Bone is an exquisite biomaterial due to its ability to adapt to an ever-changing mechanical environment. However, lack of stimulation diminishes bone structural quality and strength. Astronauts experience extreme whole-body disuse during spaceflight and consequently lose bone mass. On Earth, elderly individuals have an increased risk of bone fracture as bone’s intrinsic mechanosensitivity is greatly diminished with age. Yet, there is a gap in our understanding of the combined effects of aging and disuse on skeletal health. Most rodent models of spaceflight use young mice, which are a poor analog for skeletally mature astronauts. With NASA’s moon habitation and low-gravity commercialized laboratory plans, and an increasingly sedentary elderly population on Earth, there is a critical need to address this gap. Therefore the principal objective of this thesis is to determine if musculoskeletal disuse from microgravity disproportionately affects aged bone quality in a mouse model of disuse.

Bone’s intrinsic mechanosensitivity arises from osteocytes:​ bone cells embedded within the matrix in a complex, interconnected, fluid-filled network called the lacunar-canalicular system (LCS). Osteocytes sense mechanical stimuli in the form of shear stress within the LCS. Computational models have suggested that constriction of the LCS causes diminished shear stress and may occur with age. If osteocytes can also modulate the LCS in response to changes in their mechanical environment, and if these nano-structural changes correlate with tissue level bone structure is not yet known. Thus, this dissertation’s overarching hypothesis is that impairments of the aging osteocyte lacunar-canalicular system drive diminished bone structural quality and may in part explain why aged bone is at a greater risk under disuse conditions such as in microgravity. This work includes the design and optimization of novel X-ray microscopy (XRM) imaging methods of osteocyte lacunae. The experimental methods presented here use these XRM methods to quantify changes in lacunar morphometries as part of a multi-length scale comparison of bone structure in young and skeletally mature mice under normal gravity and following microgravity exposure. Bone micro- and nano-structural changes following microgravity exposure provide evidence of a relationship between LCS and tissue level changes, in a site- and age-dependent manner.