Meixner Cory N, Aref Mohammad W, Gupta Aryaman, McNerny Erin M B, Brown Drew, Wallace Joseph M, Allen Matthew R
Department of Anatomy and Cell Biology, Indiana University School of Medicine, MS 5035, 635 Barnhill Dr., Indianapolis, IN, 46202, USA.
Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
Calcif Tissue Int. 2017 Jul;101(1):75-81. doi: 10.1007/s00223-017-0257-4. Epub 2017 Feb 28.
Bisphosphonates represent the gold-standard pharmaceutical agent for reducing fracture risk. Long-term treatment with bisphosphonates can result in tissue brittleness which in rare clinical cases manifests as atypical femoral fracture. Although this has led to an increasing call for bisphosphonate cessation, few studies have investigated therapeutic options for follow-up treatment. The goal of this study was to test the hypothesis that treatment with raloxifene, a drug that has cell-independent effects on bone mechanical material properties, could reverse the compromised mechanical properties that occur following zoledronate treatment. Skeletally mature male C57Bl/6J mice were treated with vehicle (VEH), zoledronate (ZOL), or ZOL followed by raloxifene (RAL; 2 different doses). At the conclusion of 8 weeks of treatment, femora were collected and assessed with microCT and mechanical testing. Trabecular BV/TV was significantly higher in all treated animals compared to VEH with both RAL groups having significantly higher BV/TV compared to ZOL (+21%). All three drug-treated groups had significantly more cortical bone area, higher cortical thickness, and greater moment of inertia at the femoral mid-diaphysis compared to VEH with no difference among the three treated groups. All three drug-treated groups had significantly higher ultimate load compared to VEH-treated animals (+14 to 18%). Both doses of RAL resulted in significantly higher displacement values compared to ZOL-treated animals (+25 to +50%). In conclusion, the current work shows beneficial effects of raloxifene in animals previously treated with zoledronate. The higher mechanical properties of raloxifene-treated animals, combined with similar cortical bone geometry compared to animals treated with zoledronate, suggest that the raloxifene treatment is enhancing mechanical material properties of the tissue.
双膦酸盐是降低骨折风险的金标准药物。长期使用双膦酸盐治疗可能会导致组织脆性增加，在罕见的临床病例中表现为非典型股骨骨折。尽管这导致了越来越多要求停用双膦酸盐的呼声，但很少有研究调查后续治疗的选择。本研究的目的是检验以下假设：雷洛昔芬（一种对骨力学材料特性具有非细胞依赖性作用的药物）治疗可以逆转唑来膦酸治疗后出现的力学性能受损。对骨骼成熟的雄性C57Bl/6J小鼠给予载体（VEH）、唑来膦酸（ZOL）或唑来膦酸后给予雷洛昔芬（RAL；2种不同剂量）治疗。在8周治疗结束时，收集股骨并进行显微CT和力学测试评估。与VEH组相比，所有治疗组的小梁骨体积分数（BV/TV）均显著更高，两个RAL组的BV/TV均显著高于ZOL组（+21%）。与VEH组相比，所有三个药物治疗组在股骨干中段的皮质骨面积显著更大、皮质厚度更高且惯性矩更大，三个治疗组之间无差异。与VEH治疗的动物相比，所有三个药物治疗组的极限载荷均显著更高（+14%至18%）。与ZOL治疗的动物相比，两种剂量的RAL均导致位移值显著更高（+25%至+50%）。总之，目前的研究表明雷洛昔芬对先前接受唑来膦酸治疗的动物具有有益作用。与接受唑来膦酸治疗的动物相比，雷洛昔芬治疗的动物具有更高的力学性能，且皮质骨几何形状相似，这表明雷洛昔芬治疗正在增强组织的力学材料特性。
