Current clinical criteria for identifying bone cancer patients at high risk of fracture are not solid and comprehensive, which in many occasions result in unnecessary prophylactic stabilization. The goal of this study was to develop a validated biomechanical tool to assess bone strength, as the key determinant of its fracture risk, when the size and location of tumorous defects varied in distal femoral bone. Non-linear and heterogeneous finite element (FE) models of bones with simulated tumorous defects were created, and validated using corresponding in-vitro mechanical tests. Results of this study demonstrated a strong correlation between bone strengths predicted by in-silico analyses and in-vitro tests. Based on FE analyses, there was no considerable reduction in bone strength until the defect was 38% of epiphyseal volume or larger and laterally located defects, in comparison to the same in shape and size defects in medial, were at higher risk of fracture.