Osteoporosis is characterized by altered bone quality and compromised bone strength leading to increased fracture risk. Measurement of areal bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA) is the most widely used index of bone strength. However, BMD alone can only account for 40 to 70% of the variation of bone strength. This study aimed to determine: 1/ the respective role of cortical and trabecular microarchitecture to vertebral mechanical behavior, 2/ the role of trabecular microarchitecture heterogeneity and 3/ the mechanical behavior of a vertebra after simulated mild fracture and its determinants. Our data imply that measurements of cortical thickness and curvature as well as determination of trabecular microarchitecture heterogeneity enhance prediction of vertebral fragility. We found marked variation in the post-fracture load-bearing capacity following simulated mild vertebral fractures. Bone microarchitecture, but not bone mass, was associated with post-fracture mechanical behavior of vertebrae.