Acevedo Claire, Bale Hrishikesh, Gludovatz Bernd, Wat Amy, Tang Simon Y, Wang Mingyue, Busse Björn, Zimmermann Elizabeth A, Schaible Eric, Allen Matthew R, Burr David B, Ritchie Robert O
Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Department of Materials Science and Engineering, University of California Berkeley, CA 94720, USA.
Department of Materials Science and Engineering, University of California Berkeley, CA 94720, USA.
Bone. 2015 Dec;81:352-363. doi: 10.1016/j.bone.2015.08.002. Epub 2015 Aug 5.
Bisphosphonates are widely used to treat osteoporosis, but have been associated with atypical femoral fractures (AFFs) in the long term, which raises a critical health problem for the aging population. Several clinical studies have suggested that the occurrence of AFFs may be related to the bisphosphonate-induced changes of bone turnover, but large discrepancies in the results of these studies indicate that the salient mechanisms responsible for any loss in fracture resistance are still unclear. Here the role of bisphosphonates is examined in terms of the potential deterioration in fracture resistance resulting from both intrinsic (plasticity) and extrinsic (shielding) toughening mechanisms, which operate over a wide range of length-scales. Specifically, we compare the mechanical properties of two groups of humeri from healthy beagles, one control group comprising eight females (oral doses of saline vehicle, 1 mL/kg/day, 3 years) and one treated group comprising nine females (oral doses of alendronate used to treat osteoporosis, 0.2mg/kg/day, 3 years). Our data demonstrate treatment-specific reorganization of bone tissue identified at multiple length-scales mainly through advanced synchrotron x-ray experiments. We confirm that bisphosphonate treatments can increase non-enzymatic collagen cross-linking at molecular scales, which critically restricts plasticity associated with fibrillar sliding, and hence intrinsic toughening, at nanoscales. We also observe changes in the intracortical architecture of treated bone at microscales, with partial filling of the Haversian canals and reduction of osteon number. We hypothesize that the reduced plasticity associated with BP treatments may induce an increase in microcrack accumulation and growth under cyclic daily loadings, and potentially increase the susceptibility of cortical bone to atypical (fatigue-like) fractures.
双膦酸盐被广泛用于治疗骨质疏松症，但长期使用与非典型股骨骨折（AFFs）有关，这给老年人群带来了一个关键的健康问题。多项临床研究表明，AFFs的发生可能与双膦酸盐引起的骨转换变化有关，但这些研究结果存在很大差异，表明导致骨折抵抗能力丧失的主要机制仍不清楚。在此，我们从内在（可塑性）和外在（屏蔽）增韧机制导致的骨折抵抗能力潜在恶化方面研究双膦酸盐的作用，这两种机制在广泛的长度尺度上起作用。具体而言，我们比较了两组健康比格犬肱骨的力学性能，一组为对照组，包括8只雌性（口服生理盐水载体，1 mL/kg/天，3年），另一组为治疗组，包括9只雌性（口服用于治疗骨质疏松症的阿仑膦酸盐，0.2mg/kg/天，3年）。我们的数据表明，主要通过先进的同步加速器X射线实验，在多个长度尺度上识别出了骨组织的治疗特异性重组。我们证实，双膦酸盐治疗可在分子尺度上增加非酶促胶原交联，这在纳米尺度上严重限制了与纤维滑动相关的可塑性，从而限制了内在增韧。我们还在微观尺度上观察到治疗后骨骼皮质内结构的变化，哈弗斯管部分填充，骨单位数量减少。我们假设，与双膦酸盐治疗相关的可塑性降低可能会导致在日常循环负荷下微裂纹积累和生长增加，并可能增加皮质骨发生非典型（类疲劳）骨折的易感性。
