The aim of this study was to evaluate the ability of the bisphosphonate compounds clodronate and etidronate to prevent ovariectomy-induced bone changes. Three-month-old Sprague-Dawley rats were either ovariectomized (OVX) or sham-operated (SHAM) and further divided into groups receiving either vehicle (n = 30), 25 mg/kg/week of clodronate (n = 25) or 25 mg/kg/week of etidronate (n = 25). The subcutaneous drug administration was started immediately after the surgery and was continued for 12 weeks. OVX rats had accelerated bone turnover rates compared with the SHAM animals, as indicated by the results of dynamic histomorphometry and biochemical markers in serum and urine. Femoral and vertebral mineralized trabecular bone volume and maximum loads in compressions of the femoral neck and lumbar vertebra were lower after OVX compared with the SHAM operation. Both clodronate and etidronate prevented the decrease in trabecular bone volume and suppressed the increase in the bone turnover rate. Clodronate and etidronate also blocked the loss of bone strength in the femoral neck and lumbar vertebra of OVX rats. Both compounds resulted in an absence of double fluorochrome labels on the endocortical surface of the femoral metaphysis, which seemed, however, to be a dose-dependent response. Furthermore, etidronate also lowered serum osteocalcin and diaphyseal endocortical bone formation below the vehicle level both in the OVX and SHAM rats. In conclusion, clodronate and etidronate were effective in preventing the estrogen deficiency-induced decreases in trabecular bone volume and bone strength in rats. Treatment with a high dose of clodronate induced minor signs of abnormally low bone formation but not any impairment of bone mineralization, whereas both of these events were seen with high-dose etidronate administration.