Bone gain following loading is site-specifically enhanced by prior and concurrent disuse in aged male mice

The primary aim of osteoanabolic therapies is to strategically increase bone mass in skeletal regions likely to experience high strains. In the young healthy skeleton, this is primarily achieved by bone's adaptation to loading. This adaptation appears to fail with age, resulting in osteoporosis and fractures. We previously demonstrated that prior and concurrent disuse enhances bone gain following loading in old female mice. Here, we applied site specificity micro-computed tomography analysis to map regional differences in bone anabolic responses to axial loading of the tibia between young (19-week-old) and aged (19-month-old), male and female mice. Loading increased bone mass specifically in the proximal tibia in both sexes and ages. Young female mice gained more cortical bone than young males in specific regions of the tibia. However, these site-specific sex differences were lost with age such that bone gain following loading was not significantly different between old males and females. To test whether disuse enhances functional adaption in old male mice as it does in females, old males were subjected to sciatic neurectomy or sham surgery, and loading was initiated four days after surgery. Disuse augmented tibial cortical bone gain in response to loading in old males, but only in regions which were load-responsive in the young. Prior and concurrent disuse also increased loading-induced trabecular thickening in the proximal tibia of old males. Understanding how diminished background loading rejuvenates the osteogenic loading response in the old may improve osteogenic exercise regimes and lead to novel osteoanabolic therapies.