the therapeutic consequences.

**Keywords:** osteoporosis, postmenopausal osteoporosis, aging, mineral homeostasis, gut microbiome, metabolism, osteoimmunology, therapy, T-cells

#### **1. Introduction**

Osteoporosis (OP) is the most prevalent metabolic bone disease that affects half the women and one third of men, typically, in the sixth and seventh decade of life [1, 2]. OP is characterized by uncoupled bone resorption that leads to low bone mass, compromised microarchitecture and structural deterioration that increases the likelihood of fractures with minimal trauma, known as fragility fractures. These fractures lead to disproportionally high mortality rate and a drastic decline in quality of life for those affected.

OP is diagnosed by an X-ray (typically by dual energy X-ray absorptiometry or DEXA) scan to measure bone mineral density (BMD) [3]. Two scores are returned: a Z-score and a T-score [4]. The T-score is normalized BMD by sex and age, whereas the Z-score also accounts for weight and ethnicity. Both scores report standard deviations (σ) of BMD from mean. A T-score of −1 is normal (within 1 σ of mean), whereas less than −1 to −2.5 indicates osteopenia. A patient with T-scores less than −2.5 is considered osteoporotic. Additional factors to BMD such as smoking, family history of fractures, the diagnosis of rheumatoid arthritis, alcohol consumption and glucocorticoid use many be considered to predict the probability of fracture using a fracture risk assessment tool score or FRAX score [5, 6].

**Figure 1.** *The multifactorial nature of osteoporosis (OP). Osteoporosis is most commonly associated both aging and estrogen loss. This figure summarizes factors that affect bone health.*

The skeletal system has several physiological functions. First, it provides mechanical support that allows for locomotion. Bone is weight bearing and serves as an anchor for muscle. Osteocytes are bone matrix embedded mechanosensory cells, that promote bone loss or gain (adaptation) to loads placed on the bone (i.e., Wolff's law). The marrow space within long bones serves as the primary site of hematopoiesis in an adult. When hematopoietic-derived cells are depleted in the periphery (due to inflammation, for instance) there is demand on the bone marrow [7, 8] to release both progenitors and differentiated cells into circulation [9, 10]. Bone also serves as the primary store for calcium and phosphate, and thus is under control of hormones produced by the parathyroid gland (parathyroid hormone or PTH and calcitonin) and kidneys (fibroblast growth factor 23 or FGF23). Vitamin D facilitate calcium absorption from the diet while PTH, calcitonin and FGF23 regulate serum calcium levels and responds to different physiological needs. In recent years, there is growing appreciation of the diverse roles the skeletal system plays in a person's health, including whole body metabolism, immune regulation and neurocognitive functions [11], in addition to the previously recognized roles of mechanical support and mineral homeostasis. Based on the function of the skeleton, OP can result from dysregulation in one or more factors that we will discuss in detail below (**Figure 1**).

#### **2. Bone biology**

Bone remodeling is a coordinated process where bone resorption and bone formation occur at the same location throughout life to repair microfractures and maintain bone homeostasis. Imbalances in bone remodeling underscore the pathophysiology

**45**

*Osteoporosis: A Multifactorial Disease*

**3. Aging and osteoporosis**

of aging on bone and crosstalk with other factors.

**4. Calcium, vitamin D3 and mineral homeostasis**

*DOI: http://dx.doi.org/10.5772/intechopen.97549*

of OP. There are three major cell types involved in bone remodeling: bone resorbing osteoclasts, bone forming osteoblasts, and osteocytes. Osteoclasts (OC) are multinucleated, bone-specialized macrophages, whose differentiation depends on receptor activator of nuclear factor kappa B (NF-κB) (RANK) and its ligand (RANKL). Osteoblasts (OB) differentiate from mesenchymal stem cells (MSC) and are

responsible for bone formation. Many signaling pathways have been discovered that are critical for osteogenic differentiation, including Wingless and Int-1 (WNT)/βcatenin, bone morphogenic protein (BMP) and mechanistic target of rapamycin (mTOR). During bone remodeling, OC are recruited to the site of repair, where they will initiate bone resorption through two major mechanisms: 1) acidification of the microenvironment and 2) secretion of matrix metalloproteases. Towards the end of the resorption phase, OC will recruit MSC and osteoprogenitors and promote the differentiation and maturation of OB. At the same time, OB will secrete osteoprotegerin (OPG), a decoy receptor of RANKL, which will inhibit osteoclastogenesis and shut down bone resorption. OB will then begin producing extracellular matrix that will eventually calcify and become newly mineralized bone. As such, bone resorption and bone formation are tightly coupled and highly regulated. Together, OC and OB form the basic multicellular unit (BMU), the smallest functional unit during bone formation. During remodeling the OC and OB form the bone remodeling unit (BRU). Mature OB have three different fates when bone formation is complete. The majority will undergo apoptosis, a small fraction will become senescent bone lining cells, and an even smaller number become osteocytes. Osteocytes (Ocy) are stellate like cells embedded within mineralized bone that are mechanosensors within the bone. Ocy have a pivotal regulatory role in bone homeostasis, directing and coordinating fracture repair by regulating the BRU. Ocy they have recently been shown to have both osteolytic and anabolic functions and play a pivotal role during lactation [12].

Both men and women develop OP [13]. The skeletal system grows rapidly postnatally and through puberty. Peak bone mass is attained by mid-third decade (mid 20s) of life [14]. Beginning at the end of the third decade, both sexes start to lose bone mass [14] that continues with aging. The rate (or slope = change in bone mass/ change in time) varies by anatomical site [15] and by additional factors discussed in this chapter. It follows that the range between normal bone mass, osteopenia and OP is determined by both the peak bone mass (baseline) and the rate of age-related bone loss. Aging leads to increased senescent stem cells that repopulate OC and OB leading to deficiency in repair of microfractures that develop with use [16–18]. A recent study has shown that ablating senescent osteoclast precursors did not improve age-related bone loss [19]. There is accelerated bone loss (called the acute phase) in menopausal women [20–22]. The sex differences in age-related bone loss in humans can be recapitulated in mice [23]. In addition to the senescence of progenitor cells, increased oxidative stress during aging have been reported to decreased osteoblastogenesis while simultaneously increase osteoclastogenesis, favoring bone resorption [24]. Further research is needed to understand the effects

It is standard practice to advise supplementation of calcium and vitamin D to osteoporotic women. However, most studies have shown that subjects of European

#### *Osteoporosis: A Multifactorial Disease DOI: http://dx.doi.org/10.5772/intechopen.97549*

*Osteoporosis - Recent Advances, New Perspectives and Applications*

The skeletal system has several physiological functions. First, it provides mechanical support that allows for locomotion. Bone is weight bearing and serves as an anchor for muscle. Osteocytes are bone matrix embedded mechanosensory cells, that promote bone loss or gain (adaptation) to loads placed on the bone (i.e., Wolff's law). The marrow space within long bones serves as the primary site of hematopoiesis in an adult. When hematopoietic-derived cells are depleted in the periphery (due to inflammation, for instance) there is demand on the bone marrow [7, 8] to release both progenitors and differentiated cells into circulation [9, 10]. Bone also serves as the primary store for calcium and phosphate, and thus is under control of hormones produced by the parathyroid gland (parathyroid hormone or PTH and calcitonin) and kidneys (fibroblast growth factor 23 or FGF23). Vitamin D facilitate calcium absorption from the diet while PTH, calcitonin and FGF23 regulate serum calcium levels and responds to different physiological needs. In recent years, there is growing appreciation of the diverse roles the skeletal system plays in a person's health, including whole body metabolism, immune regulation and neurocognitive functions [11], in addition to the previously recognized roles of mechanical support and mineral homeostasis. Based on the function of the skeleton, OP can result from dysregulation in one or more factors that we will discuss in detail below (**Figure 1**).

*The multifactorial nature of osteoporosis (OP). Osteoporosis is most commonly associated both aging and* 

*estrogen loss. This figure summarizes factors that affect bone health.*

Bone remodeling is a coordinated process where bone resorption and bone formation occur at the same location throughout life to repair microfractures and maintain bone homeostasis. Imbalances in bone remodeling underscore the pathophysiology

**44**

**2. Bone biology**

**Figure 1.**

of OP. There are three major cell types involved in bone remodeling: bone resorbing osteoclasts, bone forming osteoblasts, and osteocytes. Osteoclasts (OC) are multinucleated, bone-specialized macrophages, whose differentiation depends on receptor activator of nuclear factor kappa B (NF-κB) (RANK) and its ligand (RANKL). Osteoblasts (OB) differentiate from mesenchymal stem cells (MSC) and are responsible for bone formation. Many signaling pathways have been discovered that are critical for osteogenic differentiation, including Wingless and Int-1 (WNT)/βcatenin, bone morphogenic protein (BMP) and mechanistic target of rapamycin (mTOR). During bone remodeling, OC are recruited to the site of repair, where they will initiate bone resorption through two major mechanisms: 1) acidification of the microenvironment and 2) secretion of matrix metalloproteases. Towards the end of the resorption phase, OC will recruit MSC and osteoprogenitors and promote the differentiation and maturation of OB. At the same time, OB will secrete osteoprotegerin (OPG), a decoy receptor of RANKL, which will inhibit osteoclastogenesis and shut down bone resorption. OB will then begin producing extracellular matrix that will eventually calcify and become newly mineralized bone. As such, bone resorption and bone formation are tightly coupled and highly regulated. Together, OC and OB form the basic multicellular unit (BMU), the smallest functional unit during bone formation. During remodeling the OC and OB form the bone remodeling unit (BRU). Mature OB have three different fates when bone formation is complete. The majority will undergo apoptosis, a small fraction will become senescent bone lining cells, and an even smaller number become osteocytes. Osteocytes (Ocy) are stellate like cells embedded within mineralized bone that are mechanosensors within the bone. Ocy have a pivotal regulatory role in bone homeostasis, directing and coordinating fracture repair by regulating the BRU. Ocy they have recently been shown to have both osteolytic and anabolic functions and play a pivotal role during lactation [12].

#### **3. Aging and osteoporosis**

Both men and women develop OP [13]. The skeletal system grows rapidly postnatally and through puberty. Peak bone mass is attained by mid-third decade (mid 20s) of life [14]. Beginning at the end of the third decade, both sexes start to lose bone mass [14] that continues with aging. The rate (or slope = change in bone mass/ change in time) varies by anatomical site [15] and by additional factors discussed in this chapter. It follows that the range between normal bone mass, osteopenia and OP is determined by both the peak bone mass (baseline) and the rate of age-related bone loss. Aging leads to increased senescent stem cells that repopulate OC and OB leading to deficiency in repair of microfractures that develop with use [16–18]. A recent study has shown that ablating senescent osteoclast precursors did not improve age-related bone loss [19]. There is accelerated bone loss (called the acute phase) in menopausal women [20–22]. The sex differences in age-related bone loss in humans can be recapitulated in mice [23]. In addition to the senescence of progenitor cells, increased oxidative stress during aging have been reported to decreased osteoblastogenesis while simultaneously increase osteoclastogenesis, favoring bone resorption [24]. Further research is needed to understand the effects of aging on bone and crosstalk with other factors.

#### **4. Calcium, vitamin D3 and mineral homeostasis**

It is standard practice to advise supplementation of calcium and vitamin D to osteoporotic women. However, most studies have shown that subjects of European ancestry are replete in calcium and vitamin D [25]. A number of studies and metaanalyses prior to 2010 showed an efficacy in reducing fracture risk with vitamin D alone, calcium alone and the combination [26, 27]. The lack of efficacy in some studies was attributed to lack of compliance [28]. There is a historical precedence that links rickets/osteomalacia and OP from the 17th century. The softening of bones became rampant in industrialized countries during the 19th century but rickets/osteomalacia were not clearly distinguished from OP until 1885. It was shown that rickets was due to the lack of new bone formation whereas OP was due to increased bone resorption [29]. Nonetheless, the overlap between hyperparathyroidism, under nourishment, calcium malabsorption with vitamin D insufficiency has become a paradigm for OP leading to practice of advising supplementation [30]. However, recent studies that have indicated that high serum calcium is associated with cardiovascular events, specifically stroke and increase coronary artery calcification, have led to questioning this practice [31–33]. This increase was due to supplementary calcium and not observed with natural dietary calcium [31, 32]. More recent meta-analysis found a trend for increased risk of cardiovascular events with calcium supplementation, although it was not statistically significant [34]. Additional studies are needed to resolve this question.

