Bisphosphonates have been shown to decrease bone turnover in a variety of high turnover states. We postulated that pamidronate (APD), a bisphosphonate, could prevent the increased bone turnover caused by thyroid hormone excess. Twenty-two male subjects were randomized to receive either placebo (group 1) or APD (30 mg, iv, daily for 2 days; group 2). Subsequently, all subjects received T3 (50 micrograms, twice daily, for 8 days). Biochemical indices of bone turnover were measured in blood and urine at baseline, after treatment with APD/placebo, and after treatment with T3. The urinary calcium/creatinine ratio (Uca/cr) fell significantly after treatment with APD, but not after treatment with placebo (group 1, 0.131 +/- 0.021; group 2, 0.040 +/- 0.013 mmol Ca/mmol Cr; P < 0.002). After treatment with T3, Uca/cr rose significantly in group 1, but not in group 2 (group 1, 0.275 +/- 0.042; group 2, 0.065 +/- 0.025 mmol Ca/mmol Cr; P < 0.05). Thus, APD prevented the rise in Uca/cr caused by treatment with T3. Similar results were obtained with urinary hydroxyproline and urinary pyridinoline cross-links. We conclude that 8 days of mild thyroid hormone excess in normal men increases bone turnover, and prior administration of APD prevents thyroid hormone-induced increases in bone resorption. APD may be useful in the prevention of thyroid hormone-induced osteopenia.