4.8 Thyroid disorders and bone disease

Osteoporosis is defined as a bone mineral density (BMD) of 2.5 or more standard deviations below that of a young adult (T score ≤ −2.5). It is characterized by reduced bone mass, low BMD, deterioration of bone microarchitecture, and an increased susceptibility to fragility fracture. The prevalence of postmenopausal osteoporosis increases with age from 6% at 50 years of age to over 50% at age 80 and the lifetime incidence of fracture for a 50 year old in the UK is 40% for women and 13% for men. Osteoporosis is a worldwide public health burden that costs an estimated £1.7 billion in the UK, $15 billion in the USA, and £32 billion in Europe per annum (see Chapter 4.7).

Low BMD, a prior or parental history of fracture, low body mass index, use of glucocorticoids, smoking, excessive alcohol consumption, untreated thyrotoxicosis, and other risk factors increase susceptibility to osteoporosis and fracture. Even subclinical hyperthyroidism, defined by a suppressed thyroid stimulating hormone (TSH) level in the presence of normal thyroid hormone concentrations, is associated with fracture while treatment with thyroxine (T₄) at doses that suppress TSH is associated with increased bone turnover and low BMD in postmenopausal women (1).

Thyroid disease occurs 10-fold more frequently in women and its prevalence increases with age. Hypothyroidism is a common disorder with a prevalence of 0.5% in women between the ages of 40 and 60 and greater than 2% over the age of 70. Thyrotoxicosis has a prevalence of 0.45% in women between the ages of 40 and 60 and 1.4% over the age of 60. As a result, 3% of women over 50 receive T₄ replacement for either primary hypothyroidism or the consequences of surgical or radio-iodine treatment for thyrotoxicosis, and at least 20% of them are overtreated (2). Moreover, subclinical hyperthyroidism affects an additional 1.5% of women over 60 and its prevalence also increases with age. Nevertheless, the role of thyroid hormone in the pathogenesis of osteoporosis has been under-recognized and the extent of its contribution remains uncertain.

Bone strength and fracture susceptibility are determined by the acquisition of peak bone mass and the rate of bone loss in adulthood (3). In children, congenital hypothyroidism is the most common congenital endocrine disorder with an incidence of 1 in 1800. Hypothyroidism in children results in delayed bone age and growth arrest and treatment with T₄ reverses these changes by inducing rapid ‘catch-up’ growth. Although juvenile Graves’ disease is rare, it remains the commonest cause of thyrotoxicosis in children, being characterized by advanced bone age and accelerated growth that results in short stature due to premature fusion of the growth plates (4). In adults, histomorphometry studies reveal that hypothyroidism results in reduced bone turnover but a net gain in bone mass per remodelling cycle, whereas thyrotoxicosis increases bone resorption and bone formation but induces a net 10% loss of bone per remodelling cycle (5, 6). Taken together, these studies indicate the juvenile and adult skeleton is exquisitely sensitive to thyroid hormones. Thus, euthyroid status is essential for skeletal development, bone mineralization, and acquisition of peak bone mass, and the regulation of bone maintenance in adults. Importantly, recent large population studies have shown that both hypothyroidism and thyrotoxicosis are associated with an increased risk of fracture, demonstrating the physiological importance of euthyroid status for optimization of skeletal integrity and bone strength (7–11).

In this chapter we provide an up to date analysis of the role of thyroid hormone in skeletal development and adult bone maintenance by discussing evidence from animal models and basic science in relation to a detailed review of the current clinical literature.

Circulating thyroid hormone levels are maintained in the euthyroid range by a classical endocrine negative feedback loop. Thyrotropin-releasing hormone is synthesized in the paraventricular nucleus of the hypothalamus and stimulates synthesis and secretion of TSH from thyrotrophs in the anterior pituitary gland. TSH, acting via the G-protein coupled TSH receptor (TSHR), stimulates growth of thyroid follicular cells and the synthesis and release of thyroid hormones. Thyroid hormones act via thyroid hormone receptors in the hypothalamus and pituitary to inhibit thyrotropin-releasing hormone and TSH synthesis and secretion. This negative feedback loop maintains circulating thyroid hormones and TSH in a physiological inverse relationship, which defines the hypothalamic–pituitary–thyroid (HPT) axis set point (4).

