Promising avenues for improving bone mass and fracture resistance include loading-based exercise and agents modulating Wnt/β-catenin signalling. This thesis examines the intersection between these. Murine models of tibial loading and unloading, genetic knockout (KO) models of Wnt antagonists sclerostin and dickkopf-1/DKK1 (encoded by Sost and Dkk1 genes), and neutralising antibodies for sclerostin (Scl-Ab) were applied.

Sost KO mice underwent unloading and compressive loading of the tibiae. Sclerostin was vital for the bone response to unloading yet not for loading. Rather, loading-induced anabolism was synergistically augmented in Sost KO mice. It was hypothesised that other Wnt antagonists, such as DKK1, may up-regulate following long-term sclerostin deficiency.

Similarly, Dkk1 KO mice exhibited a synergistically augmented anabolic bone response to loading compared to wild type. However, compensation by sclerostin was doubtful as the primary cause for the augmented response with similar sclerostin expression seen in non-loaded tibiae of Dkk1 KO and wild type mice, and similar down-regulation following loading.

Dkk1 KO mice treated with Scl-Ab resulted in additive increases in bone volume above either individual DKK1 or sclerostin deficiency. Prominent and synergistic effects were within cancellous bone. Immunohistochemical staining did not support the hypothesis that sclerostin up- regulates to compensate for long-term DKK1 deficiency.

Finally, Scl-Ab was co-administered to mice undergoing tibial compressive loading, with additional anabolic increases seen above either monotherapy. RNA sequencing provided insight into mechanisms involved in the augmented response to loading with Scl-Ab use. This thesis supports future clinical use of antibodies targeting Wnt antagonists, whereby load/resistance exercise or dual-agents may increase the efficacy of Scl-Ab or DKK1-Ab therapy. This may have a critical impact for treatment of osteoporosis and other conditions of bone-loss.