Estrogen deficiency in mammals is known to increase bone turnover and result in reduced bone mass. The bisphosphonate, 4-amino-1-hydroxybutylidene-1,1-bisphophonic acid disodium salt, alendronate (MK-217), is a potent inhibitor of bone resorption and was evaluated in this study for its ability to inhibit bone loss following ovariectomy in rats. Alendronate was administered sc in doses of 0.0, 0.056, 0.28, 1.40, and 7.0 mg P/kg/month, divided into two, four, or eight monthly subcutaneous injections for each dose, to female Sprague-Dawley rats (250-280 g) that underwent bilateral ovariectomy. Rats were sacrificed 12 weeks postovariectomy, the femora ashed, and the tibiae prepared for static and dynamic histomorphometric analyses. Femoral bone mass in vehicle-treated rats was reduced by 12% 12 weeks after ovariectomy compared to the nonovariectomized control group. In MK-217-treated rats femoral bone mass was significantly increased in a dose-dependent manner compared to either ovariectomized or nonovariectomized controls. Histomorphometric analysis showed significant increases in tibial trabecular bone volume with no decrease in osteoclast number. Doses delivered twice per month or eight times per month were equally effective in achieving the peak bone volume 12 weeks after ovariectomy. In conclusion, alendronate (MK-217) was effective in inhibiting bone loss due to estrogen deficiency in rats, and the magnitude of its effect was related primarily to the total amount of compound administered rather than the frequency of its administration.