Graves’ Disease and the Manifestations of Thyrotoxicosis
DeGroot LJ.
ncbi.nlm.nih.gov/books/NBK2...
SKELETON AND CALCIUM METABOLISM
Roentgenographic examination of the bones frequently discloses evidence of decalcification. Microdensitometry demonstrates this condition at all ages and in both sexes [299-301]. Patients with even mild increases in thyroid hormone lose bone mass [302], especially if postmenopausal and not receiving estrogen therapy. Those with a history of thyrotoxicosis extending over a number of years may have osteoporosis that is severe and premature9303-304. Fractures are uncommon, with the most frequent being collapsed vertebra in a chronically thyrotoxic postmenopausal woman. Skeletal mass is augmented after therapy [300-301]. Treatment restores the density in younger patients, but not usually in the elderly [300]. Although most attention has been made to the effects of thyroid hormone on bone density in women, it is not surprising to know that thyroid hormone excess also has a mild deleterious effect in males (303). A meta analysis of 289 published studies on the effect of hyperthyroidism causing bone fragility found that hyperthyroid patients had decreased bone mineral density and increased fracture risk. The bone mineral density tended to return to normal after therapy (302).
Periarthritis of the shoulder (subacromial bursitis) is occasionally associated with thyrotoxicosis. Linear bone growth may be accelerated in children. The time of epiphyseal closure may be accelerated in children, and bone age may exceed chronologic age.
Thyrotoxicosis results in an accelerated turnover of bone calcium and collagen [305-306]. TRα1, TRβ1, and TRβ2 proteins are expressed in human osteoblast cells and strongly in human bone marrow stromal cells. Endogenous receptors in these cells are functional in in vitro test systems. The specific function in vivo is unclear. As described in the section on pathology, the histologic picture of bones from the thyrotoxic patient may suggest osteitis fibrosa with increased osteoclastic activity, fibrosis, and an increased number of osteoblasts [267]. Histomorphometric evaluations with tetracycline labelling demonstrates accelerated bone resorption and formation, both in spontaneous hyperthyroidism and in women treated with excess thyroid hormone [266, 306,305]. In bone biopsy specimens the thin trabeculae of osteoporosis are seen. [267]The serum calcium level is usually normal, but may be elevated sufficiently to produce nausea and vomiting [307]and, rarely, renal damage [308, 309]. It may be made clinically evident when thyrotoxic patients become relatively immobile, for example at bed rest during illness. In contrast to what occurs in hyperparathyroidism, the hypercalcemia can usually be corrected partially or totally by the administration of glucocorticoids [310], but these have not been effective in all cases [311]. Phosphorus administration also lowers the concentration of calcium in serum and urine to normal [312]. The exchangeable calcium pool is remarkably increased [305]. Serum osteocalcin is increased in parallel with hormone levels [313]. The alkaline phosphatase level may be elevated, with a pattern showing the normal equal distribution of bone and liver isoenzymes. The changes in calcium and alkaline phosphatase correlate with serum T3 levels [314]. After therapy, the alkaline phosphatase level tends to increase, and bone isoenzyme becomes predominant, probably due to skeletal repair [314].
Fecal and urinary calcium excretion is greatly augmented, and it is remarkable that renal stones are rarely formed. This is because there is a concomitant increase in excretion of colloids that stabilize the calcium. Urinary hydroxyproline and pyridium cross-link excretion are increased and fall to normal after therapy [306]. Serum carboxy-terminal-1-telopeptide and serum osteocalcin levels and urinary osteocalcin secretion are increased and return to normal with therapy[268,313,315].
The serum phosphorus level is in the normal range or depressed. Renal phosphorus resorption is in the normal range or elevated [309, 310]. Although some of the observations suggest the presence of hyperparathyroidism, it is most likely that the changes actually reflect the direct metabolic effects of thyroid hormone. The parathyroid glands are histologically normal. In fact, parathyroid hormone (PTH) levels tend to be suppressed in hyperthyroidism, apparently in response to the elevated calcium levels [201]; 1,25-dihydroxyvitamin D3 levels are likewise about 40% below normal [202].
The increased fractional tubular phosphate reabsorption characteristic of hypoparathyroidism may also occur in thyrotoxicosis, probably because of reduced PTH levels. In one reported study [308], urinary phosphorus excretion was depressed after calcium infusion. Thus, a normal response was obtained rather than that found in hyperparathyroidism.
The hypercalcemia appears to be a direct manifestation of thyroid hormone action on bone metabolism [316,317], and calcium absorption from the intestine is usually reduced. [318]Both catabolism and anabolism of bone are accelerated. Negative calcium balance can sometimes be corrected by administration of calcium, an observation that perhaps should be given more attention in the management of thyrotoxic patients. Hypercalcemia can be corrected by propranolol therapy in some patients [319]. Bone turnover can be reduced by pamidronate and by calcitonin, which may therefore have a useful role in reducing thyrotoxicosis-induced osteopenia [320-321].
Two exceptional cases have been reported with coincident thyrotoxicosis and hypercalcemia with elevated PTH levels. Treatment of thyrotoxicosis eliminated all abnormalities, for reasons unknown. [322].
Calcium levels, hypo and hyperthyroidism - implications for bone health
