Michael C. Sheppard
Neil J.L. Gittoes
Over a century ago a young woman who died from thyrotoxicosis was noted to have bones that looked “worm-eaten.” The first systematic study of the clinical effects of thyrotoxicosis on the skeleton was published in 1972 (1). Among 187 patients with thyrotoxicosis, 15 (8%) had skeletal symptoms, and of these 80% were over 50 years old, and two thirds had a fracture or severe bone pain. Radiographic studies demonstrated generalized osteoporosis, and vertebral compression fractures were common. Since then, symptomatic osteoporosis and fractures resulting from thyrotoxicosis have become rare, as a result of earlier diagnosis and the widespread availability of effective treatments for thyrotoxicosis.
Although there is general acceptance that thyrotoxicosis increases bone turnover in general and bone resorption in particular, leading to osteopenia and osteoporosis, considerable controversy remains surrounding the relationship between thyrotoxicosis and bone, particularly in terms of fracture risk (Table 40.1).
TABLE 40.1. EFFECTS OF THYROID HORMONE EXCESS ON THE SKELETON
Decreased bone mineral density (osteopenia and osteoporosis)
Increased risk of hip and vertebral fractures
Increased mortality due to hip fracture
Exogenous thyroid hormone therapy
No increase in fracture risk with thyroid hormone therapy per se
TSH-suppressive therapy with thyroid hormone is associated with reduced bone mineral density in postmenopausal women
TSH suppressive therapy is associated with an increased risk of hip and vertebral fracture
THYROID HORMONE ACTIONS ON THE SKELETON
The skeleton is a metabolically active tissue in which mineralized bone is continuously remodeled by the coordinated recruitment of osteoclasts and osteoblasts that respectively resorb and form new bone. These processes are regulated by autocrine, paracrine, and endocrine pathways. Steroid hormones, particularly glucocorticoids (2), estrogens (3), androgens (3), and vitamin D (4), are particularly important regulators of bone metabolism. The effects of thyroid hormone on bone metabolism are perhaps less well characterized than are those of other hormones, but it is clear that perturbations in thyroid status have important effects on skeletal development, linear growth, and maintenance of normal bone mass.
BONE REMODELING IN THYROTOXICOSIS
In adults, the mechanical integrity of the skeleton is maintained by bone remodeling. Normally, recruitment and activation of osteoclasts and osteoblasts are tightly coupled (Fig. 40.1), resulting in maintenance of bone mass and strength. Osteoclasts initiate excavation of an area of bone; osteoblasts then invade the site to lay down new matrix that in turn is mineralized to form new bone. The activation-resorption-formation sequence occurs in discrete bone-remodeling units. In thyrotoxicosis, the processes of bone resorption, matrix deposition, and mineralization are accelerated and the activation frequency (rate at which sites undergo remodeling) is increased. Studies in vitro have demonstrated that thyroid hormone can stimulate bone resorption within a few days (5). Osteoclast and osteoblast activities are both increased (albeit disproportionately), and the duration of the remodeling cycle is reduced by approximately 50%. The uncoupling of osteoclast-osteoblast activation leads to an increase in the ratio of bone surface undergoing resorption to that undergoing formation. The net result is loss of bone, amounting to approximately 10% of mineralized bone per cycle in severe thyrotoxicosis (6,7,8,9).
FIGURE 40.1. Schematic representation of the phases of bone remodeling.
In keeping with increased activity of both osteoclasts and osteoblasts, serum and urinary biochemical markers of bone turnover are high in thyrotoxicosis. They include markers of both bone formation (serum alkaline phosphatase and osteocalcin) and bone resorption (urinary excretion of pyridinoline and deoxypyridinoline cross-links and hydroxyproline), and the values are correlated with disease severity (10,11,12,13).
In addition to its direct effects on osteoclast-osteoblast cell function, thyrotoxicosis results in a negative calcium balance. Urinary calcium excretion is increased. Intestinal calcium absorption is decreased, and therefore fecal calcium excretion is increased. The increase in bone resorption raises serum calcium concentrations, sometimes enough to cause hypercalcemia. Years ago hypercalcemia was reported in up to 20% of patients with thyrotoxicosis, but the frequency is much lower now. Any increase in serum calcium concentration inhibits parathyroid hormone secretion, thus accounting, at least in part, for the increase in urinary calcium excretion. Another consequence of decreased parathyroid hormone secretion is reduced renal conversion of 25-hydroxyvitamin D (calcidiol) to 1,25 dihydroxyvitamin D (calcitriol). Reduced activation of vitamin D is exacerbated by increased metabolic clearance of vitamin D and its metabolites. Normal calcium homeostasis and parathyroid hormone secretion are restored after treatment for thyrotoxicosis. Administration of thyroid hormone to normal subjects results in similar changes in calcium homeostasis, with a prompt increase in both urinary and fecal calcium excretion.
