Metastatic bone disease is incurable with an associated increase in skeletal-related events, particularly a 17–50% risk of pathologic fractures. Current surgical and oncological treatments are palliative, do not reduce overall mortality, and therefore optimal management of adults at risk of pathologic fractures presents an unmet medical need. Plain radiography lacks specificity and may result in unnecessary prophylactic fixation. Radionuclide imaging techniques primarily supply information on the metabolic activity of the tumor or the bone itself. Magnetic resonance imaging and computed tomography provide excellent anatomical and structural information but do not quantitatively assess bone matrix. Research has now shifted to developing unbiased data-driven tools that can predict risk of impending fractures and guide individualized treatment decisions. This review discusses the state-of-the-art in clinical and experimental approaches for prediction of pathologic fractures with bone metastases. Alterations in bone matrix quality are associated with an age-related increase in skeletal fragility but the impact of metastases on the intrinsic material properties of bone is unclear. Engineering-based analyses are non-invasive with the capability to evaluate oncological treatments and predict failure due to the progression of metastasis. The combination of these approaches may improve our understanding of the underlying deterioration in mechanical performance.