Vascular Mechanisms Underlying Skeletal Fragility in Older Adults

血管供应对骨骼至关重要，但血管功能障碍对骨骼的临床意义 人们对骨骼的脆弱性知之甚少。研究表明血管疾病和 老年人的骨质疏松症。然而，目前尚不清楚血管功能障碍本身是否是这些疾病的基础。 联想。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会增加骨折风险 富含皮质的外周骨骼。我们的初步数据表明，血管变化与 高分辨率外周扫描评估的脆性骨折和皮质骨微结构缺陷增加 定量计算机断层扫描(HR-pQCT)。这些数据为我们拟议的工作提供了强有力的理由， 特别是因为以前没有研究全面调查血液流动的机制措施 大动脉和微循环都与骨骼脆性有关。我们的长期目标是改进 了解老年人的骨骼脆性，通过关注如何老化来减轻骨折的负担 血管系统的相关变化会影响外周骨骼。我们的中心假设是，有 更严重的主动脉僵硬和钝化的外周充血反应将有更严重的恶化 在皮质骨微结构中，骨强度丧失，骨折发生率较高。先进成像技术 HR-pQCT等技术提供了骨室体积的特定测量方法 密度和微结构，而无创血管眼压测量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。总而言之，这些创新提供了必要的工具 对骨骼脆性背后的血管机制的高级知识，并将确定新的靶点 预防骨折。因此，在弗雷明翰心脏研究的独特背景下，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；(2)确定 血管功能对骨密度、微结构和强度的纵向变化的贡献。vbl.使用 对血管功能障碍和皮质骨缺陷的最先进评估，调查小组拥有 经验和互补的专业知识领域，以成功地实现具体目标。通过识别 骨骼脆性背后的血管机制，这个项目有可能转变范式，提供 为减少老年人口骨折造成的巨大公共卫生负担而采取的干预措施的新目标。

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.