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.
We propose to generate new information about how skeletal aging differs predictably among individuals by identifying a new biomarker of bone strength, fragility, and the biology of aging. Establishing robustness as a biomarker of age-related changes in structure and tissue-level properties may fill an unmet clinical need for non-invasively assessing a broader range of fracture resistance properties on a personalized basis.
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