Investigating the Effects of Age and Exercise on Bone Composition and the Impact of Composition on Mechanical Integrity.

Abstract

Fractures are the most frequent health problem associated with bone and represent a significant clinical and economic burden. Clinically, fracture risk is diagnosed by low bone mass and interventions to reduce fracture risk are designed to increase mass. However, aging and interventions, like exercise, influence fracture risk by more than what changes in mass predict, indicating that exercise and aging alter skeletal integrity by altering tissue quality, not just quantity. Currently, there is no clear understanding of how tissue quality contributes to skeletal integrity or how it can be altered by external influences. Therefore, this study examined the hypothesis that exercise and aging in adult mice would alter bone composition leading to altered mechanical competence, even when adjusting for changes to bone size and shape. Exercise significantly improved strength and resistance to fatigue-induced damage in young mice, but had no measured benefit in old mice. In young mice, exercise also increased mineralization and decreased carbonate substitution. Aging significantly reduced structural and tissue-level mechanical properties and increased mineral crystal size, carbonate substitution, and microcracking. Compositional changes with exercise and aging occurred in pre-existing bone (determined by micro-CT and calcein labeling) and mechanical improvements were observed without significant increases in bone size, demonstrating that bone can adapt to external stimuli by altering tissue quality without requiring modeling or remodeling. Further, colocalization of compositional and mechanical measurements by Raman microspectroscopy and nanoindentation provided corroborative evidence that the observed compositional changes contributed significantly to the observed changes in mechanical competence, but in an age dependent manner. This work challenges conventional theories about bone adaptation and the influence of bone composition on mechanical integrity. It was demonstrated for the first time that exercise and aging can modulate bone composition, and therefore tissue-level mechanical properties, even in the absence of bone formation or remodeling. Therefore, changes in tissue quality may often be overlooked because they may occur without significant changes in bone mass. This work also illustrates the potential utility of using compositional markers in diagnosing skeletal fragility but warns against making sweeping conclusions about the consequences of compositional changes in bone.Ph.D.Biomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/62281/1/nsahar_1.pd