Seedor J G, Quartuccio H A, Thompson D D
Department of Bone Biology and Osteoporosis Research, Merck, Sharp and Dohme Research Laboratories, West Point, PA 19486.
J Bone Miner Res. 1991 Apr;6(4):339-46. doi: 10.1002/jbmr.5650060405.
Estrogen deficiency in mammals is known to increase bone turnover and result in reduced bone mass. The bisphosphonate, 4-amino-1-hydroxybutylidene-1,1-bisphophonic acid disodium salt, alendronate (MK-217), is a potent inhibitor of bone resorption and was evaluated in this study for its ability to inhibit bone loss following ovariectomy in rats. Alendronate was administered sc in doses of 0.0, 0.056, 0.28, 1.40, and 7.0 mg P/kg/month, divided into two, four, or eight monthly subcutaneous injections for each dose, to female Sprague-Dawley rats (250-280 g) that underwent bilateral ovariectomy. Rats were sacrificed 12 weeks postovariectomy, the femora ashed, and the tibiae prepared for static and dynamic histomorphometric analyses. Femoral bone mass in vehicle-treated rats was reduced by 12% 12 weeks after ovariectomy compared to the nonovariectomized control group. In MK-217-treated rats femoral bone mass was significantly increased in a dose-dependent manner compared to either ovariectomized or nonovariectomized controls. Histomorphometric analysis showed significant increases in tibial trabecular bone volume with no decrease in osteoclast number. Doses delivered twice per month or eight times per month were equally effective in achieving the peak bone volume 12 weeks after ovariectomy. In conclusion, alendronate (MK-217) was effective in inhibiting bone loss due to estrogen deficiency in rats, and the magnitude of its effect was related primarily to the total amount of compound administered rather than the frequency of its administration.
已知哺乳动物体内雌激素缺乏会增加骨转换并导致骨量减少。双膦酸盐4-氨基-1-羟基丁叉-1,1-二膦酸二钠盐阿仑膦酸钠（MK-217）是一种强效的骨吸收抑制剂，本研究对其抑制大鼠卵巢切除术后骨质流失的能力进行了评估。将阿仑膦酸钠以0.0、0.056、0.28、1.40和7.0 mg P/kg/月的剂量皮下注射给接受双侧卵巢切除的雌性斯普拉格-道利大鼠（250-280 g），每个剂量分为每月两次、四次或八次皮下注射。大鼠在卵巢切除术后12周处死，股骨进行灰化处理，胫骨则用于静态和动态组织形态计量学分析。与未进行卵巢切除的对照组相比，接受赋形剂处理的大鼠在卵巢切除术后12周股骨骨量减少了12%。与卵巢切除或未卵巢切除的对照组相比，在接受MK-217治疗的大鼠中，股骨骨量以剂量依赖性方式显著增加。组织形态计量学分析显示胫骨小梁骨体积显著增加，破骨细胞数量没有减少。每月给药两次或八次的剂量在卵巢切除术后12周达到峰值骨体积方面同样有效。总之，阿仑膦酸钠（MK-217）可有效抑制大鼠因雌激素缺乏引起的骨质流失，其作用程度主要与给药化合物的总量有关，而非给药频率。
