FDA Guidelines and animal models for osteoporosis.

The recent FDA Guidelines For Preclinical and Clinical Evaluation of Agents Used in the Treatment or Prevention of Postmenopausal Osteoporosis (1994) delineate specific preclinical animal models to demonstrate the efficacy and safety of new, potential agents for osteoporosis therapy. The Guidelines recommend that agents be evaluated in two animal species, including the ovariectomized (OVX) rat and in a second non-rodent model. We have performed a series of studies to determine whether the recommended OVX rat models, endpoints, and study design adequately address the efficacy and safety of therapeutic agents for the treatment or prevention of osteoporosis. Our study results indicate that the rat OVX model mimics postmenopausal cancellous bone loss when examined over relatively short periods of time. These data illustrate that cancellous bone turnover increases following OVX and this increased bone turnover produces bone loss. Estrogen completely blocks the activation of bone turnover and bone loss. Thus, our data suggest that the rat OVX model in the proximal tibia, distal femur, and lumbar vertebrae mimics conditions in the postmenopausal woman and is suitable for the evaluation of potential therapeutic agents for the prevention of osteoporosis. However, when the duration of the studies extends to 12 months as suggested by the Guidelines, the indices of cancellous bone turnover return to the value of sham controls, although the trabecular bone volume remains lower than that of sham controls in OVX rats. Therefore, it is difficult to determine the effects of potential therapeutic agents on the bone turnover in estrogen deficient conditions.(ABSTRACT TRUNCATED AT 250 WORDS)