Effect of clodronate treatment on established bone loss in ovariectomized rats

The ability of clodronate to prevent bone loss and weakening of bone strength was studied in adult rats with established osteopenia. Six-month-old female Sprague Dawley rats were randomized into 13 groups. One group was killed at the start of the study, nine groups were ovariectomized (ovx), and three groups sham-operated (sham). After 4 months, the ovx rats were given either clodronate or vehicle subcutaneously (s.c.), once a week for 3 or 6 months, the cumulative doses of both dosing regimens being 36, 84, and 300 mg/kg. Clodronate reduced the increase in bone turnover as evidenced by serum osteocalcin and urinary deoxypyridinoline. Cancellous bone loss was more severe in distal femur than in lumbar vertebral body already at 4 months after ovx. Cortical osteopenia of femoral middiaphysis was significant at 7 and 10 months after operation and was in accordance with the impaired bending strength of the femoral shaft. In the tibia, the bending strength was, by contrast, increased at each timepoint after ovx. In distal femur, higher values of cancellous bone volume (BV/TV) were found after 6 months of clodronate treatment than in ovx/vehicle-treated rats. In lumbar vertebrae, only the lowest dose of clodronate slightly counteracted the ovx-induced further decrease in BV/TV, but reduced, at all dosages, the impairment of lumbar vertebral compression strength. The maximum load of femoral neck did not differ between vehicle-treated ovx and sham groups after clodronate treatment, but clodronate reduced the weakening of femoral shaft. A further increase in the bending strength of the tibia was found after clodronate treatment. There was a positive correlation between bending strength and ash weight in both the tibia and the femur. Histomorphometry further showed that long-term use of clodronate does not impair bone mineralization or affect modeling-dependent bone formation. In conclusion, clodronate treatment clearly slows down the progress of bone loss and prevents further weakening of bone strength in femoral shaft and vertebrae, even though it cannot completely reverse the effects of ovariectomy-induced changes in established osteopenia.