The purpose of the present study was to determine the effects of supraphysiologic doses of triiodothyronine (T(3)) on skeletal metabolism, calcium balance, and the calciotropic hormones. Seven healthy, lean men were studied in an inpatient metabolic unit over a 63-day period. All volunteers received oral T(3) at doses of 50-75 microg/d. There was a prompt and sustained increase in calciuria and an overall net negative calcium balance. The pattern of changes in serum osteocalcin, urinary deoxypyridinoline (DPD)/creatinine ratio, and serum bone-specific alkaline phosphatase indicated an early increase in bone resorption followed by a late, incomplete compensatory increase in bone formation. Cumulative net calcium loss was 18.5 +/- 5.4 g over the 63-day treatment period, averaging 218.5 +/- 41.4 mg/d. This represents 0.22% +/- 0.075% of the total skeletal calcium content. The cumulative net calcium loss over the 63-day treatment period was highly correlated with the change in DPD (r = -0.95, p = 0.001). Prompt increases in corrected serum calcium values resulted in serum intact parathyroid hormone (iPTH) levels decreasing by 30.4% (p = 0.08). Bone mineral density showed no change. We conclude that T(3) accelerates bone turnover and that bone formation does not increase acutely to prevent bone loss.