The purpose of the present study was to compare the therapeutic effects of alendronate and alfacalcidol on the cancellous and cortical bone mass and mechanical properties in ovariectomized osteopenic rats in a head-to-head fashion. Twenty-five female Sprague-Dawley rats, 7 mo of age, were randomly divided by the stratified weight method into four groups: the sham-operated control (Sham) group and three ovariectomized groups treated with vehicle, alendronate (2.5 mg/kg, p.o., daily), or alfacalcidol (0.5 μg/kg, p.o., daily). Treatment was started 6 wk after the surgery and continued for 6 wk. At the end of the experiment, urinary deoxypyridinoline (DPD) and serum osteocalcin (OC) levels were evaluated, and cancellous and cortical bone histomorphometric analyses were performed for the proximal tibial metaphysis and tibial diaphysis, respectively. Alendronate prevented the elevation of the urinary DPD level induced by ovariectomy (OVX), and markedly decreased the serum OC level to below the value observed in the Sham group, while alfacalcidol prevented the elevation of the urinary DPD and serum OC levels induced by OVX. Alendronate increased the cancellous bone volume/total tissue volume (BV/TV) relative to the values observed in the OVX-Vehicle group by preventing the increases in the eroded surface/bone surface (ES/BS), osteoclast surface (OcS)/BS, and bone formation rate (BFR)/BS induced by OVX. However, it decreased the mineral apposition rate (MAR) in the ovariectomized osteopenic rats to below the value observed in the Sham group. It also prevented the increase in the marrow area (Ma Ar) caused by OVX. Alfacalcidol increased the BV/TV relative to the values observed in the OVX-Vehicle group by decreasing the ES/BS and OcS/BS, but maintaining the BFR/BS. The effect of alfacalcidol on the BV/TV was more pronounced than that of alendronate, despite the less pronounced suppression of OcS/BS by this drug in the ovariectomized osteopenic rats. In addition, this drug increased the cortical area (Ct Ar) and prevented the increase in the Ma Ar in the ovariectomized osteopenic rats by decreasing the endocortical ES/BS, and even increasing the endocortical BFR/BS. Furthermore, it also prevented the reduction in the maximum load of the femoral distal metaphysis in the ovariectomized osteopenic rats. Thus, the present study clearly showed that alendronate and alfacalcidol had differential therapeutic effects on the cancellous and cortical bone mass and mechanical properties in ovariectomized osteopenic rats.