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.

The lacunar-canaliculi system is a network of channels that is created and maintained by osteocytes as they are embedded throughout cortical bone. As osteocytes modify their lacuna space, the local tissue composition and tissue strength are subject to change. Although continual exposure to parathyroid hormone (PTH) can induce adaptation at the lacunar wall, the impact of intermittent PTH treatment on perilacunar adaptation remains unclear. Therefore, the primary objective of this study was to establish how intermittent PTH(1–34) treatment influences perilacunar adaptation with respect to changes in tissue composition. We hypothesized that local changes in tissue composition following PTH(1–34) are associated with corresponding gains in tissue strength and resistance to microdamage at the whole bone level. Adult male C57BL/6J mice were treated daily with PTH(1–34) or vehicle for 3 weeks. In response to PTH(1–34), Raman spectroscopy revealed a significant decrease in the carbonate-to-phosphate ratio and crystallinity across the entire tissue, while the mineral-to-matrix ratio demonstrated a significant decrease in just the perilacunar region. The shift in perilacunar composition largely explained the corresponding increase in tissue strength, while the degree of new tissue added at the endosteum and periosteum did not produce any significant changes in cortical area or moment of inertia that would explain the increase in tissue strength. Furthermore, fatigue testing revealed a greater resistance to crack formation within the existing tissue following PTH(1–34) treatment. As a result, the shift in perilacunar composition presents a unique mechanism by which PTH(1–34) produces localized differences in tissue quality that allow more energy to be dissipated under loading, thereby increasing tissue strength and resistance to microdamage. In addition, our findings demonstrate the potential for PTH(1–34) to amplify osteocytes’ mechanotransduction by producing a more compliant tissue. Overall, the present study demonstrates that changes in tissue composition localized at the lacuna wall contribute to the strength and fatigue resistance of cortical bone gained in response to intermittent PTH(1–34) treatment.

Exercise and physical activity are critical to maintain bone mass and strength throughout life. Both exercise and physical activity subject bone to a unique combination of stimuli in the forms of dynamic loading and a systemic increase in parathyroid hormone (PTH). Although dynamic loading is considered to be the primary osteogenic stimuli, the influence of increasing PTH levels remains unclear. We hypothesize that activation of the PTH/PTH-related peptide type 1 receptor (PPR) along the osteoblast lineage facilitates bone formation and improved mechanical properties in response to exercise. To test this hypothesis, conditional PPR-knockout mice (PPRcKO) were generated in which PPR expression was deleted along the osteoblast lineage under the osterix promoter. At 8-weeks of age, both PPRfl/fl and PPRcKO mice were subjected to treadmill running or sedentary conditions for 5-weeks. Under sedentary conditions, PPRcKO mice displayed significantly less bone mass as well as smaller structural-level strength (yield-load and ultimate load), while tissue level properties were largely unaffected. However, PPRcKO mice exposed to exercise displayed significantly less structural-level and tissue-level mechanical properties when compared to exercised PPRfl/fl mice. Overall, these data demonstrate that PPR expression along the osteoblast lineage is essential for exercise to improve the mechanical properties of cortical bone. Furthermore, the influence of PPR activation on material properties is unique to exercise and not during normal growth and development.