#### **5. Body mass index (BMI) and metabolism**

Epidemiological studies have shown elderly men and postmenopausal women with low BMI have lower T-scores and are classified as osteopenic or osteoporotic. A positive correlation has been observed in postmenopausal women between high BMI and prevalence of osteoarthritis (OA) and a negative correlation with prevalence of OP [35–37]. Adipocytes produce hormones (adipokines) that have been shown to regulate bone mass [38, 39]. Adipose tissue, especially visceral adipose tissue, has also been shown to harbor proinflammatory T-cells [40, 41]. Recently, Zou et al. showed that ablation of bone marrow adipocytes in mice cause a dramatic increase in bone mass [42]. Therefore, adipose tissue and obesity forms a complex link to bone health. First, white adipose tissue directly influences OB via adipokines [43]. Second, adipose tissue activates T-cells to produce proinflammatory cytokines tumor necrosis factor alpha (TNFα), interleukin (IL)-1β and IL-6. Additionally, insulin resistance is associated with obesity, thus altered glucose metabolism also affects bone metabolism, which has been shown to impede OB differentiation [44]. Further studies are needed to understand the mechanism(s) connecting inflammation, lipid and glucose metabolism to OA and OP.

#### **6. Prescribed medicines contribute to osteoporosis**

Recent studies have shown that patients taking certain commonly prescribed medicines have higher incidence of OP [45]. The best understood drug-induced bone loss is with glucocorticoids [46, 47]. There are also data suggesting that anticoagulants such as warfarin and heparin, which effect Vitamin K levels, are detrimental to bone health [48, 49]. This class of drugs also alters the gut microbiome adding to the complexity of interpretation [50]. Other drugs, including antiepileptics, proton pump inhibitors, opioid analgesics and aromatase inhibitors induce osteoporosis as well [51–54]. Further confounding the interpretation of data, these medications are often prescribed long-term in elderly populations who are already at risk due to age of osteoporosis. Even if the effect size of each medication is small, the combined drug–drug interactions can be more than additive [55, 56].

**47**

*Osteoporosis: A Multifactorial Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.97549*

**7. Modulation by the gut microbiome**

formation or inhibit bone resorption.

**8. Chronic inflammation and regulation by the immune system**

The recognition that T-cell derived cytokines affect bone has given rise to the field of osteoimmunology. The word *osteoimmunology* was first coined in 2000 by Arron and Choi [68], describing the crosstalk between the skeletal system and the immune system. Takayanagi et al. first reported such cross talk, demonstrating that T-cell produced interferon gamma (IFN-γ) can inhibit RANKL signaling during OC differentiation [69]. Since then, many studies have shown that TNFα and IL-17A promote osteoclastogenesis. Both cytokines are also increase in chronic inflammatory diseases such as rheumatoid arthritis, Crohn's, and some viral (i.e., human immunodeficiency virus or HIV) infections, which may explain why these patients have decreased bone mass [70–75]. TNFα has been shown to promote the production of RANKL from OB and osteocytes in addition to directly acting on OC precursors in synergy with RANKL [76–79]. PTH acts through T-cells to promote bone formation [80]. Th17 cells have been shown to increase osteoclastogenesis and resorption activity Th17 cells are the key pathogenic drive in immune-mediated bone destruction [81]. A number of studies have confirmed that IL-17A is a potent promoter of bone destruction, particularly in the context of autoimmune pathologies [82–84]. The field of osteoimmunology have thus far focused on OC, and additional studies are needed to assess how Th17 cells and the cytokines TNFα and IL-17A affect OB to limit bone formation. Inflammation has two effects: first, a direct effect where cytokines produced by T-cells act on the BRU to modulate bone

The human digestive tract harbors trillions of microorganisms collectively known as the gut microbiome (GMB), which contain magnitudes more genetic information than our own genome. It is well recognized that the GMB plays an important role in educating the immune system, as germfree (GF) mice have reduced T cell populations. A number of studies have shown an association between GMB and bone health in both animal models [57, 58] and in humans [50]. However, Sjögrne et.al were the first to present evidence of direct interaction between the GMB and the bone [59]. They showed that GF mice had increased bone mass compared to conventionally raised (CONV-R) mice, and that transplantation of a GMB from CONV-R normalized bone mass. Since then, a number of studies have been conducted to investigate the regulation of bone homeostasis by the GMB. Estrogen (E2) loss increases gut permeability [60–62], which leads to increased priming and activation of inflammation in the gut mucosa, leading to the generation of type 17 helper T-cells (Th17 cells). Segmented filamentous bacterium (SFB) have been shown to induce Th17 in the mice intestine and to promote decreased bone mass [63]. Th17 cells are potent inducers of osteoclastogenesis leading to increased bone resorption and bone loss. Li et al. demonstrated that bone loss in ovariectomized (OVX) mice is depended on the GMB and it can be prevented with supplementation of probiotics [64]. There is clear correlation between GMB and bone health, however the precise mechanisms remain elusive. Recent studies have suggested GMB produce microbial metabolites that have regulatory function on distal organs, including the bone. GMB derived butyrate, polyamines and short-chain fatty acids have been shown to induce regulatory T cell (TREG) generation in the colon [65–67] and to regulate bone health. Thus, GMB modulate bone mass through a number of mechanisms, *viz.* by negatively by increasing Th17 cells, positively by inducing regulatory T-cells, and positively by producing metabolites that promote bone

*Osteoporosis - Recent Advances, New Perspectives and Applications*

Additional studies are needed to resolve this question.

**5. Body mass index (BMI) and metabolism**

tion, lipid and glucose metabolism to OA and OP.

**6. Prescribed medicines contribute to osteoporosis**

ancestry are replete in calcium and vitamin D [25]. A number of studies and metaanalyses prior to 2010 showed an efficacy in reducing fracture risk with vitamin D alone, calcium alone and the combination [26, 27]. The lack of efficacy in some studies was attributed to lack of compliance [28]. There is a historical precedence that links rickets/osteomalacia and OP from the 17th century. The softening of bones became rampant in industrialized countries during the 19th century but rickets/osteomalacia were not clearly distinguished from OP until 1885. It was shown that rickets was due to the lack of new bone formation whereas OP was due to increased bone resorption [29]. Nonetheless, the overlap between hyperparathyroidism, under nourishment, calcium malabsorption with vitamin D insufficiency has become a paradigm for OP leading to practice of advising supplementation [30]. However, recent studies that have indicated that high serum calcium is associated with cardiovascular events, specifically stroke and increase coronary artery calcification, have led to questioning this practice [31–33]. This increase was due to supplementary calcium and not observed with natural dietary calcium [31, 32]. More recent meta-analysis found a trend for increased risk of cardiovascular events with calcium supplementation, although it was not statistically significant [34].

Epidemiological studies have shown elderly men and postmenopausal women with low BMI have lower T-scores and are classified as osteopenic or osteoporotic. A positive correlation has been observed in postmenopausal women between high BMI and prevalence of osteoarthritis (OA) and a negative correlation with prevalence of OP [35–37]. Adipocytes produce hormones (adipokines) that have been shown to regulate bone mass [38, 39]. Adipose tissue, especially visceral adipose tissue, has also been shown to harbor proinflammatory T-cells [40, 41]. Recently, Zou et al. showed that ablation of bone marrow adipocytes in mice cause a dramatic increase in bone mass [42]. Therefore, adipose tissue and obesity forms a complex link to bone health. First, white adipose tissue directly influences OB via adipokines [43]. Second, adipose tissue activates T-cells to produce proinflammatory cytokines tumor necrosis factor alpha (TNFα), interleukin (IL)-1β and IL-6. Additionally, insulin resistance is associated with obesity, thus altered glucose metabolism also affects bone metabolism, which has been shown to impede OB differentiation [44]. Further studies are needed to understand the mechanism(s) connecting inflamma-

Recent studies have shown that patients taking certain commonly prescribed medicines have higher incidence of OP [45]. The best understood drug-induced bone loss is with glucocorticoids [46, 47]. There are also data suggesting that anticoagulants such as warfarin and heparin, which effect Vitamin K levels, are detrimental to bone health [48, 49]. This class of drugs also alters the gut microbiome adding to the complexity of interpretation [50]. Other drugs, including antiepileptics, proton pump inhibitors, opioid analgesics and aromatase inhibitors induce osteoporosis as well [51–54]. Further confounding the interpretation of data, these medications are often prescribed long-term in elderly populations who are already at risk due to age of osteoporosis. Even if the effect size of each medication is small,

the combined drug–drug interactions can be more than additive [55, 56].

**46**

### **7. Modulation by the gut microbiome**

The human digestive tract harbors trillions of microorganisms collectively known as the gut microbiome (GMB), which contain magnitudes more genetic information than our own genome. It is well recognized that the GMB plays an important role in educating the immune system, as germfree (GF) mice have reduced T cell populations. A number of studies have shown an association between GMB and bone health in both animal models [57, 58] and in humans [50]. However, Sjögrne et.al were the first to present evidence of direct interaction between the GMB and the bone [59]. They showed that GF mice had increased bone mass compared to conventionally raised (CONV-R) mice, and that transplantation of a GMB from CONV-R normalized bone mass. Since then, a number of studies have been conducted to investigate the regulation of bone homeostasis by the GMB. Estrogen (E2) loss increases gut permeability [60–62], which leads to increased priming and activation of inflammation in the gut mucosa, leading to the generation of type 17 helper T-cells (Th17 cells). Segmented filamentous bacterium (SFB) have been shown to induce Th17 in the mice intestine and to promote decreased bone mass [63]. Th17 cells are potent inducers of osteoclastogenesis leading to increased bone resorption and bone loss. Li et al. demonstrated that bone loss in ovariectomized (OVX) mice is depended on the GMB and it can be prevented with supplementation of probiotics [64]. There is clear correlation between GMB and bone health, however the precise mechanisms remain elusive. Recent studies have suggested GMB produce microbial metabolites that have regulatory function on distal organs, including the bone. GMB derived butyrate, polyamines and short-chain fatty acids have been shown to induce regulatory T cell (TREG) generation in the colon [65–67] and to regulate bone health. Thus, GMB modulate bone mass through a number of mechanisms, *viz.* by negatively by increasing Th17 cells, positively by inducing regulatory T-cells, and positively by producing metabolites that promote bone formation or inhibit bone resorption.

### **8. Chronic inflammation and regulation by the immune system**

The recognition that T-cell derived cytokines affect bone has given rise to the field of osteoimmunology. The word *osteoimmunology* was first coined in 2000 by Arron and Choi [68], describing the crosstalk between the skeletal system and the immune system. Takayanagi et al. first reported such cross talk, demonstrating that T-cell produced interferon gamma (IFN-γ) can inhibit RANKL signaling during OC differentiation [69]. Since then, many studies have shown that TNFα and IL-17A promote osteoclastogenesis. Both cytokines are also increase in chronic inflammatory diseases such as rheumatoid arthritis, Crohn's, and some viral (i.e., human immunodeficiency virus or HIV) infections, which may explain why these patients have decreased bone mass [70–75]. TNFα has been shown to promote the production of RANKL from OB and osteocytes in addition to directly acting on OC precursors in synergy with RANKL [76–79]. PTH acts through T-cells to promote bone formation [80]. Th17 cells have been shown to increase osteoclastogenesis and resorption activity Th17 cells are the key pathogenic drive in immune-mediated bone destruction [81]. A number of studies have confirmed that IL-17A is a potent promoter of bone destruction, particularly in the context of autoimmune pathologies [82–84]. The field of osteoimmunology have thus far focused on OC, and additional studies are needed to assess how Th17 cells and the cytokines TNFα and IL-17A affect OB to limit bone formation. Inflammation has two effects: first, a direct effect where cytokines produced by T-cells act on the BRU to modulate bone

homeostasis. Second, inflammation has an indirect effect that is due to increased demand on hematopoiesis. For instance, neutrophils and mast cells have short halflives when they participate in inflammatory response. As they die, the immune cells are replenished by increased hematopoiesis and efflux of precursors and mature cells from the bone is mediated via regulation of osteoclastic activity [85–87]. The prolonged demand may also lead to bone erosion.