The thyroid gland secretes the prohormone T₄ and a small amount of the physiologically active hormone 3,5,3′-l-triiodothyronine (T₃). The majority of circulating T₃, however, is thought to be generated via 5′-deiodination of T₄ by the type 1 iodothyronine deiodinase enzyme (DIO1) in liver and kidney. Circulating free T₄ levels are maintained at approximately three to fourfold higher concentrations than free T₃. Intracellular availability of T₃ is determined by active uptake of the free hormones by specific cell membrane transporters, including monocarboxylate transporter-8 and -10, and organic acid transporter protein-1c1, and by the activities of the type 2 and 3 deiodinase enzymes (DIO2 and DIO3). DIO2 converts T₄ to the active hormone T₃ by catalysing removal of a 5′-iodine atom. By contrast, DIO3 prevents activation of T₄ and inactivates T₃ by removal of a 5-iodine atom to generate the metabolites 3,3′,5′-l-triiodothyronine (reverse T₃) and 3,3′-diiodothyronine (T₂), respectively. Thus, the relative levels of DIO2 and DIO3 ultimately determine the concentration of intracellular T₃ available to the nuclear T₃ receptors (TRs) (12).

TRs act as hormone-inducible transcription factors that regulate expression of T₃-responsive target genes. The THRA and THRB genes encode three functional TRs: TRα1, TRβ1, and TRβ2. TRα1 and TRβ1 are expressed widely but their relative levels differ during development and in adulthood due to tissue-specific and temporospatial regulation. Expression of TRβ2, however, is restricted. In the hypothalamus and pituitary it mediates inhibition of thyrotropin-releasing hormone and TSH expression whilst in the cochlea and retina it has a key role to control the timing of sensory organ development (13).

The skeleton develops via two distinct processes. Endochondral ossification is the process by which long bones form and linear growth occurs. A cartilage anlage forms from mesenchyme condensations to form a scaffold for subsequent bone formation. Mesenchyme progenitor cells differentiate into chondrocyte precursors, which undergo a tightly regulated sequence of clonal expansion, proliferation, hypertrophic differentiation, and apoptosis. Chondrocytes secrete a cartilage matrix that mineralizes and is subsequently remodelled by the activities of bone resorbing osteoclasts and bone forming osteoblasts, resulting in formation of the diaphysis. Linear growth continues throughout development by a similar process within the epiphyseal growth plates, which are located at the proximal and distal ends of long bones. By contrast, the skull vertex forms by intramembranous ossification, in which mesenchymal cells differentiate directly into osteoblasts, resulting in bone formation in the absence of a cartilage scaffold. Linear growth continues until fusion of the growth plates during puberty but bone mineralization and consolidation of bone mass accrual continues into early adulthood so that peak bone mass is achieved during the third to fourth decade (14, 15).

Functional integrity and strength of the skeleton is maintained by the process of bone remodelling, which is achieved by the integrated and coupled activities of osteocytes, osteoclasts, and osteoblasts. Osteocytes comprise 90–95% of all adult bone cells. They derive from osteoblasts that have become embedded in bone matrix. The osteocyte network is thought to sense changes in mechanical load and regulate local initiation of bone remodelling by the release of cytokines and chemotactic signals or by osteocyte apoptosis. Bone remodelling begins with the recruitment of mature osteoclasts and their precursors to sites of altered mechanical load or microdamage. Osteoclasts excavate a resorption cavity over a period of 3–5 weeks until this process is terminated by apoptosis and followed by recruitment of osteoblast precursors. Subsequently, osteoblasts undergo a programme of maturation during which they secrete and mineralize osteoid to replace the resorbed bone over a period of approximately 3 months. Coupling of osteoclast and osteoblast activities via signalling between the two cell lineages regulates the bone remodelling cycle and results in skeletal homoeostasis with preservation of bone strength. In summary, the bone remodelling cycle is initiated and orchestrated by osteocytes, and regulated by coupled crosstalk between osteoblasts and osteoclasts.

