Risk Factors for Age Related Bone Loss

 描述(由申请人提供)：弗雷明翰骨质疏松症研究(R01 AR41398“年龄相关骨丢失的风险因素”)是弗雷明翰心脏研究的辅助研究，在过去25年中对了解导致骨质疏松症、骨质疏松症和骨折的遗传和生活方式因素做出了重大贡献。基于日益流行的肥胖，以及关于内脏肥胖对肌肉骨骼健康的作用的相互矛盾的数据，在Framingham骨质疏松症研究的继续中，我们将确定内脏脂肪组织(VAT)对骨密度、微结构和强度以及肌肉密度和骨折的作用。我们提出了三个目标。在目标1中，为了确定VAT与骨密度、微结构和强度之间的关联，我们将使用纵向全身DXA扫描来测量VAT(这是先前获得的基线，后续将作为该项目的一部分获得)，并在Framingham Study第三代队列(Gen3)的临床访问期间对桡骨远端和胫骨进行高分辨率外周定量计算机断层扫描(HR-pQCT)测量。在目标2中，我们将使用已经在Gen3队列中获得的纵向QCT扫描来确定VAT和肌肉密度之间的关联。对于目标1和目标2，我们还将确定增值税对骨密度、微结构和强度(目标1)以及肌肉密度(目标2)的影响是否部分归因于体力活动水平、炎症、脂肪因子或性类固醇代谢。在目标3中，我们将进行孟德尔随机化分析，通过使用遗传风险分数(“工具变量”)来预测骨折事件，从而获得对VAT-骨折相关性的无偏估计。这项拟议的研究将是关于内脏肥胖对肌肉骨骼系统潜在有害影响的最大规模的调查。我们的每个假设都是基于我们过去的资助周期或其他涉及弗雷明翰研究的研究资助的初步数据。该项目之所以意义重大，有几个原因。首先，肥胖已经成为美国最重要的健康问题之一。其次，内脏肥胖对肌肉骨骼系统的确切作用之前还没有研究过，拟议的工作将填补这一空白，特别是利用增值税的纵向数据，并使用现有的CT扫描获得肌肉密度的纵向测量。第三，我们将研究增值税对肌肉骨骼系统影响的潜在潜在机制。最后，我们将通过孟德尔随机化分析得到VAT-骨折相关性的无偏估计。总体而言，这项研究的结果将为内脏肥胖对肌肉骨骼系统的影响提供最好的可用数据。

 DESCRIPTION (provided by applicant): The Framingham Osteoporosis Study (R01 AR41398 "Risk Factors for Age Related Bone Loss"), an ancillary study of the Framingham Heart Study, has contributed significantly over the past 25 years to the understanding of genetic and lifestyle factors contributing to osteoporosis, sarcopenia, and fractures. Based on the growing epidemic of obesity, and conflicting data regarding the role of visceral adiposity on musculoskeletal health, in this continuation of the Framingham Osteoporosis Study, we will determine the role of visceral adipose tissue (VAT) on bone density, microarchitecture, and strength, as well as on muscle density, and fracture. We are proposing three aims. In Aim 1, to determine the association between VAT and bone density, microarchitecture, and strength, we will measure VAT using longitudinal whole body DXA scans (a baseline previously obtained, and a follow up to be acquired as part of this project) and perform High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT) measurements of the distal radius and tibia, and during a clinic visit of the Framingham Study 3rd Generation Cohort (Gen3). In Aim 2 we will determine the association of VAT and muscle density using longitudinal QCT scans already obtained in the Gen3 Cohort. For both Aim 1 and Aim 2, we will also determine if the effects of VAT on bone density, microarchitecture and strength (Aim 1), and on muscle density (Aim 2), are partly attributable to physical activity levels, inflammation, adipokines, or sex steroid metabolism. In Aim 3, we will perform a Mendelian randomization analysis to obtain an unbiased estimate of the VAT-fracture association by using a genetic risk score ("instrumental variable") to predict incident fracture. The proposed study will be the largest investigation of the potentially deleterious effects of visceral adiposity on the musculoskeletal system. Each of our hypotheses is based on preliminary data from our past grant cycle or from other research grants involving the Framingham Study. The project is significant for several reasons. First, obesity has become one of the most important health problems in the U.S. Second, the precise role of visceral adiposity on the musculoskeletal system has not been previously investigated, and the proposed work will fill this gap, especially with longitudinal data on VAT and to be obtained longitudinal measures of muscle density using existing CT scans. Third, we will investigate potential underlying mechanisms for the effects of VAT on the musculoskeletal system. Finally we will obtain an unbiased estimate of the VAT-fracture association using Mendelian randomization analysis. Overall, the results of this study will provide the best available data on the effects of visceral adiposity on the musculoskeletal system.