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.