Bone Robustness as a Biomarker of Skeletal Aging and Fragility

描述（由申请人提供）：减少与年龄相关的脆性骨折仍然是肌肉骨骼研究的主要目标。目前，骨折风险增加是在个体失去骨量和力量后诊断出来的。这种策略作为长期的骨折复位策略并不是最佳的，因为它会导致短暂的强度损失，在治疗前不必要地增加了骨折的风险。理想的骨折复位策略应该是长期保持骨强度，而不是在骨明显丢失后试图替换骨。然而，我们缺乏关于骨骼衰老的个体间差异的关键信息，这限制了现有技术在与年龄相关的骨质流失之前准确预测一个人未来的骨骼强度。我们研究了骨骼的复杂适应性，发现了一种共同的形态学特征，即坚固性，这可能作为一种新的生物标志物，用于预测生命早期的骨折风险，并为了解脆性相关的生物活性提供见解。健壮性（相对于长度的横向尺寸的测量）是在出生后早期建立的，个体之间差异很大。我们的主要发现是，健全性的自然变化伴随着皮质面积和组织矿物质密度的高度协调变化。我们在人骨方面的工作在全骨刚度（机械稳态）的背景下建立了这些功能相互作用，并且所检查的特征在很大程度上仅限于那些可以非侵入性测量的特征。其他基质变量（如胶原交联）协调调整以适应鲁棒性自然变化的程度，这些扩展特性之间的功能相互作用如何影响抗断裂性能（如强度、延展性、韧性、疲劳性），以及这些关系如何随老化而变化

DESCRIPTION (provided by applicant): Reducing age-related fragility fractures remains a major objective of musculoskeletal research. Currently, increased fracture risk is diagnosed after an individual loses bone mass and strength. This strategy is not optimal as a long-term fracture reduction strategy because it leads to a transient loss in strength that unnecessarily increases fracture risk prior to treatment. An ideal fracture-reduction strategy would aim to maintain bone strength over time rather than attempt to replace bone after significant loss. However, we lack crucial information about inter-individual differences in skeletal aging that limits existing technologies from accurately predicting a person's future bone strength prior to age-related bone loss. Our research examining the complex adaptive nature of bone identified a common morphological trait, robustness, that may serve as a new biomarker for predicting fracture risk earlier in life and for providing insight into fragility-related biological activitie. Robustness (a measure of transverse size relative to length) is established early postnatally and varies widely among individuals. Our key finding was that the natural variation in robustness was accompanied by highly coordinated changes in cortical area and tissue mineral density. Our work in human bone established these functional interactions in the context of whole bone stiffness (mechanical homeostasis), and the traits examined were largely limited to those that could be measured non-invasively. The extent to which other matrix variables (e.g., collagen crosslinking) are coordinately adjusted to accommodate the natural variation in robustness, how the functional interactions among these extended traits affect fracture resistance properties (e.g., strength, ductility, toughness, fatigability), and how these relationships change with aging remain unclear. To address these questions, we propose to study bone as a complex adaptive system using the natural variation in robustness as an experimental model to predict inter-individual differences in BMU-based remodeling (Aim 1), fracture resistance (Aim 2), and skeletal aging (Aim 3). Successful completion of these Aims will provide fundamental new knowledge about the functional adaptation process in bone, and will establish the complex adaptive nature of the skeletal system as a biomechanical mechanism contributing to differential aging and fracture resistance among individuals. Our long term goal is to use this knowledge to develop preventative personalized technologies aimed at maintaining bone strength with aging to reduce fracture incidence.