Breast cancer most frequently metastasizes to the skeleton. Bone metastatic cancer is incurable and induces wide-spread bone osteolysis, resulting in significant patient morbidity and mortality. Mechanical stimuli in the skeleton are an important microenvironmental parameter that modulates tumor formation, osteolysis, and tumor cell-bone cell signaling, but which mechanical signals are the most beneficial and the corresponding molecular mechanisms are unknown. This work focused on bone matrix deformation and interstitial fluid flow based on their well-known roles in bone remodeling and in primary breast cancer. The goal of our research was to establish a platform that could define the relationship between applied dynamic mechanical forces and the resulting phenotype in bone metastatic breast cancer cells. To achieve this goal, we employed a high-throughput, multi-modal in vitro mechanical loading bioreactor to apply forces to 3D in vitro bone-mimetic scaffolds, thereby recapitulating the physiological skeletal mechanical environment. We combined this with multi-physics micro-CT-based computational simulation models to estimate the internal mechanical microenvironment during in vitro experimentation.