The skeletal changes differ somewhat in children with thyrotoxicosis. In them, linear growth and bone age tend to be accelerated, and premature closure of growth plates and cranial sutures can occur in children with severe thyrotoxicosis (Chapter 76).
MECHANISMS OF THYROID HORMONE ACTION IN BONE
Understanding of the cellular and molecular mechanisms of thyroid hormone action in bone is incomplete; what is known has been recently and comprehensively reviewed (14). Thyroid hormone receptor (TR) expression and function have been characterized in bone cells; the α1, α2, and β1 isoforms of the receptor are present in osteoblasts (15,16,17,18,19,20) and some chondrocytes (21,22) (Chapter 8). However, the results of studies of thyroid hormone effects in osteoblasts are conflicting, seemingly dependent on variables such as species, cell line/primary culture, and state of differentiation. Overall, thyroid hormone appears to stimulate osteoblast differentiation and activity, and increase synthesis of type 1 collagen, alkaline phosphatase (23), osteocalcin (24,25,26), and receptor activator of nuclear factor κB ligand (RANKL, a key molecule in osteoclast function) (27). Furthermore, thyroid hormone potentiates osteoblast responses to parathyroid hormone by increasing the expression of parathyroid hormone receptors (28). These effects of thyroid hormone appear to be mediated both directly and indirectly via other signaling pathways, such as fibroblast growth factor receptor-1 (29). Some of the effects of thyroid hormone on bone are extremely rapid and involve mobilization of intracellular calcium stores, suggesting that the hormone has nongenomic, TR-independent actions (30).
Although thyroid hormone stimulates osteoclastic bone resorption (the predominant mechanism responsible for reduced bone mineral density in patients with thyrotoxicosis), this effect is mediated indirectly via thyroid hormone–responsive osteoblasts (31,32); isolated osteoclasts alone cannot resorb bone (33). Osteoblast-derived signals, such as interleukin-6, prostaglandins, and RANKL (27), induce recruitment and differentiation of osteoclast progenitor cells or increase the activity of mature osteoclasts to effect osteoclastic bone resorption.
An important determinant of thyroid hormone action is prereceptor regulation of ligand availability (i.e., iodothyronine deiodinase function), although this is a poorly understood phenomenon in bone (27,34) (Chapter 7). Type 2 iodothyronine deiodinase (D2) has been identified in osteoblasts (27), and D2 knockout mice have a mild transient period of growth retardation that curiously occurs only in males (35). D3 knockout mice develop severe progressive growth restriction soon after birth (36). It is likely that deiodinase function plays a critical role in determining the availability of triiodothyronine (T3) and therefore its action in bone.
Autocrine effects mediated by thyroid hormone are also likely to be involved in regulation of bone turnover. Thyroid hormone stimulates the production of insulin-like growth factor-1 (IGF-1) in rat osteoblasts in vitro (37) and increases IGF-1 messenger RNA (mRNA) in mouse osteoblasts (38). IGF-1 in turn increases bone formation (39). Thyroid hormone increases IGF-1 mRNA in cultured vertebral, but not femoral, bone marrow cells (40), suggesting skeletal site-dependent differences in the in vitro responses of cells of osteoblastic lineage to thyroid hormone. Furthermore, thyroid hormone stimulates the production of interleukins in human bone marrow cultures (41,42); these cytokines may be additional mediators of thyroid hormone–induced bone loss.
