Osteoporosis is a skeletal disease characterized by decreased bone mass and alterations in tissue material composition. Anabolic therapeutics, such as parathyroid hormone (PTH) improve bone mass and reduce fracture risk, but their efficacy is limited. Mechanical loading also improves bone mass, and the anabolic effects of loading and PTH are synergistic. However, the mechanisms that underlie this synergy are unclear. Understanding factors that influence the efficacy of PTH treatment and loading is crucial to maximize the benefit of combined treatment.

The synergism of mechanical loading and PTH varies in cancellous bone. We investigated the efficacy of priming bone tissue with PTH prior to concurrent PTH treatment and loading in mice to improve this synergy. Pre-treatment with PTH improved the synergism in cortical bone and rescued load-induced changes in cancellous bone mass that diminished when PTH was administered during loading.

To understand the influence of mechanical strain on the synergy of PTH and loading, we assessed the effect of these treatments in regions of cortical bone experiencing tension and compression. We examined this relationship in a mouse model of low bone mass due to decreased estrogen bioavailability. PTH increased the anabolic load-response in regions experiencing compression earlier and to a greater extent compared to tensile regions. In wildtype mice, PTH pre-treatment was required to increase the cortical load-response long term.

To identify potential stem cell populations driving the skeletal load-response, we examined the effect of ablating Cathepsin K-lineage cells on the tibial response to cyclic compression. These cells originate from periosteal stem cells that mediate intramembranous bone formation. Ablating these cells altered the material composition of bone formed in response to loading.

To understand the molecular mechanisms underlying the site-specificity of PTH and loading, we examined transcriptomic changes with these treatments in cortical and cancellous bone of the murine tibia. The metaphyseal shell, a cortical site experiencing predominantly compressive forces, had the greatest response to both PTH treatment and loading.

In summary, this thesis improves our understanding of the mechanisms underlying the skeletal response to PTH treatment and mechanical loading and helps identify potential therapeutic targets for treating osteoporosis.