Kashii Masafumi, Hashimoto Jun, Nakano Takayoshi, Umakoshi Yukichi, Yoshikawa Hideki
Department of Orthopedic Surgery, Faculty of Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
J Bone Miner Metab. 2008;26(1):24-33. doi: 10.1007/s00774-007-0782-8. Epub 2008 Jan 10.
There are safety concerns regarding administration of bisphosphonates to children. Little is known about the effects of bisphosphonates on bone matrix organization during bone modeling. The present study examined the effects of alendronate (ALN) on bone matrices formed by intramembranous ossification in the appendicular growing skeleton. ALN was administered to 1-week-old Sprague-Dawley rats at a dose of 0, 35, or 350 microg/kg/week for 4 or 8 weeks. The position of femoral diaphysis formed exclusively by intramembranous ossification was identified, and cross sections of cortical bone at this position were analyzed. Bone mineral density (BMD) and geometric parameters were evaluated using peripheral quantitative computed tomography. The preferential orientation degree of biological apatite (BAp) crystals in the bone longitudinal direction, which shows the degree of bone matrix anisotropy, was evaluated using microbeam X-ray diffraction analysis. We analyzed bone histomorphometrical parameters and performed bone nanomechanical tests to examine the material properties of newly developing cortical bone. The preferential orientation degree of BAp crystals significantly decreased in 35 microg/kg/week ALN-treated groups compared with vehicle-treated groups, although there were no significant differences in BMD between the two groups. The periosteal mineral apposition rate significantly increased in the 35 microg/kg/week ALN-treated group. We found a high negative correlation between bone matrix anisotropy and the regional periosteal mineral apposition rate (r = -0.862, P < 0.001). Nanomechanical tests revealed that 35 microg/kg/week ALN administration caused deterioration of the material properties of the bone microstructure. These new findings suggest that alendronate affects bone matrix organization and promotes bone formation with a less anisotropic microstructure during intramembranous ossification.
双膦酸盐用于儿童给药存在安全性问题。关于双膦酸盐在骨骼塑形过程中对骨基质组织的影响，人们了解甚少。本研究考察了阿仑膦酸钠（ALN）对附肢生长骨骼中通过膜内成骨形成的骨基质的影响。将1周龄的Sprague-Dawley大鼠以0、35或350微克/千克/周的剂量给予ALN，持续4周或8周。确定仅由膜内成骨形成的股骨干的位置，并分析该位置皮质骨的横截面。使用外周定量计算机断层扫描评估骨密度（BMD）和几何参数。使用微束X射线衍射分析评估骨纵向方向生物磷灰石（BAp）晶体的择优取向度，该择优取向度显示骨基质各向异性程度。我们分析了骨组织形态计量学参数并进行了骨纳米力学测试，以检查新形成的皮质骨的材料特性。与赋形剂处理组相比，35微克/千克/周ALN处理组中BAp晶体的择优取向度显著降低，尽管两组之间的BMD没有显著差异。35微克/千克/周ALN处理组的骨膜矿物质沉积率显著增加。我们发现骨基质各向异性与局部骨膜矿物质沉积率之间存在高度负相关（r = -0.862，P < 0.001）。纳米力学测试表明，给予35微克/千克/周的ALN会导致骨微观结构材料特性的恶化。这些新发现表明，阿仑膦酸钠在膜内成骨过程中会影响骨基质组织，并促进具有较低各向异性微观结构的骨形成。