#### **9. Postmenopausal osteoporosis**

In women, aging leads to menopause, the cessation of ovarian function that is one of the leading causes of secondary osteoporosis. Early studies suggested that E2 directly regulates OC [88–91] and OB [92, 93] and its loss at menopause results in long lived OC and impaired OB, and to uncoupled bone resorption [94]. Postmenopausal osteoporosis (PMOP) has been traditionally regarded as an endocrinal, E2 deficiency mediated disease. Over the last two decades, it has become apparent that E2-loss promotes persistent activation of T-cell that promotes acute phase of osteoporosis [80, 95, 96]. The mechanistic studies for linking E2 loss at menopause and activation of the T-cells has come from ovariectomy (OVX) of rodents and key outcomes have been validated in human studies. OVX of female rodents is a well-established and widely used model for menopause. E2 loss leads to both increased bone resorption and formation, however, this process is uncoupled where the former greatly exceeds the latter, resulting in net bone loss. Pacifici and colleagues first reported in 1990 that there is increased monocytic production of IL-1 in osteoporotic patients, indicating that in the absence of sex steroids, cytokines promote bone loss [97]. OVX of sexually mature mice that were T-cell

#### **Figure 2.**

*Novel pathway of E2 loss induced chronic inflammations leading to bone loss.* Left panel*: BMDC secrete IL-7, IL-15 or both to promote survival of TMEM. E2 induces FasL in the BMDC, resulting in shorter lifespans. In addition, IL-15 induces Fas in proliferating TMEM in response to IL-7 and IL-15 thus maintain a homeostatic pool of TMEM.* Right panel*: In absence of E2, BMDC have reduced FasL expression, resulting in their proliferation and high concentrations of IL-7 and IL-15. Under these conditions, all TMEM proliferate and a subset (~5 to 10%) become reactivated TEM which produce TNF*α *and IL-17A, promoting bone resorption and also limits bone formation. BMDC = bone marrow resident dendritic cells, TMEM = memory T-cells, TEM = effector memory T-cells.* This figure was created in *BioRender.com*

**49**

in CD8+

*Osteoporosis: A Multifactorial Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.97549*

in uncoupled bone loss [82, 106–110].

in varying sensitivity of reactivation.

tooth extraction or in people with type 2 diabetes).

longer than patient who received antiresorptives first [118].

use of immunomodulatory therapies in PMOP.

**10. Therapeutics**

deficient showed decreased bone loss, which provided further evidence that T-cells play a key role in promoting bone resorption [98–102], as did blockade of TNFα [103] and IL-17A [104]. At the same time, Takayanagi et al. showed that IFN-γ regulated osteoclastogenesis [69, 105]. In the past decade, there is mounting evidence suggesting that the immune system and inflammation play a critical pathogenic role

Recently, our lab has described a new pathway where E2 loss leads to chronic low-grade production of the proinflammatory cytokines TNFα and IL-17 by memory T-cells (TMEM) that was dependent on IL-7 and IL-15 in mice [111] (**Figure 2**). The increased production of IL-7 and IL-15 was mediated by bone marrow dendritic cells (BMDCs), which in the absence of E2 do not express FasL, leading to an antigen-independent activation of TMEM. These TMEM proliferate, and a subset become effector memory T-cells (TEM) to produce TNFα and IL-17A. TMEM encode a lifetime of exposures to antigens and only a subset of these could be converted to IL-17A and TNFα expressing. This notion would explain the variance at the population level in the development of PMOP. We hypothesize that the difference in the bone marrow TMEM population based on the life-time antigen exposure would result

The therapeutics prescribed most commonly for osteoporosis are anti-resorptives like bisphosphonates or denosumab. One issue with this class of medications are the adverse effects, most notably osteonecrosis of the jaw (ONJ). Although ONJ is rare (1–3%), it has been observed with anti-resorptive therapies (both bisphosphonates and denosumab) in patients with certain predisposing factors (i.e., after

The second class of therapies are bone anabolics. Two examples of this class are teriparatide [112] and more recently romosozumab that targets sclerostin [113]. The bone anabolic therapies are also limited in their use because of potential adverse effects with prolonged use [114–116] and in special populations as well [117]. Furthermore, there is a limited window for the efficacy of many bone anabolic therapies due to adaptations in the bone in response to therapy. Interestingly, it has been observed in randomized control trials that the sequence of medication has substantial impacts on the long-term outcome. Patients who received teriparatide for 2 years first, followed by anti-resorptives maintained bone mass significantly

As we discussed in this chapter, OP can arise from a combination of multiple causes. It follows that the treatment of osteoporosis should target additional mechanisms. All current therapies target the cells of the BRU, to suppress resorption of to promote bone formation. Furthermore, the current therapies have shortcomings and adverse effects with prolonged use necessitating drug holidays [119]. Therefore, additional therapies are needed, including a more precision medicine approach to treat osteoporosis. Immunomodulatory options such as anti-TNFα, anti-IL-17A and anti-RANKL have yielded inconsistent results in patients. Recently, Chong et al. [120] showed that neutralization of IL-17A induces compensatory increase of other Th17 cytokines, including IL-17F, IL-22 and GM-CSF. This has implication for the

Our laboratory discovered that OC are antigen presenting cells that induce Forkhead box protein 3 (FoxP3), cluster of differentiation (CD) 25, cytotoxic T-lymphocyte-associated protein (CTLA) 4 and expression of IFN-γ and IL-10

regulatory

T-cells in vitro (**Figure 3**). We have validated that these CD8<sup>+</sup>

#### *Osteoporosis: A Multifactorial Disease DOI: http://dx.doi.org/10.5772/intechopen.97549*

*Osteoporosis - Recent Advances, New Perspectives and Applications*

prolonged demand may also lead to bone erosion.

**9. Postmenopausal osteoporosis**

homeostasis. Second, inflammation has an indirect effect that is due to increased demand on hematopoiesis. For instance, neutrophils and mast cells have short halflives when they participate in inflammatory response. As they die, the immune cells are replenished by increased hematopoiesis and efflux of precursors and mature cells from the bone is mediated via regulation of osteoclastic activity [85–87]. The

In women, aging leads to menopause, the cessation of ovarian function that is one of the leading causes of secondary osteoporosis. Early studies suggested that E2 directly regulates OC [88–91] and OB [92, 93] and its loss at menopause results in long lived OC and impaired OB, and to uncoupled bone resorption [94]. Postmenopausal osteoporosis (PMOP) has been traditionally regarded as an endocrinal, E2 deficiency mediated disease. Over the last two decades, it has become apparent that E2-loss promotes persistent activation of T-cell that promotes acute phase of osteoporosis [80, 95, 96]. The mechanistic studies for linking E2 loss at menopause and activation of the T-cells has come from ovariectomy (OVX) of rodents and key outcomes have been validated in human studies. OVX of female rodents is a well-established and widely used model for menopause. E2 loss leads to both increased bone resorption and formation, however, this process is uncoupled where the former greatly exceeds the latter, resulting in net bone loss. Pacifici and colleagues first reported in 1990 that there is increased monocytic production of IL-1 in osteoporotic patients, indicating that in the absence of sex steroids, cytokines promote bone loss [97]. OVX of sexually mature mice that were T-cell

*Novel pathway of E2 loss induced chronic inflammations leading to bone loss.* Left panel*: BMDC secrete IL-7, IL-15 or both to promote survival of TMEM. E2 induces FasL in the BMDC, resulting in shorter lifespans. In addition, IL-15 induces Fas in proliferating TMEM in response to IL-7 and IL-15 thus maintain a homeostatic pool of TMEM.* Right panel*: In absence of E2, BMDC have reduced FasL expression, resulting in their proliferation and high concentrations of IL-7 and IL-15. Under these conditions, all TMEM proliferate and a subset (~5 to 10%) become reactivated TEM which produce TNF*α *and IL-17A, promoting bone resorption and also limits bone formation. BMDC = bone marrow resident dendritic cells, TMEM = memory T-cells,* 

*TEM = effector memory T-cells.* This figure was created in *BioRender.com*

**48**

**Figure 2.**

deficient showed decreased bone loss, which provided further evidence that T-cells play a key role in promoting bone resorption [98–102], as did blockade of TNFα [103] and IL-17A [104]. At the same time, Takayanagi et al. showed that IFN-γ regulated osteoclastogenesis [69, 105]. In the past decade, there is mounting evidence suggesting that the immune system and inflammation play a critical pathogenic role in uncoupled bone loss [82, 106–110].

Recently, our lab has described a new pathway where E2 loss leads to chronic low-grade production of the proinflammatory cytokines TNFα and IL-17 by memory T-cells (TMEM) that was dependent on IL-7 and IL-15 in mice [111] (**Figure 2**). The increased production of IL-7 and IL-15 was mediated by bone marrow dendritic cells (BMDCs), which in the absence of E2 do not express FasL, leading to an antigen-independent activation of TMEM. These TMEM proliferate, and a subset become effector memory T-cells (TEM) to produce TNFα and IL-17A. TMEM encode a lifetime of exposures to antigens and only a subset of these could be converted to IL-17A and TNFα expressing. This notion would explain the variance at the population level in the development of PMOP. We hypothesize that the difference in the bone marrow TMEM population based on the life-time antigen exposure would result in varying sensitivity of reactivation.

#### **10. Therapeutics**

The therapeutics prescribed most commonly for osteoporosis are anti-resorptives like bisphosphonates or denosumab. One issue with this class of medications are the adverse effects, most notably osteonecrosis of the jaw (ONJ). Although ONJ is rare (1–3%), it has been observed with anti-resorptive therapies (both bisphosphonates and denosumab) in patients with certain predisposing factors (i.e., after tooth extraction or in people with type 2 diabetes).

The second class of therapies are bone anabolics. Two examples of this class are teriparatide [112] and more recently romosozumab that targets sclerostin [113]. The bone anabolic therapies are also limited in their use because of potential adverse effects with prolonged use [114–116] and in special populations as well [117]. Furthermore, there is a limited window for the efficacy of many bone anabolic therapies due to adaptations in the bone in response to therapy. Interestingly, it has been observed in randomized control trials that the sequence of medication has substantial impacts on the long-term outcome. Patients who received teriparatide for 2 years first, followed by anti-resorptives maintained bone mass significantly longer than patient who received antiresorptives first [118].

As we discussed in this chapter, OP can arise from a combination of multiple causes. It follows that the treatment of osteoporosis should target additional mechanisms. All current therapies target the cells of the BRU, to suppress resorption of to promote bone formation. Furthermore, the current therapies have shortcomings and adverse effects with prolonged use necessitating drug holidays [119]. Therefore, additional therapies are needed, including a more precision medicine approach to treat osteoporosis. Immunomodulatory options such as anti-TNFα, anti-IL-17A and anti-RANKL have yielded inconsistent results in patients. Recently, Chong et al. [120] showed that neutralization of IL-17A induces compensatory increase of other Th17 cytokines, including IL-17F, IL-22 and GM-CSF. This has implication for the use of immunomodulatory therapies in PMOP.

