The heterogeneity of skeletal bone mineral density, measured on a single dual-energy X-ray absorptiometer, was examined in a large cohort of 7050 women and 702 men referred for investigation of osteoporosis. The men were significantly older (64.8 ± 13.2 vs 60.2 ± 11.5 years) and had an increased prevalence of nontraumatic fractures (ODR: 2.18; 95% CI: 1.82–2.61). The detection rate (sensitivity) for any osteoporosis (spine or hip) in women was 87.1% and 45.1% when assessed at the anteroposterior (AP) spine and femoral neck respectively. The corresponding osteoporosis detection rate in men was 69.3% and 67.5% at the AP spine and femoral neck respectively. Age-related AP spine degenerative changes increased significantly and at a similar rate for both women and men. Misclassification, that is osteoporosis (T-score <−2.5) at one site and normal (T-score >−1) bone mass at the other, was low in both genders (<4.5%), but 3.1 (95% CI: 2.1–4.6) times more likely in women when the diagnosis was based on the femoral neck compared with the AP spine. Our findings suggest that there are significant age- and gender-related bone mineral density differences between the spine and hip skeletal sites which have to be considered if only one site is selected for investigation.