Effects of DHEA and exercise on bone marrow fat in postmenopausal women

摘要 美国65岁以上人口的比例将从2000年的12.7%增加到2050年的20.3%， 预计到2025年，骨折数量将超过300万，相关成本约为25.3美元 每年10亿。DAMES是一项正在进行的临床试验（NCT 03227458），旨在首次评估- 治疗后的面积骨密度（aBMD）和去脂质量（FFM）的变化 肾上腺皮质类固醇脱氢表雄酮（DHEA）单独和联合骨负荷运动（EX）在老年人 骨质流失的女性DAMES中提出的激素和机械策略代表了一种低成本的 替代治疗，以改善骨量与其他一些健康的好处，不提供典型的 药理学方法。然而，骨强度-骨折的主要决定因素-是以下因素的函数： 不仅骨密度和微观结构，而且其微环境，包括骨髓脂肪（BMF）。这 DAMES临床试验的辅助研究在这里，我们建议利用特征良好的队列， 受试者，运动训练，来自DAMES的临床，实验室和成像数据，并添加一小组 对照组的三个现有组（仅DHEA、EX+安慰剂和EX+DHEA），以研究DHEA的作用 使用先进的成像、数字工程和图像分析对老年女性BMF的治疗和EX 技术.特别是，我们的目标是确定在腰椎和髋关节的老年妇女与低骨量 或中度骨质疏松症：1）DHEA或EX是否导致BMF含量变化; 2）BMF含量是否 与基线时的骨强度相关，以及BMF含量的变化是否与 骨强度的变化，评估DHEA或EX对这些关联的影响;以及3）空间 响应于DHEA或EX的BMF含量变化的分布。将使用化学位移测量BMF- 基于水脂分离磁共振成像，骨强度将估计与有限元 定量计算机断层扫描建模，以及BMF空间分布的差异 使用基于体素的形态测定法评估组间的变化。最终，我们将利用 DAMES临床试验揭示了新的信息，以提高我们对DHEA和EX对骨量的理解 和质量本辅助提案中骨质量的纵向评估，以及骨数量的纵向评估 在母体研究中，已经失去骨量的女性是前所未有的。了解如何 骨质疏松症的治疗-包括运动-对BMF的作用可能导致产生新的方法， 骨折风险评估、治疗监测程序和骨丢失治疗。

ABSTRACT The proportion of the U.S. population older than 65 years will increase from 12.7% in 2000 to 20.3% in 2050, and the number of fractures is expected to exceed 3 million by 2025 with associated costs in the order of $25.3 billion per year. DAMES is an ongoing clinical trial (NCT03227458) that aims to assess –for the first time– changes in areal bone mineral density (aBMD) and fat-free mass (FFM) in response to therapy with the adrenal steroid dehydroepiandrosterone (DHEA) alone and combined with bone-loading exercise (EX) in older women with bone loss. The hormonal and mechanical strategies proposed in DAMES represent a low-cost alternative treatment to improve bone quantity with a number of other health benefits not afforded by typical pharmacological approaches. However, bone strength –the main determinant of bone fracture– is a function of not only BMD and microstructure, but also of its microenvironment, including bone marrow fat (BMF). This in an ancillary study to the DAMES clinical trial. Here, we propose to leverage the well-characterized cohort of subjects, exercise training, clinical, laboratory and imaging data from DAMES, and add a small group of controls to its three existing arms (DHEA only, EX+Placebo, and EX+DHEA) to investigate the effects of DHEA therapy and EX on BMF in older women using advanced imaging, numerical engineering, and image analysis techniques. In particular, we aim to determine in the lumbar spine and hip of older women with low bone mass or moderate osteoporosis: 1) whether DHEA or EX leads to changes in BMF content; 2) whether BMF content is associated with bone strength at baseline, and whether changes in BMF content are associated with changes in bone strength, evaluating the impact of DHEA or EX on these associations; and 3) the spatial distribution of changes in BMF content in response to DHEA or EX. BMF will be measured with chemical shift– based water-fat separation magnetic resonance imaging, bone strength will be estimated with finite element modeling from quantitative computed tomography scans, and differences in the spatial distribution of BMF changes between groups will be assessed using voxel-based morphometry. Ultimately, we will leverage the DAMES clinical trial to unveil new information to improve our understanding of DHEA and EX on bone quantity and quality. The longitudinal assessments of bone quality in this ancillary proposal, with those of bone quantity in the parent study, in women who have already lost bone mass is unprecedented. Understanding how osteoporosis treatments –including exercise– act on BMF could lead to the generation of novel approaches for fracture risk assessment, procedures for therapy monitoring, and treatments for bone loss.