Vascular Mechanisms Underlying Skeletal Fragility in Older Adults

血管供应对骨骼至关重要，然而血管功能障碍的临床意义

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.