Estrogen replacement therapy, in spite of efficacy in the prevention of osteoporotic fractures, has significant side effects and risks that limit its widespread usage in postmenopausal women. Thus significant medical need exists to find modalities that prevent osteoporosis, but without the side effects of estrogen. Selective estrogen receptor modulators (SERMs) have the potential to provide the skeletal benefits of estrogen without the increased risk of uterine and breast cancer. Tamoxifen, a first generation SERM is approved for the prevention and treatment of breast cancer, and raloxifene, a second generation SERM has been approved for the prevention and treatment of osteoporosis. Lasofoxifene, a new potent, nonsteroidal SERM, binds with high affinity to human estrogen receptors and acts as a tissue selective estrogen antagonist or agonist. In preclinical models of postmenopausal osteoporosis, lasofoxifene inhibited bone turnover and prevented bone loss throughout the skeleton. In studies designed to investigate the combination of lasofoxifene with estrogen, lasofoxifene blocked the hypertrophic effects of estrogen in the uterus, but did not block the bone protective effects. In immature and aged female rats, lasofoxifene did not affect the uterine weight and uterine histology. In preclinical studies designed to evaluate the effects of lasofoxifene on the uterus, a slight increase in wet uterine weight was observed in immature and aged female rats, but this difference was not observed in dry uterine weight suggesting that the increased uterine weight was due to increased water content in the tissue. In preclinical studies designed to evaluate the effects of lasofoxifene in breast cancer, lasofoxifene inhibited breast tumor formation in mice injected with human MCF-7 breast cancer cells and in rats bearing mammary carcinomas. Thus, in preclinical models, lasofoxifene, a next generation SERM, prevents estrogen deficiency-induced bone loss, inhibits breast tumor formation, and reduces serum cholesterol, without causing uterine hypertrophy. These data suggest that lasofoxifene is a new potential therapy for the prevention of osteoporosis in postmenopausal women.