TRα1 and TRβ1 are expressed in growth plate chondrocytes, bone marrow stromal cells, and osteoblasts but it is uncertain whether they are present in osteoclasts (4, 16).

In vivo and in vitro studies have shown that T₃ acts via the Indian hedgehog/ parathyroid hormone-related peptide feedback loop, growth hormone/ insulin-like growth factor-1, and fibroblast growth factor receptor-3 (FGFR3) signalling pathways to inhibit growth plate chondrocyte proliferation and stimulate hypertrophic chondrocyte differentiation. In childhood hypothyroidism, growth arrest and delayed bone formation are consequences of gross disruption of growth plate architecture (epiphyseal dysgenesis), which results from disorganization of the growth plates and a failure of hypertrophic chondrocyte differentiation. By contrast, thyroid hormone excess accelerates hypertrophic chondrocyte differentiation resulting in advanced bone formation (4, 16).

Studies of bone marrow stromal cells suggest that many of the actions of T₃ involve complex cytokine and growth factor signalling pathways that regulate communication between osteoblast and osteoclast cell lineages within the bone marrow microenvironment. In vivo and in vitro studies have further shown that T₃ regulates osteoblast differentiation and activity at least in part via the FGFR1 signalling pathway. Activating mutations of FGFR1 cause Pfeiffer’s craniosynostosis syndrome and, consistent with this, craniosynostosis is a recognized manifestation of severe juvenile thyrotoxicosis in which FGFR1 activity is increased in osteoblasts.

The regulation of adult bone turnover by thyroid hormones has been investigated by bone histomorphometry (5, 6). The skeletal manifestations of hypothyroidism include reduced osteoblast activity, impaired osteoid apposition, and a prolonged period of secondary bone mineralization. Consistent with a state of low bone turnover, osteoclast activity and bone resorption are also reduced. The effect of the low bone turnover state in hypothyroidism is a net increase in mineralization without a change in bone volume. By contrast, thyrotoxicosis results in a state of high bone turnover. The frequency of initiation of bone remodelling is markedly increased and the duration of the bone remodelling cycle is reduced. The net result is that the duration of bone formation and mineralization is reduced to a greater extent than the reduction in duration of bone resorption. This leads to a net 10% loss of bone per remodelling cycle, resulting in high bone turnover osteoporosis.

In vivo studies in mutant mice have demonstrated that TRα1 mediates T₃ action in bone (17). Mutation or deletion of TRα results in transient growth retardation, impaired ossification, and reduced bone mineralization during growth (Table 4.8.1). In adults, there is a defect in bone remodelling, a marked increase in bone mass, and increased bone mineralization. By contrast, mutation or deletion of TRβ results in an opposite phenotype of accelerated growth, advanced ossification with increased mineralization during growth but short stature, which results from premature quiescence of the growth plates (Table 4.8.1). In adults, increased bone remodelling results in osteoporosis and reduced bone mineralization. Taken together, these features indicate that thyroid hormones exert anabolic actions during skeletal growth but catabolic responses in adult bone (17). Mutation of TRα disrupts T₃ action in bone cells resulting in skeletal hypothyroidism, whereas mutation of TRβ disrupts the HPT axis, leading to elevated levels of circulating thyroid hormones which activate TRα in bone cells, resulting in skeletal hyperthyroidism. Consistent with these phenotypes, levels of TRα mRNA expression are 10- to 100-fold greater than TRβ in adult bone.

Recently, a direct role for TSH as a negative regulator of bone turnover has also been proposed (4). Osteoblasts and osteoclasts were shown to express the TSHR, and congenitally hypothyroid TSHR knockout mice treated with thyroid hormone displayed a phenotype of high bone turnover osteoporosis. As a result of these findings, it was suggested that bone loss was a consequence of TSH deficiency. However, the susceptibility of patients with Graves’ disease to osteoporosis and fracture is inconsistent with the hypothesis that TSH negatively regulates bone turnover because the presence of TSHR-stimulating antibodies would be predicted to protect patients from osteoporosis. Thus, the skeletal consequences of thyrotoxicosis are most likely to result primarily from thyroid hormone excess although TSH deficiency cannot be excluded as a contributing factor (4).