BONE MINERAL DENSITY, FRACTURES, AND THYROTOXICOSIS
Many studies have reported reduced bone mineral density in patients with thyrotoxicosis. In addition, in some studies thyrotoxicosis was associated with an increase in risk for hip and spine fracture (43,44,45,46,47,48). A 2003 meta-analysis examined changes in bone mineral density and fracture risk after treatment for thyrotoxicosis (49). Using the terms hyperthyroidism, bone mineral density, and fracture, 289 references were retrieved; 20 references describing bone mineral density (902 patients) and 5 describing fracture risk (62) patients and control subjects) were included in the analysis. The bone mineral density of the spine and hip were significantly lower than normal in patients with thyrotoxicosis before treatment. After treatment, bone mineral density increased significantly, and it was normal in those patients studied more than 1 year after diagnosis and initiation of therapy. Hip fracture risk in patients with previous thyrotoxicosis increased significantly with age, as compared with normal subjects (pooled risk estimate risk for hip fracture after diagnosis 1.6). A direct comparison of bone mineral density in patients treated with an antithyroid drug and those treated with radioiodine revealed no difference between the groups, but the groups differed in age and time after treatment. The hip fracture risk after diagnosis predicted from studies of bone mineral density was close to that observed in clinical studies comparing fracture risk in patients with thyrotoxicosis with normal subjects.
In sum, this analysis demonstrated that bone mineral density is decreased and fracture risk is increased in untreated patients with thyrotoxicosis. Antithyroid treatment alone, in the absence of any antiosteoporosis treatment, results in restoration of normal bone density. The increasing risk with age indicates that thyrotoxicosis augments age-related bone loss. These observations are consistent with previous reports that bone loss is greater in postmenopausal than premenopausal women with thyrotoxicosis (50,51).
With respect to fracture risk, a case control study of 116 postmenopausal women with hip fracture and 402 postmenopausal control women in Germany reported an odds ratio for thyrotoxicosis (present and past) among the women with hip fracture of 2.5 (48). Although screening for thyroid disease in elderly patients is not recommended by most authorities, the approximate 20% prevalence of thyroid disorders in this sample suggests the need for a high index of suspicion for thyroid disease in women who have fractures. In this study thyroxine (T4) therapy was not a risk for hip fracture (odds ratio 0.67).
In another study, potential risk factors for hip fracture were assessed in 9,516 white women 65 years of age or older; 12% were taking thyroid hormone, and 9% had a history of thyrotoxicosis (43). These women were then followed for an average of 4.1 years to determine the frequency of hip fracture, validated by review of x-ray films. During the follow-up period 192 women had a first hip fracture not due to motor vehicle accidents. Independent risk factors for hip fracture included previous thyrotoxicosis, a maternal history of hip fracture, previous fractures of any type after the age of 50 years, and treatment with long-acting benzodiazepine or anticonvulsant drugs. A history of thyrotoxicosis independently increased the risk for hip fracture (relative risk 1.8), even after adjusting for femoral neck bone density. In this study, reduced bone mass did not account for the strong association between previous thyrotoxicosis and the risk for hip fracture, suggesting that thyrotoxicosis may cause long-lasting impairment of bone strength not detected by densitometry, or long-lasting muscle weakness that increases susceptibility to falls. Women taking thyroid hormone also appeared to have an increased risk for fracture; current thyroid hormone therapy was significantly associated with hip fracture (relative risk 1.6). However, current thyroid hormone therapy was not associated with the risk for hip fracture after adjustment for a history of thyrotoxicosis, which was reported by 36% of those women who were taking thyroid hormone.
In contrast, in a study of 300 postmenopausal white women, there was no difference in the frequency of a history of hip, vertebral, or forearm fracture in the 160 women who had a history of thyroid disease and the 140 women with no history of thyroid disease (52). In this cohort, 37 women (23%) with thyroid disease and 45 women (32%) without thyroid disease had a history of fracture. There were no differences between these groups in the number or type of fractures. Also, the duration of thyroid disease or therapy or dose of thyroid hormone did not affect fracture occurrence, although women with a history of thyrotoxicosis had their first fracture slightly earlier than women without thyroid disease.
A major study from Denmark reinforced these observations and clarified the risks. The study subjects consisted of 617 consecutive patients with toxic nodular goiter or diffuse toxic goiter (Graves' disease) treated between 1991 and 1997 (46). For each patient, an age- and sex-matched control subject was drawn from a random sample of the general population. Within the 5 years before the diagnosis of thyrotoxicosis there was no increase in fracture among the patients as compared with the controls. After diagnosis there was a significantly increased risk for fracture (relative risk 1.7), especially in patients over 50 years of age (relative risk 2.2). The sites of increased fracture were the spine and forearm, but not the femur, including the femoral neck. The fracture rates were similar in the patients with diffuse toxic goiter and those with toxic nodular goiter. There was no association between baseline serum T4 or T3concentrations and subsequent fracture risk, suggesting that it may be the duration rather than the severity of the thyrotoxicosis that determines the detrimental effect on bone. Where this study conflicts with others is the absence of an increased frequency of hip fracture. Because the fracture rates in the control subjects and among the patients before the diagnosis of thyrotoxicosis were similar to the rate in the general population in Denmark, it seems unlikely that overreporting of fractures biased the results.
