The thyroid and the skeleton

The relationship between the thyroid and the skeleton was first suggested in 1891 when Von Recklinghausen (1891) reported a patient with hyperthyroidism and multiple fractures. Thyroid disease is common; more than 1% of British women receive thyroxine treatment, increasing to over 3% in those over 50 years of age, and the concern is that patients with a history of hyperthyroidism or those receiving thyroxine treatment may be at increased risk of osteoporosis and fractures (Parle et al., 1993). While the clinical consequences of overt hyperthyroidism on bone have been known for many years the molecular mechanism of action of thyroid hormone on bone has remained incompletely understood. Furthermore, earlier recognition of thyroid disease and effective treatment for clinical symptoms has meant that severe bone disease is now uncommonly seen. It is only in more recent years, with the development of more sensitive TSH assays and the recognition that even so-called subclinical thyroid disease, associated with a suppressed TSH but normal FT4 and FT3 levels, may have effects on fracture risk that there has been a renewed interest in the role of thyroid hormone in bone (Klee & Hay, 1988; Bauer et al., 2001). The molecular actions of thyroid hormone in bone have recently been comprehensively reviewed (Harvey et al., 2002; Bassett & Williams, 2003). This review will therefore only briefly summarize this information and instead concentrate in detail on some of the clinical aspects of thyroid hormone effects on bone growth and development in childhood and bone turnover and maintenance in adults. Tables are used to illustrate the effects of thyroid hormone suppressive therapy for thyroid cancer and thyroid hormone replacement on bone mineral density (BMD), and the effects of thyroid hormone on fracture risk. Each clinical section concludes with a summary of the salient points discussed. The role of calcitonin, a hormone also synthesized and secreted by the thyroid gland, and its effects on bone has recently been reviewed and will not be discussed further here (Inzerillo et al., 2002). In adults, the mechanical integrity of the skeleton is maintained by bone remodelling, which results from the localized removal of old bone and its replacement with newly formed bone (Ng et al., 1997). Remodelling enables bone to adapt to mechanical stress and to repair micro-damage, thus maintaining its strength. Alterations in bone remodelling are responsible for most metabolic bone diseases, including osteoporosis and the reduction in BMD seen with uncontrolled hyperthyroidism. Osteoporosis is defined as a BMD value 2·5SDs or more below the mean value for young adults (T score ≤−2·5) (Anonymous, 1991). As well as low bone mass, osteoporosis is characterized by microarchitectural deterioration of bone, with a consequent increase in bone fragility. The major end point of osteoporosis is fracture, especially of the distal forearm, vertebrae or hip, with a two- to threefold increase in fracture incidence for each SD reduction in BMD. It is not clear what initiates remodelling at a particular site on bone but it may be in response to paracrine factors secreted by osteocytes when subjected to mechanical stimuli. During the initial 'activation' phase, interactions between osteoblast (bone-forming) and osteoclast (bone-resorbing) precursors leads to the differentiation, migration and fusion of large multinucleated osteoclasts. Activated osteoclasts adhere closely to the mineralized bone surface. They then secrete hydrogen ions through a proton pump system, and digestive lysosomal enzymes that dissolve the protein matrix of bone at a low pH. Once resorption is complete, osteoclasts undergo programmed cell death (apoptosis) during the 'reversal' phase. Once a certain resorption depth is achieved, the final 'formation' phase begins. Osteoblasts invade the area, lay down new matrix and begin mineralization. The activities of the two cell types, osteoclasts and osteoblasts, are thus tightly coupled. The activation–resorption–formation sequence normally lasts about 200 days. However, when there is either enhanced osteoclastic activity or decreased osteoblastic activity each resorption cavity is only partially filled, resulting in net bone loss. Reconstruction of the bone remodelling sequence in uncontrolled hyperthyroid patients indicates that the duration of remodelling is significantly reduced with a negative balance between resorption and formation, resulting in a net loss of about 10% of mineralized bone per cycle, with ultimately a reduction in BMD and a predisposition to fractures (Eriksen et al., 1985). Calcium kinetic studies in hyperthyroid patients have shown that intestinal calcium and phosphate absorption is reduced, while urinary, faecal and dermal calcium excretion is increased (Mosekilde et al., 1990). Thus thyrotoxicosis is a condition of negative calcium balance and this negative balance may also contribute to the increased fracture risk. In addition, levels of biochemical markers of both bone formation [alkaline phosphatase, osteocalcin, carboxyterminal propeptide of type 1 collagen (P1NP)] and bone resorption [pyridinoline and deoxypyridinoline collagen cross-links, hydroxyproline, carboxyterminal cross-linked telopeptide of type 1 collagen (CTX)] are elevated in thyrotoxicosis and generally correlate with thyroid hormone concentrations (Allain & McGregor, 1993; Miyakawa et al., 1996; Nagasaka et al., 1997). The thyroid gland synthesizes and secretes the prohormone 3,5,3′,5′-l-tetraiodothyronine (thyroxine, T4) together with a small amount of the active hormone 3,5,3′-l-triiodothyronine (T3) in response to TSH stimulation. However, most circulating T3 is generated by the iodothyronine deiodinase enzymes D1 and D2, which convert T4 to T3 by 5′ monodeiodination. A D3 deiodinase enzyme is responsible for monodeiodination of T4 and T3 at the 5 position resulting in generation of the inactive metabolites reverse T3 (rT3) and rT2. It is the relative activities of these three deiodinases, D1, D2 and D3, that determines the intracellular level of the physiologically active hormone, T3 (Bianco et al., 2002). The cellular actions of T3 are mediated by nuclear T3 receptors, which are members of the steroid receptor superfamily and function as T3 inducible transcription factors that regulate the expression of hormone-sensitive target genes (Lazar, 1993). The T3 receptors (TRs) α and β are encoded by two separate genes, THRA and THRB, located on chromosomes 17 and 3 respectively in humans. At physiological levels, T4 is inactive because it possesses 100-fold lower affinity than T3 for binding to the TR and does not enter the cell nucleus at high enough concentrations to occupy the ligand binding site of the TR (Bianco et al., 2002). Within the nucleus, TRs bind as heterodimers with the retinoid X receptor (RXR) to specific hormone response elements located in the promoter regions of target genes (Zhang & Lazar, 2000; Fig. 1). In the absence of T3 unliganded RXR-TR heterodimers mediate transcriptional repression. Binding of T3 leads to the dissociation of co-repressors and the binding of co-activators and thyroid receptor-associated proteins, thereby promoting active thyroid responsive gene transcription. Mechanism of action of thyroid hormone. The prohormone T4 is converted to active T3 by type 1 (D1) or type 2 (D2) deiodinase. Type 3 (D3) deiodinase inactivates T4 and T3. Thyroid hormone receptors (TR) preferentially form heterodimers with retinoid X receptors (RXR), but can also form homodimers. Unliganded RXR-TR heterodimers bind thyroid-response elements (TREs) and mediate transcriptional repression via a co-repressor complex (nuclear receptor co-repressor (NCoR) or silencing mediator of retinoic acid receptor and TR (SMRT) proteins), which possess histone deacetylase activity. Binding of T3 leads to the dissociation of the co-repressor complex and recruitment of a co-activator complex [steroid receptor co-activators (p160/SRCs)], possessing histone deacetylase activity. This allows chromatin remodelling. In addition, further thyroid receptor-associated proteins (TRAPs) are recruited, promoting active gene transcription. Both the THRA and THRB genes are transcribed as multiple RNA isoforms (for details of the molecular mechanism of TR action see Lazar, 1993, Harvey et al., 2002 and O'Shea & Williams, 2002). Functional TRα and TRβ proteins have been shown to be expressed in bone marrow stromal cells, osteoblasts and bone growth plate chondrocytes both in vitro and in vivo (Robson et al., 2000; Stevens et al., 2000). Data from cell and organ cultures have identified roles for T3 in the production of cytokines, growth factors, markers of bone turnover and proangiogenic factors involved in bone development and growth, bone turnover and bone maintenance (Milne et al., 1998, 2001; Siddiqi et al., 1998; Kim et al., 1999; Pereira et al., 1999; Salto et al., 2001; Stevens et al., 2003). Analysis of information gained from genetically modified mice has recently been summarized (O'Shea & Williams, 2002; Bassett et al., 2003). TRα is expressed at about 10-fold higher levels than TRβ in bone and is functionally predominant in the skeleton, though TRβ also plays a role (O'Shea et al., 2003; Stevens et al., 2003). TRα(0/0) mice, which lack all TRα isoforms but are biochemically euthyroid have growth retardation with delayed bony ossification and impaired mineralization, features that are very similar to the skeletal consequences of childhood hypothyroidism (Gauthier et al., 2001). TRβ(–/–) mice, which lack all TRβ isoforms and display thyroid hormone resistance are reported to have normal growth and no skeletal abnormalities have been identified to date (Forrest et al., 1996; Gauthier et al., 1999). Nevertheless, TRα(0/0)TRβ(–/–) have a more severe phenotype than TRα(0/0) mice indicating the ability of TRβ to partially compensate for the lack of TRα in bone (Gauthier et al., 1999). Classical thinking has always attributed the reduction in BMD associated with overt thyrotoxicosis to the high circulating levels of thyroid hormone. The concomitant suppressed TSH levels had not been considered to have any direct physiological effects on bone. Data from a recently published paper have challenged this viewpoint by suggesting a direct role for TSH in the maintenance of bone mass. A TSH receptor (TSHR–/–) knockout mouse model, in which thyroid hormone replacement was given from weaning, was generated (Abe et al., 2003). These mice have high bone turnover osteoporosis, suggesting that TSH is a negative regulator of bone