Neil J.L. Gittoes
Michael C. Sheppard
Skeletal growth is the result of a complex interplay of nutritional, genetic, and hormonal factors. Linear growth occurs throughout development and the childhood years until epiphyseal fusion occurs as the result of endochondral ossification in the growth plates of long bones. Thyroid hormones are essential for normal skeletal development, as is evidenced by poor bone growth and mineralization, delayed bone age, epiphyseal dysgenesis, and immature body proportions in children with hypothyroidism (1). Thyroxine (T4) replacement therapy in these children induces a rapid phase of catch-up growth that is often incomplete because bone age advances more rapidly than height, leading to early fusion of the epiphyseal growth plates. Catch-up growth may be particularly compromised when treatment is initiated at the onset of puberty; it may be appropriate to treat pubertal children with hypothyroidism with lower doses of T4and add therapy to slow pubertal development and hence delay epiphyseal fusion. The deficit in final height correlates with the duration of untreated hypothyroidism (2). Other important endocrine regulators of skeletal development and growth are growth hormone, insulin-like growth factor 1 (IGF-1), glucocorticoids, and sex steroids, and their production may be decreased by hypothyroidism (see the section Acquired Hypothyroidism in Children in Chapter 75).
BONE REMODELING IN HYPOTHYROIDISM
Hypothyroidism decreases recruitment, maturation, and activity of bone cells, leading to decreased bone resorption and bone formation (3). Despite the decrease in bone resorption, trabecular bone volume (3) and bone mineral density (4) are comparable with those of age-matched normal subjects, presumably because there is a corresponding decrease in osteoblastic activity. Biochemical markers of bone metabolism also suggest that skeletal turnover is decreased in hypothyroidism. Serum alkaline phosphatase concentrations are often low (5,6,7,8), as are serum osteocalcin concentrations (6,8,9). Urinary excretion of hydroxyproline also is decreased in both adults and children with hypothyroidism (8,10,11,12).
The decrease in bone resorption in hypothyroidism results in a tendency for serum calcium concentrations to decline, but in fact serum calcium concentrations are usually normal (13). Serum parathyroid hormone concentrations tend to be increased (14,15), presumably as a result of the decrease in bone resorption (16). Induction of hypocalcemia acutely in patients with hypothyroidism results in a greater decline in serum calcium concentrations, and the concentrations return to normal more slowly, as compared with normal subjects (14). Urinary and fecal calcium excretion tends to be low, presumably due to increased parathyroid hormone secretion (13).
THYROID HORMONE AND INTERACTIONS WITH OTHER HORMONES IN BONE
The skeletal abnormalities of hypothyroidism may be mediated, at least in part, by decreased growth hormone and IGF-1 production and signaling (see Chapter 58). Thyroid hormone has little effect on growth in hypophysectomized rats (17,18). In contrast, growth hormone stimulates growth in thyroid hormone–deficient rats (18), and the effect of growth hormone is augmented when thyroid hormone is given with growth hormone (19,20,21). In thyroparathyroidectomized rats treated with growth hormone, T4, or both, T4 reversed the decrease in growth plate width, articular cartilage thickness, and trabecular bone volume (22). Growth hormone had no effect on the growth plate but partially restored trabecular bone volume, and growth hormone and T4 in combination increased growth plate width and trabecular bone volume more than did T4 alone. Thyroid hormone thus appears to have some direct effects on the growth plate and trabecular bone formation, independent of growth hormone (22). However, the two hormones also appear to potentiate each other's effects not only in rats (17,18,20), but also in humans (19,21).
The effects of thyroid hormone on cartilage and bone may be mediated in part through stimulation of IGF-1 production. Serum IGF-1 concentrations tend to be low in patients with hypothyroidism (23,24,25,26,27,28,29,30,31), although whether this is directly related to thyroid deficiency per se or is secondary to growth hormone deficiency remains unclear. The serum growth hormone response to stimulation in patients with hypothyroidism is diminished, suggesting that the low serum IGF-1 concentrations in hypothyroidism may be caused by decreased growth hormone secretion (32,33,34). However, thyroid hormone directly increases the expression of several components of IGF-1 signaling in bone. It increases IGF-1 mRNA expression and IGF-1 production in osteoblastic cells (35), IGF-1 receptor mRNA in chondrocytes (36), and IGF binding protein 4 in osteoblastic cells (37). This binding protein is an inhibitor of cell proliferation, and it may contribute to the antiproliferative effect of thyroid hormone in osteoblasts. Thyroid hormone also stimulates IGF-1 production in rat calvarial osteoblasts, whereas growth hormone has no effect (38). In vivo, T4 increases the production of IGF-1 and IGF binding protein 3 in patients with congenital hypothyroidism (39,40).
