It was hypothesized that damage to bone tissue would be most detrimental to the structural integrity of the vertebral body if it occurred in regions with high strain energy density, and not necessarily in regions of high or low trabecular bone apparent density, or in a particular anatomic location. The reduction in stiffness due to localized damage was computed in 16 finite element models of 10-mm-thick human vertebral sections. Statistical analyses were performed to determine which characteristic at the damage location — strain energy density, apparent density, or anatomic location — best predicted the corresponding stiffness reduction. There was a strong positive correlation between regional strain energy density and structural stiffness reduction in all 16 vertebral sections for damage in the trabecular centrum (p < 0.05, r² = 0.43–0.93). By contrast, regional apparent density showed a significant negative correlation to stiffness reduction in only four of the sixteen bones (p < 0.05, r² = 0.47 – 0.58). While damage in different anatomic locations did lead to different reductions in stiffness (p < 0.0001, ANOVA), no single location was consistently the most critical location for damage. Thus, knowledge of the characteristics of bone that determine strain energy density distributions can provide an understanding of how damage reduces whole bone mechanical properties. A patient-specific finite element model displaying a map of strain energy density can help optimize surgical planning and reinforcement of bone in individuals with high fracture risk.