In this study we test the hypotheses that mechanical bone strength in elderly individuals displays substantial heterogeneity among clinically relevant skeletal sites, that ex situ dual-energy X-ray absorptiometry (DXA) provides better estimates of bone strength than in situ DXA, but that a site-specific approach of bone densitometry is nevertheless superior for optimal prediction of bone failure under in situ conditions. DXA measurements were obtained of the lumbar spine, the left femur, the left radius, and the total body in 110 human cadavers (age, 80.6 ± 10.5 years; 72 female, 38 male), including the skin and soft tissues. The bones were then excised, spinal and femoral DXA being repeated ex situ. Mechanical failure tests were performed on thoracic vertebra 10 and lumbar vertebra 3 (compressive loading of a functional unit), the left and right femur (side impact and vertical loading configuration), and the left and right distal radius (fall configuration, axial compression, and 3-point-bending). The failure loads displayed only very moderate correlation among sites (r = 0.39 to 0.63). Ex situ DXA displayed slightly higher correlations with failure loads compared with those of in situ DXA, but the differences were not significant and relatively small. Under in situ conditions, DXA predicted 50-60% of the variability in bone failure loads at identical (or closely adjacent) sites, but only around 20-35% at distant sites, advocating a site-specific approach of densitometry. These data suggest that mechanical competence in the elderly is governed by strong regional variation, and that its loss in osteoporosis may not represent a strictly systemic process.