Despite the remarkable advances in musculoskeletal biomechanics during the last decade, realistic physiological tissue-level strain fields in whole bones are not yet known as these cannot be measured experimentally and the numerical simulations targeting this aim either do not include microstructural and elastic information or investigate a sub-volume with simplified loading. However, this knowledge would be essential for unravelling the relation of micro-structure and function, and for understanding the rules dictating process of mechanosensation for bone remodelling and healing.The aims of this project are to (I) assess the realistic physiological mechanical environment in cortical bone tissue with previously unmatched accuracy to understand the functional adaptation of the intact microstructure and (II) use this knowledge to investigate the variations observed in altered conditions, e.g. fracture healing.These goals will be achieved using and unprecedented combination of tools and data of an ovine lower limb model available at the research groups and European collaborators of the host. In Phase 1, organ-scale homogenized finite element (FE) models will be developed which include tissue-specific, experimentally assessed anisotropic micro-elastic properties via a multi-scale homogenization approach and physiologically relevant loading histories from musculoskeletal models to compute macro-scale strain and stress fields. In Phase 2, these local macro-scale stresses will be applied on micro-FE models of experimentally assessed meso-scale tissue volumes to compute the micro-scale strains and stresses. In Phase 3 the developed approaches will be incorporated into a numerical framework suitable for the investigation of altered conditions, e.g. fractures. This will be applied on an established sheep osteotomy model, which is anticipated to elucidate the optimum strain levels required to promote the endogenous healing process, which is of direct clinical relevance.