Abstract: There is growing awareness that therapeutic decision-making may be confounded by discrepancies in the prevalence of osteoporosis by World Health Organization criteria when bone density is measured at different skeletal sites. To explore this issue, we measured bone density at a variety of skeletal sites in a population-based sample of 348 men (age 22–90 years) and 351 women (age 21–93 years). Men had greater areal bone mineral density (BMD, g/cm2) than women at almost every subregion on total body, anteroposterior (AP) and lateral lumbar spine, proximal femur and forearm scans by dual-energy X-ray absorptiometry. However, adjustment for height or, where possible, calculation of bone mineral apparent density (BMAD, g/cm3) reduced or eliminated these differences. In addition, three different patterns of change in bone density over life were observed at the various skeletal sites as judged from cross-sectional data: no apparent age-related bone loss (e.g., AP spine BMD in men); linear bone loss over life in both sexes beginning in young adulthood (e.g., femoral neck BMD); and bone loss beginning around the time of menopause or a comparable age in men (e.g., midradius BMD). The various adjustments for bone size and the different patterns of age-related change in bone density had profound effects on the estimated prevalence of osteoporosis by World Health Organization criteria, which ranged from 2% to 45% among postmenopausal women and from 0 to 36% among men 50 years of age and older depending upon the skeletal parameter that was assessed. These observations emphasize the difficulties involved in attempts to standardize BMD scores and definitions of osteoporosis for clinical use.