These two possibilities cannot be differentiated readily because the HPT axis maintains thyroid hormones and TSH in a physiological reciprocal relationship. Nevertheless, studies in mutant mice have enabled the issue to be addressed in vivo. Thus, the skeletal phenotypes of two different mouse models of congenital hypothyroidism were compared. Pax8 knockout mice lack a transcription factor that is essential for thyroid follicular cell development and have undetectable thyroid hormone levels, a 2000-fold elevation of TSH, and a fully functional TSHR. By contrast, hyt/hyt mice have gross congenital hypothyroidism also accompanied by a 2000-fold increase in TSH but they harbour a point mutation in the Tshr gene, leading to complete loss of TSHR protein function. Both mutants exhibited a similar phenotype of growth retardation and delayed ossification typical of hypothyroidism despite the divergence in TSH signalling (4).

In summary, the skeleton is exquisitely sensitive to thyroid status during growth and in adulthood. T₃ exerts important anabolic responses during skeletal growth and has significant catabolic effects on adult bone. Both of these actions are mediated by TRα1.

Congenital hypothyroidism results in growth arrest, epiphyseal dysgenesis, delayed bone age, and short stature. Thyroxine replacement therapy induces rapid catch-up growth and as a result children that are treated early ultimately reach their predicted adult height and achieve normal BMD after 8.5 years’ follow-up. Nevertheless, a single study has suggested that adult BMD may be reduced despite treatment from the neonatal period. Children with juvenile acquired hypothyroidism also display growth arrest, delayed bone maturation, and short stature. T₄ replacement again induces rapid catch-up growth, but these individuals may fail to achieve final predicted height and the resulting permanent height deficit is related to the duration of thyroid hormone deficiency prior to replacement (18).

Juvenile thyrotoxicosis results in accelerated growth, advanced bone age, and short stature, which is a consequence of the premature fusion of the epiphyseal growth plates due to accelerated skeletal maturation. In severe cases in young children, early closure of the cranial sutures may result in craniosynostosis (19). To date, there are no data relating to the effects of childhood thyrotoxicosis on BMD.

Resistance to thyroid hormone is an autosomal dominant condition resulting from a dominant negative mutation of TRβ (20). The mutant TRβ protein disrupts negative feedback in the HPT axis, leading to increased circulating thyroid hormone concentrations in the presence of inappropriately normal or elevated TSH levels. The syndrome results in a complex mixed phenotype of hyperthyroidism and hypothyroidism depending on the target tissue studied and the specific mutation present in TRβ. Thus, an individual patient can have symptoms of both thyroid hormone deficiency and excess. A broad range of skeletal abnormalities have been described in association with resistance to thyroid hormone. These include craniofacial abnormalities, craniosynostosis, delayed or advanced bone age, short stature, increased bone turnover, osteoporosis, and fracture, although only a few patients have been studied in detail.

A large number of studies have attempted to characterize the skeletal consequences of altered thyroid function in adults. Unfortunately, many of these studies have been confounded by inclusion of patients with a variety of thyroid diseases and by comparison of mixed cohorts of patients, which have included pre- and postmenopausal women or men. Furthermore, many studies have lacked sufficient statistical power because of the inclusion of small numbers of patients and the absence of long-term follow-up. In addition, in many studies there has been inadequate control for other confounding factors that influence bone mass and fracture susceptibility, including: age, prior or family history of fracture, body mass index, physical activity, use of oestrogens, glucocorticoids, bisphosphonates, and vitamin D, prior history of thyroid disease or use of thyroxine, and smoking or alcohol intake. For these reasons, the literature in this field has been difficult to investigate by meta-analysis and conclusions can only be uncertain (1).

Few studies have determined bone turnover markers in euthyroid populations. Zofkova et al. in a study of bone turnover markers in a population of 60 healthy postmenopausal women reported that high circulating TSH levels correlated with low urinary deoxypyridinoline concentrations but not with serum procollagen type I C propeptide levels (21). This study illustrates difficulties with interpretation of thyroid hormone effects on bone turnover as only a small number of subjects were investigated and individuals with treated hypothyroidism, subclinical hyperthyroidism, and secondary hyperparathyroidism were not excluded.

