It is well accepted that inter-fragmentary movement influences the fracture healing process. Small axial movement can stimulate callus formation whereas larger shear movement delays the healing process. It is, therefore, essential for optimal fracture healing to minimize shear and to control axial movement. Unfortunately, the complex gap movements are mostly unknown under the large variety of clinical as well as experimental conditions of fracture fixation. To further understand the complex interactions of musculoskeletal loading and inter-fragmentary movements in bones and to reduce the need for animal experiments, a three-dimensional (3D) musculoskeletal model of the left hind limb of a sheep was developed. From 3D ground reaction forces and inverse dynamics, resultant joint loading was determined over a gait cycle. Muscle and joint contact forces were derived from an optimization routine and internal loads in the tibia and metatarsus from beam theory. Finally, inter-fragmentary movements were calculated from the bony loading condition and experimentally determined stiffness matrices of monolateral AISF external fixator constructs. Both the joint contact forces at the hip and gap movement of a mid-shaft tibial fracture agree with in vivo data reported in the literature. The bones proved to be mainly axially loaded with slightly increasing shear forces toward their ends. The results suggest that inter-fragmentary movement of metatarsal fractures is fairly independent of the fracture location whereas the movement increases in proximal tibial fractures compared to those in the distal and diaphyseal tibia. Considerable shear movement was found for all locations and external fixator mountings. However, shear movement could be minimized with a cranio-lateral rather than a cranio-medial shift from the cranial fixator plane.