**1. Introduction**

The skeletal system maintains a dynamic characteristic throughout its life by continuously undergoing bone modeling and bone remodeling processes [1–7]. Both bone modeling and remodeling processes include bone resorption mediated by osteoclasts and bone formation mediated by osteoblasts. Bone modeling is the predominant event during childhood, whereas in adults bone remodeling is the principal event [8]. In the case of bone modeling, both bone resorption and bone formation lead to major cur independently of one another at different sites of the skeletal system and lead to major change in the skeletal framework, whereas in the case of bone remodeling, both the processes of bone resorption and formation are closely related both in terms of time and site so that bone volume and density both remain more or less unchanged. The continuous process of bone remodeling repairs micro fractures, prevents formation of brittle bones, and balances calcium and phosphate homeostasis [6–8].

A number of systemic and local factors regulate the process of bone remodeling. Whenever the tightly coupled processes of bone resorption and bone formation in bone remodeling are disturbed, bone mineral diseases occur, excessive bone resorption leads to osteoporosis, and excessive bone formation leads to osteopetrosis [9].

Osteoblasts and osteoclasts are the two key players of bone remodeling; other cells involved in the process are osteocytes (derived from osteoblasts and acting as mechanosensor) and the bone lining cells [9]. The process of bone remodeling increases with aging; in both perimenopausal and menopausal women, the remodeling is faster than premenopausal women [9].

There are a number of factors which are responsible for the development, maturation, and normal functioning of the skeletal system; these are genetic factors, maintenance of hormonal and metabolic harmony, adhering to balanced diet, exercise, etc. Any change in the abovementioned factors might lead to skeletal abnormality including restricted stature, deformity, osteoporosis, etc. [8, 10].

Osteoporosis leads to poor bone mass along with increased risk of fracture. Osteoporosis has emerged as a global healthcare problem with an estimated huge economic burden. Around 40% of women and 13–22% of men above 50 years will experience at least one episode of fracture (usually of spine, femur, or forearm) due to underlying osteoporosis in his or her lifetime [11]. Besides postmenopausal women and men above 50 years of age, the risk of secondary osteoporosis has increased in younger people as well [11].

Due to the increase in the number of patients with osteoporosis, all the secondary risk factors attributed to osteoporosis should be thoroughly investigated.

A number of factors are responsible for maintenance and development of the skeletal system; these are genetic factors, adequate hormonal and metabolic functions, intake of balanced diet, and exercise (mechanical load) [11]. Any type of imbalance among the abovementioned factors might lead to severe consequences like short stature, bony deformities, and fractures. The final outcome depends upon age, type, severity, and duration of the underlying imbalance. Although not all of the abovementioned factors can be modified (like genetic factors), some of them can be modified [11, 12].

A rising number of new osteoporosis cases both in elderly and in young patients warrant the need for thorough investigations to identify all other secondary conditions that might affect the disease negatively. Of all the secondary conditions, hormonal conditions are the most important ones that can lead to or aggravate osteoporosis [12]. Most commonly implicated endocrinological conditions are Cushing's syndrome, hyperthyroidism, hypogonadism, acromegaly, diabetes mellitus, etc. Fortunately, majority of the negative effects of these hormonal disorders on the skeletal system can be modified [10–12].

#### **1.1 Osteoblasts**

Osteoblasts, the bone-forming cells in bone remodeling process, are derived from the pluripotent mesenchymal stem cells. Osteoblasts are also responsible for the secretion of Type I collagen which in turn is the major bone matrix protein. Besides the abovementioned functions, osteoblasts are also responsible for adequate mineralization of the new bone (osteoid). Bone mineralization occurs due to the locally released phosphates from the osteoblast-derived vesicles located within the osteoid. Extracellular calcium also contributes to the process of bone formation by the production of hydroxyapatite crystals. Maintenance of correct balance between bone matrix and minerals is the key factor for ensuring the right amount of rigidity and flexibility of the skeletal structure. Adult human cortical bones consist of 60% mineral, 20% organic material, and 20% water [8, 9].

#### **1.2 Osteoclasts**

These are micronucleated cells that are derived from the mononuclear monocyte-macrophage cells. Osteoclasts, the only bone-resorbing cells, depend on two cytokines, colony-stimulating factor-1 or the macrophage colony-stimulating factor (CSF-1) and receptor activator of NF-kB ligand (RANKL), for production, expansion, and survival. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL and

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*Thyroid Disorders and Osteoporosis*

*DOI: http://dx.doi.org/10.5772/intechopen.87129*

**2. Physiology of thyroid hormones**

inhibit own synthesis and secretion.

**2.1 Intracellular T3 supply**

three to four times [13, 14].

is an estimated genetic variation of 45–65% [13, 14].

activation of T3 by producing reverse T3 [16].

