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

双磷酸盐如何影响骨基质和重塑：对非典型股骨骨折的影响

• 批准号: 10586949
• 负责人: Thomas Levin Geiser Andersen
• 金额: $ 46.49万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-12 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586949
• 关键词: Address; Affect; Alendronate; Automobile Driving; Awareness; Biological; Bone Matrix; Bone remodeling; Cell Density; Cells; Compensation; Contralateral; Data; Depressed mood; Development; Diet; Fatigue; Femoral Fractures; Formulation; Fracture; Functional disorder; Grant; Holidays; Ibandronate; Impairment; Individual; Kinetics; Laboratories; Lactation; Life; Long-Term Effects; Low Prevalence; Modeling; Molecular Structure; Operative Surgical Procedures; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Population; Pre-Clinical Model; Predisposition; Prevention; Prevention strategy; Process; Property; Qualifying; Radiology Specialty; Raloxifene; Rattus; Reporting; Research; Risedronate; Risk; Role; Secondary to; Selective Estrogen Receptor Modulators; Site; Skeleton; Surface; Testing; Tissues; Work; Zoledronate; bisphosphonate; bone; bone fatigue; improved; innovation; interest; medication compliance; negative affect; novel; osteoblast proliferation; osteoprogenitor cell; response; side effect; skeletal; treatment strategy

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.

项目摘要 /摘要 非典型股骨骨折（AFF）是长期双膦酸盐（BP）的罕见但毁灭性的副作用 治疗。尽管AFF的患病率相对较低，但公众的意识却非常沮丧 骨质疏松药物的依从性。驱动BP相关AFF的机制仍然难以捉摸，有几个 已经提出了机制，包括骨骼重塑受损，骨基质成熟的改变和 组织微型塑料的积累。了解BP对骨骼的负面影响的关键障碍 完整性是分离改变重塑动力学的个体贡献的困难（被抑制 骨基质成熟的吸收和形成）。我们将通过我们最近克服这个障碍 经过验证的诱导皮质重塑的大鼠模型，以研究机制和治疗 在三个多人的实验室中的初步工作。目前的提议，以回应 关于AFF病理生理学特殊兴趣的通知（NOT-AR-21-006）将检验BPS的中心假设 通过影响骨骼形成和基质成熟的启动来降低骨骼完整性。在目标1和 2，我们将重点放在alendronate上，因为它与AFF的发展有很强的联系 作为潜在的缓解治疗，由于其报告对形成和基质的积极影响 成熟过程。具体而言，我们将研究alendronate和raloxifene对起始的影响 骨形成，集中于逆转细胞的作用（AIM 1）和重塑的独立效应 这两种有关基质成熟和疲劳寿命的药物（AIM 2）。确定BP分子结构是否可以 在AFF敏感性中发挥作用，我们还将比较Alendronate，Zoleronate，Risesronate和 ibandronate会影响骨形成，基质成熟和疲劳寿命（AIM 3）。我们将利用创新 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AFF相关。如果成功，该项目将（i）进一步理解BP的后果 通过解开骨形成的启动和基质成熟，在骨骼上使用，鉴定了因素 有助于BP引起的疲劳寿命的丧失，（ii）将雷昔芬作为一种新型快速治疗选择 有BP引起的AFF风险的患者。