Post-transplantation bone disease is an increasingly recognized clinical entity whose etiology is multifactorial. The immunosuppressant agent cyclosporine-A (CsA) has repeatedly been shown experimentally to induce a high-turnover osteopenic state. Alendronate (Alen.) is a new generation bisphosphonate having far greater antiresorptive potency than previous bisphosphonates. It inhibits osteoclast resorption in vitro and in vivo without adversely affecting bone mineralization. This study was designed to investigate whether alendronate could prevent CsA-induced osteopenia in the rat. Forty-eight 8-month-old male Sprague Dawley rats were randomized into four groups to receive the following for 28 days: (1) CsA vehicle (veh.) p.o. daily and alendronate vehicle subcutaneously (s.c.) twice/week, (2) CsA 15 mg/kg p.o. daily and Alen. veh. s.c. twice/week, (3) Alen. 70 micrograms/kg s.c. twice/ week and CsA veh. p.o. daily, and (4) CsA 15 mg/kg p.o. daily and Alen. 70 micrograms/kg s.c. twice/week. Rats were weighed and bled and serum was assayed serially for calcium, PTH, 1,25(OH)2vit.D, and osteocalcin. Tibiae were removed following sacrifice on day 28, after double demeclocycline and calcein labeling, for histomorphometric analysis. Treated groups were compared to the vehicle-treated control. We confirmed previous findings that CsA produces elevated 1,25(OH)2 vitamin D and serum osteocalcin levels. Alendronate treatment by itself decreased osteocalcin by day 28 and resulted in a marginal decrease in serum total calcium on day 14. The histomorphometry findings reconfirmed that the administration of CsA induces a state of high-turnover osteopenia. Alendronate prevented CsA's adverse effects, particularly in maintaining trabecular bone volume, presumably by decreasing bone remodeling. Alendronate would seem to hold therapeutic promise in post-transplantation bone disease.