Comparison of Effects of the Bisphosphonate Alendronate Versus the RANKL Inhibitor Denosumab on Murine Fracture Healing
Comparison of Effects of the Bisphosphonate Alendronate Versus the RANKL Inhibitor Denosumab on Murine Fracture Healing
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DOI：
10.1359/jbmr.081113
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发表时间：
2009-02-01
影响因子：
6.2
通讯作者：
Einhorn, Thomas A.
中科院分区：
文献类型：
--
作者：
Gerstenfeld, Louis C.;Sacks, Daniel J.;Einhorn, Thomas A.
评估了破骨细胞介导的吸收在骨折愈合过程中的作用。研究了两种作用机制不同的破骨细胞抑制剂——阿仑膦酸盐（ALN）和地诺单抗（DMAB）在骨折愈合过程中的影响。表达嵌合（人/鼠）形式核因子κB受体活化因子配体（RANKL）的雄性人RANKL基因敲入小鼠接受单侧股骨横断骨折。小鼠每两周接受0.1毫克/千克的阿仑膦酸盐、10毫克/千克的地诺单抗或0.1毫升的磷酸盐缓冲盐水（对照）治疗，直至骨折后21天和42天处死。通过抗酒石酸酸性磷酸酶5b（TRACP 5b）血清水平评估治疗效果，结果显示地诺单抗治疗的动物中TRACP 5b水平几乎完全消除，而阿仑膦酸盐治疗的小鼠血清水平仅降低约25%。力学测试表明，与对照组相比，阿仑膦酸盐组和地诺单抗组在第42天骨折的股骨力学性能显著提高。微计算机断层扫描（μCT）分析显示，在第21天和第42天，地诺单抗治疗的小鼠的骨痂组织的骨体积百分比和骨密度（BMD）均显著高于对照组和阿仑膦酸盐治疗组，而阿仑膦酸盐治疗的骨骼仅在第42天的骨体积百分比和骨矿物质含量（BMC）高于对照组。定性组织学分析表明，与对照组相比，第21天和第42天的阿仑膦酸盐组和地诺单抗组有更多未吸收的软骨或矿化的软骨基质，而在骨折后第42天的地诺单抗组仍可看到未吸收的软骨。尽管阿仑膦酸盐和地诺单抗延迟了软骨的去除和骨折骨痂的重塑，但这并没有降低接受这些治疗的小鼠愈合骨折的力学完整性。相反，与对照组骨骼相比，这些治疗组的强度和刚度有所提高。
The role of osteoclast-mediated resorption during fracture healing was assessed. The impact of two osteoclast inhibitors with different mechanisms of action, alendronate (ALN) and denosumab (DMAB), were examined during fracture healing. Male human RANKL knock-in mice that express a chimeric (human/murine) form of RANKL received unilateral transverse femur fractures. Mice were treated biweekly with ALN 0.1. mg/kg, DMAB 10 mg/kg, or PBS (control) 0.1 ml until death at 21 and 42 days after fracture. Treatment efficacy assessed by serum levels of TRACP 5b showed almost a complete elimination of TRACP 5b levels in the DMAB-treated animals but only similar to 25% reduction of serum levels in the ALN-treated mice. Mechanical testing showed that fractured femurs from both ALN and DMAB groups had significantly increased mechanical properties at day 42 compared with controls. mu CT analysis showed that callus tissues from DMAB-treated mice had significantly greater percent bone volume and BMD than did both control and ALN-treated tissues at both 21, and 42 days, whereas ALN-treated bones only had greater percent bone volume and BMC than control at 42 days. Qualitative histological analysis showed that the 21-and 42-day ALN and DMAB groups had greater amounts of unresorbed cartilage or mineralized cartilage matrix compared with the controls, whereas unresorbed cartilage could still be seen in the DMAB groups at 42 days after fracture. Although ALN and DMAB delayed the removal of cartilage and the remodeling of the fracture callus, this did not diminish the mechanical integrity of the healing fractures in mice receiving these treatments. In contrast, strength and stiffness were enhanced in these treatment groups compared with control bones.