Bone Microarchitecture: The Framingham Osteoporosis Study

描述(申请人提供)：美国有2800多万人患有骨质疏松症，患骨质疏松症相关疾病的终生风险高于女性患乳腺癌、子宫内膜癌和卵巢癌的风险总和。目前，骨质疏松症患者的医疗保健支出每年近130亿美元，预计由于人口老龄化，这一支出将大幅增加；因此，重要的是了解影响骨骼强度和骨折风险的因素。随着高分辨率外周定量计算机断层扫描(HR-pQCT)等骨骼成像手段的出现，现在可以确定骨骼微结构对骨折风险的贡献。这项R01应用是一项新的提议，旨在资助一个时间敏感的机会，使用HR-pQCT对Framingham子代队列进行成像，以了解导致骨微结构的生活方式和遗传因素，并确定骨微结构是否提供了独立于传统双能X射线吸收测量(DXA)的有关骨折风险的额外信息。这项提议是“时间敏感的”，因为第9次子女检查于2011年春季开始，我们获准在完成第9次研究访问后，对2565名在世的子女进行HR-pQCT扫描。我们将使用三维HR-pQCT测量Framingham后代队列中1,411名女性和1,154名男性的桡骨远端和胫骨远端的体积骨密度、骨微结构和骨强度。使用这些数据，我们将确定体重、体力活动、既往骨折、钙摄入量、维生素D摄入量、饮酒和骨微结构之间的关系，年龄在45-100岁的男性和女性。由于这一队列的长期随访，我们将能够使用短期和长期暴露数据来评估这些因素对骨微结构的影响。此外，我们将通过在瑞典的Framingham队列中进行全基因组关联研究(Gwas)来确定基因对骨微结构的贡献，并将在梅奥诊所的第三个队列中获得全基因组密集基因分型。GWAS对这3个发现队列的荟萃分析的结果将在具有相同的HR-pQCT衍生措施和可用的全基因组基因分型或DNA的其他5个队列中复制。最后，在Framingham以及合作的GWAS队列中，我们还将确定通过微观有限元分析测量的骨骼微结构和骨强度对女性和男性非脊椎脆性骨折发生率的贡献，并确定女性和男性骨骼微结构和骨折发生率之间的关联是否独立于DXA面骨密度和“FRAX(R)”风险评分。这项研究具有重要意义，因为它将是在一个具有良好特征的人群中最大的以社区为基础的研究，以检查骨微结构的危险因素，第一次进行全基因组微结构与复制的关联研究，以及第一次检查骨微结构和强度对骨折发生率的贡献的前瞻性研究。 公共卫生相关性：这项研究与公共健康相关，因为如果我们证明骨骼微结构为预测骨折风险增加了重要信息，这可能会通过促进新的成像工具的开发而改变医疗实践，这些工具将变得更广泛。此外，通过研究这些微结构和骨强度表型，我们可能有更好的机会发现有助于骨骼完整性的基因，而不是使用面积骨密度。这将为风险分层以及确定治疗发展的新靶点提供重要信息。

DESCRIPTION (provided by applicant): Osteoporosis affects more than 28 million people in the U.S. and the lifetime risk for osteoporosis-related morbidity is higher than a woman's combined risk for breast, endometrial and ovarian cancer combined. Health care expenditures for osteoporotic patients are currently nearly 13 billion dollars per annum and are predicted to increase markedly due the aging of the population; therefore, it is important to understand the factors that contribute to bone strength and fracture risk. With the advent of skeletal imaging modalities such as high resolution peripheral quantitative computed tomography (HR-pQCT), it is now possible to determine the contribution of bone microarchitecture to the risk for fracture. This R01 application is a new proposal to fund a time-sensitive opportunity to image the Framingham Offspring Cohort using HR-pQCT to understand lifestyle and genetic factors contributing to bone microarchitecture, and to determine if bone microarchitecture provides additional information about fracture risk independent of traditional dual-energy X-ray absorptiometry (DXA). This proposal is "time sensitive" because the 9th Offspring examination began in the spring of 2011, and we are approved to perform HR-pQCT scans on 2,565 surviving women and men in the Offspring following completion of their 9th study visit. We will measure volumetric BMD, bone microarchitecture and bone strength at the distal radius and distal tibia using three-dimensional HR-pQCT in 1,411 women and 1,154 men in the Framingham Offspring Cohort. Using these data we will determine the association between weight, physical activity, prior fracture, calcium intake, vitamin D intake, and alcohol use and bone microarchitecture in men and women, aged 45-100 years. Because of long-term follow-up of this cohort, we will be able to evaluate the influence of these factors on bone microarchitecture using both short-term and long-term exposure data. In addition we will determine the genetic contribution to bone microarchitecture by performing a genome-wide association study (GWAS) in the Framingham Cohort, a cohort from Sweden, and will obtain genome wide dense genotyping in a third cohort from the Mayo Clinic. Results from a GWAS meta-analysis of these 3 discovery cohorts will be replicated in 5 other cohorts who have the same HR-pQCT-derived measures and available genome-wide genotyping or DNA. Finally, in Framingham as well as the collaborating GWAS cohorts, we will also determine the contribution of bone microarchitecture, and bone strength measured by micro-finite element analysis, to incidence of non-vertebral fragility fracture in women and men, and determine if the association between bone microarchitecture and fracture incidence in women and men is independent of DXA areal BMD and "FRAX(R)" risk score. This study is significant because it will be the largest community-based study in a well- characterized population to examine risk factors for bone microarchitecture, the first to conduct a genome wide association study of microarchitecture with replication, and the first prospective study to examine the contribution of bone microarchitecture and strength to fracture incidence. PUBLIC HEALTH RELEVANCE: This research is relevant to public health because if we demonstrate that bone microarchitecture adds important information to the prediction of fracture risk, this could change medical practice by promoting the development of new imaging tools that would become more widely accessible. Also by studying these microarchitecture and bone strength phenotypes, we may have a better chance of discovering genes that contribute to skeletal integrity than has been possible using areal BMD. This would provide important information to risk stratification as well as the possibility of identifying new targets for theraputic development.