Our laboratory discovered that OC are antigen presenting cells that induce Forkhead box protein 3 (FoxP3), cluster of differentiation (CD) 25, cytotoxic T-lymphocyte-associated protein (CTLA) 4 and expression of IFN-γ and IL-10 in CD8+ T-cells in vitro (**Figure 3**). We have validated that these CD8+ regulatory

#### **Figure 3.**

*Osteoclasts induce tolerogenic TcREG. OC use three signals to induce TcREG: Antigen-loaded MHC I, CD200 (a costimulation molecule that activates NF-*κ*B) and the notch ligand DLL4. Treatment with pRANKL leads to increased expression DLL4 and therefore increased induction of TcREG. TcREG secrete IFN-*γ *that suppress osteoclastogenesis by degrading TRAF6 and resorption by mature OC. TcREG also secrete IL-10, which is required for the bone anabolic activity but not resolution of inflammation. IL-10 may also target Ocy to improve cortical bone mass. Resolution of inflammation appears to be mediated by CTLA4 expressed on TcREG.*  This figure was created in *BioRender.com.*

T-cell (TcREG) are induced by OC during bone resorption in vivo [121, 122]. Bone resorbing OC induce TcREG and TcREG suppress bone resorption by OC to form a negative feedback loop [123]. TcREG are also immunosuppressive like their CD4+ counter parts [124]. Both in vivo induction by low dose pulse RANKL (pRANKL) and adoptive transfer of ex vivo generated TcREG suppressed bone resorption, TNFα production and promoted bone formation to ameliorate osteoporosis in OVX mice [125]. In unpublished studies, OVX IL-10 deficient mice were unresponsive to the bone anabolic effects of pRANKL. However, TcREG retained its ability to inhibit TNFα production in TEM, suggesting that the immunosuppressive effects are IL-10 independent. Further investigation showed that IL-10 directly regulates OB at the gene expression level. Taken together, our observations indicate that the immune system plays a fundamental role in modulating bone homeostasis, able to tip the balance either in favor of uncoupled bone resorption or bone formation.

#### **11. Conclusions**

In this chapter, we highlighted the multifactorial nature of osteoporosis. Bone loss occurs with age and slope associated with this decline may be enhanced with decreased vitamin D3, calcium deficiency in diet, medicines and polypharmacy, excess secretion of phosphate by kidneys, by hyperparathyroidism, chronic inflammation by persistent infections and autoimmune disease. E2 loss also triggers a low-grade persistent inflammation in a subset of memory T-cells that promotes rapid bone erosion. Emerging evidence demonstrates significant interplay between these factors revealing the tradeoffs between organismal homeostasis and organspecific regulation. Research in current decade is likely to provide new insights and mechanisms into the crosstalk. Revealing the mechanistic details will provide

**51**

*Osteoporosis: A Multifactorial Disease*

in the aging population.

**Acknowledgements**

**Author Contributions**

discussion of the review.

**Conflict of interest**

**Appendix 1: Abbreviations**

OC osteoclasts

OB osteoblasts

OPG osteoprotegerin BMU basic multicellular unit BRU bone remodeling unit BIM body mass index OA osteoarthritis

IL interleukin GMB gut microbiome CONV-R conventionally raised

Th helper T cell

BMD bone mineral density FRAX fracture risk assessment tool PTH parathyroid hormone FGF23 fibroblast growth factor 23

NF-κB nuclear factor kappa B RANK receptor activator of NF-κB RANKL receptor activator of NF-κB ligand

MSC mesenchymal stem cells WNT wingless and Int-1

BMP bone morphogenic protein mTOR mechanistic target of rapamycin

TNFα tumor necrosis factor alpha

OVX ovariectomy (surgery) or ovariectomized

**Appendices**

*DOI: http://dx.doi.org/10.5772/intechopen.97549*

additional unpublished experiments referenced herein.

The authors declare no conflict of interest.

DEXA dual energy X-ray absorptiometry

exciting new targets for therapies. Furthermore, determining the factors in each individual would allow for precision medicine approach to promoting bone health

We thank Daniel Goering, Yiyi Zhang and Lizzie Geerling for contributing to

RA conceived of the manuscript. DW and RA drafted the manuscript. ACS and ES provided literature search and edits. All authors were involved in scientific exciting new targets for therapies. Furthermore, determining the factors in each individual would allow for precision medicine approach to promoting bone health in the aging population.

### **Acknowledgements**

*Osteoporosis - Recent Advances, New Perspectives and Applications*

T-cell (TcREG) are induced by OC during bone resorption in vivo [121, 122]. Bone resorbing OC induce TcREG and TcREG suppress bone resorption by OC to form a negative feedback loop [123]. TcREG are also immunosuppressive like their CD4+ counter parts [124]. Both in vivo induction by low dose pulse RANKL (pRANKL) and adoptive transfer of ex vivo generated TcREG suppressed bone resorption, TNFα production and promoted bone formation to ameliorate osteoporosis in OVX mice [125]. In unpublished studies, OVX IL-10 deficient mice were unresponsive to the bone anabolic effects of pRANKL. However, TcREG retained its ability to inhibit TNFα production in TEM, suggesting that the immunosuppressive effects are IL-10 independent. Further investigation showed that IL-10 directly regulates OB at the gene expression level. Taken together, our observations indicate that the immune system plays a fundamental role in modulating bone homeostasis, able to tip the

*Osteoclasts induce tolerogenic TcREG. OC use three signals to induce TcREG: Antigen-loaded MHC I, CD200 (a costimulation molecule that activates NF-*κ*B) and the notch ligand DLL4. Treatment with pRANKL leads to increased expression DLL4 and therefore increased induction of TcREG. TcREG secrete IFN-*γ *that suppress osteoclastogenesis by degrading TRAF6 and resorption by mature OC. TcREG also secrete IL-10, which is required for the bone anabolic activity but not resolution of inflammation. IL-10 may also target Ocy to improve cortical bone mass. Resolution of inflammation appears to be mediated by CTLA4 expressed on TcREG.* 

balance either in favor of uncoupled bone resorption or bone formation.

In this chapter, we highlighted the multifactorial nature of osteoporosis. Bone loss occurs with age and slope associated with this decline may be enhanced with decreased vitamin D3, calcium deficiency in diet, medicines and polypharmacy, excess secretion of phosphate by kidneys, by hyperparathyroidism, chronic inflammation by persistent infections and autoimmune disease. E2 loss also triggers a low-grade persistent inflammation in a subset of memory T-cells that promotes rapid bone erosion. Emerging evidence demonstrates significant interplay between these factors revealing the tradeoffs between organismal homeostasis and organspecific regulation. Research in current decade is likely to provide new insights and mechanisms into the crosstalk. Revealing the mechanistic details will provide

**50**

**11. Conclusions**

**Figure 3.**

This figure was created in *BioRender.com.*

We thank Daniel Goering, Yiyi Zhang and Lizzie Geerling for contributing to additional unpublished experiments referenced herein.

### **Author Contributions**

RA conceived of the manuscript. DW and RA drafted the manuscript. ACS and ES provided literature search and edits. All authors were involved in scientific discussion of the review.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Appendices**

#### **Appendix 1: Abbreviations**


#### *Osteoporosis - Recent Advances, New Perspectives and Applications*


### **Author details**

Di Wu, Anna Cline-Smith, Elena Shashkova and Rajeev Aurora\* Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA

\*Address all correspondence to: rajeev.aurora@health.slu.edu

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**53**

1065-1070.

*Osteoporosis: A Multifactorial Disease*

[1] Melton LJ. The prevalence of osteoporosis: gender and racial comparison. Calcified tissue international. 2001;69(4):179.

[2] Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. Journal of

[3] Authority VIAE. Dual energy x-ray absorptiometry for bone mineral density and body composition

[4] Sahota O, Pearson D, Cawte SW, San P, Hosking DJ. Site-Specific Variation in the Classification of Osteoporosis, and the Diagnostic Reclassification Using the Lowest Individual Lumbar Vertebra T-score Compared with the L1–L4 Mean, in Early Postmenopausal Women. Osteoporosis International. 2000;11(10):852-857.

[5] Kanis JA, Borgstrom F, De Laet C, Johansson H, Johnell O, Jonsson B, et al. Assessment of fracture risk. Osteoporos

[6] Kanis JA, Johnell O, Oden A, De Laet C, de Terlizzi F. Ten-year probabilities of clinical vertebral fractures according to phalangeal quantitative ultrasonography. Osteoporos Int. 2005;16(9):

[7] Kuznetsov SA, Riminucci M, Ziran N, Tsutsui TW, Corsi A, Calvi L, et al. The interplay of osteogenesis and

hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone

Int. 2005;16(6):581-589.

Bone and Mineral Research. 2014;29(11):2520-2526.

assessment. 2010.

**References**

*DOI: http://dx.doi.org/10.5772/intechopen.97549*

marrow. J Cell Biol. 2004;167(6):

the hierarchical structure of hematopoiesis. Stem Cells. 2008;26(12):3228-3236.

[8] Yahata T, Muguruma Y, Yumino S, Sheng Y, Uno T, Matsuzawa H, et al. Quiescent human hematopoietic stem cells in the bone marrow niches organize

[9] Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6(2):93-106.

[10] Heideveld E, van den Akker E. Digesting the role of bone marrow macrophages on hematopoiesis. Immunobiology. 2017;222(6):814-822.

[11] Karsenty G, Ferron M. The

[12] Tsourdi E, Jähn K, Rauner M, Busse B, Bonewald LF. Physiological and pathological osteocytic osteolysis. Journal of musculoskeletal & neuronal interactions. 2018;18(3):292-303.

[13] Bonnick SL. Osteoporosis in men and women. Clin Cornerstone.

[14] Burr DB. Muscle strength, bone mass, and age-related bone loss. Journal

of bone and mineral research.

[15] Aerssens J, Boonen S, Joly J, Dequeker J. Variations in trabecular bone composition with anatomical site and age: potential implications for bone quality assessment. J Endocrinol.

[16] Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-1217.

1997;12(10):1547-1551.

1997;155(3):411-421.

physiology. Nature. 2012; 481(7381):314-320.

2006;8(1):28-39.

contribution of bone to whole-organism

1113-1122.

### **References**

*Osteoporosis - Recent Advances, New Perspectives and Applications*

CTLA4 cytotoxic T-lymphocyte-associated protein 4

HIV human immunodeficiency virus

BMDC bone marrow dendritic cells TEM effector memory T cell ONJ osteonecrosis of the jaw

CD cluster of differentiation

TREG regulatory T cell IFNγ interferon gamma

TMEM memory T cell

FoxP3 forkhead box P3

**52**

**Author details**

Di Wu, Anna Cline-Smith, Elena Shashkova and Rajeev Aurora\*

\*Address all correspondence to: rajeev.aurora@health.slu.edu

School of Medicine, St. Louis, MO, USA

provided the original work is properly cited.

Department of Molecular Microbiology and Immunology, Saint Louis University

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, [1] Melton LJ. The prevalence of osteoporosis: gender and racial comparison. Calcified tissue international. 2001;69(4):179.

[2] Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. Journal of Bone and Mineral Research. 2014;29(11):2520-2526.

[3] Authority VIAE. Dual energy x-ray absorptiometry for bone mineral density and body composition assessment. 2010.

[4] Sahota O, Pearson D, Cawte SW, San P, Hosking DJ. Site-Specific Variation in the Classification of Osteoporosis, and the Diagnostic Reclassification Using the Lowest Individual Lumbar Vertebra T-score Compared with the L1–L4 Mean, in Early Postmenopausal Women. Osteoporosis International. 2000;11(10):852-857.

[5] Kanis JA, Borgstrom F, De Laet C, Johansson H, Johnell O, Jonsson B, et al. Assessment of fracture risk. Osteoporos Int. 2005;16(6):581-589.

[6] Kanis JA, Johnell O, Oden A, De Laet C, de Terlizzi F. Ten-year probabilities of clinical vertebral fractures according to phalangeal quantitative ultrasonography. Osteoporos Int. 2005;16(9): 1065-1070.

[7] Kuznetsov SA, Riminucci M, Ziran N, Tsutsui TW, Corsi A, Calvi L, et al. The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone

marrow. J Cell Biol. 2004;167(6): 1113-1122.

[8] Yahata T, Muguruma Y, Yumino S, Sheng Y, Uno T, Matsuzawa H, et al. Quiescent human hematopoietic stem cells in the bone marrow niches organize the hierarchical structure of hematopoiesis. Stem Cells. 2008;26(12):3228-3236.

[9] Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6(2):93-106.

[10] Heideveld E, van den Akker E. Digesting the role of bone marrow macrophages on hematopoiesis. Immunobiology. 2017;222(6):814-822.

[11] Karsenty G, Ferron M. The contribution of bone to whole-organism physiology. Nature. 2012; 481(7381):314-320.

[12] Tsourdi E, Jähn K, Rauner M, Busse B, Bonewald LF. Physiological and pathological osteocytic osteolysis. Journal of musculoskeletal & neuronal interactions. 2018;18(3):292-303.

[13] Bonnick SL. Osteoporosis in men and women. Clin Cornerstone. 2006;8(1):28-39.