turnover. This is the first evidence to suggest that TSH may have a direct effect on the skeleton but requires further exploration before it can be related to human physiology. Thus, it is unclear at this stage whether bone loss in hyperthyroidism results from thyroid hormone excess, TSH deficiency or a combination of both. In this context the role of TSH receptor stimulating antibodies in Graves' thyrotoxicosis needs to be explained. Paradoxically, it would be predicted that TSH receptor stimulation by such antibodies would mitigate against bone loss, whereas in fact, patients with Graves' disease are more at risk of bone loss and osteoporosis. The clinical effects of childhood thyroid dysfunction are well documented. Untreated congenital hypothyroidism is characterized by growth arrest, epiphyseal dysgenesis, delayed bone age and short stature (Bucher et al., 1985; Virtanen, 1988; Leger & Czernichow, 1989; Virtanen & Perheentupa, 1989; Newland et al., 1991; Chiesa et al., 1994). Early treatment with thyroxine replacement increases growth velocity, allowing children to reach their predicted adult height (Bucher et al., 1985; Chiesa et al., 1994; Dickerman & De Vries, 1997; Salerno et al., 2001). Follow-up of children with congenital hypothyroidism treated with thyroxine replacement for a mean of 8·5 years, indicates that they have normal BMD, as measured by dual-energy X-ray absorptiometry (DXA), when compared with controls (Kooh et al., 1996; Leger et al., 1997). However, adult women treated since the neonatal period for congenital hypothyroidism have been shown to have a 10% reduction in radial BMD (Demeester-Mirkine et al., 1990). No data exist on lifetime fracture risk for individuals with congenital hypothyroidism treated with long-term thyroxine replacement. Similarly, patients with juvenile acquired hypothyroidism have growth arrest, delayed bone maturation and short stature. Following thyroxine replacement, rapid catch-up growth occurs 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 (Rivkees et al., 1988). Conversely, childhood thyrotoxicosis results in accelerated growth, advanced bone age and short stature, resulting from premature closure of the epiphyseal growth plates. In severe cases, premature closure of the cranial sutures results in craniosynostosis (Segni & Gorman, 2001). Resistance to thyroid hormone (RTH) is an autosomal dominant condition of impaired tissue responsiveness to thyroid hormone caused by dominant negative mutations of the thyroid hormone receptor β (Weiss & Refetoff, 1996). The clinical presentation and skeletal phenotype of RTH is highly variable, although few patients have been studied in detail. The syndrome results in a complex mixed hyper- and hypothyroid phenotype depending on the target tissue studied. Thus an individual patient can have symptoms of both thyroid hormone deficiency and excess. Skeletal features including short stature, advanced bone age, delayed bone age, increased bone turnover, osteoporosis, fractures, craniofacial abnormalities and craniosynostosis have all been recorded. The clinical variability of this condition is thought to be related to the precise properties of the mutant TRβ and the genetic heterogeneity of the cofactors (co-activators and co-repressors) that modulate the receptor-mediated action of thyroid hormone (Weiss & Refetoff, 1999). Physiological concentrations of thyroid hormone are essential for normal growth and skeletal development. Thyroid hormones influence the formation of long bones (endochondral ossification) and flat bones (intramembranous ossification). The remainder of this review will focus on the relationships between thyroid status, BMD and fracture risk. Current knowledge regarding the effects on BMD of TSH suppressive therapy, subclinical hyperthyroidism and thyroid hormone replacement is summarized. Much of the literature in this field is heterogenous and Tables 1–3 can only give an overview of findings. Factors such as careful case–control matching, dietary calcium intake, smoking, alcohol intake, physical activity, co-existent hypoparathyroidism and variable techniques in bone are not always and between it is to the literature in to and those that an Current for the treatment of thyroid including and is or with or in to of is then given to the stimulating effects of TSH on cell The disease for patients with thyroid cancer is over that any effects of suppressive thyroxine treatment a of et al., 1997). The British Thyroid that thyroxine be given in a to TSH to in a sensitive most patients this to a of thyroxine They also suggest that the consequences of thyroxine therapy, including osteoporosis, as patients The of of for the of Thyroid that long-term thyroxine suppressive therapy may have effects on bone, including accelerated bone turnover and osteoporosis, but short of any for they suggest the of clinical and of thyroxine therapy for patients with thyroid as for those individuals in lower risk a of long-term TSH may 1 data on the effects of suppressive of thyroxine in patients treated for thyroid cancer on bone. A recent review has considered of the more of these in which information was on and as well as BMD measured at et al., 2002). of these in patients had been on long-term suppressive therapy for at 5 women and or no in BMD as a of long-term