An Improved Stress Fracture Model to Study Drug Effects on Bone Damage Repair

 描述(申请人提供)：美国有1000万骨质疏松症患者，其中约一半接受过双膦酸类药物治疗。双膦酸盐抑制骨吸收，在增加/保持骨密度和减少骨折发生率方面有效。最近，长期使用双磷酸盐与一种新发现的称为非典型股骨骨折(AFF)的骨折有关。有证据表明，AFF是应力性骨折，会随着时间的推移而发展，不会愈合。但导致AFF的潜在原因和患者因素尚不清楚。一般来说，当骨微损伤扩散和愈合的速度快于破骨细胞启动的重建修复时，应力性骨折就会发生。双膦酸盐可能通过抑制骨吸收和应修复骨微损伤的耦合重塑而增加AFF的风险。然而，没有直接证据表明抑制损伤驱动的重塑有助于AFF。AFF病因不明的一个原因是缺乏合适的动物模型来研究其病理生理学。事实上，美国骨与矿物研究协会2010年的特别工作组表示，“需要开发更准确地模拟非典型骨折的动物模型”。该R21项目的目标是开发一种具有非典型股骨骨折关键特征的新型应力骨折模型。这些特征包括：在拉伸侧发生应力性骨折，以及在应力性骨折之前存在微损伤驱动的骨重建。目前的应力性骨折模型缺乏这些临床相关特征。通过新的模型，我们将开始检验一般的假设，即双膦酸盐通过干扰骨微损伤的靶向重塑而增加非愈合性应力性骨折的风险。临床相关应力性骨折模型的建立将为阐明AFF的发病机制提供新的工具，包括双膦酸盐的作用。开发一种新的模型，以满足翻译骨生物学中尚未满足的需求，是适合R21资助机制的。

 DESCRIPTION (provided by applicant): There are 10 million people with osteoporosis in the U.S., and approximately one-half have been treated with bisphosphonates. Bisphosphonates suppress bone resorption, and are effective in increasing/maintaining bone mineral density and reducing fracture incidence. Recently, long-term bisphosphonate use has been linked to a newly recognized type of bone fracture called an atypical femoral fracture (AFF). Evidence suggests that AFFs are stress fractures that develop over time and do not heal. But the underlying causes and patient factors contributing to AFFs are not known. In general, stress fractures develop when bone microdamage propagates and coalesces faster than it can be repaired by osteoclast-initiated remodeling. Bisphosphonates may increase the risk of AFF by inhibiting bone resorption and the coupled remodeling that should repair bone microdamage. However, there is no direct evidence that suppression of damage-driven remodeling contributes to AFFs. One reason why the cause of AFFs is unknown is the lack of a suitable animal model to study the pathophysiology. In fact, the 2010 task force of the American Society of Bone and Mineral Research stated that "animal models that more accurately mimic atypical fractures need to be developed". The goal of this R21 project is to develop a novel stress fracture model with the key features of an atypical femur fracture. These features include: stress fracture developing on the tensile side, and presence of microdamage-driven bone remodeling prior to stress fracture. Current stress fracture models lack these clinically relevant features. With the new model we will begin to test the general hypothesis that bisphosphonates increase the risk of a non-healing stress fracture by interfering with targeted remodeling of bone microdamage. Development of a clinically relevant stress fracture model will provide a new tool to elucidate the pathogenesis of AFFs including the role of bisphosphonates. Development of a novel model that fits an unmet need in translational bone biology is appropriate to the R21 funding mechanism.