Exercise is a key determinate of fracture risk and provides a clinical means to promote bone formation. However, the efficacy of exercise to increase bone mass declines with age. The purpose of this study was to identify age-related differences in the anabolic response to exercise at the cellular and tissue level. To this end, young (8-weeks of age) and adult (36-weeks of age) male mice were subjected to a moderate exercise regimen of running on a treadmill. As a result, exercise had a significant effect on PTHrP and SOST gene expression during the first week that was dependent upon age. In particular, young mice displayed an increase in PTHrP expression and decrease in SOST expression, both of which remained unaffected by exercise in the adult mice. After 5-weeks of exercise, a significant decrease in the percentage of osteocytes expressing sclerostin at the protein level was found in young mice, but not adult mice. Mechanical testing of the tibia found exercise to have a significant influence on tissue-level mechanical properties, specifically ultimate-stress and modulus that was dependent on age. Adult mice in particular experienced a significant decrease in modulus despite an increase in cortical area and cortical thickness compared to sedentary controls. Altogether, this study demonstrates a shift in the cellular response to exercise with age, and that gains in bone mass at the adult stage fail to improve bone strength.

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