Graham R. Williams

Thyroid Function within the Upper Normal Range Is Associated with Reduced Bone Mineral Density and an Increased Risk of Nonvertebral Fractures in Healthy Euthyroid Postmenopausal Women

CONTEXT The relationship between thyroid function and bone mineral density (BMD) is controversial. Existing studies are conflicting and confounded by differences in study design, small patient numbers, and sparse prospective data. OBJECTIVE We hypothesized that variation across the normal range of thyroid status in healthy postmenopausal women is associated with differences in BMD and fracture susceptibility. DESIGN The Osteoporosis and Ultrasound Study (OPUS) is a 6-yr prospective study of fracture-related factors. SETTING We studied a population-based cohort from five European cities. PARTICIPANTS A total of 2374 postmenopausal women participated. Subjects with thyroid disease and nonthyroidal illness and those receiving drugs affecting thyroid status or bone metabolism were excluded, leaving a study population of 1278 healthy euthyroid postmenopausal women. INTERVENTIONS There were no interventions. MAIN OUTCOME MEASURES We measured free T(4) (fT4) (picomoles/liter), free T(3) (fT3) (picomoles/liter), TSH (milliunits/liter), bone turnover markers, BMD, and vertebral, hip, and nonvertebral fractures. RESULTS Higher fT4 (beta = -0.091; P = 0.004) and fT3 (beta = -0.087; P = 0.005) were associated with lower BMD at the hip, and higher fT4 was associated with increasing bone loss at the hip (beta = -0.09; P = 0.015). After adjustment for age, body mass index, and BMD, the risk of nonvertebral fracture was increased by 20% (P = 0.002) and 33% (P = 0.006) in women with higher fT4 or fT3, respectively, whereas higher TSH was protective and the risk was reduced by 35% (P = 0.028). There were independent associations between fT3 and pulse rate (beta = 0.080; P = 0.006), increased grip strength (beta = 0.171; P<0.001), and better balance (beta = 0.099; P < 0.001), indicating that the relationship between thyroid status and fracture risk is complex. CONCLUSIONS Physiological variation in normal thyroid status is related to BMD and nonvertebral fracture.

Iodothyronine deiodinase enzyme activities in bone.

Euthyroid status is essential for normal skeletal development and maintenance of the adult skeleton, but the mechanisms which control supply of thyroid hormone to bone cells are poorly understood. Thyroid hormones enter target cells via monocarboxylate transporter-8 (MCT8), which provides a functional link between thyroid hormone uptake and metabolism in the regulation of T3-action but has not been investigated in bone. Most circulating active thyroid hormone (T3) is derived from outer ring deiodination of thyroxine (T4) mediated by the type 1 deiodinase enzyme (D1). The D2 isozyme regulates intra-cellular T3 supply and determines saturation of the nuclear T3-receptor (TR), whereas a third enzyme (D3) inactivates T4 and T3 to prevent hormone availability and reduce TR-saturation. The aim of this study was to determine whether MCT8 is expressed in the skeleton and whether chondrocytes, osteoblasts and osteoclasts express functional deiodinases. Gene expression was analyzed by RT-PCR and D1, D2 and D3 function by sensitive and highly specific determination of enzyme activities. MCT8 mRNA was expressed in chondrocytes, osteoblasts and osteoclasts at all stages of cell differentiation. D1 activity was undetectable in all cell types, D2 activity was only present in mature osteoblasts whereas D3 activity was evident throughout chondrocyte, osteoblast and osteoclast differentiation in primary cell cultures. These data suggest that T3 availability especially during skeletal development may be limited by D3-mediated catabolism rather than by MCT8 mediated cellular uptake or D2-dependent T3 production.

The Thyroid Hormone Receptor β‐Specific Agonist GC‐1 Selectively Affects the Bone Development of Hypothyroid Rats

We investigated the effects of GC‐1, a TRβ‐selective thyromimetic, on bone development of hypothyroid rats. Whereas T3 reverted the IGF‐I deficiency and the skeletal defects caused by hypothyroidism, GC‐1 had no effect on serum IGF‐I or on IGF‐I protein expression in the epiphyseal growth plate of the femur, but induced selective effects on bone development. Our findings indicate that T3 exerts some essential effects on bone development that are mediated by TRβ1.

Activated Invariant NKT Cells Regulate Osteoclast Development and Function

Invariant NKT (iNKT) cells modulate innate and adaptive immune responses through activation of myeloid dendritic cells and macrophages and via enhanced clonogenicity, differentiation, and egress of their shared myeloid progenitors. Because these same progenitors give rise to osteoclasts (OCs), which also mediate the egress of hematopoietic progenitors and orchestrate bone remodeling, we hypothesized that iNKT cells would extend their myeloid cell regulatory role to the development and function of OCs. In this study, we report that selective activation of iNKT cells by α-galactosylceramide causes myeloid cell egress, enhances OC progenitor and precursor development, modifies the intramedullary kinetics of mature OCs, and enhances their resorptive activity. OC progenitor activity is positively regulated by TNF-α and negatively regulated by IFN-γ, but is IL-4 and IL-17 independent. These data demonstrate a novel role of iNKT cells that couples osteoclastogenesis with myeloid cell egress in conditions of immune activation.

MELAS syndrome, diabetes and thyroid disease: the role of mitochondrial oxidative stress

The mitochondrial DNA mutation MTTL1 A3243G causes MELAS syndrome (Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like episodes). The A3243G mutation is also associated with multiple endocrinopathies such as diabetes mellitus, neuroendocrine deficiencies, hypoparathyroidism and, pertinently, hyperthyroidism. 1 We describe two case-histories of patients with the A3243G mutation who presented with thyroid disease.

Does serum TSH level have thyroid hormone independent effects on bone turnover

Hyperthyroidism-associated bone loss has been attributed to excess of thyroid hormones. Animal studies, however, suggest that TSH deficiency might affect bone turnover independently of thyroid hormones. Here, I discuss the study by Heemstra and colleagues, who assessed the relationship between serum TSH level and markers of bone turnover in patients with thyroid cancer receiving supraphysiological doses of levothyroxine. The effect of thyroid hormones could not be distinguished from that of TSH as the intact hypothalamic–pituitary–thyroid axis maintained the typical inverse relationship between thyroid hormones and TSH. The study included 27 men and 76 premenopausal women, although previous data indicate that suppressive doses of levothyroxine have no effect on BMD in such patients. Accordingly, Heemstra et al. did not identify a relationship between TSH level and BMD. Although mechanisms of thyrotoxicosis-related bone loss remain controversial, postmenopausal women with thyroid cancer who require long-term TSH suppression should be monitored carefully for osteoporosis.