suppressive thyroxine et al., 1991; et al., et al., et al., 1994; et al., 1994; et al., et al., 1996; et al., Similarly, in the three studies that no in BMD was seen in suppressive of thyroxine et al., et al., 1996; et al., 1997). A small a reduction in BMD at the at a of per from the initial of thyroxine in women et al., while a a reduction in BMD at the but not in the or when compared with controls et al., 1991). studies including women of these two and no in BMD between patients with thyroid cancer treated with suppressive of thyroxine and controls et al., et al., 1994; et al., 1994; et al., et al., 1996; et al., 1997). a small in BMD at the distal only et al., both of TSH in all have reported decreased BMD at all measured in women receiving thyroxine et al., 1991; et al., 1993; & 1996). this from the two most in which to it is to reach a as to the of suppressive TSH therapy to reduction in BMD in The review on no in BMD occurs as a of suppressive thyroxine treatment in women or et al., 2002). The in women is and for risk factors for osteoporosis, BMD with dietary and or The studies summarized in 2 also give results with three studies an effect of suppressive thyroxine on BMD in women et al., et al., et al., and an of studies no effect et al., et al., 1993; et al., of for thyroid cancer treatment, have or no effect on the BMD of women or The in women is clear and it is that all risk factors for osteoporosis be considered in these in a lower for of BMD by also be hyperthyroidism is defined as clinical in the context of a normal T4 and T3 with a TSH below the normal in a sensitive The increases with age and although many patients have a such as overt or dysfunction to be considered & 2002). The precise and long-term of subclinical hyperthyroidism is and of the literature is to the of patients with A small of published studies have considered the effects of subclinical hyperthyroidism on bone. that women treated with for subclinical hyperthyroidism had an increase in BMD of the and 2 years whereas similar patients had a reduction of BMD et al., have been reported in patients treated with et al., 1994). A lower BMD at the and in women but not in women et al., 1993). In a BMD was to be in women with subclinical hyperthyroidism compared with controls & 1999). subclinical hyperthyroidism has no effect on the BMD of Untreated women have an increased of bone loss compared with women receive data exist on the influence of subclinical hyperthyroidism on the skeleton in from the literature evidence on the effects of thyroid hormone replacement on bone is also with of the studies the effects of thyroid hormones on BMD a mixed of including those with euthyroid and treated hyperthyroidism. of these be considered to have factors bone patients with euthyroid are by euthyroid and are then hyperthyroid by thyroxine treatment in to their patients and with hyperthyroidism have had to high circulating levels of thyroid hormone for of prior to their thyroxine replacement therapy and may have a period of catch-up with to their bone thyroxine replacement is (Mosekilde & with hypothyroidism may have a higher than normal bone prior to thyroxine therapy, which then treatment is Thyroid hormone replacement therapy is defined as a of thyroxine that will TSH the normal as measured by a sensitive TSH all those treated before the of highly sensitive TSH are treated to some are in with lower TSH or higher thyroid hormone levels than In 2 summarize the data those results down to of only those patients treated with thyroxine for either hypothyroidism or hypothyroidism in the duration of the hyperthyroid phase is to have been In the studies that only there was no effect of thyroid hormone replacement on bone et al., 1993; 1993; et al., 1994; et al., 1994; et al., 1997). studies only women and that thyroid hormone replacement had an effect on bone, although the and between the studies & 1991; et al., 1994). small as well as and women and in BMD at all measured 1 of treatment et al., 1990). This also a case–control in which no effect on BMD was seen in women had been treated with thyroid hormone for at 2 years, suggesting that the bone loss over the first of treatment in the be a the of the bone remodelling from an of to 200 days. studies on adult bone from patients receiving thyroid hormone replacement for have an increase in bone resorption with loss of both and bone for to treatment is et al., A that also both and women no effect of thyroid hormone replacement on BMD in patients with hypothyroidism et al., A of not in 2 for discussed a of women and from the of no effects of thyroid hormone replacement on bone et al., have in BMD at the not the or the not the in women on replacement therapy et al., 1988; et al., 1991). no in in either or women thyroxine replacement compared with controls but that these women had lower a which was more in women et al., 2000). thyroid hormone replacement has no effect on the BMD of replacement therapy may have a effect on the BMD of but whether this is more at the or the is unclear from The major of many of the studies the relationship between thyroid disease of thyroxine replacement and its effects on bone is to on and duration of the clinical of fracture has not been reduction in BMD has been shown to correlate well with fracture risk it is a that