Changes in Periosteal and Endocortical Width Across the Menopausal Transition

项目摘要 对于女性来说，绝经过渡期（MT）是骨强度下降的关键时期，在此期间， 骨矿物质密度（BMD）的一半寿命损失发生。在临床和研究中，BMD是 作为骨质疏松症的主要指标，它不能揭示骨结构的变化， 与年龄有关的力量损失。这项建议旨在更好地阐明造成损失的结构性变化， 通过检查皮质内扩张（骨丢失）与骨膜扩张的相对变化， 骨增长（bone gain）这两个特征定义了骨强度，但是其中每一个特征的方式 MT期间的结构指数变化在很大程度上未被探索。我们的核心假设是骨骼强度 与骨窄的女性相比，骨宽的女性下降得更早更快。这 我们的流行病学和尸体研究中有希望的初步数据结果指导了这一假设， 表明个体化的力量下降轨迹可以在骨的初始阶段建立， 女性的损失，以及外部骨骼大小（例如，骨宽度、总横截面积）可以识别女性 在一个高危人群中。我们将首先验证新的骨强度指标，并测试 我们在尸体组织中的假设（目的1）。我们对尸体组织的研究表明， 与窄骨相比，宽骨中的孔隙率，表明不同的强度下降轨迹可能源于 基于BMU的重塑。因为这只能用组织切片来精确研究，我们将 将联合收割机尸体研究（目标1）与活体研究（目标2，3）结合起来，为 来自纵向数据的观察。我们将测试我们的中心假设使用两个现有的纵向 在40-60岁的妇女中，当她们从怀孕前过渡到怀孕后， 到绝经后我们将把基线骨性状与MT期间的结构和强度变化联系起来， 承重、易骨折骨（股骨近端）和非承重、非易骨折骨 （掌骨），以评估其诊断髋关节力量变化的临床价值。具体来说，我们建议 1)测试基线外部骨大小与MT期间强度指数变化之间的相关性， 白色妇女在密歇根州骨骼健康和代谢研究（MBHMS），然后2）测试是否 在MT期间，区分白色女性骨强度损失更多与更少的因素 MBHMS可以预测白色和黑人女性在MT中与MT相关的力量下降， 全国妇女健康研究20年（SWAN）。这项研究解决了一个重大差距， 科学知识阻碍了我们优化骨折预防策略的能力。如果我们的假设证明 正确的基线外骨骼大小可作为一个额外的参数，以确定最有可能 在MT期间迅速失去骨强度，并且可能从早期干预中受益。成功完成 我们的目标将提供有关具体结构和材料参数的基本新信息， 可以最好地为临床决策提供信息。

Project Summary For women, the menopausal transition (MT) is a critical period of decline in bone strength, during which about half the lifetime loss in bone mineral density (BMD) occurs. While clinically, and in research, BMD is the primary indicator for osteoporosis, it does not reveal the changes in bone structure needed to fully understand age-related loss in strength. This proposal seeks to better elucidate the structural changes that underlie loss in strength during the MT by examining relative changes in endocortical expansion (bone loss) versus periosteal expansion (bone gain). These two features define bone strength, but the manner in which each of these structural indices changes during the MT is largely unexplored. Our central hypothesis is that bone strength declines earlier and more rapidly in women with wide bones compared to women with narrow bones. This hypothesis is guided by promising preliminary data findings in our epidemiologic and cadaver studies which suggest that individualized trajectories of strength-decline may be established during the initial phase of bone loss for women, and that external bone size (e.g., bone width, total cross-sectional area) may identify women in a high fracture-risk group. We will first validate new bone strength indices and test for the biological basis of our hypothesis in cadaveric tissue (Aim 1). Our work in cadaveric tissue has shown greater intra-cortical porosity in wide compared to narrow bones, suggesting different strength-decline trajectories may arise from BMU-based remodeling. Because this can only be studied precisely using histological sections, we will combine cadaveric studies (Aim 1) with living human studies (Aims 2,3) to provide a biological basis for observations derived from longitudinal data. We will test our central hypothesis using two existing longitudinal databases with image-data acquired over 20 years among 40-60 year-old women as they transition from pre- to post-menopause. We will relate baseline bone traits to structural and strength changes during the MT in a weight-bearing, fracture prone bone (proximal femur) and a nonweight-bearing, non-fracture prone bone (metacarpal) to assess its clinical value for diagnosing strength changes at the hip. Specifically, we propose to 1) test for associations between baseline external bone size and changes in strength indices during the MT for white women in the Michigan Bone Health and Metabolism Study (MBHMS) and then 2) test whether the factors that differentiate between white women who lose more vs. less bone strength during the MT in the MBHMS are predictive of MT-related strength declines in white and black women followed across the MT over 20 years in the Study of Women’s Health Across the Nation (SWAN). This study addresses a significant gap in scientific knowledge that impedes our ability to optimize fracture prevention strategies. If our hypotheses prove correct, baseline external bone size may be used as an additional parameter to identify women most likely to lose bone strength rapidly during the MT and who might benefit from early intervention. Successful completion of our Aims will provide fundamental new information about what specific structural and material parameters can best inform clinical decisions.