[14] Burr DB. Muscle strength, bone mass, and age-related bone loss. Journal of bone and mineral research. 1997;12(10):1547-1551.

[15] Aerssens J, Boonen S, Joly J, Dequeker J. Variations in trabecular bone composition with anatomical site and age: potential implications for bone quality assessment. J Endocrinol. 1997;155(3):411-421.

[16] Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-1217.

[17] Laurent MR, Dedeyne L, Dupont J, Mellaerts B, Dejaeger M, Gielen E. Age-related bone loss and sarcopenia in men. Maturitas. 2019;122:51-56.

[18] Morgan EF, Unnikrisnan GU, Hussein AI. Bone Mechanical Properties in Healthy and Diseased States. Annu Rev Biomed Eng. 2018;20:119-143.

[19] Kim HN, Chang J, Iyer S, Han L, Campisi J, Manolagas SC, et al. Elimination of senescent osteoclast progenitors has no effect on the ageassociated loss of bone mass in mice. Aging Cell. 2019;18(3):e12923.

[20] Riggs BL. The mechanisms of estrogen regulation of bone resorption. J Clin Invest. 2000;106(10):1203-1204.

[21] Riggs BL, Khosla S, Atkinson EJ, Dunstan CR, Melton LJ, 3rd. Evidence that type I osteoporosis results from enhanced responsiveness of bone to estrogen deficiency. Osteoporos Int. 2003;14(9):728-733.

[22] Riggs BL, Khosla S, Melton LJ, 3rd. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res. 1998;13(5):763-773.

[23] Glatt V, Canalis E, Stadmeyer L, Bouxsein ML. Age-related changes in trabecular architecture differ in female and male C57BL/6J mice. J Bone Miner Res. 2007;22(8):1197-1207.

[24] Ucer S, Iyer S, Kim HN, Han L, Rutlen C, Allison K, et al. The Effects of Aging and Sex Steroid Deficiency on the Murine Skeleton Are Independent and Mechanistically Distinct. J Bone Miner Res. 2017;32(3):560-574.

[25] Ringe JD. Plain vitamin D or active vitamin D in the treatment of osteoporosis: where do we stand today? Arch Osteoporos. 2020;15(1):182.

[26] Nordin BE. Evolution of the calcium paradigm: the relation between vitamin D, serum calcium and calcium absorption. Nutrients. 2010;2(9): 997-1004.

[27] Nowson CA. Prevention of fractures in older people with calcium and vitamin D. Nutrients. 2010;2(9):975-984.

[28] Hill TR, Aspray TJ, Francis RM. Vitamin D and bone health outcomes in older age. Proc Nutr Soc. 2013;72(4): 372-380.

[29] Pommer DG. Untersuchungen über Osteomalacie und Rachitis nebst Beiträgen zur Kenntniss der Knochenresorption und-apposition in verschiedenen Altersperioden und der durchbohrenden Gefässe, von Dr Gustav Pommer: FCW Vogel; 1885.

[30] Need AG, O'Loughlin PD, Morris HA, Coates PS, Horowitz M, Nordin BE. Vitamin D metabolites and calcium absorption in severe vitamin D deficiency. J Bone Miner Res. 2008;23(11):1859-1863.

[31] Anderson JJ, Kruszka B, Delaney JA, He K, Burke GL, Alonso A, et al. Calcium Intake From Diet and Supplements and the Risk of Coronary Artery Calcification and its Progression Among Older Adults: 10-Year Follow-up of the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Heart Assoc. 2016;5(10).

[32] Li K, Kaaks R, Linseisen J, Rohrmann S. Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg). Heart. 2012;98(12):920-925.

**55**

1736-1743.

2020;45(4):1112-1120.

and Down-Regulation of

(Lausanne). 2019;10:815.

*Osteoporosis: A Multifactorial Disease*

[34] Jenkins DJA, Spence JD, Giovannucci EL, Kim YI, Josse R, Vieth R, et al. Supplemental Vitamins and Minerals for CVD Prevention and

Treatment. J Am Coll Cardiol. 2018;71(22):2570-2584.

[35] Chen Z, Klimentidis YC, Bea JW, Ernst KC, Hu C, Jackson R, et al. Body Mass Index, Waist Circumference, and Mortality in a Large Multiethnic Postmenopausal Cohort-Results from the Women's Health Initiative. J Am Geriatr Soc. 2017;65(9):1907-1915.

[36] Ichchou L, Allali F, Rostom S,

Abourazzak FZ, et al. Relationship between spine osteoarthritis, bone mineral density and bone turn over markers in post menopausal women. BMC Womens Health. 2010;10:25.

[37] Wright NC, Riggs GK, Lisse JR, Chen Z, Women's Health I. Self-

reported osteoarthritis, ethnicity, body mass index, and other associated risk factors in postmenopausal womenresults from the Women's Health Initiative. J Am Geriatr Soc. 2008;56(9):

[38] Liu Z, Liu H, Li Y, Wang Y, Xing R, Mi F, et al. Adiponectin inhibits the differentiation and maturation of osteoclasts via the mTOR pathway in multiple myeloma. Int J Mol Med.

[39] Yang J, Park OJ, Kim J, Han S, Yang Y, Yun CH, et al. Adiponectin Deficiency Triggers Bone Loss by Up-Regulation of Osteoclastogenesis

Osteoblastogenesis. Front Endocrinol

Bennani L, Hmamouchi I,

*DOI: http://dx.doi.org/10.5772/intechopen.97549*

[40] Kintscher U, Hartge M, Hess K, Foryst-Ludwig A, Clemenz M, Wabitsch M, et al. T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arteriosclerosis, thrombosis, and vascular biology. 2008;28(7):

[41] Maury E, Brichard S. Adipokine dysregulation, adipose tissue

inflammation and metabolic syndrome. Molecular and cellular endocrinology.

[42] Zou W, Rohatgi N, Brestoff JR, Li Y, Barve RA, Tycksen E, et al. Ablation of Fat Cells in Adult Mice Induces Massive

[43] de Paula FJA, Rosen CJ. Marrow Adipocytes: Origin, Structure, and Function. Annu Rev Physiol. 2020;82:

[44] Wei J, Shimazu J, Makinistoglu MP, Maurizi A, Kajimura D, Zong H, et al. Glucose Uptake and Runx2 Synergize to Orchestrate Osteoblast Differentiation

[45] Nguyen KD, Bagheri B, Bagheri H. Drug-induced bone loss: a major safety concern in Europe. Expert Opin Drug

1304-1310.

2010;314(1):1-16.

461-484.

Bone Gain. Cell Metab. 2020;32(5):801-13.e6.

and Bone Formation. Cell. 2015;161(7):1576-1591.

Saf. 2018;17(10):1005-1014.

2021;145:115861.

449-453.

[47] Sandru F, Carsote M,

Dumitrascu MC, Albu SE, Valea A. Glucocorticoids and Trabecular Bone Score. J Med Life. 2020;13(4):

[46] Kline GA, Morin SN, Lix LM, Leslie WD. Bone densitometry

categories as a salient distracting feature in the modern clinical pathways of osteoporosis care: A retrospective 20-year cohort study. Bone.

Adams MA, Holden RM. Changes in vascular calcification and bone mineral density in calcium supplement users from the Canadian Multi-center Osteoporosis Study (CaMOS). Atherosclerosis. 2020;296:83-90.

[33] Hulbert M, Turner ME, Hopman WM, Anastassiades T,

#### *Osteoporosis: A Multifactorial Disease DOI: http://dx.doi.org/10.5772/intechopen.97549*

*Osteoporosis - Recent Advances, New Perspectives and Applications*

[26] Nordin BE. Evolution of the calcium paradigm: the relation between vitamin

[27] Nowson CA. Prevention of fractures

D, serum calcium and calcium absorption. Nutrients. 2010;2(9):

in older people with calcium and

[28] Hill TR, Aspray TJ, Francis RM. Vitamin D and bone health outcomes in older age. Proc Nutr Soc. 2013;72(4):

[29] Pommer DG. Untersuchungen über Osteomalacie und Rachitis nebst Beiträgen zur Kenntniss der

Knochenresorption und-apposition in verschiedenen Altersperioden und der durchbohrenden Gefässe, von Dr Gustav Pommer: FCW Vogel; 1885.

[30] Need AG, O'Loughlin PD, Morris HA, Coates PS, Horowitz M, Nordin BE. Vitamin D metabolites and calcium absorption in severe vitamin D

deficiency. J Bone Miner Res. 2008;23(11):1859-1863.

Heart Assoc. 2016;5(10).

[32] Li K, Kaaks R, Linseisen J, Rohrmann S. Associations of dietary

calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg).

Heart. 2012;98(12):920-925.

[33] Hulbert M, Turner ME, Hopman WM, Anastassiades T,

[31] Anderson JJ, Kruszka B, Delaney JA, He K, Burke GL, Alonso A, et al. Calcium Intake From Diet and Supplements and the Risk of Coronary Artery Calcification and its Progression Among Older Adults: 10-Year Follow-up of the Multi-Ethnic Study of Atherosclerosis (MESA). J Am

vitamin D. Nutrients. 2010;2(9):975-984.

997-1004.

372-380.

[17] Laurent MR, Dedeyne L, Dupont J, Mellaerts B, Dejaeger M, Gielen E. Age-related bone loss and sarcopenia in

men. Maturitas. 2019;122:51-56.

[18] Morgan EF, Unnikrisnan GU, Hussein AI. Bone Mechanical Properties in Healthy and Diseased States. Annu Rev Biomed Eng. 2018;20:119-143.

[19] Kim HN, Chang J, Iyer S, Han L, Campisi J, Manolagas SC, et al. Elimination of senescent osteoclast progenitors has no effect on the ageassociated loss of bone mass in mice. Aging Cell. 2019;18(3):e12923.

[20] Riggs BL. The mechanisms of estrogen regulation of bone resorption. J Clin Invest. 2000;106(10):1203-1204.

[21] Riggs BL, Khosla S, Atkinson EJ, Dunstan CR, Melton LJ, 3rd. Evidence that type I osteoporosis results from enhanced responsiveness of bone to estrogen deficiency. Osteoporos Int.

[22] Riggs BL, Khosla S, Melton LJ, 3rd. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner

[23] Glatt V, Canalis E, Stadmeyer L, Bouxsein ML. Age-related changes in trabecular architecture differ in female and male C57BL/6J mice. J Bone Miner

[24] Ucer S, Iyer S, Kim HN, Han L, Rutlen C, Allison K, et al. The Effects of Aging and Sex Steroid Deficiency on the Murine Skeleton Are Independent and Mechanistically Distinct. J Bone Miner

[25] Ringe JD. Plain vitamin D or active

osteoporosis: where do we stand today? Arch Osteoporos. 2020;15(1):182.

2003;14(9):728-733.

Res. 1998;13(5):763-773.

Res. 2007;22(8):1197-1207.

Res. 2017;32(3):560-574.

vitamin D in the treatment of

**54**

Adams MA, Holden RM. Changes in vascular calcification and bone mineral density in calcium supplement users from the Canadian Multi-center Osteoporosis Study (CaMOS). Atherosclerosis. 2020;296:83-90.

[34] Jenkins DJA, Spence JD, Giovannucci EL, Kim YI, Josse R, Vieth R, et al. Supplemental Vitamins and Minerals for CVD Prevention and Treatment. J Am Coll Cardiol. 2018;71(22):2570-2584.

[35] Chen Z, Klimentidis YC, Bea JW, Ernst KC, Hu C, Jackson R, et al. Body Mass Index, Waist Circumference, and Mortality in a Large Multiethnic Postmenopausal Cohort-Results from the Women's Health Initiative. J Am Geriatr Soc. 2017;65(9):1907-1915.

[36] Ichchou L, Allali F, Rostom S, Bennani L, Hmamouchi I, Abourazzak FZ, et al. Relationship between spine osteoarthritis, bone mineral density and bone turn over markers in post menopausal women. BMC Womens Health. 2010;10:25.

[37] Wright NC, Riggs GK, Lisse JR, Chen Z, Women's Health I. Selfreported osteoarthritis, ethnicity, body mass index, and other associated risk factors in postmenopausal womenresults from the Women's Health Initiative. J Am Geriatr Soc. 2008;56(9): 1736-1743.