LESSONS FROM GENE KNOCKOUT/ KNOCK-IN STUDIES IN ANIMALS
Impaired skeletal development and growth is a key feature of untreated hypothyroidism (see sections Congenital Hypothyroidism and Acquired Hypothyroidism in Children in Chapter 75). Studies of mice in which the different isoforms of the thyroid receptor (TR) have been knocked out have provided information about the effects of thyroid hormone deficiency on bone, and at the same time have highlighted some of the complexities of thyroid hormone action (Table 62.1) (see Chapter 8). Selective inactivation of the α1 isoform of TR [with preservation of the α2 isoform, which does not bind triiodothyronine (T3)] results in normal skeletal development (41), suggesting that the β isoforms of the receptor are functional in bone in the absence of TRα1. Mice with no TRα isoforms (TRα0/0) do, however, have growth delay, defective bone mineralization, and disorganized growth plate architecture (42). TRβ0/0 mice have no developmental abnormalities in bone and cartilage (43). Combined TRα0/0/β0/0 mice have more severe growth retardation than their TRα0/0counterparts (44). Taken together, these results suggest that TRα is functionally predominant in bone, and that its deficiency can be partly compensated for by TRβ. However, skeletal development in TRα0/0/β0/0 mice is not as poor as it is in Pax8-/- mice, which have severe congenital hypothyroidism as a result of agenesis of thyroid follicular cells (see Chapter 2). Possible explanations for this difference are signaling through an as yet unidentified TR, nongenomic actions of thyroid hormone (45), and an action of unliganded TRs (46). The latter possibility is supported by the observation that Pax8-/-/TRα0/0 mice have fairly normal skeletal development (47).
TABLE 62.1. EFFECTS OF MUTATIONS IN THE GENES FOR THYROID HORMONE RECEPTORS AND THYROID DEVELOPMENT ON THE SKELETON IN MICE
Growth retardation, delayed endochondral bone formation, ossification, and mineralization; reduced bone mass and disorganized growth plate
Growth retardation. Growth plate disorganized; reduced mineralization and reduced bone mineral density
RTH + goiter
RTH + goiter
Similar to TRα-/-; no abnormalities at birth; delayed ossification and mineralization, and growth arrest and death at weaning; phenotype not rescued by T4 treatment
RTH + goiter
Growth retardation, delayed ossification, and disorganized growth plate; delayed bone age
RTH + goiter
More severe phenotype than TRα0/0; impaired ossification and delayed bone maturation
Severe growth retardation; mice die at weaning; rescued by T4treatment
Growth retardation less than Pax8-/- mice; mice survived to adulthood
Similar phenotype to Pax8-/- mice; mice die before weaning
Severe RTH + goiter
Growth retarded, advanced bone age and craniosynostosis
Mild RTH + goiter
Similar but less severe phenotype than homozygous mice
Severe growth retardation from shortly after birth, suggesting a hypothyroid bone phenotype
PV, a dominant-negative mutation of TRβ that results in severe thyroid hormone resistance in humans; RTH, resistance to thyroid hormone; T4, thyroxine; TR, thyroid hormone receptor; TRα0/0 mice, mice that express no TRα gene products; TR-/- mice, mice that express TRΔα1 and TRΔα2.
Modified from Duncan Bassett J, Williams G. The molecular actions of thyroid hormone in bone, Trends Endocrinol Metab 2003;14:356, with permission.
Gene knock-in studies, using mutant TRβ genes derived from patients with resistance to thyroid hormone, have afforded further insight into the molecular mechanisms of thyroid hormone action in bone. Many patients with resistance to thyroid hormone have short stature and epiphyseal dysgenesis, indicating that TRβ is important in mediating thyroid hormone effects on skeletal development (see Chapter 81) (48). However, knock-in mice with a TRβ mutation associated with severe resistance to thyroid hormone in humans have advanced bone age, craniosynostosis, and growth retardation (features more suggestive of thyrotoxicosis than hypothyroidism) (49). When this TRβ mutation is introduced into the TRα1 gene in mice, the result is severe growth retardation, a phenotype suggestive of hypothyroidism (50). These results further support the importance of TRα1 in mediating the effects of thyroid hormone in bone.
