Bone Microarchitecture: The Framingham Osteoporosis Study

描述（由申请人提供）：骨质疏松症在美国影响着超过2800万人，骨质疏松症相关发病率的终生风险高于女性患乳腺癌、子宫内膜癌和卵巢癌的总风险。骨质疏松症患者的医疗保健支出目前每年近130亿美元，预计由于人口老龄化，这一支出将显著增加；因此，了解影响骨强度和骨折风险的因素非常重要。随着高分辨率外周定量计算机断层扫描（HR-pQCT）等骨骼成像方式的出现，现在可以确定骨微结构对骨折风险的影响。这项R01应用是一项新的建议，旨在利用HR-pQCT对Framingham后代队列进行时间敏感的成像，以了解生活方式和遗传因素对骨微结构的影响，并确定骨微结构是否提供了与传统双能x射线吸收仪（DXA）无关的额外骨折风险信息。这个建议是“时间敏感的”，因为第9次子代检查开始于2011年春天，我们被批准在完成第9次研究访问后对后代中2565名幸存的女性和男性进行HR-pQCT扫描。我们将在Framingham后代队列中使用三维HR-pQCT测量1411名女性和1154名男性的体积骨密度、骨微结构和桡骨远端和胫骨远端骨强度。利用这些数据，我们将确定45-100岁男性和女性体重、身体活动、骨折史、钙摄入量、维生素D摄入量和酒精使用与骨微结构之间的关系。由于该队列的长期随访，我们将能够使用短期和长期暴露数据评估这些因素对骨微结构的影响。此外，我们将通过在来自瑞典的Framingham队列中进行全基因组关联研究（GWAS）来确定遗传对骨微结构的影响，并将在来自Mayo诊所的第三个队列中获得全基因组密集基因分型。对这3个发现队列的GWAS荟萃分析结果将在其他5个具有相同hr - pqct衍生测量和可用全基因组基因分型或DNA的队列中重复。最后，在Framingham以及合作的GWAS队列中，我们还将确定骨微结构和通过微有限元分析测量的骨强度对女性和男性非椎体脆性骨折发生率的贡献，并确定骨微结构与女性和男性骨折发生率之间的关联是否独立于DXA面积骨密度和“FRAX(R)”风险评分。这项研究意义重大，因为它将是在一个特征明确的人群中进行的最大的以社区为基础的研究，以检查骨微结构的危险因素，第一个进行微结构与复制的全基因组关联研究，以及第一个检查骨微结构和强度对骨折发生率贡献的前瞻性研究。

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.