[38] Liu Z, Liu H, Li Y, Wang Y, Xing R, Mi F, et al. Adiponectin inhibits the differentiation and maturation of osteoclasts via the mTOR pathway in multiple myeloma. Int J Mol Med. 2020;45(4):1112-1120.

[39] Yang J, Park OJ, Kim J, Han S, Yang Y, Yun CH, et al. Adiponectin Deficiency Triggers Bone Loss by Up-Regulation of Osteoclastogenesis and Down-Regulation of Osteoblastogenesis. Front Endocrinol (Lausanne). 2019;10:815.

[40] Kintscher U, Hartge M, Hess K, Foryst-Ludwig A, Clemenz M, Wabitsch M, et al. T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arteriosclerosis, thrombosis, and vascular biology. 2008;28(7): 1304-1310.

[41] Maury E, Brichard S. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Molecular and cellular endocrinology. 2010;314(1):1-16.

[42] Zou W, Rohatgi N, Brestoff JR, Li Y, Barve RA, Tycksen E, et al. Ablation of Fat Cells in Adult Mice Induces Massive Bone Gain. Cell Metab. 2020;32(5):801-13.e6.

[43] de Paula FJA, Rosen CJ. Marrow Adipocytes: Origin, Structure, and Function. Annu Rev Physiol. 2020;82: 461-484.

[44] Wei J, Shimazu J, Makinistoglu MP, Maurizi A, Kajimura D, Zong H, et al. Glucose Uptake and Runx2 Synergize to Orchestrate Osteoblast Differentiation and Bone Formation. Cell. 2015;161(7):1576-1591.

[45] Nguyen KD, Bagheri B, Bagheri H. Drug-induced bone loss: a major safety concern in Europe. Expert Opin Drug Saf. 2018;17(10):1005-1014.

[46] Kline GA, Morin SN, Lix LM, Leslie WD. Bone densitometry categories as a salient distracting feature in the modern clinical pathways of osteoporosis care: A retrospective 20-year cohort study. Bone. 2021;145:115861.

[47] Sandru F, Carsote M, Dumitrascu MC, Albu SE, Valea A. Glucocorticoids and Trabecular Bone Score. J Med Life. 2020;13(4): 449-453.

[48] Signorelli SS, Scuto S, Marino E, Giusti M, Xourafa A, Gaudio A. Anticoagulants and Osteoporosis. Int J Mol Sci. 2019;20(21).

[49] Dadwal G, Schulte-Huxel T, Kolb G. Effect of antithrombotic drugs on bone health. Z Gerontol Geriatr. 2020;53(5): 457-462.

[50] Das M, Cronin O, Keohane DM, Cormac EM, Nugent H, Nugent M, et al. Gut microbiota alterations associated with reduced bone mineral density in older adults. Rheumatology (Oxford). 2019;58(12):2295-2304.

[51] Ghebre YT. Proton Pump Inhibitors and Osteoporosis: Is Collagen a Direct Target? Front Endocrinol (Lausanne). 2020;11:473.

[52] Huang YL, Tsay WI, Her SH, Ho CH, Tsai KT, Hsu CC, et al. Chronic pain and use of analgesics in the elderly: a nationwide populationbased study. Arch Med Sci. 2020;16(3): 627-634.

[53] Byreddy DV, Bouchonville MF, 2nd, Lewiecki EM. Drug-induced osteoporosis: from Fuller Albright to aromatase inhibitors. Climacteric. 2015;18 Suppl 2:39-46.

[54] Miller AS, Ferastraoaru V, Tabatabaie V, Gitlevich TR, Spiegel R, Haut SR. Are we responding effectively to bone mineral density loss and fracture risks in people with epilepsy? Epilepsia Open. 2020;5(2):240-247.

[55] Al-Qurain AA, Gebremichael LG, Khan MS, Williams DB, Mackenzie L, Phillips C, et al. Prevalence and Factors Associated with Analgesic Prescribing in Poly-Medicated Elderly Patients. Drugs Aging. 2020;37(4):291-300.

[56] Oshiro CES, Frankland TB, Rosales AG, Perrin NA, Bell CL, Lo SHY, et al. Fall Ascertainment and Development of a Risk Prediction Model Using Electronic Medical Records. J Am Geriatr Soc. 2019;67(7):1417-1422.

[57] Ohlsson C, Engdahl C, Fåk F, Andersson A, Windahl SH, Farman HH, et al. Probiotics protect mice from ovariectomy-induced cortical bone loss. PLoS One. 2014;9(3):e92368.

[58] Britton RA, Irwin R, Quach D, Schaefer L, Zhang J, Lee T, et al. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol. 2014;229(11):1822-1830.

[59] Sjögren K, Engdahl C, Henning P, Lerner UH, Tremaroli V, Lagerquist MK, et al. The gut microbiota regulates bone mass in mice. J Bone Miner Res. 2012;27(6):1357-1367.

[60] Sabui S, Skupsky J, Kapadia R, Cogburn K, Lambrecht NW, Agrawal A, et al. Tamoxifen-induced, intestinalspecific deletion of Slc5a6 in adult mice leads to spontaneous inflammation: involvement of NF-kappaB, NLRP3, and gut microbiota. Am J Physiol Gastrointest Liver Physiol. 2019;317(4):G518-GG30.

[61] Roomruangwong C, Carvalho AF, Geffard M, Maes M. The menstrual cycle may not be limited to the endometrium but also may impact gut permeability. Acta Neuropsychiatr. 2019;31(6):294-304.

[62] Rizzetto L, Fava F, Tuohy KM, Selmi C. Connecting the immune system, systemic chronic inflammation and the gut microbiome: The role of sex. J Autoimmun. 2018;92:12-34.

[63] Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, et al. Induction of Intestinal Th17 Cells by Segmented Filamentous Bacteria. Cell. 2009;139(3):485-498.

[64] Li JY, Chassaing B, Tyagi AM, Vaccaro C, Luo T, Adams J, et al.

**57**

*Osteoporosis: A Multifactorial Disease*

2016;126(6):2049-2063.

regulatory T cells. Nature. 2013;504(7480):446-450.

Treg cell homeostasis. Science. 2013;341(6145):569-573.

575-90e7.

(6812):535-536.

(6812):600-605.

2018;27(1):45-56.

*DOI: http://dx.doi.org/10.5772/intechopen.97549*

Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J Clin Invest.

et al. Vertebral fractures in ankylosing spondylitis are associated with lower bone mineral density in both central and peripheral skeleton. J Rheumatol.

[73] Shaiykova A, Pasquet A, Goujard C, Lion G, Durand E, Bayan T, et al. Reduced bone mineral density among HIV-infected, virologically controlled young men: prevalence and associated factors. AIDS. 2018;32(18):2689-2696.

[74] Moran CA, Weitzmann MN, Ofotokun I. Bone Loss in HIV Infection.

[75] Piodi LP, Poloni A, Ulivieri FM. Managing osteoporosis in ulcerative colitis: something new? World J

[76] Zhao B, Grimes SN, Li S, Hu X,

osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J. The Journal

Curr Treat Options Infect Dis.

2014;20(39):14087-14098.

Ivashkiv LB. TNF-induced

of experimental medicine. 2012;209(2):319-334.

of Biological Chemistry. 2000;275(7):4858-4864.

Experimental Medicine. 2000;191(2):275-286.

[79] Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK

[77] Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A. Tumor Necrosis Factor-α Induces Differentiation of and Bone Resorption by Osteoclasts. Journal

[78] Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, et al. Tumor Necrosis Factor α Stimulates Osteoclast Differentiation by a Mechanism Independent of the Odf/ Rankl–Rank Interaction. Journal of

2017;9(1):52-67.

Gastroenterol.

2012;39(10):1987-1995.

[65] Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, et al. Commensal microbe-derived butyrate induces the differentiation of colonic

[66] Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, et al. The microbial metabolites, short-chain fatty acids, regulate colonic

[67] Chevalier C, Kieser S, Colakoglu M, Hadadi N, Brun J, Rigo D, et al. Warmth Prevents Bone Loss Through the Gut Microbiota. Cell Metab. 2020;32(4):

[68] Arron JR, Choi Y. Bone versus immune system. Nature. 2000;408

[69] Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, et al. T-cellmediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature. 2000;408

[70] Blaschke M, Koepp R, Cortis J, Komrakova M, Schieker M, Hempel U, et al. IL-6, IL-1beta, and TNF-alpha only in combination influence the osteoporotic phenotype in Crohn's patients via bone formation and bone resorption. Adv Clin Exp Med.

[71] Sapir-Koren R, Livshits G. Postmenopausal osteoporosis in rheumatoid arthritis: The estrogen deficiency-immune mechanisms link.

[72] Klingberg E, Geijer M, Gothlin J, Mellstrom D, Lorentzon M, Hilme E,

Bone. 2017;103:102-115.

*Osteoporosis: A Multifactorial Disease DOI: http://dx.doi.org/10.5772/intechopen.97549*

*Osteoporosis - Recent Advances, New Perspectives and Applications*

Using Electronic Medical Records. J Am Geriatr Soc. 2019;67(7):1417-1422.

[57] Ohlsson C, Engdahl C, Fåk F, Andersson A, Windahl SH, Farman HH, et al. Probiotics protect mice from ovariectomy-induced cortical bone loss.

[58] Britton RA, Irwin R, Quach D, Schaefer L, Zhang J, Lee T, et al. Probiotic L. reuteri treatment prevents

ovariectomized mouse model. J Cell Physiol. 2014;229(11):1822-1830.

[59] Sjögren K, Engdahl C, Henning P, Lerner UH, Tremaroli V, Lagerquist MK, et al. The gut microbiota regulates bone

mass in mice. J Bone Miner Res.

[60] Sabui S, Skupsky J, Kapadia R, Cogburn K, Lambrecht NW, Agrawal A, et al. Tamoxifen-induced, intestinalspecific deletion of Slc5a6 in adult mice leads to spontaneous inflammation: involvement of NF-kappaB, NLRP3, and

gut microbiota. Am J Physiol Gastrointest Liver Physiol. 2019;317(4):G518-GG30.

2019;31(6):294-304.

[61] Roomruangwong C, Carvalho AF, Geffard M, Maes M. The menstrual cycle may not be limited to the

endometrium but also may impact gut permeability. Acta Neuropsychiatr.

[62] Rizzetto L, Fava F, Tuohy KM, Selmi C. Connecting the immune system, systemic chronic inflammation and the gut microbiome: The role of sex.

[63] Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, et al. Induction of Intestinal Th17 Cells by Segmented Filamentous Bacteria. Cell.

[64] Li JY, Chassaing B, Tyagi AM, Vaccaro C, Luo T, Adams J, et al.

J Autoimmun. 2018;92:12-34.

2009;139(3):485-498.

2012;27(6):1357-1367.

PLoS One. 2014;9(3):e92368.

bone loss in a menopausal

[48] Signorelli SS, Scuto S, Marino E, Giusti M, Xourafa A, Gaudio A. Anticoagulants and Osteoporosis. Int J

[49] Dadwal G, Schulte-Huxel T, Kolb G. Effect of antithrombotic drugs on bone health. Z Gerontol Geriatr. 2020;53(5):

[50] Das M, Cronin O, Keohane DM, Cormac EM, Nugent H, Nugent M, et al. Gut microbiota alterations associated with reduced bone mineral density in older adults. Rheumatology (Oxford).

[51] Ghebre YT. Proton Pump Inhibitors and Osteoporosis: Is Collagen a Direct Target? Front Endocrinol (Lausanne).

[53] Byreddy DV, Bouchonville MF, 2nd,

osteoporosis: from Fuller Albright to aromatase inhibitors. Climacteric.

Tabatabaie V, Gitlevich TR, Spiegel R, Haut SR. Are we responding effectively to bone mineral density loss and fracture risks in people with epilepsy? Epilepsia Open. 2020;5(2):240-247.

[55] Al-Qurain AA, Gebremichael LG, Khan MS, Williams DB, Mackenzie L, Phillips C, et al. Prevalence and Factors Associated with Analgesic Prescribing in Poly-Medicated Elderly Patients. Drugs Aging. 2020;37(4):291-300.