HYPOTHYROIDISM AND SKELETAL MATURATION
Skeletal maturation, defined as the appearance of secondary centers of ossification, depends largely on the presence of thyroid hormone (51,52,53,54,55), and the retardation of skeletal maturation in children with hypothyroidism manifests itself as a delay in ossification at epiphyseal centers (see sections Congenital Hypothyroidism and Acquired Hypothyroidism in Children in Chapter 75). When ossification does occur, the pattern is irregular and mottled, with multiple foci that coalesce to give a porous or fragmented appearance known as epiphyseal dysgenesis (56,57) (Fig. 62.1). These changes are most often noted in large cartilaginous centers, such as the head of the femur and the tarsal navicular bone. Changes in the upper lumbar vertebrae result in wedge-shaped anterior margins, which appear between the ages of 6 months and 2 years, and may lead to spondylolisthesis (58).
FIGURE 62.1. Skeletal abnormalities in children with hypothyroidism. A: Radiograph of the knee in a 2-year-old boy with delayed bone maturation due to hypothyroidism. There is no ossification of the epiphysis of the distal femur and that of the proximal tibia. Both epiphyses should be ossified by 1 month of age. B: Anteroposterior radiograph of the left hip in another child with hypothyroidism showing a fragmented, irregular (arrow) proximal femoral epiphysis.
The onset of thyroid deficiency can be determined by the presence of dysgenesis at an epiphyseal ossification site. Absence of osseous retardation excludes the diagnosis of hypothyroidism unless thyroid deficiency is of recent onset (57). Because the various epiphyseal centers begin to ossify at different times during childhood, the presence of epiphyseal dysgenesis at a particular site will date the onset of thyroid deficiency. For example, the presence of stippled epiphyses in the femoral head of a 4-year-old child indicates that thyroid deficiency began before the 9th to 12th month, the age when these centers usually ossify. Likewise, the presence of dysgenesis in centers that ossify before birth suggests prenatal hypothyroidism. The observation that epiphyseal dysgenesis occurs in infants with thyroid agenesis whose mothers had normal thyroid function during pregnancy indicates that the maternal thyroid is not able to protect the fetal skeleton fully against hypothyroidism. Normal infants born of hypothyroid mothers do not have retardation of epiphyseal ossification.
CLINICAL CONSEQUENCES OF HYPOTHYROIDISM
In patients with hypothyroidism, trabecular bone turnover is decreased and cortical thickness is increased, as determined by histomorphometry (59,60). T4therapy results in rapid increases in resorption of trabecular bone and in cortical porosity, and after therapy for 6 months in trabecular and cortical bone loss, as compared with pretreatment measurements (60).
Fracture risk and risk factors for fractures were studied in 412 patients with primary hypothyroidism seen in five Danish hospitals between 1990 and 1998 (61). Overall fracture risk was increased in the patients as compared with normal subjects (relative risk 1.6). However, the increase was limited to the 2-year period after the diagnosis of hypothyroidism; the risk before diagnosis and more than 2 years after diagnosis was similar to that in normal subjects. The increase was significant only in patients over 50 years of age and was limited to the forearm. Although serum thyrotropin (TSH) was not measured in these patients, only 8% had to have their dose of T4 reduced, suggesting that overtreatment was not a major determinant of fracture (see Chapter 40).
A further extensive study from Denmark (62) illustrated some of the risks associated with hypothyroidism, but also accentuated the difficulty in separating the effects of hypothyroidism from those of T4 therapy. All patients with autoimmune hypothyroidism diagnosed for the first time between 1983 and 1996 in Denmark were identified through the National Patient Discharge Register. Each patient was matched with three age- and sex-matched normal subjects. Among the 4,473 patients with hypothyroidism (mean age 66 years), the frequency of fracture was significantly increased both before and after diagnosis, with a peak at about the time of diagnosis (incidence rate ratio 2.2–2.4). Fractures were increased at most skeletal sites, including the spine and hip. In the small number of patients who underwent bone densitometry several years after diagnosis and treatment, the mean Z score did not deviate from that of the general population. These results indicate that fracture risk is increased in both untreated and treated hypothyroid patients. The more marked increase in fracture risk and the increased distribution of sites affected compared with the earlier study were probably due to a more reliable population-based estimate and more complete follow-up.
In patients with hypothyroidism, bone turnover is reduced and bone mass is normal or slightly increased (16). The most plausible explanation for the increase in fracture risk in untreated hypothyroid patients is reduced renewal of bone, leading to accumulation of stress fractures. An additional factor may be an increased risk for falling because of poor muscular function, poor coordination, increased sensitivity to sedating drugs, and other illnesses. After initiation of T4 therapy, an increase in bone turnover, a decrease in bone mass, and an increased risk for falls may contribute to the increased fracture risk.
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