Currently, the nonhuman primate is the most widely used large animal model to evaluate the safety and efficacy of new drug entities to treat or prevent estrogen-deficiency-induced bone loss and osteoporosis. Surgical ovariectomy (OVX) induces a state of high bone turnover and rapid bone loss establishing a new steady-state bone mass within 8-9 months. Many systems in the monkey are similar to humans, including skeletal and reproductive physiology and the immune system, making this a plausible model suitable to evaluate the effects of new bone drugs. The long-term sequelae following OVX and withdrawal of monthly exposure to cyclic reproductive hormones in older female monkeys (cynomolgus and rhesus) mimics estrogen depletion and postmenopausal bone loss occurring in women. Characterization of the primate model revealed an apparent limitation to the extent of bone loss. Animals lose bone mass after OVX, but the extent of the bone loss cannot be described as osteoporotic. The small differences between OVX and sham-operated controls in many important bone measurements is overcome by including 15-20 animals per group to provide adequate statistical power. The long-term, at least 16 month, bone safety studies performed to satisfy regulatory guidelines provide an opportunity to study treatment effects for an extended period not covered in shorter-term safety studies. In vivo end-points such as densitometry and biochemical markers translate easily to clinical use, while biomechanical end-points that cannot be measured clinically can be used to predict fracture prevention. To date, the monkey OVX model has been used to support submissions for many new drugs including anabolics, bisphosphonates and selective estrogen receptor modulators. Despite its limitations, the OVX monkey model remains the best characterized of the large animal models of osteopenia and has become integral to osteoporosis drug development.