[56] Oshiro CES, Frankland TB,

et al. Fall Ascertainment and

Rosales AG, Perrin NA, Bell CL, Lo SHY,

Development of a Risk Prediction Model

Lewiecki EM. Drug-induced

[54] Miller AS, Ferastraoaru V,

2015;18 Suppl 2:39-46.

[52] Huang YL, Tsay WI, Her SH, Ho CH, Tsai KT, Hsu CC, et al. Chronic pain and use of analgesics in the elderly: a nationwide populationbased study. Arch Med Sci. 2020;16(3):

Mol Sci. 2019;20(21).

2019;58(12):2295-2304.

2020;11:473.

627-634.

457-462.

**56**

Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J Clin Invest. 2016;126(6):2049-2063.

[65] Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504(7480):446-450.

[66] Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341(6145):569-573.

[67] Chevalier C, Kieser S, Colakoglu M, Hadadi N, Brun J, Rigo D, et al. Warmth Prevents Bone Loss Through the Gut Microbiota. Cell Metab. 2020;32(4): 575-90e7.

[68] Arron JR, Choi Y. Bone versus immune system. Nature. 2000;408 (6812):535-536.

[69] Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, et al. T-cellmediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature. 2000;408 (6812):600-605.

[70] Blaschke M, Koepp R, Cortis J, Komrakova M, Schieker M, Hempel U, et al. IL-6, IL-1beta, and TNF-alpha only in combination influence the osteoporotic phenotype in Crohn's patients via bone formation and bone resorption. Adv Clin Exp Med. 2018;27(1):45-56.

[71] Sapir-Koren R, Livshits G. Postmenopausal osteoporosis in rheumatoid arthritis: The estrogen deficiency-immune mechanisms link. Bone. 2017;103:102-115.

[72] Klingberg E, Geijer M, Gothlin J, Mellstrom D, Lorentzon M, Hilme E, et al. Vertebral fractures in ankylosing spondylitis are associated with lower bone mineral density in both central and peripheral skeleton. J Rheumatol. 2012;39(10):1987-1995.

[73] Shaiykova A, Pasquet A, Goujard C, Lion G, Durand E, Bayan T, et al. Reduced bone mineral density among HIV-infected, virologically controlled young men: prevalence and associated factors. AIDS. 2018;32(18):2689-2696.

[74] Moran CA, Weitzmann MN, Ofotokun I. Bone Loss in HIV Infection. Curr Treat Options Infect Dis. 2017;9(1):52-67.

[75] Piodi LP, Poloni A, Ulivieri FM. Managing osteoporosis in ulcerative colitis: something new? World J Gastroenterol. 2014;20(39):14087-14098.

[76] Zhao B, Grimes SN, Li S, Hu X, Ivashkiv LB. TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J. The Journal of experimental medicine. 2012;209(2):319-334.

[77] Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A. Tumor Necrosis Factor-α Induces Differentiation of and Bone Resorption by Osteoclasts. Journal of Biological Chemistry. 2000;275(7):4858-4864.

[78] Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, et al. Tumor Necrosis Factor α Stimulates Osteoclast Differentiation by a Mechanism Independent of the Odf/ Rankl–Rank Interaction. Journal of Experimental Medicine. 2000;191(2):275-286.

[79] Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. The Journal of Clinical Investigation. 2000;106(12):1481-1488.

[80] Yu M, D'Amelio P, Tyagi AM, Vaccaro C, Li JY, Hsu E, et al. Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice. EMBO Rep. 2018;19(1):156-171.

[81] Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203(12): 2673-2682.

[82] Tyagi AM, Srivastava K, Mansoori MN, Trivedi R, Chattopadhyay N, Singh D. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis. PLoS One. 2012;7(9):e44552.

[83] Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014;20(1):62-68.

[84] Zhao R, Wang X, Feng F. Upregulated Cellular Expression of IL-17 by CD4+ T-Cells in Osteoporotic Postmenopausal Women. Annals of nutrition & metabolism. 2016;68(2): 113-118.

[85] Kollet O, Dar A, Lapidot T. The multiple roles of osteoclasts in host defense: bone remodeling and hematopoietic stem cell mobilization. Annu Rev Immunol. 2007;25:51-69.

[86] Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y, et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med. 2006;12(6):657-664.

[87] Mansour A, Abou-Ezzi G, Sitnicka EW, Jacobsen SE, Wakkach A, Blin-Wakkach C. Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow. Journal of Experimental Medicine. 2012;209(3): 537-549.

[88] Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, et al. Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell. 2007;130(5): 811-823.

[89] Oursler MJ, Landers JP, Riggs BL, Spelsberg TC. Oestrogen effects on osteoblasts and osteoclasts. Ann Med. 1993;25(4):361-371.

[90] Oursler MJ, Osdoby P, Pyfferoen J, Riggs BL, Spelsberg TC. Avian osteoclasts as estrogen target cells. Proc Natl Acad Sci U S A. 1991;88(15): 6613-6617.

[91] Oursler MJ, Pederson L, Pyfferoen J, Osdoby P, Fitzpatrick L, Spelsberg TC. Estrogen modulation of avian osteoclast lysosomal gene expression. Endocrinology. 1993;132(3):1373-1380.

[92] Kovacic N, Lukic IK, Grcevic D, Katavic V, Croucher P, Marusic A. The Fas/Fas ligand system inhibits differentiation of murine osteoblasts but has a limited role in osteoblast and osteoclast apoptosis. J Immunol. 2007;178(6):3379-3389.

[93] Krum SA, Miranda-Carboni GA, Hauschka PV, Carroll JS, Lane TF, Freedman LP, et al. Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival. EMBO J. 2008;27(3): 535-545.

[94] Vanderschueren D, Gaytant J, Boonen S, Venken K. Androgens and bone. Curr Opin Endocrinol Diabetes Obes. 2008;15(3):250-254.

**59**

*Osteoporosis: A Multifactorial Disease*

[95] Weitzmann MN. Bone and the Immune System. Toxicol Pathol.

[96] Horvathova M, Ilavska S,

2017;45(7):911-924.

Health. 2017;14(7).

[98] Cenci S, Toraldo G,

2003;100(18):10405-10410.

[100] Roggia C, Gao Y, Cenci S, Weitzmann MN, Toraldo G, Isaia G, et al. Up-regulation of TNF-producing T

cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc Natl Acad Sci U S A. 2001;98(24):

[101] Roggia C, Tamone C, Cenci S, Pacifici R, Isaia GC. Role of TNF-alpha producing T-cells in bone loss induced by estrogen deficiency. Minerva Med.

[102] Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest.

1229-1237.

13960-13965.

2004;95(2):125-132.

2006;116(5):1186-1194.

*DOI: http://dx.doi.org/10.5772/intechopen.97549*

[103] Kimble RB, Bain S, Pacifici R. The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice. Journal of Bone and Mineral Research. 1997;12(6):935-941.

[104] Deselm CJ, Takahata Y, Warren J, Chappel JC, Khan T, Li X, et al. IL-17 mediates estrogen-deficient osteoporosis in an Act1-dependent manner. J Cell Biochem. 2012;113(9):2895-2902.

[105] Takayanagi H, Sato K, Takaoka A,

interferon and other cytokine systems in

Taniguchi T. Interplay between

bone metabolism. Immunol Rev.

[106] Duque G, Huang DC, Dion N, Macoritto M, Rivas D, Li W, et al. Interferon-γ plays a role in bone formation in vivo and rescues

osteoporosis in ovariectomized mice. Journal of Bone and Mineral Research.

[107] Osta B, Benedetti G, Miossec P. Classical and Paradoxical Effects of TNF-α on Bone Homeostasis. Frontiers

Srivastava K, Khan MP, Kureel J, Dixit M, et al. Enhanced immunoprotective effects by anti-IL-17 antibody translates to improved skeletal parameters under estrogen deficiency compared with anti-RANKL and anti-TNF-α antibodies. J Bone Miner Res. 2014;29(9):1981-1992.

2005;208:181-193.

2011;26(7):1472-1483.

in Immunology. 2014;5(48).

[108] Tyagi AM, Mansoori MN,

[109] Ginaldi L, De Martinis M, Ciccarelli F, Saitta S, Imbesi S, Mannucci C, et al. Increased levels of interleukin 31 (IL-31) in osteoporosis. BMC Immunology. 2015;16(1):60.

2018;117:161-170.

[110] Du D, Zhou Z, Zhu L, Hu X, Lu J, Shi C, et al. TNF-alpha suppresses osteogenic differentiation of MSCs by accelerating P2Y2 receptor in estrogendeficiency induced osteoporosis. Bone.

Stefikova K, Szabova M, Krivosikova Z, Jahnova E, et al. The Cell Surface Markers Expression in Postmenopausal Women and Relation to Obesity and Bone Status. Int J Environ Res Public

[97] Pacifici R, Rifas L, McCracken R, Avioli LV. The role of interleukin-1 in postmenopausal bone loss. Exp Gerontol. 1990;25(3-4):309-316.

Weitzmann MN, Roggia C, Gao Y, Qian WP, et al. Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II

transactivator. Proc Natl Acad Sci U S A.

[99] Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J, et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNFalpha. J Clin Invest. 2000;106(10):

*Osteoporosis: A Multifactorial Disease DOI: http://dx.doi.org/10.5772/intechopen.97549*

[95] Weitzmann MN. Bone and the Immune System. Toxicol Pathol. 2017;45(7):911-924.

*Osteoporosis - Recent Advances, New Perspectives and Applications*

[87] Mansour A, Abou-Ezzi G,

537-549.

811-823.

6613-6617.

1993;25(4):361-371.

Sitnicka EW, Jacobsen SE, Wakkach A, Blin-Wakkach C. Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow. Journal of Experimental Medicine. 2012;209(3):

[88] Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, et al. Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell. 2007;130(5):

[89] Oursler MJ, Landers JP, Riggs BL, Spelsberg TC. Oestrogen effects on osteoblasts and osteoclasts. Ann Med.

[90] Oursler MJ, Osdoby P, Pyfferoen J,

osteoclasts as estrogen target cells. Proc Natl Acad Sci U S A. 1991;88(15):

[91] Oursler MJ, Pederson L, Pyfferoen J, Osdoby P, Fitzpatrick L, Spelsberg TC. Estrogen modulation of avian osteoclast lysosomal gene expression. Endocrinology. 1993;132(3):1373-1380.

[92] Kovacic N, Lukic IK, Grcevic D, Katavic V, Croucher P, Marusic A. The

[93] Krum SA, Miranda-Carboni GA, Hauschka PV, Carroll JS, Lane TF, Freedman LP, et al. Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival. EMBO J. 2008;27(3):

[94] Vanderschueren D, Gaytant J, Boonen S, Venken K. Androgens and bone. Curr Opin Endocrinol Diabetes

Obes. 2008;15(3):250-254.

Fas/Fas ligand system inhibits differentiation of murine osteoblasts but has a limited role in osteoblast and osteoclast apoptosis. J Immunol.

2007;178(6):3379-3389.

535-545.

Riggs BL, Spelsberg TC. Avian

ligand. The Journal of Clinical

[80] Yu M, D'Amelio P, Tyagi AM, Vaccaro C, Li JY, Hsu E, et al. Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice. EMBO Rep.

[81] Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y,

osteoclastogenic helper T cell subset that

[82] Tyagi AM, Srivastava K, Mansoori MN, Trivedi R, Chattopadhyay N, Singh D. Estrogen deficiency induces the differentiation of IL-17 secreting Th17 cells: a new candidate in the pathogenesis of osteoporosis. PLoS One.

[83] Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014;20(1):62-68.

[84] Zhao R, Wang X, Feng F. Upregulated Cellular Expression of IL-17 by CD4+ T-Cells in Osteoporotic Postmenopausal Women. Annals of nutrition & metabolism. 2016;68(2):

[85] Kollet O, Dar A, Lapidot T. The multiple roles of osteoclasts in host defense: bone remodeling and

hematopoietic stem cell mobilization. Annu Rev Immunol. 2007;25:51-69.

[86] Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y, et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat

Med. 2006;12(6):657-664.

2018;19(1):156-171.

2673-2682.

2012;7(9):e44552.

