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Effect of Thyrotoxicosis on bone : A Review Article

BY : DR. GAURAV ARORA

Introduction:
Thyrotoxicosis, a clinical syndrome characterized by manifestation of excess thyroid hormone, is one of the commonly-recognised conditions of the thyroid gland. It is a hypermetabolic condition associated with elevated levels of thyroxine (T4) and/or triiodothyronine (T3).

Thyrotoxicosis causes acceleration of bone remodelling and one of the known risk factors for osteoporosis. Studies have shown that thyroid hormones have effects on bone, both in vitro and in vivo. Treatment of thyrotoxicosis leads to reversal of bone loss and metabolic alterations, and decreases the fracture risk.

Clinical presentation of thyrotoxicosis :
Thyrotoxicosis leads to an apparent increase in sympathetic nervous system symptoms.

Younger patients exhibit symptoms of more sympathetic activation, such as anxiety, hyperactivity, palpitations, sweating and tremor, while older patients have more cardiovascular symptoms, including dyspnoea, atrial fibrillation and unexplained weight loss.

One of the first reports of hyperthyroid bone disease was found in 1891 when von Recklinghausen described the "worm eaten" appearance of the long bones of a young woman who died from hyperthyroidism.

Mechanism:
Thyroid hormone directly stimulates bone resorption. This action may be mediated by a nuclear triiodothyronine (T3) receptor which has been found in rat and human osteoblast cell lines and in osteoclasts derived from an osteoclastoma . Thus, thyroid hormone may affect bone calcium metabolism either by a direct action on osteoclasts, or by acting on osteoblasts which in turn mediate osteoclastic bone resorption . Experimental studies in mice lacking either the thyroid receptor- α or -β, suggest that bone loss is mediated by thyroid receptor. Thyroid stimulating hormone (TSH) may also have a direct effect on bone formation and bone resorption, mediated via the TSH receptor on osteoblast and osteoclast precursors. However, bone loss appeared independent of TSH levels in the experiments with mice lacking specific TR isoforms.

Increased serum interleukin-6 (IL-6) concentrations in hyperthyroid patients may also play a role in thyroid hormone-stimulated bone loss. Interleukin-6 stimulates osteoclast production and may be an effector of the action of parathyroid hormone (PTH) on bone.

Biochemical markers: Biochemical markers of bone and mineral metabolism are also affected. The serum concentrations of alkaline phosphatase, osteocalcin, and osteoprotegerin , and fibroblast growth factor-23 (FGF-23) are increased in hyperthyroidism and may remain high for months after treatment, presumably due to a persistent increase in osteoblastic activity . Urinary excretion of bone collagen-derived pyridinium cross-links is increased, and falls to normal shortly after treatment

Prevention and Treatment of Reduced Bone Density:
With the introduction of antithyroid drugs and radioiodine in the 1940s, clinically apparent hyperthyroid bone disease became less common. However, bone density measurements during the last decade have demonstrated that bone loss is common in patients with overt hyperthyroidism and to a lesser extent in those with subclinical hyperthyroidism, whether caused by nodular goitre or excessive doses of thyroid hormone.

There are several measures that may prevent loss of bone density, such as titration of suppressive therapy to maintain a slightly low serum TSH concentration (e.g. between 0.1-0.5 mU/l), calcium supplementation, estrogen replacement therapy while keeping an eye on the adverse effect, and inhibitors of bone resorption (bisphosphonates or calcitonin). Guo et al, demonstrated the benefit of titrating T4 dose in patients on replacement/ suppressive dose of T4. Both lumbar and femoral bone density increased, and serum osteocalcin and urinary excretion of bone collagen-derived pyridinium cross-links decreased when the T4 dose was reduced in post-menopausal women whose initial serum TSH concentration was low.

Adequate dietary calcium intake is essential to ameliorate the adverse effects of thyroid hormone on bone. In a study of 46 post-menopausal women taking suppressive doses of T4, those taking placebo had 5 to 8 per cent reductions in bone density over a two-year period, while those given 1000 mg of calcium daily had no measurable bone loss

Conclusion
Loss of bone density and elevation of markers of bone resorption is common in thyrotoxicosis. After control of thyrotoxicosis partial recovery takes place. Treatment with anti-resorptive agents results in a better recovery. Similar phenomenon is seen during replacement therapy of patients with overt and subclinical hypothyroidism. Even euthyroid with inhibitors of bone resorption may be useful in patients with continuing bone loss. In short-term studies pamidronate reduced thyroid hormone-mediated increase in measures of bone turnover. Calcitonin reduced urinary hydroxyproline excretion and serum calcium in patients with overt patients with lower TSH values has been shown to have a lower bone density than those with high normal TSH.




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