Non-physiological direction loading increases bone adaptive responses by enhancing lacunocanalicular fluid dynamics.

It's been proposed that bone adaptation is "error-driven", namely, bone is more sensitive to non-physiological loading (e.g., loading in a non-physiological direction). However, the effect of physiological vs. non-physiological loading on bone adaptation and its underlying mechanism are not fully understood. We hypothesized that loading in a non-physiological direction would increase osteogenesis via enhancing fluid flow within the lacunocanalicular network (LCN), independent of the strain magnitude. To test this hypothesis, we first examined the effects of physiological and non-physiological direction loading on bone formation responses with axial and transversal in vivo loading models of the mouse tibia, respectively, under a strain-matched condition. Next, an in silico whole bone-LCN multiscale model was developed to compute loading-induced strains and fluid shear stresses within the LCN. Lastly, regression analyses were performed to examine the spatial correlations between bone mechanoresponses and fluid shear stress (and strain). Results showed that the transversal loading led to an increased cortical bone response compared to the axial loading even though the strains were matched. The transversal loading-induced increase in bone response was associated with enhanced lacunocanalicular fluid flow rather than strain. Additionally, strong correlations existed between bone mechanoresponses and fluid shear stress whereas no correlation was detected between bone responses and strain. These results support our hypothesis and may explain why bone adaptation is more sensitive to loading in a non-physiological direction. The findings also highlight the key role of the fluid dynamic microenvironment within LCN in regulating bone mechanoadaptation.