113-118.

et al. Th17 functions as an

links T cell activation and bone destruction. J Exp Med. 2006;203(12):

Investigation. 2000;106(12):1481-1488.

**58**

[96] Horvathova M, Ilavska S, Stefikova K, Szabova M, Krivosikova Z, Jahnova E, et al. The Cell Surface Markers Expression in Postmenopausal Women and Relation to Obesity and Bone Status. Int J Environ Res Public Health. 2017;14(7).

[97] Pacifici R, Rifas L, McCracken R, Avioli LV. The role of interleukin-1 in postmenopausal bone loss. Exp Gerontol. 1990;25(3-4):309-316.

[98] Cenci S, Toraldo G, Weitzmann MN, Roggia C, Gao Y, Qian WP, et al. Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator. Proc Natl Acad Sci U S A. 2003;100(18):10405-10410.

[99] Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J, et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNFalpha. J Clin Invest. 2000;106(10): 1229-1237.

[100] Roggia C, Gao Y, Cenci S, Weitzmann MN, Toraldo G, Isaia G, et al. Up-regulation of TNF-producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc Natl Acad Sci U S A. 2001;98(24): 13960-13965.

[101] Roggia C, Tamone C, Cenci S, Pacifici R, Isaia GC. Role of TNF-alpha producing T-cells in bone loss induced by estrogen deficiency. Minerva Med. 2004;95(2):125-132.

[102] Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest. 2006;116(5):1186-1194.

[103] Kimble RB, Bain S, Pacifici R. The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice. Journal of Bone and Mineral Research. 1997;12(6):935-941.

[104] Deselm CJ, Takahata Y, Warren J, Chappel JC, Khan T, Li X, et al. IL-17 mediates estrogen-deficient osteoporosis in an Act1-dependent manner. J Cell Biochem. 2012;113(9):2895-2902.

[105] Takayanagi H, Sato K, Takaoka A, Taniguchi T. Interplay between interferon and other cytokine systems in bone metabolism. Immunol Rev. 2005;208:181-193.

[106] Duque G, Huang DC, Dion N, Macoritto M, Rivas D, Li W, et al. Interferon-γ plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice. Journal of Bone and Mineral Research. 2011;26(7):1472-1483.

[107] Osta B, Benedetti G, Miossec P. Classical and Paradoxical Effects of TNF-α on Bone Homeostasis. Frontiers in Immunology. 2014;5(48).

[108] Tyagi AM, Mansoori MN, Srivastava K, Khan MP, Kureel J, Dixit M, et al. Enhanced immunoprotective effects by anti-IL-17 antibody translates to improved skeletal parameters under estrogen deficiency compared with anti-RANKL and anti-TNF-α antibodies. J Bone Miner Res. 2014;29(9):1981-1992.

[109] Ginaldi L, De Martinis M, Ciccarelli F, Saitta S, Imbesi S, Mannucci C, et al. Increased levels of interleukin 31 (IL-31) in osteoporosis. BMC Immunology. 2015;16(1):60.

[110] Du D, Zhou Z, Zhu L, Hu X, Lu J, Shi C, et al. TNF-alpha suppresses osteogenic differentiation of MSCs by accelerating P2Y2 receptor in estrogendeficiency induced osteoporosis. Bone. 2018;117:161-170.

[111] Cline-Smith A, Axelbaum A, Shashkova E, Chakraborty M, Sanford J, Panesar P, et al. Ovariectomy activates chronic low-grade inflammation mediated by memory T-cells which promotes osteoporosis in mice. J Bone Miner Res. 2020.

[112] Hodsman AB, Bauer DC, Dempster DW, Dian L, Hanley DA, Harris ST, et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocrine reviews. 2005;26(5):688-703.

[113] Lim SY, Bolster MB. Profile of romosozumab and its potential in the management of osteoporosis. Drug design, development and therapy. 2017;11:1221.

[114] Fixen C, Tunoa J. Romosozumab: a Review of Efficacy, Safety, and Cardiovascular Risk. Curr Osteoporos Rep. 2021.

[115] Saag KG, Zanchetta JR, Devogelaer JP, Adler RA, Eastell R, See K, et al. Effects of teriparatide versus alendronate for treating glucocorticoidinduced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis Rheum. 2009;60(11):3346-3355.

[116] Tashjian AH, Jr., Gagel RF. Teriparatide [human PTH(1-34)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis. J Bone Miner Res. 2006;21(3):354-365.

[117] Brandenburg VM, Verhulst A, Babler A, D'Haese PC, Evenepoel P, Kaesler N. Sclerostin in chronic kidney disease-mineral bone disorder think first before you block it! Nephrol Dial Transplant. 2019;34(3):408-414.

[118] Cosman F, Nieves JW, Dempster DW. Treatment sequence matters: anabolic and antiresorptive therapy for osteoporosis. Journal of bone and mineral research. 2017;32(2):198-202.

[119] Fink HA, MacDonald R, Forte ML, Rosebush CE, Ensrud KE, Schousboe JT, et al. Long-Term Drug Therapy and Drug Holidays for Osteoporosis Fracture Prevention: A Systematic Review. AHRQ Comparative Effectiveness Reviews. Rockville (MD)2019.

[120] Chong WP, Mattapallil MJ, Raychaudhuri K, Bing SJ, Wu S, Zhong Y, et al. The Cytokine IL-17A Limits Th17 Pathogenicity via a Negative Feedback Loop Driven by Autocrine Induction of IL-24. Immunity. 2020.

[121] Buchwald ZS, Kiesel JR, DiPaolo R, Pagadala MS, Aurora R. Osteoclast Activated FoxP3+ CD8+ T-Cells Suppress Bone Resorption in vitro. PLoS ONE. 2012;7(6):e38199–e38112.

[122] Buchwald ZS, Yang C, Nellore S, Shashkova EV, Davis JL, Cline A, et al. A Bone Anabolic Effect of RANKL in a Murine Model of Osteoporosis Mediated Through FoxP3 +CD8 T Cells. Journal of Bone and Mineral Research. 2015;30(8):1508-1522.

[123] Buchwald ZS, Aurora R. Osteoclasts and CD8 T Cells Form a Negative Feedback Loop That Contributes to Homeostasis of Both the Skeletal and Immune Systems. Clin Dev Immunol. 2013;2013. Article ID 429373.

[124] Buchwald ZS, Kiesel J, Yang C, DiPaolo R, Novack D, Aurora R. Osteoclast-induced Foxp3+ CD8 T-Cells Limit Bone Loss in Mice. Bone. 2013;56:163-173.

[125] Cline-Smith A, Gibbs J, Shashkova E, Buchwald ZS, Aurora R. Pulsed low-dose RANKL as a potential therapeutic for postmenopausal osteoporosis. JCI Insight. 2016;1(13):433-412.

**61**

**Chapter 5**

**Abstract**

**1. Introduction**

**2. Osteoporosis**

Bone Quality of the

*Plauto Christopher Aranha Watanabe,* 

Dento-Maxillofacial Complex

Radiographic Interpretation

and Osteoporosis. Opportunistic

*Giovani Antonio Rodrigues, Marcelo Rodrigues Azenha,* 

*Michel Campos Ribeiro, Enéas de Almeida Souza Filho,* 

Research suggests the use of different indexes on panoramic radiography as a way to assess BMD and to be able to detect changes in bone metabolism before fractures occur. Therefore, the objective of this chapter is to describe the use of these parameters as an auxiliary mechanism in the detection of low bone mineral density, as well as to characterize the radiographic findings of patients with osteoporosis.

Osteoporosis is a chronic disease that affects the mineral density of bone tissue (BMD), leaving it more fragile and predisposing its carriers to a higher risk of fractures. The gold standard for the diagnosis of osteoporosis is dual X-ray densitometry (DXA), an exam that is difficult to access in some countries worldwide. Over the years, researchers have dedicated themselves to studying the radiographic findings of osteoporosis in gnathic bones in an attempt to create indexes or patterns that could assess BMD and thereby detect changes in bone metabolism before fractures occur. Thus, the objective of this chapter is to present concisely data on osteoporosis and to deepen themes related to the presence of the disease in the maxillomandibular region, as well as to review the literature presenting recent research on the use of imaging tests (X-rays, beam computed tomography, among others) to identify and

Osteo Metabolic diseases are a set of disorders that affect the metabolism of bone

tissue promoting a decrease in its mass and consequently causing bone fragility

*Rafael Angelo Soares Vieira and Fabio Santos Bottacin*

**Keywords:** osteoporosis, oral cavity, panoramic radiography,

mineral density of bone tissue, fractal dimension

aid in the diagnosis of osteoporosis [1].

#### **Chapter 5**

*Osteoporosis - Recent Advances, New Perspectives and Applications*

therapy for osteoporosis. Journal of

[119] Fink HA, MacDonald R, Forte ML, Rosebush CE, Ensrud KE, Schousboe JT, et al. Long-Term Drug Therapy and Drug Holidays for Osteoporosis Fracture Prevention: A Systematic Review. AHRQ Comparative Effectiveness Reviews.

bone and mineral research.

2017;32(2):198-202.

Rockville (MD)2019.

[120] Chong WP, Mattapallil MJ, Raychaudhuri K, Bing SJ, Wu S, Zhong Y, et al. The Cytokine IL-17A Limits Th17 Pathogenicity via a Negative Feedback Loop Driven by Autocrine Induction of IL-24. Immunity. 2020.

[121] Buchwald ZS, Kiesel JR, DiPaolo R, Pagadala MS, Aurora R. Osteoclast Activated FoxP3+ CD8+ T-Cells

Suppress Bone Resorption in vitro. PLoS

[122] Buchwald ZS, Yang C, Nellore S, Shashkova EV, Davis JL, Cline A, et al. A Bone Anabolic Effect of RANKL in a Murine Model of Osteoporosis Mediated Through FoxP3 +CD8 T Cells. Journal of

ONE. 2012;7(6):e38199–e38112.

Bone and Mineral Research. 2015;30(8):1508-1522.

[123] Buchwald ZS, Aurora R. Osteoclasts and CD8 T Cells Form a Negative Feedback Loop That

ID 429373.

2013;56:163-173.

Contributes to Homeostasis of Both the Skeletal and Immune Systems. Clin Dev Immunol. 2013;2013. Article

[124] Buchwald ZS, Kiesel J, Yang C, DiPaolo R, Novack D, Aurora R.

Limit Bone Loss in Mice. Bone.

[125] Cline-Smith A, Gibbs J,

Osteoclast-induced Foxp3+ CD8 T-Cells

Shashkova E, Buchwald ZS, Aurora R. Pulsed low-dose RANKL as a potential therapeutic for postmenopausal osteoporosis. JCI Insight. 2016;1(13):433-412.

[111] Cline-Smith A, Axelbaum A, Shashkova E, Chakraborty M, Sanford J, Panesar P, et al. Ovariectomy activates chronic low-grade inflammation mediated by memory T-cells which promotes osteoporosis in mice. J Bone

[112] Hodsman AB, Bauer DC, Dempster DW, Dian L, Hanley DA, Harris ST, et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocrine reviews. 2005;26(5):688-703.

[113] Lim SY, Bolster MB. Profile of romosozumab and its potential in the management of osteoporosis. Drug design, development and therapy.

[114] Fixen C, Tunoa J. Romosozumab: a

Review of Efficacy, Safety, and Cardiovascular Risk. Curr Osteoporos

[115] Saag KG, Zanchetta JR, Devogelaer JP, Adler RA, Eastell R, See K, et al. Effects of teriparatide versus alendronate for treating glucocorticoidinduced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis Rheum.

2009;60(11):3346-3355.

2006;21(3):354-365.

[116] Tashjian AH, Jr., Gagel RF. Teriparatide [human PTH(1-34)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis. J Bone Miner Res.

[117] Brandenburg VM, Verhulst A, Babler A, D'Haese PC, Evenepoel P, Kaesler N. Sclerostin in chronic kidney disease-mineral bone disorder think first before you block it! Nephrol Dial Transplant. 2019;34(3):408-414.

Dempster DW. Treatment sequence matters: anabolic and antiresorptive

[118] Cosman F, Nieves JW,

Miner Res. 2020.

2017;11:1221.

Rep. 2021.

**60**
