Cyclosporin-A (CsA) inhibits the in vitro bone-resorbing effects of cytokines. We investigated the in vivo effects of CsA on rat bone mineral metabolism. Three groups of male Sprague-Dawley rats were administered vehicle or low dose (7.5 mg/kg) or high dose (15 mg/kg) CsA for 14 and 28 days. Ionized calcium, PTH, serum bone Gla protein, blood urea nitrogen, creatinine, magnesium, and 1,25-dihydroxyvitamin D were determined serially. No significant changes in calciotropic hormones or renal function were noted. Significant bone resorption and trabecular bone loss occurred in the high dose group by day 14 and in both groups by day 28. Bone Gla protein was significantly increased within 2 weeks in both dosage groups (P less than 0.005), reflecting increased bone remodeling. CsA in vivo resulted in an unexpected and significant increase in bone remodeling, with striking bone loss. These effects are dependent on the duration and dose of CsA and appear to be mediated at a local level.