Maeda Tomoko, Ke Hua Zhu, Simmons Hollis, Thompson David
Pfizer Japan Inc., Pfizer Global Research and Development, Tokyo laboratories.
Clin Calcium. 2004 Oct;14(10):85-93.
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.
尽管雌激素替代疗法在预防骨质疏松性骨折方面有效，但它具有显著的副作用和风险，这限制了其在绝经后女性中的广泛应用。因此，迫切需要找到预防骨质疏松但无雌激素副作用的方法。选择性雌激素受体调节剂（SERM）有可能提供雌激素对骨骼的益处，同时不会增加子宫癌和乳腺癌的风险。他莫昔芬是第一代SERM，已被批准用于预防和治疗乳腺癌，雷洛昔芬是第二代SERM，已被批准用于预防和治疗骨质疏松症。拉索昔芬是一种新型强效非甾体SERM，与人雌激素受体具有高亲和力，可作为组织选择性雌激素拮抗剂或激动剂。在绝经后骨质疏松症的临床前模型中，拉索昔芬抑制骨转换并防止全身骨骼骨质流失。在旨在研究拉索昔芬与雌激素联合使用的研究中，拉索昔芬可阻断雌激素对子宫的肥大作用，但不阻断其对骨骼的保护作用。在未成熟和老年雌性大鼠中，拉索昔芬不影响子宫重量和子宫组织学。在旨在评估拉索昔芬对子宫影响的临床前研究中，未成熟和老年雌性大鼠的子宫湿重略有增加，但干重未观察到这种差异，这表明子宫重量增加是由于组织中水分含量增加所致。在旨在评估拉索昔芬对乳腺癌影响的临床前研究中，拉索昔芬可抑制注射人MCF-7乳腺癌细胞的小鼠和患有乳腺癌的大鼠的乳腺肿瘤形成。因此，在临床前模型中，新一代SERM拉索昔芬可预防雌激素缺乏引起的骨质流失，抑制乳腺肿瘤形成，并降低血清胆固醇，而不会导致子宫肥大。这些数据表明，拉索昔芬是预防绝经后女性骨质疏松症的一种新的潜在疗法。
