FDA GUIDELINES AND ANIMAL-MODELS FOR OSTEOPOROSIS

The recent FDA Guidelines For Preclinical and Clinical Evaluation of A gents Used in the Treatment or Prevention of Postmenopausal Osteoporos is (1994) delineate specific preclinical animal models to demonstrate the efficacy and safety of new, potential agents for osteoporosis ther apy. The Guidelines recommend that agents be evaluated in two animal s pecies, including the ovariectomized (OVX) rat and in a second non-rod ent 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 treatme nt 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 can cellous 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 O VX model in the proximal tibia, distal femur, and lumbar vertebrae mim ics conditions in the postmenopausal woman and is suitable for the eva luation of potential therapeutic agents for the prevention of osteopor osis. However, when the duration of the studies extends to 12 months a s suggested by the Guidelines, the indices of cancellous bone turnover return to the value of sham controls, although the trabecular bone vo lume remains lower than that of sham controls in OVX rats. Therefore, it is difficult to determine the effects of potential therapeutic agen ts on the bone turnover in estrogen deficient conditions. Further, in long term OVX, the effects of increased skeletal size on the cancellou s and cortical bone compartments of the skeleton become less clear. Th e effect that the increased bone area has on biomechanical strength pa rameters remains to be determined. Because bone strength and quality a re two key endpoints to the animal pharmacology studies, it is essenti al to determine how the increase in skeletal size impacts the bone str ength measurements. It therefore may be reasonable to restrict studies of potential therapeutic agents in OVX rats to a duration of less tha n 12 months and probably no more than 6 months. Combined with previous ly published data, our preclinical data on OVX rat model suggest that the proposed animal models by the Guidelines are appropriate for evalu ation of agents to prevent bone loss in postmenopausal women. However, modification of endpoints and study duration of the rat OVX studies c ontained in the Guidelines is recommended. Furthermore, we found that the Guidelines should be modified to evaluate agents for the treatment of osteoporosis. Also, the Guidelines fail to account for osteoporosi s therapy which uses combination or cyclical regimens.