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

 描述（由申请人提供）：在美国有1000万人患有骨质疏松症，并且大约一半已经用双膦酸盐治疗。双膦酸盐抑制骨吸收，并有效增加/维持骨矿物质密度和降低骨折发生率。最近，长期使用双膦酸盐与一种新认识的骨折类型有关，称为非典型股骨骨折（AFF）。有证据表明，AFFS是应力性骨折，随着时间的推移而发展，并且不会愈合。但导致AFFS的潜在原因和患者因素尚不清楚。一般来说，当骨微损伤的传播和融合速度超过破骨细胞启动的重塑修复速度时，就会发生应力性骨折。双膦酸盐可能通过抑制骨吸收和修复骨微损伤的偶联重建来增加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AFFs。AFFS的原因不明的一个原因是缺乏合适的动物模型来研究病理生理学。事实上，2010年美国骨与矿物质研究协会的工作组指出，“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性骨折模型。这些特征包括：应力性骨折在拉伸侧发展，以及应力性骨折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。通过新模型，我们将开始检验一般假设，即双膦酸盐通过干扰骨微损伤的靶向重塑而增加不愈合应力性骨折的风险。临床相关的应力性骨折模型的发展将提供一个新的工具来阐明AFFs的发病机制，包括双膦酸盐的作用。开发适合转化骨生物学未满足需求的新型模型适合R21资助机制。

 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.