Raloxifene in the Mechanism of Bone Metabolism

雌激素缺乏可引起明显的骨质流失，可通过雌激素替代疗法加以预防，雷洛昔芬作为一种公认的选择性雌激素受体调节剂，有报道称可在不使用雌激素的情况下减少子宫内骨质流失。GnRH激动剂（GnRHa）对雌激素依赖性疾病有用，因为促性腺激素的节律性分泌减少，但GnRHa的长期治疗会增加骨吸收导致骨质流失。在本研究中，我们研究了GnRHa对小鼠继发性骨质流失的影响，以及雷洛昔芬对其的影响。8只雌性小鼠每4周注射一次GnRHa (5 mg/kg)，持续4 ~ 12周。一些GnRHa治疗小鼠使用Alzet泵皮下注射雷洛昔芬（1毫克/公斤/天）或17β-雌二醇（1微克/公斤/天）。制备卵巢切除（OVX）小鼠，分别给予雷洛昔芬或17β-雌二醇作为对照。OVX组小鼠子宫重量明显减轻，子宫萎缩，而GnRHa组小鼠子宫重量轻微减轻。与对照小鼠相比，大鼠血清FSH水平明显升高，子宫萎缩程度最大，可能是GnRHa所致。GnRHa小鼠股骨骨密度（BMD）明显降低，与OVX小鼠相似。在OVX小鼠中，17β-雌二醇可以恢复子宫重量和骨质流失，而雷洛昔芬只能防止骨质流失。同样，在GnRHa治疗的小鼠中，雷洛昔芬恢复了骨质流失，但子宫重量没有影响。GnRHa处理小鼠血清OPG水平高于对照小鼠，雷洛昔芬使其降低至低于对照小鼠。综上所述，这些结果表明，GnRHa处理导致雌性小鼠骨质流失，雷洛昔芬可以防止子宫内骨质流失而不产生雌激素作用。雷洛昔芬可能对GnRHa的加回治疗非常有用。

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.