Long term fracture risk and change in peripheral bone in the oldest old men: The MrOS study

在这个竞争性修订申请中，我们的目标是解决三个关键目标，以了解决定因素 以及骨折和周围骨丢失的影响。 在我们的第一个目标，我们将描述骨折的情况下，在最古老的老。我们将利用 对MrOS男性进行纵向随访，以仔细确定年龄最大的男性中发生骨折的情况。 居住在社区的老人我们假设，骨折的类型和情况将不同， 活跃的非虚弱男性与不活跃的虚弱男性相比。 在我们的第二个目标中，我们将提高对年龄相关的外周骨丢失的理解。开大宗 骨折对周围骨骼的影响，我们将分析最近获得的5年随访HR-pQCT 测量外周骨微结构，以了解外周骨骼的骨骼脆弱性。 具体而言，我们将a）确定老年男性外周骨丢失的速率和特征。我们假设 我们将识别皮质骨与松质骨退化的不同模式;皮质骨丢失 通过µFEA分析，与骨小梁丢失相比，对骨强度下降的贡献更大，B）确定是否低 肌肉质量和低活动性与外周骨丢失有关。我们假设他们会很强壮， 骨丢失的独立预测因子，以及c）利用系统生物学方法来鉴定新的途径 与周围骨密度、结构和强度的损失有关。我们假设最先进的多- 组学方法，利用全面的蛋白质组学和代谢组学措施，将确定生物 与老年男性外周骨丢失增加和结构下降相关的通路。 在我们的第三个目标中，我们将确定髋关节和脊柱CT预测老年男性骨折风险的实用性。与FDA 批准和最近授予CPT代码，使用腹部盆腔CT图像获取老年医疗 原因有希望作为一个新的临床范例，以扩大那些在骨折的高风险的识别。 我们将使用现有的MrOS CT扫描计算3695名男性的骨强度新估计值，以解决关键问题。 如何最好地利用CT-FEA进行断裂预测的知识差距。具体而言，我们将a）确定 髋关节和脊柱的CT-FEA骨强度是否可预测短期和长期骨折风险。我们 假设股骨和椎骨强度的组合比任何一个更好地预测骨折事件 股骨和椎骨强度预测短期和长期骨折风险以及DXA- BMD，和B）模拟多个跌倒载荷方向以量化髋关节强度。我们把股骨的力量 “最弱”载荷方向比“标准”侧向跌落载荷方向更好地预测髋部骨折。 MrOS是唯一适合解决几个关键的临床和机械知识差距，有关骨骼 老年人的脆弱性这项研究的全面的骨成像，长期的随访和非常老的年龄， 队列提供了前所未有的机会，以产生新的信息。

In this competitive revision application, we aim to address three critical aims to understand the determinants and impact of fractures and peripheral bone loss in the ongoing MrOS study. In our first aim, we will characterize circumstances of fractures in the oldest old. We will leverage the longitudinal follow-up of MrOS men to carefully determine the circumstances of incident fractures in the oldest old, community-dwelling men. We hypothesize that the types and circumstances of fractures will differ between active non-frail men compared to inactive frail men. In our second aim, we will improve understanding of age-related loss of peripheral bone. Given the large impact of fractures in the peripheral skeleton, we will analyze recently obtained 5-year follow-up HR-pQCT measures of peripheral bone microarchitecture to gain insight into skeletal fragility in the peripheral skeleton. Specifically, we will a) establish the rate and character of peripheral bone loss in older men. We hypothesize that we will identify distinct patterns of cortical vs. trabecular bone deterioration; with cortical bone loss contributing more to declines in bone strength by µFEA than trabecular bone loss, b) determine whether low muscle mass and low activity are related to peripheral bone loss. We hypothesize that they will be robust, independent predictors of bone loss, and c) utilize systems biology approaches to identify novel pathways related to loss of peripheral bone density, structure and strength. We hypothesize that state-of-the-art multi- omic approaches, leveraging comprehensive proteomic and metabolomic measures, will identify biological pathways associated with increased peripheral bone loss and structural declines in older men. In our third aim, we will determine the utility of hip and spine CT to predict fracture risk in older men. With FDA approval and recent awarding of a CPT code, use of abdominal-pelvic CT images acquired for older medical reasons holds promise as a new clinical paradigm to expand the identification of those at high risk of fractures. We will compute new estimates of bone strength in 3695 men with existing MrOS CT scans to address key knowledge gaps for how to best utilize CT-FEA for fracture prediction. Specifically, we will a) determine whether bone strength from CT-FEA at the hip and spine predicts short- and long-term with fracture risk. We hypothesize that the combination of femoral and vertebral strength predicts incident fracture better than either alone, and that femoral and vertebral strength predict both short- and long-term fracture risk as well as DXA- BMD, and b) simulate multiple fall-loading directions to quantify hip strength. We posit that femoral strength in the “weakest” loading direction better predicts hip fracture than the “standard” sideways fall loading direction. MrOS is uniquely suited to address several key clinical and mechanistic knowledge gaps regarding skeletal fragility in older men. The study's comprehensive bone imaging, its long follow-up and the very old age of the cohort provide unparalleled opportunities to generate novel information.