Four large population studies have investigated the relationship between thyroid status and BMD (Table 4.8.2). van der Deure et al. studied a population of 1151 euthyroid men and women over 55 from Rotterdam (22). BMD at the femoral neck was positively correlated with TSH levels and inversely correlated with free T₄, and the association with free T₄ was much stronger than the association with TSH. No relationships between free T₄ or TSH and fracture were identified in this study. Kim et al. studied 959 Korean postmenopausal women and showed that individuals with low-normal TSH levels between 0.5 and1.1 mU/l had lower lumbar spine and femoral neck BMD than women with high-normal TSH between 2.8 and 5.0 mU/l, although no fracture data were reported (23). Morris studied 581 postmenopausal American women and showed that subjects with a low-normal TSH were nearly five times more likely to have osteoporosis than women with a high-normal TSH (24). Grimnes et al. studied a population of 993 postmenopausal women and 968 men from Tromso. This study revealed that individuals with TSH below the 2.5th percentile had a low forearm BMD whereas those with TSH above the 97.5th percentile had a high femoral neck BMD compared with the rest of the population (25). Neither of these studies investigated the incidence of fracture. Finally, the incidence of fracture in 367 UK women over 50 was prospectively studied for 10 years by Finigan et al. and no associations between free T₃, free T₄, or TSH and incident vertebral fracture were identified (26).

In summary, these studies suggest the hypothesis that thyroid status in the upper normal range is associated with reduced BMD whereas thyroid status in the lower normal range is associated with increased BMD. A definitive conclusion, however, is not possible as these studies unfortunately did not account for a number of confounding variables. Prospective population studies of sufficient size and duration will be required to determine the relationship between thyroid status and fracture risk.

Histomorphometric analyses have demonstrated that bone turnover is decreased in hypothyroidism (5, 6) but studies of the effect of hypothyroidism on bone turnover markers have included only very small numbers of patients and were inconclusive. Consistent with histomorphometric data showing normal bone volume in hypothyroid patients, Vestergaard and Mosekilde, and Stamato et al. have reported that BMD is normal in patients newly diagnosed with hypothyroidism (10, 27).

Large population studies, however, have demonstrated an association between hypothyroidism and fracture. Patients with a prior history of hypothyroidism had a two to three-fold increased relative risk of fracture, which persisted for up to 10 years following initial diagnosis (7, 10, 11, 28) (Table 4.8.3).

In summary, hypothyroidism results in low bone turnover and an increased risk of fracture.

The severe bone disease associated with overt uncontrolled thyrotoxicosis in now rare because of early diagnosis and treatment, although several studies have investigated the skeleton in thyrotoxic patients prior to treatment.

The effect of thyrotoxicosis on bone turnover markers is consistent with histomorphometric data reported by Eriksen et al. (5). Thus, levels of bone resorption markers such as urinary pyridinoline and deoxypyridinoline are increased. Bone formation markers, including bone-specific alkaline phosphatase and osteocalcin, are also elevated. A meta-analysis of 20 eligible studies by Vestergaard and Mosekilde (37) calculated that BMD at the time of diagnosis of thyrotoxicosis was reduced compared to age-matched controls (Table 4.8.4).

Two cross-sectional case–controlled (11, 43) and four population studies (7, 8, 29, 30) have identified an association between fracture and a prior history of thyrotoxicosis (Table 4.8.3). Similarly, a meta-analysis of patients with thyrotoxicosis revealed an increased relative risk of hip fracture (37). The majority of these studies did not determine whether the increased fracture risk could be accounted for by reduced BMD, although one prospective study (29) showed that a prior history of thyroid disease is associated with hip fracture even after adjustment for BMD. Furthermore, Bauer et al. (8, 44) demonstrated that low TSH was associated with a three to fourfold increased risk of fracture even though a relationship between TSH and BMD was not identified. In agreement with these observations, Franklyn et al. showed an increased standardized mortality ratio due to fractured femur in a follow-up register of thyrotoxic patients treated with radio-iodine (31). Nevertheless, several studies have failed to demonstrate an association between thyrotoxicosis and fracture (32–34).

