Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism

Thyrotoxicosis is an important but under recognized cause of osteoporosis. Recently, TSH deficiency, rather than thyroid hormone excess, has been suggested as the underlying cause. To investigate the molecular mechanism of osteoporosis in thyroid disease, we characterized the skeleton in mice lacking either thyroid hormone receptor alpha or beta (TR alpha(0/0), TR beta(-/-)). Remarkably, in the presence of normal circulating thyroid hormone and TSH concentrations, adult TR alpha(0/0) mice had osteosclerosis accompanied by reduced osteoclastic bone resorption, whereas juveniles had delayed endochondral ossification with reduced bone mineral deposition. By contrast, adult TR beta(-/-) mice with elevated TSH and thyroid hormone levels were osteoporotic with evidence of increased bone resorption, whereas juveniles had advanced ossification with increased bone mineral deposition. Analysis of T-3 target gene expression revealed skeletal hypothyroidism in TR alpha(0/0) mice, but skeletal thyrotoxicosis in TR beta(-/-) mice. These studies demonstrate that bone loss in thyrotoxicosis is independent of circulating TSH levels and mediated predominantly by TR alpha, thus identifying TR alpha as a novel drug target in the prevention and treatment of osteoporosis.