An unexpected finding of this study (46) was that an increase in fracture occurred only in patients who had been treated with radioiodine alone, but not those treated with radioiodine and methimazole or those treated with methimazole alone. The observation of an increase in fracture after radioiodine therapy, even after adjustment for age and other risk factors, agrees with the findings of a study published over 30 years ago (44). In the latter study, there was an increase in fracture in patients treated with radioiodine, but not those treated with either an antithyroid drug or thyroidectomy. It seems unlikely that radioiodine itself has an adverse skeletal effect. More likely, the difference was due to the older age of patients treated with radioiodine or slower correction of thyrotoxicosis by this treatment.
A contrasting study was reported from Malmo, Sweden (53). In this study of 333 patients who were treated for thyrotoxicosis for the first time during the 5-year period 1970 to 1974 and 618 age- and sex-matched control subjects, there was no difference in the 20-year frequency of fracture in the two groups. The size and design of this study did not allow, however, for analysis of the effect of duration of thyrotoxicosis or type of antithyroid treatment.
The close relationship between observed fracture risk and fracture risk based on the results of bone densitometry in patients with thyrotoxicosis, particularly as identified in the meta-analysis (49), leads to the conclusion that most of the changes in fracture risk are related to changes in bone mineral density. This conclusion is supported by the clear evidence that the decreased bone density associated with thyrotoxicosis is reversible after effective treatment (49,54,55,56,57,58,59) (Fig. 40.2). However, it is important to remember that fracture risk may also be increased as a result of decreased muscle strength (myopathy) and hyperactivity that occur in some patients with thyrotoxicosis (46).
FIGURE 40.2. Mean (±SD) change in bone mineral density (z-score) in the lumbar spine and femoral neck before (week 0) and 1 year (week 52) after initiation of treatment in 17 patients with thyrotoxicosis. *p < 0.01, as compared with week 0. (From Siddiqi A, Burrin JM, Noonan K, et al. A longitudinal study of markers of bone turnover in Graves' disease and their value in predicting bone mineral density. J Clin Endocrinol Metab 1997; 82:753, with permission.)
MORTALITY AND FRACTURES
The relationship between thyrotoxicosis and mortality was examined in a population-based study in the United Kingdom with a long follow-up period (60). Among 7, patients with thyrotoxicosis treated with radioiodine between 1950 and 1989, there was an increase in all-cause mortality, particularly due to cardiovascular and cerebrovascular disease, as compared with the general population (Chapter 77). In addition, there was an increase in mortality due to fractures of the femur (26 excess deaths; standardized mortality ratio 2.9). The risk for death due to fracture of the femur was limited to patients at least 59 years of age at the time of treatment, but it was not significantly associated with time after treatment. The influence of postradioiodine hypothyroidism or its treatment with T4 on mortality in this cohort is not known.
EFFECTS OF EXOGENOUS THYROID HORMONE ON BONE MINERAL DENSITY AND FRACTURE RATES
While overt thyrotoxicosis is associated with osteopenia and sometimes osteoporosis, the effect of subclinical thyrotoxicosis [low serum thyrotropin (TSH) but normal serum T4 and T3 concentrations] on the skeleton is less clear (Chapter 77 and 79). This is most often caused by T4 therapy, even when it is prescribed as replacement therapy (61,62). In some, but not all, studies, patients taking T4 in doses sufficient to cause subclinical thyrotoxicosis have had low bone density.
In the late 1980s and early 1990s, several studies revealed low bone density at multiple sites in patients, mostly women, receiving prolonged T4 therapy who had low serum TSH concentrations (63,64,65,66,67,68,69,70). These studies were confounded by the inclusion of women who had previously had thyrotoxicosis and women of varying age and menopausal status. The results of subsequent cross-sectional and prospective studies of premenopausal women who had never had thyrotoxicosis and were taking TSH-suppressive doses of T4 were contradictory; some revealed low bone density at one or more sites (64,65,71,72,73), whereas others did not (13,70,74,75,76,77,78). Similarly, in postmenopausal women, TSH-suppressive doses of T4 have been reported to decrease (63,64,65,66,69,70,78) or have no effect (74,77,79,80) on bone mineral density. Many of these studies involved small numbers of women, most were cross-sectional, and there were variations in the doses of T4 (and therefore the degree of TSH suppression), the extent to which TSH secretion was suppressed during the sometimes long follow-up period, and the extent to which the patients were matched with control subjects.