In summary, a prior history of thyrotoxicosis may be associated with reduced bone density and a long-term increased risk of fracture, although data are conflicting and limited by confounding factors.

Either elevated or normal levels of the bone resorption markers urinary deoxypyridinoline and hydroxyproline have been reported in patients with subclinical hyperthyroidism. Similarly, levels of the bone formation markers osteocalcin, alkaline phosphatase, and procollagen I C-terminal extension propeptide have been reported to be elevated or normal. Subclinical hyperthyroidism has also been associated with reduced BMD at the femoral neck and other sites, although other studies have not found such a relationship. Accordingly, a meta-analysis was inconclusive (38) (Table 4.8.4).

Although no prospective studies of fracture risk in subclinical hyperthyroidism have been published, data from Bauer et al. suggest that suppressed TSH levels may be associated with an increased risk of fracture (8). Additionally, Jamal et al. reported a subanalysis of the Fracture Intervention Trial and demonstrated that a TSH level suppressed below 0.5 mIU/l was associated with an increased risk of vertebral fracture (9). Unfortunately, there was insufficient information provided to determine whether patients in this study had subclinical hyperthyroidism or untreated thyrotoxicosis.

In summary, subclinical hyperthyroidism may be associated with increased bone turnover, reduced BMD, and increased fracture risk although again insufficient data are currently available to draw definitive conclusions.

The long-term management of patients with differentiated thyroid cancer frequently involves treatment with doses of thyroxine that suppress circulating TSH concentrations and which may have detrimental effects on the skeleton.

A number of small studies have investigated the effect of suppressive doses of T₄ on bone turnover markers. Three studies reported increased levels of bone resorption markers in patients receiving T₄ and two of these also demonstrated an increase in bone formation markers (45). Nevertheless, other studies reported no effect on markers of bone resorption or formation (46).

A large number of studies have investigated the effects of suppressive doses of T₄ on BMD in pre- and postmenopausal women and in men at various anatomical locations.

Most studies showed no effect of TSH suppression therapy on BMD at the lumber spine, femur, or radius in premenopausal women. By contrast, three studies have reported reduced BMD at the femur in premenopausal women receiving suppressive doses of T₄. Heemstra et al. analysed 12 cross-sectional and four prospective studies of premenopausal women receiving suppressive doses of T₄, but a meta-analysis could not be performed due to heterogeneity of the cohorts (39). The authors concluded that treatment with suppressive doses of T₄ did not affect BMD in premenopausal women (Table 4.8.4). This finding supported results of an earlier review of eight studies by Quan et al. (40).

The effects of suppressive doses of T₄ on BMD in postmenopausal women are less clear as the two most rigorous cross-sectional studies reported conflicting results (47, 48). Franklyn et al. investigated 26 UK postmenopausal women treated for 8 years and demonstrated no effect of TSH suppression on BMD (47), whereas Kung and Yeung studied 34 postmenopausal Asian women and found a decrease in total body, lumbar spine, and femoral BMD in patients treated with suppressive doses of T₄ (48). However, direct comparison between the two studies is difficult because in the study by Franklyn et al. TSH was fully suppressed in only 80% of patients, whilst mean calcium intake was low in the study by Kung et al. Similar conflicting results have been reported at various anatomical sites in less well-controlled cross-sectional and longitudinal studies. Eight cross-sectional studies also included investigation of male patients, but only Jodar et al. reported a reduction in lumber spine and femur BMD in men receiving suppressive doses of T₄ (49).

A meta-analysis of 27 studies investigating the effect of suppressive doses of T₄ on BMD (41) concluded there were no effects on BMD in premenopausal women or men, although such treatment in postmenopausal women for up to 10 years led to reductions in BMD at the distal radius, lumbar spine, and femoral neck of between 5 and 7% (Table 4.8.4). Although the long-term effects of suppressive doses of T₄ on BMD in postmenopausal women remain uncertain, further reviews of this topic support the findings of Uzzan et al. and recommend monitoring of BMD in such patients (1, 39, 40).

