Raloxifene in the Mechanism of Bone Metabolism

雌激素缺乏会导致明显的骨丢失，可以通过雌激素替代治疗来预防，雷洛昔芬是公认的选择性雌激素受体调节剂之一，已有报道在子宫内不含雌激素的情况下减少骨丢失。促性腺激素释放激素激动剂(GnRHa)对雌激素依赖型疾病有用，因为促性腺激素的节律性分泌减少，但长期治疗GnRHa会增加骨吸收，导致骨丢失。本研究旨在探讨GnRHa对小鼠继发性骨丢失的影响，以及雷洛昔芬对此的影响。8周龄雌性ddy小鼠每4周注射一次GnRHa(5 mg/kg)，连续4~12周。GnRHa治疗的一些小鼠使用阿尔茨海默泵联合雷洛昔芬(1毫克/公斤/天)或17β-雌二醇(1微克/公斤/天)皮下注射。用雷洛昔芬或17β-雌二醇治疗去卵巢小鼠，发现去卵巢小鼠子宫重量明显减轻，子宫萎缩，而GnRHa治疗组小鼠子宫重量略有减轻。而血清FSH水平明显高于模型组，提示子宫萎缩程度最大，可能与GnRHa有关。GnRHa组小鼠股骨骨密度(BMD)显著降低，与OVX组相似。在去卵巢小鼠中，17β-雌二醇恢复了子宫重量和骨丢失，但雷洛昔芬只阻止了骨丢失。同样，在GnRHa治疗的小鼠中，雷洛昔芬恢复了骨丢失，但子宫重量没有影响。GnRHa治疗组小鼠血清OPG水平高于赋形剂组小鼠，雷洛昔芬治疗组小鼠血清OPG水平低于赋形剂组，提示GnRHa治疗可导致雌性小鼠骨丢失，雷洛昔芬在子宫内无雌激素作用，可预防骨丢失。雷洛昔芬可能是非常有用的加回治疗激动剂GnRHa。

Estrogen deficiency causes markedly bone loss, and can be prevent by estrogen replacement therapy, Raloxifene, which is recognized as one of Selective Estrogen Receptor Modulator, have reported that reduced bone loss without estrogenic in uterus. GnRH agonist (GnRHa) is useful for estrogen dependent disease since rhythmical secretion of gonadotropin is decreased, but long-term treatment of GnRHa is led to bone loss by increasing bone resorption. In the present study, we examined that to cause secondary bone loss in mice by GnRHa, and the effect of raloxifene to this.8w female ddy mice were injected with GnRHa (5 mg/kg) every 4 weeks for 4 weeks to 12 weeks. Some of the GnRHa treated mice combined Raloxifene (1 mg/kg/day) or 17β-Estradiol (1 microg/kg/day) subcutaneously using an Alzet pump. Ovariectmized (OVX) mice were prepared and treated with Raloxifene or 17β-estradiol for control.In OVX mice, uterine weight were markedly decreased and uteri were atrophied, but in GnRHa treated mice, uterine weight were slightly reduced. However, serum FSH level were remarkably high as compared with vehicle mice, we concluded that the atrophic level of uterine is maximum which may be caused by GnRHa. The femoral bone mineral density (BMD) in GnRHa mice were significantly reduced, and these were similar to OVX mice. In OVX mice, 17β-Estradiol recovered both uterine weight and bone loss, but Raloxifene only prevent bone loss. Similarly, in GnRHa treated mice, Raloxifene recovered bone loss, but uterine weight did not have effect. Serum OPG level were higher in GnRHa treated mice than in vehicle mice, furthermore Raloxifene decreased these till lower than vehicle level.In conclusion, these results indicate that treatment of GnRHa caused bone loss in female mice, and Raloxifene can be prevent bone loss without estrogenic action in uterus. It is possible that Raloxifene is very useful for add-back therapy agonist GnRHa.