In a meta-analysis of 13 cross-sectional studies in which bone mineral density was measured in the distal forearm, femoral neck, or lumbar spine in T4-treated women with low serum TSH concentrations and control women, there was no difference in bone density in the T4-treated and control premenopausal women, but among postmenopausal women those taking T4 had lower bone density (81). The rate of excess bone loss in these women was estimated to be approximately 1% per year after 10 years (p < 0.007). The observed changes were distributed equally throughout the skeleton. The researchers concluded that suppressive T4 thyroxine therapy caused significant bone loss in postmenopausal women, but not in premenopausal women.
A further meta-analysis of all published controlled cross-sectional studies between 1982 and 1984 (41 studies including approximately 1,250 patients) was performed concerning the impact of thyroid hormone therapy on bone mineral density (82). Women who were receiving estrogen therapy or who had a history of thyrotoxicosis were excluded, as were those with postoperative hypoparathyroidism. T4 suppressive therapy was associated with significant bone loss at all sites, including lumbar spine and femoral neck, in postmenopausal women (but not in premenopausal women). Somewhat surprisingly, T4 replacement therapy was associated with bone loss in premenopausal women (spine and hip), but not in postmenopausal women. The authors of this meta-analysis came to the same conclusion as above, namely that overtreatment with T4 probably contributes to the development of osteoporosis in postmenopausal women.
In a study of 1,180 patients receiving T4 replacement therapy in the United Kingdom, the rates of hip fracture were similar in patients with low serum TSH concentrations, as compared with those with normal serum TSH concentrations and with the general population (83). There was a trend toward an increased overall fracture rate in patients over 65 years of age with low serum TSH values (2.5% vs. 0.9%). However, the risk of hospitalization for fracture was approximately two times greater in persons over 65 years of age with low serum TSH concentrations.
The Study of Osteoporotic Fractures in the United States has provided important data relating to the risk for bone loss and fractures in older women with low serum TSH concentrations, many of whom were receiving T4 (79). After adjustment for age, weight, previous thyrotoxicosis, and estrogen therapy, bone loss over 4 to 6 years was similar in women with low (< 0.1 mU/L), normal (0.1–5 to 5 mU/L), and high (>5 mU/L) serum TSH values. At baseline, there were no differences in bone density of the calcaneus, spine, or femoral neck, but total hip density was 6% lower (p = 0.01) in the women with low serum TSH values. This was the first large prospective study of thyroid function and bone loss in a population-based group of postmenopausal women.
A subsequent study of the Study of Osteoporotic Fractures cohort examined the association between low serum TSH concentrations at baseline and subsequent fracture in 695 women over 65 years of age (84). During a mean follow-up period of 3.7 years, 148 women had a hip fracture, 149 women had a vertebral fracture, and 398 women had no fractures. The women with baseline serum TSH concentrations less than 0.1 mU/L, most of whom were taking thyroid hormone, had a greater than threefold increased risk for hip fracture and a fourfold increased risk for vertebral fracture, as compared with women who had normal serum TSH concentrations (0.5–5.5 mU/L).
In a similar but much larger study, the United Kingdom General Practice Research database was used to investigate the frequency of hip fracture in a large cohort of patients taking T4 (84). Among 23,183 patients (88% women) who had taken T4 for at least 1 year, 1.6% had a hip fracture, as compared with 1.4% of 92,732 control subjects (p = 0.06). Prescription of T4 did not predict fracture occurrence in women but was an independent predictor in men. Serum TSH was not measured, so whether T4 therapy was excessive is not known.
In summary, supraphysiologic doses of T4 may decrease bone density and increase fracture risk, but the effects are small and most likely to occur only in postmenopausal women and those taking sufficient T4 to decrease serum TSH concentrations to well below the normal range. In patients in whom high doses of T4 are indicated, for example, those with recurrent thyroid carcinoma, a bisphosphonate or estrogen can be given to inhibit the detrimental effects of T4 on the skeleton (85,86,87,88).
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