How bisphosphonates affect bone matrix and remodeling: implications for atypical femoral fractures

项目总结/摘要 非典型股骨骨折（AFFs）是一种罕见的，但破坏性的副作用，长期双膦酸盐（BP） 治疗尽管AFFS的发病率相对较低，但公众意识却相当低落， 骨质疏松症药物治疗依从性。驱动BP相关AFF的机制仍然难以捉摸， 已提出的机制包括骨重建受损、骨基质成熟改变和 组织微损伤的累积。了解BP如何对骨骼产生负面影响的关键障碍 完整性是分离改变的重塑动力学（抑制的）的个体贡献的困难 吸收和形成）。我们将克服这一障碍， 经验证的诱导皮质重塑大鼠模型，以研究机制和治疗，基于鲁棒性 在三个multiPI实验室的初步工作。目前的提案是根据一项 关于AFF病理生理学的特别关注通知（NOT-AR-21-006）将检验中心假设，即BP 通过影响骨形成和基质成熟的起始而降低骨骼的完整性。在目标1和 2、我们将重点关注阿仑膦酸钠，因为它与AFF和雷洛昔芬的开发有密切联系 作为一种潜在的缓解处理，因为据报道其对地层和基质都有积极影响 成熟过程。具体来说，我们将研究阿仑膦酸钠和雷洛昔芬对启动的影响， 骨形成，集中在逆转细胞的作用（目的1）和重建的独立影响， 这两种药物对基质成熟和疲劳寿命的影响（目的2）。为了确定BP分子结构是否能 在AFF易感性中发挥作用，我们还将比较阿仑膦酸钠、唑来膦酸盐、利塞膦酸盐和 伊班膦酸盐影响骨形成、基质成熟和疲劳寿命（目的3）。我们将采用创新的 临床前模型，并利用高素质研究团队的专业知识来解决关键问题 与AFFS有关。如果成功，该项目将（i）进一步了解BP的后果 通过解开骨形成起始和基质成熟，鉴定 有助于BP引起的疲劳寿命的损失和（ii）检查雷洛昔芬作为一种新的快速治疗选择， 有BP诱发AFF风险的患者。

Project Summary / Abstract Atypical femoral fractures (AFFs) are a rare but devastating side effect of long-term bisphosphonate (BP) treatment. Despite the relatively low prevalence of AFFs, public awareness has considerably depressed osteoporosis medication adherence. The mechanisms driving BP associated AFFs remain elusive and several mechanisms have been proposed, including impaired bone remodeling, altered bone matrix maturation, and the accumulation of tissue microdamage. A critical barrier to understanding how BPs negatively affect skeletal integrity is the difficulty in separating the individual contributions of altered remodeling kinetics (suppressed resorption and formation) from bone matrix maturation. We will overcome this barrier with our recently validated rat model of induced cortical remodeling to investigate mechanism and treatment, based on robust preliminary work in the laboratories of the three multiPIs. The current proposal, submitted in response to a notice of special interest on AFF pathophysiology (NOT-AR-21-006), will test the central hypothesis that BPs degrade skeletal integrity by affecting both the initiation of bone formation and matrix maturation. In Aims 1 and 2, we will focus on alendronate because of its strong association with the development of AFFs and raloxifene as a potential mitigating treatment due to its reported positive effects on both the formation and matrix maturation processes. Specifically, we will investigate the effects of alendronate and raloxifene on the initiation of bone formation, concentrating on the role of reversal cells (Aim 1) and the remodeling independent effects of these two drugs on matrix maturation and fatigue life (Aim 2). To determine if BP molecular structure could play a role in AFF susceptibility, we will also compare how alendronate, zoledronate, risedronate, and ibandronate affect bone formation, matrix maturation, and fatigue life (Aim 3). We will utilize an innovative preclinical model and leverage the expertise of a highly qualified research team to address critical questions associated with AFFs. If successful, the project will (i) further the understanding of the consequences of BP usage on the skeleton by disentangling bone formation initiation and matrix maturation, identifying factors that contribute to BP-induced loss of fatigue life and (ii) examine raloxifene as a novel rapid treatment option for patients at risk for BP-induced AFF.