The Role of Suppressed Bone Turnover in Cortical Bone Material Composition, Organization, and Fracture Resistance

双膦酸盐是最常用的骨质疏松症治疗药物，通过抑制骨转换有效预防骨质疏松性骨折。周转是指组织的再吸收和替换。尽管双磷酸盐的有益效果，有积累的证据表明，一个潜在的并发症的形式，非典型股骨骨折。最近关于非典型股骨骨折与长期使用双膦酸盐可能相关的报告引起了人们对骨转换广泛抑制导致骨不良机械改变的可能性的关注。该奖项的总体目标是通过多尺度计算建模促进对骨的材料组成、组织和抗骨折性变化的理解，这些变化是由于骨转换受到抑制而引起的。该项目将对社会产生广泛而重大的影响，因为它将及时提供与最常用的骨质疏松症药物治疗相关的重大潜在公共卫生问题的信息。该项目的结果将提供新的知识，将建立一个更好地了解骨质疏松症治疗对骨质量的影响，并将有助于确定非典型股骨骨折的风险下的患者。此外，研究计划将纳入一个积极的教育和外联部分，将扩大代表性不足的群体在工程中的参与。该研究项目将显著提高目前对骨中基本骨折机制变化的理解，这些变化是由于骨转换受到抑制而导致材料组成和组织发生变化。该项目将利用一种新的基于断裂力学的有限元建模方法，并将在多个尺度上进行系统和受控的评价，以量化将损害骨抗断裂性的材料性能变化的临界水平。具体而言，该研究将确定骨矿物质和基质异质性对裂纹生长的影响，量化矿化增加和晚期糖基化终产物积累对裂纹扩展的影响，并确定骨中微裂纹积累的临界水平，这将对骨中的骨折增韧机制产生不利影响。 本研究项目中新颖和创新的计算评估方法将提供无法通过实验测量的独特信息。

Bisphosphonates are the most commonly used osteoporosis treatment that has been effective in preventing osteoporotic fractures by suppressing bone turnover. Turnover refers to the resorption and replacement of tissue. Despite the beneficial effects of bisphosphonates, there is accumulating evidence of a potential complication in the form of atypical femoral fracture. The recent reports of possible association of atypical femoral fracture with prolonged bisphosphonate use brought into attention the possibility of adverse mechanical modifications in bone due to extensive suppression of bone turnover. The overall goal of this award is to advance the understanding of the changes in material composition, organization, and fracture resistance of bone due to suppressed bone turnover via multiscale computational modeling. This project will have a broad and major impact on the society as it will provide timely information on a significant potential public health problem associated with the most commonly used drug therapy for osteoporosis. The results of the project will provide new knowledge that will establish a better understanding of the effects of osteoporosis treatments on bone quality and will help determine patients under risk of atypical femoral fracture. In addition, the research plan will integrate an active educational and outreach component that will broaden the participation of underrepresented groups in engineering. This research project will significantly improve the current understanding of the changes in fundamental fracture mechanisms in bone as a result of alterations in material composition and organization due to suppressed bone turnover. The project will utilize a new fracture mechanics-based finite element modeling approach and will perform systematic and controlled evaluations at multiple scales to quantify the critical levels of material property changes that will impair the fracture resistance of bone. Specifically, the study will determine the effect of bone mineral and matrix heterogeneity on crack growth, quantify the influence of increased mineralization and accumulation of advanced glycation end products on crack propagation, and identify the critical level of microcrack accumulation in bone that will adversely affect the fracture toughening mechanisms in bone. The novel and innovative computational evaluation approach in this research project will provide unique information that cannot be measured by experiments.