Preclinical development of agents for the treatment of osteoporosis

Because of the high cost and long time frame of clinical testing, animal mo dels play a crucial role in the identification and selection of agents for the treatment of osteoporosis. The use of animal models early in a program focuses on the establishment of efficacy, while animal models used later in a program to examine bone safety. More specifically, animal models are use d to gain information on the skeletal mechanism of action, to examine multi ple skeletal sites (axial and appendicular), and to examine the effects of higher doses than will be used in humans. Animal models also predict the us efulness of surrogate markers in clinical trials, such as formation and res orption markers, as well as bone density. The hazard of using surrogate mar kers for fracture prevention is highlighted by high dose fluoride administr ation, which can increase bone density (considered a strong predictor of fr acture protection) while not protecting against fractures. Estrogen-deficie nt models are most commonly used to mimic the postmenopausal bone loss in w omen; these models are characterized by increased bone turnover and a negat ive bone balance. The timing of the administration of the new therapy in an imal models can help determine whether the agent will be more effective in the prevention of osteoporosis or in the treatment of established osteoporo sis. New methods for the measurement of bone mass or Volume are less invasi ve, require shorter acquisition time, and have enhanced resolution, resulti ng in increased knowledge concerning architectural changes and specific sit es of bone deposition. Finally, the measurement of biomechanical strength o f bones from animal models can be used to predict protective effects on fra cture rates in clinical trials. When used in combination with other methods , animal models can greatly increase our understanding of the pathophysiolo gy of osteoporosis and can expedite the development of new therapies.