information on bone et al., 1996). It is also to that although BMD can fracture it is only of a of risk factors for fracture and those individuals will have a fracture et al., 1991; et al., et al., studies are with to data on of thyroxine replacement and duration of and the influence of treatment or no published has the of subclinical hyperthyroidism and fracture risk. However, a of recently published studies have to the of the of thyroid disease on fracture risk summarize with to the of thyroid hormone, studies have shown no in fracture risk in those individuals treated with thyroid hormone compared to those not treated et al., et al., 1993; et al., et al., Bauer et al., 2001; et al., 2003). of these studies women has shown that thyroid hormone fracture of risk in but not women et al., 2002). A in the an increased risk of fracture with the of thyroid in both risk and women et al., 2001). are two of the whether or not there is an between hyperthyroidism per and fracture risk. by whether a of hyperthyroidism is in associated with an increased fracture risk at the from whether a fracture is associated with a history of hyperthyroidism is in the small of published the of studies in women with few including either women or increased fracture risk in with a history of hyperthyroidism has been in studies in as & et al., et al., et al., vertebrae et al., et al., or et al., 1996). published was with no in fracture or between women with hyperthyroidism and those et al., 1993). In this women with hyperthyroidism to have their first fracture earlier in than those of the studies used to fractures. In those studies it was thyroxine replacement was not associated with an increased risk of fracture for a history of hyperthyroidism et al., 1993; et al., et al., A of identified patients with hyperthyroidism with and with over a period and for prior to and to et al., 2002). Each patient was compared with three and controls and information on fracture incidence was from the as that used to the A though increase in fracture risk was seen in patients with a before only This increase was for by fractures of the and In patients with had no in fracture although there was an increase in fractures both before and and fractures risk factors for Thyroid as a treatment for both and reduced the risk of fracture and for and The mechanism this is not as only patients with had a higher BMD but it may to of the hyperthyroid with reduced to high circulating thyroid hormone The have recently published a in which a was used to BMD from published studies a fracture risk & 2003). this the relative risk for both and fractures was increased in patients with hyperthyroidism. However, this increased fracture risk not to normal a to this a large of had shown a increased to in patients treated with for hyperthyroidism et al., in and in women both in have the influence of a on fracture risk et al., 1997; et al., 2000). It is that may be associated with bone loss via a of including of thyroxine prior to replacement of thyroxine of bone resorption to deficiency or a combination of However, there was no increase in fracture risk seen for either or women for and for Both had though increases in fracture while the women also had increases in and fractures. These results with the reduction in et al., or lack of et al., with fracture risk seen thyroid in two studies an between a history of hyperthyroidism prior to thyroxine replacement and fracture risk. A is that by Bauer et as it an increased risk of fracture associated with low levels of TSH in a large of women shown to have similar BMD to reported a history of hyperthyroidism as well as women thyroid hormone had similar of bone loss to those not hyperthyroidism or thyroid hormone. Thyroid hormone per was not associated with an increased risk of fracture, while a history of hyperthyroidism was associated with a higher risk of fracture but no increase in either or fractures. These data that the increased fracture risk may be of in BMD and suggest that to fractures in The from this is that the high turnover bone loss seen in hyperthyroidism may in bone microarchitectural and increased that requires more sensitive techniques for studies to fractures and bone will to this point fracture risk is to be in thyroid In suppressed TSH from is associated with an increased risk of However, thyroid hormone per does not increase fracture risk in although it may have an effect in A history of hyperthyroidism to be associated with an increased risk of fracture which may to the duration of to thyroid data suggest that an increase in fracture risk is not associated with a reduction in BMD. In of the that the predominant thyroid hormone receptor in bone is it to that thyroxine with a of TRβ bone and osteoporosis. a has been synthesized and shown to have no effect on BMD in adult treated with suppressive for 2 compared with controls treated with suppressive does of T3 et al., 1998; et al., 2001; et al., 2003). In addition, does not have the direct effects of thyroxine as bone, is a tissue et al., 2000). has similar effects to T3 in and TSH but to have effects to T3 in some including and tissue et al., 2001; et al., 2002). Thus, further needs to be in the and of such in thyroxine or T3 This an for with the for in long-term thyroid hormone therapy with to effects on and bone.