To assess the protective effect of bisphosphonates on the biomechanical repercussion of glucocorticoid-induced osteopenia, intraperitoneal doses of 1 or 10 mg/kg/d of disodium etidronate or 1 or 50 mg/kg/day of pamidronate were given to groups of 6 growing rats simultaneously receiving subcutaneous doses of 4.8 mg/kg/day of betamethasone for 20 days. Betamethasone impaired strength and stiffness of femur diaphyses through a reduction of geometric properties, abnormally enhancing bone ability to absorb energy. Both bisphosphonates partially prevented betamethasone effects on diaphyseal stiffness (but not strength) through positive, dose-related effects on material modulus of elasticity and slighter improvements in diaphyseal geometry, avoiding the enhancement of energy-absorbing ability and the subsequent tendency to production of comminute fractures. These results and others obtained treating normal rats with (pamidronate) APD suggest that the sign of bisphosphonate effects on bone biomechanics may depend not only on the type of compound but also on eventual interactions with concomitant treatments.