**3. Thyroid hormone and the skeletal system**

elements at the target genes [14–16].

extent of osteoclast maturation and expansion [8, 9].

inhibits the action of RANKL; hence the ration of RANKL to OPG determines the

The level of thyroid hormones in the circulation is controlled by the hypothalamic-pituitary-thyroid axis (HPT axis) [13]. Thyrotropin-releasing hormone (TRH) is produced and secreted from the medial neurons of the paraventricular nucleus (PVN) of the hypothalamus. TRH in turn regulates both production and secretion of thyroid-stimulating hormone (TSH) from the anterior pituitary cells. Next, TSH through action on its receptor (TSHR) located on the follicular cells of the thyroid gland stimulates synthesis and secretion of the thyroid hormones. There are two types of thyroid hormones, 3,5,30,50-L-tetraiodothyronine (T4), the pro-

Thyroid hormones exert negative feedback effect on TRH and TSH and thus

Thus the HPT axis maintains a balanced relationship between the circulating thyroid hormones and their regulators like TSH and TRH. The set point for adequate functioning of the HPT axis is partly determined by genetic factors; there

Circulating concentrations of both T4 and T3 along with target tissue uptake of the same and local activation or inactivation determine the intracellular supply of T3 (the active hormone). The thyroid gland secretes the pro-hormone T4 in larger proportions which is converted to the active form T3 in the liver and kidney through deiodination of T4 by type 1 iodothyronine deiodinase enzyme (DIO1). A major part (around 90%) of the circulating thyroid hormone remains bound to plasma proteins, and the concentration of free T3 (fT3) exceeds that of free T4 (fT4) by

There are specific membrane transporters associated with target tissue uptake of thyroid hormones; considered as monocarboxylate transporters (MCT8, MCT10), and organic acid transporter protein-1c1 (OATP1C1) [15]. Activity of T3 inside the cell is regulated by DIO2 and DIO3, as DIO2 converts T4 to T3 and DIO3 blocks the

Action of T3 hormone on the skeletal system is rather complex and not completely understood. T3 mediates its action on the bones via direct and indirect pathways and affects the different phases of bone remodeling. T3 facilitates both osteoblastic (bone formation) and osteoclastic actions (bone resorption). T3 facilitates osteoblastic

Thyroid hormones mediate their actions through interaction with thyroid receptors (TRs). Unbound TRs bind with corepressor proteins and bind with thyroid response elements located at the promoter regions of the target genes and suppress transcription. Once thyroid hormone binds with its receptor, the receptor undergoes a conformational change with the unbinding of the corepressor proteins and facilitation of gene transcription following binding with the thyroid response

hormone, and 3,5,30-L-triiodothyronine (T3), the active hormone [14].

*Clinical Implementation of Bone Regeneration and Maintenance*

increased in younger people as well [11].

on the skeletal system can be modified [10–12].

mineral, 20% organic material, and 20% water [8, 9].

can be modified [11, 12].

**1.1 Osteoblasts**

**1.2 Osteoclasts**

There are a number of factors which are responsible for the development, maturation, and normal functioning of the skeletal system; these are genetic factors, maintenance of hormonal and metabolic harmony, adhering to balanced diet, exercise, etc. Any change in the abovementioned factors might lead to skeletal abnormality including restricted stature, deformity, osteoporosis, etc. [8, 10]. Osteoporosis leads to poor bone mass along with increased risk of fracture. Osteoporosis has emerged as a global healthcare problem with an estimated huge economic burden. Around 40% of women and 13–22% of men above 50 years will experience at least one episode of fracture (usually of spine, femur, or forearm) due to underlying osteoporosis in his or her lifetime [11]. Besides postmenopausal women and men above 50 years of age, the risk of secondary osteoporosis has

Due to the increase in the number of patients with osteoporosis, all the second-

A number of factors are responsible for maintenance and development of the skeletal system; these are genetic factors, adequate hormonal and metabolic functions, intake of balanced diet, and exercise (mechanical load) [11]. Any type of imbalance among the abovementioned factors might lead to severe consequences like short stature, bony deformities, and fractures. The final outcome depends upon age, type, severity, and duration of the underlying imbalance. Although not all of the abovementioned factors can be modified (like genetic factors), some of them

A rising number of new osteoporosis cases both in elderly and in young patients warrant the need for thorough investigations to identify all other secondary conditions that might affect the disease negatively. Of all the secondary conditions, hormonal conditions are the most important ones that can lead to or aggravate osteoporosis [12]. Most commonly implicated endocrinological conditions are Cushing's syndrome, hyperthyroidism, hypogonadism, acromegaly, diabetes mellitus, etc. Fortunately, majority of the negative effects of these hormonal disorders

Osteoblasts, the bone-forming cells in bone remodeling process, are derived from the pluripotent mesenchymal stem cells. Osteoblasts are also responsible for the secretion of Type I collagen which in turn is the major bone matrix protein. Besides the abovementioned functions, osteoblasts are also responsible for adequate mineralization of the new bone (osteoid). Bone mineralization occurs due to the locally released phosphates from the osteoblast-derived vesicles located within the osteoid. Extracellular calcium also contributes to the process of bone formation by the production of hydroxyapatite crystals. Maintenance of correct balance between bone matrix and minerals is the key factor for ensuring the right amount of rigidity and flexibility of the skeletal structure. Adult human cortical bones consist of 60%

These are micronucleated cells that are derived from the mononuclear monocyte-macrophage cells. Osteoclasts, the only bone-resorbing cells, depend on two cytokines, colony-stimulating factor-1 or the macrophage colony-stimulating factor (CSF-1) and receptor activator of NF-kB ligand (RANKL), for production, expansion, and survival. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL and

ary risk factors attributed to osteoporosis should be thoroughly investigated.

**114**

inhibits the action of RANKL; hence the ration of RANKL to OPG determines the extent of osteoclast maturation and expansion [8, 9].
