Osteoporosis is an age-related deterioration of bone mass and structure, which leads to debilitating and costly fractures. Bone is a dynamic tissue that adapts to external loads. In young and mature healthy bone, high loads promote bone formation by osteoblasts, and reduced loads promote bone resorption by osteoclasts. With age, a myriad of factors contribute to bone loss. In particular, the mechano-adaptive response is impaired in old bone, which is the focus of this thesis. The central idea behind this work is that old bone is lacking cells to respond to mechanical cues:​ compared to young bone, osteoclasts are more numerous and active, osteoblasts are fewer and less active, and mesenchymal stem cells in the marrow tend to differentiate into adipocytes rather than osteoblasts. In turn, osteoclastic resorption overtakes osteoblastic formation.

This thesis used a mouse model to examine the decrease in mechano-adaptation in aged bone (over 20 months of age). The research questions underlying this thesis are the following:​ Is old bone capable of a robust osteogenic response? Can old bone be primed to increase the adaptive response to loading?

This thesis used the in vivo tibial loading model to deliver controlled compressive loads, intense treadmill running to deliver physiological loading, and sciatic neurectomy to induce disuse. Marrow aspiration was used to alter marrow adipose content. Intermittent parathyroid hormone (iPTH) and IL-15 were injected to promote a potential systemic response. Bone’s response to mechanical and biochemical cues was analyzed with quantitative micro-CT imaging, histomorphometry, and 3-point bending tests.

The in vivo tibial loading model was able to induce a small amount of bone formation in aged mice, even though the response was reduced compared to mature mice and only visible with high resolution methods. When tibial loading model was preceded by disuse (sciatic neurectomy), the mechano-adaptive response was increased, because disuse had increased bone turnover and recruited a pool of cells to mediate adaptation. iPTH, a pro-remodeling treatment, promoted such a potent response in old bone that the combined effects of tibial loading were negligible. Physiological loading induced by intense treadmill running and systemic injections of the exercise-induced cytokine IL-15 did not alter bone geometry or mechanical competence, indicating that exercise alone or exercise-induced cytokines were insufficient for adaptation. Marrow aspiration in old mice resulted in a robust formation of bone in the medullary canal, but increased marrow adipose volume and reduced the mechano-adaptive response.

This work demonstrated the importance of combining quantitative data from micro-CT imaging with surface-specific histomorphometry to understand bone’s adaptive response. While micro-CT imaging could only measure the amount and distribution of bone, surface-specific histomorphometry was able to detect localized changes in osteoblastic formation and osteoclastic resorption. This enabled interpretations on how these changes in cell populations and activity were related to each other, and to mechanical cues.

To summarize these results, old bone is capable of forming bone in response to induced loading, iPTH treatment, and marrow aspiration, but not in response to physiological loading in intense treadmill running. The mechano-adaptive response of old bone was modulated by the cell populations that were recruited prior to loading. This work provides a deeper understanding of the mechano-adaptive response in old bone, which is required for addressing osteoporosis in the elderly.