Role of Bone Tissue Material Properties in Atypical Femoral Fractures

描述(由申请人提供)：在骨质疏松患者的临床治疗中，长期使用双膦酸盐可能会增加非典型股骨骨折的风险，这是一个日益令人担忧的问题。这些骨折发生在股骨粗隆下或骨干区域，创伤很小，通常没有摔倒。虽然非典型股骨骨折无疑是罕见的，但它们的后果是深远的，并改变了人们的生活，因此必须确定它们是否与双磷酸盐有关。我们的长期目标是确定非典型股骨骨折的潜在机制，以便更好地识别谁是这些罕见骨折的危险因素，并改进关于启动或中断的临床决策。 双膦酸类药物治疗。目前，关于谁可能易患上与双膦酸盐相关的非典型股骨骨折的认识存在巨大的差距。因此，本研究的目的是确定一种新的微创活体测量皮质骨材料特性的方法是否可以识别那些有非典型股骨骨折风险的人。我们的工作假设是，患有非典型股骨骨折的女性改变了皮质骨材料的特性，使她们容易患上这种罕见的骨折。我们进一步认为，这些改变的骨基质属性是临床上无法检测到的传统检测方法，如骨密度，骨转换标志物或骨微结构。为了验证这一假设，我们提出了两个目标：目的1)确定患有非典型股骨骨折的女性是否改变了被称为参考点压痕的新的微创方法在体内评估的皮质骨材料特性；以及目的2)确定通过体内参考点压痕评估的皮质骨材料特性的预测因子。对于目标1，我们将比较三组绝经后妇女的皮质骨材料特性，通过在胫骨中段的新型活体压痕进行评估：1)最近有非典型股骨骨折的妇女(n=25)；2)长期(e 5岁)使用双磷酸盐的妇女(n=25)；以及3)年龄相似的对照组(n=50)。此外，我们将通过DXA评估髋部和脊柱的骨密度，并通过高分辨率外周定量计算机断层扫描(HR-pQCT)评估胫骨远端的体积密度和微结构。对于目标2，将通过HR-pQCT确定体内压痕测量与髋部和脊柱骨密度以及体积骨密度和微结构之间的关联。该项目的成功完成将解决解决紧迫临床问题所需的知识的关键缺口。 在使用双膦酸盐相关的非典型股骨骨折的研究中，还将提供有关微创活体骨压痕测量可能的临床应用的新信息。根据R21机制的目标，我们将使用新的技术和概念方法来克服目前在这一领域取得进展的障碍。尽管风险很高，但这项拟议的研究可能会对骨质疏松症患者的临床治疗产生重大影响。

DESCRIPTION (provided by applicant): The possibility that long-term bisphosphonate use increases the risk of atypical femoral fractures is a growing concern in the clinical management of patients with osteoporosis. These fractures occur in the subtrochanteric or diaphyseal region of the femur with minimal trauma, usually without a fall. While atypical femoral fractures are undoubtedly rare, their consequences are profound and life altering, making it imperative to determine whether they are linked to bisphosphonates. Our long term goal is to determine the mechanisms underlying atypical femoral fractures, in order to better identify who is at risk for these rare fractures, and improve clinical decision making regarding the initiation or interruption of bisphosphonate therapy. Currently, there is a huge gap in knowledge about who may be susceptible to developing a bisphosphonate-related atypical femoral fracture. Thus, the objective of the current study is to determine whether a novel minimally invasive method for in vivo measurement of cortical bone material properties can identify those who are at risk for atypical femoral fractures. Our working hypothesis is that women with atypical femoral fractures have altered cortical bone material properties that make them susceptible to this rare fracture. We further posit that these altered bone matrix properties are not clinically detectable with traditional testing methods, such as BMD, bone turnover markers or bone microarchitecture. To test this hypothesis, we propose two aims: Aim 1) Determine whether women with atypical femoral fractures have altered cortical bone material properties, as assessed in vivo by a new minimally invasive approach called reference point indentation; and Aim 2) Determine the predictors of cortical bone material properties assessed by in vivo reference point indentation. For Aim 1, we will compare cortical bone material properties, as assessed by novel in vivo indentation at the mid-tibia, in three groups of postmenopausal women: 1) those with recent atypical femoral fractures (n=25); 2) long term (e 5 yrs) bisphosphonate users (n=25); and 3) age-similar controls with no bisphosphonate exposure (n=50). In addition, we will assess hip and spine BMD by DXA, and volumetric density and microarchitecture by high- resolution peripheral quantitative computed tomography (HR-pQCT) at the distal tibia. For Aim 2 will determine the association between in vivo indentation measures and hip and spine BMD, as well as volumetric bone density and microarchitecture by HR-pQCT. Successful completion of this project will address a critical gap in knowledge needed to address the pressing clinical issue of atypical femoral fractures associated with bisphosphonate use, and will also provide novel information about possible clinical utility of minimally invasive, in vivo bone indentation measurements. In line with the goals of the R21 mechanism, we will use novel technical and conceptual approaches to overcome current barriers to progress in the field. Albeit high risk, the proposed study has the potential to have a major impact on clinical management of patients with osteoporosis.