Vascular Mechanisms Underlying Skeletal Fragility in Older Adults

血管供应对骨骼至关重要，但血管功能障碍的临床意义， 骨骼脆弱性知之甚少。研究表明，血管疾病与 老年人的骨质疏松症然而，尚不清楚血管功能障碍本身是否是这些疾病的基础。 协会.我们建议使用亚临床血管张力测量和血流动力学测量来测试 假设血管损伤对皮质骨微结构产生负面影响， 皮质丰富的外周骨骼我们的初步数据表明，血管变化与 脆性骨折增加和皮质骨微结构缺陷，通过高分辨率外周血细胞计数评估 定量计算机断层扫描（HR-pQCT）。这些数据为我们提出的工作提供了强有力的理由， 特别是因为以前的研究没有全面研究血液流动的机械测量， 大动脉和微循环与骨骼脆弱性的关系。我们的长期目标是改善 了解老年人的骨骼脆弱性，以减少骨折的负担，通过关注衰老如何 脉管系统中的相关变化影响外周骨骼。我们的中心假设是， 主动脉僵硬和外周充血血流反应迟钝越严重，恶化越严重 在皮质骨微结构中，骨强度损失，和骨折发生率较高。先进的成像 技术，如HR-pQCT，提供体积骨的体积骨室特异性测量 密度和微结构，而非侵入性血管张力测定和血流动力学提供了关键的洞察力， 大动脉和微血管缺陷的起源。总之，这些创新提供了必要的工具， 推进骨骼脆弱性的血管机制的知识，并将确定新的目标， 骨折预防因此，在心脏病研究的独特背景下，我们将解决以下问题 具体目标：（1）确定血管功能对骨折发生率的贡献，以及（2）确定 血管功能对骨密度、微结构和强度纵向变化的贡献。使用 血管功能障碍和皮质骨缺损的最先进评估，研究小组有 经验和互补的专门知识领域，以成功实现具体目标。通过识别 血管机制的骨骼脆弱性，这个项目有可能是范式转变，提供 新的干预目标，以减少我们老年人口骨折的巨大公共卫生负担。

The vascular supply is critically important to the skeleton, yet the clinical implications of vascular dysfunction for skeletal fragility are poorly understood. Studies demonstrate associations between vascular disease and osteoporosis in older adults. However, it is unknown whether vascular dysfunction itself underlies these associations. We propose to use subclinical vascular tonometry and hemodynamic measures to test the hypothesis that vascular impairments negatively affect cortical bone microarchitecture increasing fracture risk in the cortical-rich peripheral skeleton. Our preliminary data demonstrate that vascular changes are associated with increased fragility fractures and deficits in cortical bone microstructure, as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT). These data provide strong rationale for our proposed work, particularly since no previous studies have comprehensively investigated mechanistic measures of blood flow in both large arteries and microcirculation in relation to skeletal fragility. Our long-term goal is to improve understanding of skeletal fragility in older adults to reduce the burden of fractures, by focusing on how aging related changes in the vasculature affect the peripheral skeleton. Our central hypothesis is that individuals with more severe aortic stiffness and blunted peripheral hyperemic flow response will have more severe deterioration in cortical bone microarchitecture, loss of bone strength, and higher incidence of fracture. Advanced imaging techniques, such as HR-pQCT, provide volumetric skeletal compartment specific measures of volumetric bone density and microarchitecture, while non-invasive vascular tonometry and hemodynamics lend key insight into the origins of large artery and microvascular deficits. Together, these innovations provide necessary tools to advance knowledge of the vascular mechanisms underlying skeletal fragility, and will identify novel targets for fracture prevention. Thus, in the unique setting of the Framingham Heart Study, we will address the following specific aims: (1) Determine the contribution of vascular function to incidence of fracture, and (2) Determine the contribution of vascular function to longitudinal changes in bone density, microarchitecture, and strength. Using state-of-the-art assessments of vascular dysfunction and cortical bone deficits, the investigative team has the experience and complementary areas of expertise to successfully carry out the specific aims. By identifying the vascular mechanisms underlying skeletal fragility, this project has the potential to be paradigm shifting, providing new targets for interventions to reduce the tremendous public health burden of fractures in our older population.