Iwamoto J, Yeh J K, Schmidt A, Rowley E, Stanfield L, Takeda T, Sato M
Department of Sports Medicine, Keio University School of Medicine, Tokyo, Japan.
Calcif Tissue Int. 2005 Aug;77(2):119-26. doi: 10.1007/s00223-004-0277-8. Epub 2005 Jul 28.
We evaluated the skeletal effects of two osteoporosis therapies in an ovariectomized rat model, raloxifene and vitamin K2, as well as the vitamin K2 plus raloxifene (K + Ral) combination. In two studies, 6-month-old rats were ovariectomized, except for sham-ovariectomy controls (Sham), and dosed orally with vehicle, 30 mg/kg vitamin K2, 1 mg/kg raloxifene, or the combination of K + Ral for 6 weeks following surgery. Vitamin K2 had no effect on serum estrogen, low-density lipoprotein cholesterol (LDL-C), or urinary deoxypyridinoline levels, but slightly increased osteocalcin levels compared to Ovx. Raloxifene lowered total cholesterol, LDL-C, osteocalcin, and urinary deoxypyridinoline levels to below Ovx levels, while having no effect on estrogen levels. Raloxifene, but not vitamin K2, prevented ovariectomy-induced loss of bone in the distal femoral metaphysis and proximal tibial metaphysis, as did the K + Ral combination. Raloxifene, but not vitamin K2, partially prevented, loss of vertebral bone mineral density (BMD), whereas K + Ral had BMD greater than that of Ovx. Vitamin K2 increased bone formation rate to above Ovx, whereas raloxifene and K + Ral reduced bone formation rate to Sham levels. Vitamin K2 had no effect on eroded surface compared to Ovx, while raloxifene and K + Ral reduced eroded surface to Sham levels. Groups were not different in the BMD of femoral midshaft; however vitamin K2 was observed to increase periosteal mineralizing surface of the tibial shaft to above Ovx, while raloxifene reduced periosteal mineralizing surface toward Sham levels. Femoral neck strength was not different between groups, indicating no significant beneficial effect of either raloxifene or vitamin K2 at this site. However, K + Ral had reproducibly greater femoral neck strength than Ovx or Sham. Raloxifene, but not vitamin K2, partially prevented loss of lumbar vertebra strength; but K + Ral was not different from Sham or Ovx. Therefore, raloxifene and vitamin K2 had complementary effects on bone resorption and formation activities, respectively, resulting in a reproducible, significant improvement of femoral neck strength. These rat data suggest interesting therapeutic possibilities that may require clinical verification.
我们在去卵巢大鼠模型中评估了两种骨质疏松症治疗方法（雷洛昔芬和维生素K2）以及维生素K2加雷洛昔芬（K + Ral）联合用药对骨骼的影响。在两项研究中，除假手术对照组（Sham）外，将6月龄大鼠进行去卵巢手术，并在术后6周口服赋形剂、30 mg/kg维生素K2、1 mg/kg雷洛昔芬或K + Ral组合药物。维生素K2对血清雌激素、低密度脂蛋白胆固醇（LDL-C）或尿脱氧吡啶啉水平无影响，但与去卵巢组相比，骨钙素水平略有升高。雷洛昔芬可降低总胆固醇、LDL-C、骨钙素和尿脱氧吡啶啉水平至去卵巢组水平以下，而对雌激素水平无影响。雷洛昔芬（而非维生素K2）可预防去卵巢诱导的股骨远端干骺端和胫骨近端干骺端骨量丢失，K + Ral组合也有此作用。雷洛昔芬（而非维生素K2）可部分预防椎体骨矿物质密度（BMD）的丢失，而K + Ral的BMD高于去卵巢组。维生素K2可使骨形成率升高至高于去卵巢组，而雷洛昔芬和K + Ral可将骨形成率降低至假手术组水平。与去卵巢组相比，维生素K2对侵蚀表面无影响，而雷洛昔芬和K + Ral可将侵蚀表面降低至假手术组水平。各组股骨骨干中部的BMD无差异；然而，观察到维生素K2可使胫骨干的骨膜矿化表面增加至高于去卵巢组，而雷洛昔芬可使骨膜矿化表面向假手术组水平降低。各组股骨颈强度无差异，表明雷洛昔芬或维生素K2在此部位均无显著有益作用。然而，K + Ral的股骨颈强度始终高于去卵巢组或假手术组。雷洛昔芬（而非维生素K2）可部分预防腰椎强度的丢失；但K + Ral与假手术组或去卵巢组无差异。因此，雷洛昔芬和维生素K2分别对骨吸收和形成活动具有互补作用，从而可重复性地显著提高股骨颈强度。这些大鼠实验数据提示了一些有趣的治疗可能性，可能需要临床验证。
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