No studies with sufficient statistical power to determine the effect of treatment with suppressive dose of T₄ on fracture risk have been reported.

In summary, treatment with suppressive dose of T₄ does not affect BMD in premenopausal women or men but may lead to reduced BMD in postmenopausal women. Effects on bone turnover are inconclusive and there are no data regarding fracture risk.

Histomorphometric studies have suggested an increase in bone turnover in response to T₄ replacement in hypothyroidism (5) but the effect on bone markers has not been reported. The majority of cross-sectional studies of pre- and postmenopausal women receiving long-term T₄ replacement for hypothyroidism have not identified any significant effect on BMD. However, in premenopausal women Paul et al. (50) reported a 10% reduction BMD in the femur but no change at the lumbar spine following T₄ replacement, whilst Kung and Pun (51) reported reduced BMD at both lumbar spine and hip. There are no prospective studies investigating the effects of T₄ replacement in hypothyroid patients on fracture risk, although population studies have not identified an association between T₄ replacement therapy and fracture (29, 33, 34).

Two prospective studies of patients with thyrotoxicosis have shown that elevated levels of bone resorption and bone formation markers return to normal levels within 1 month of initiation of treatment. A meta-analysis of 20 studies investigating the effect of treatment for thyrotoxicosis on BMD (37) demonstrated that the low BMD at diagnosis returned to normal after 5 years (Table 4.8.4). In a subsequent study, treatment for thyrotoxicosis was shown to result in a 4% increase in BMD within 1 year (52). Nevertheless, in a large population study Vestergaard et al. (11) reported that an increased relative risk of fracture risk persisted for 5 years following a diagnosis of thyrotoxicosis (Table 4.8.3).

In summary, treatment of patients with thyrotoxicosis results in normalization of bone turnover and BMD by 5 years, although the increased risk of fracture may persist for longer.

In healthy individuals free T₃, free T₄, and TSH levels fluctuate over a range that is less than 50% of the normal reference range. Thus, variation in thyroid status within an individual is narrower than the broad interindividual variation seen in the population. Each person has a unique HPT axis set point that lies within the population reference range, indicating there is variation in tissue sensitivity to thyroid hormones between normal individuals (53). Data from the UK Adult Twin Registry estimate heritability for free T₃ concentration at 23%, free T₄ at 39%, and TSH at 65%, whilst estimates from a Danish twin study were 64%, 65%, and 64%, respectively (54, 55). A genome-wide screen identified eight quantitative trait loci linked to circulating free T₃, free T₄, and TSH levels, indicating that thyroid status is inherited as a complex genetic trait (56). Similarly, unbiased genome-wide association studies and candidate gene approaches have shown that osteoporosis is a polygenic disorder in which many genes and signalling pathways exert small contributions that influence bone size, BMD, and fracture susceptibility (57).

These observations raise the possibility that variations in bone turnover, BMD, and fracture susceptibility in normal individuals may be associated with differences in their HPT axis set points. Furthermore, genes that establish the HPT axis set point and thus regulate thyroid status may also influence the acquisition of peak bone mass, skeletal growth, and bone turnover and thereby contribute to the genetic determination of fracture risk. This hypothesis is consistent with observations in other physiological complex traits including body mass index, blood pressure, heart rate, atherosclerosis, serum cholesterol, and psychological well-being, in which variations have been associated with small alterations in thyroid function and with polymorphisms in thyroid pathway genes that are themselves associated with altered serum thyroid hormone and TSH concentrations (58). These new developments in our understanding the physiological regulation of the HPT axis and thyroid hormone action in target tissues have been extended recently to investigation of the skeleton and these studies suggest common genetic factors may be involved in the determination of thyroid status, bone turnover, and BMD (22, 59).

Future prospective studies investigating the relationships between variations in the HPT axis set point and genes regulating thyroid hormone transport, metabolism, and action with bone mass and fracture risk will need to be well designed and adequately powered. Stringent exclusion criteria will be required to define large populations of individuals which can be followed up prospectively for prolonged periods. Nevertheless, such studies have the potential to individualize fracture risk prediction and inform the choice of preventative therapy (58).