We conducted a cross-sectional study in 1868 healthy Chinese and Caucasian women and men aged 18 to 93 years to define the structural and biomechanical basis for racial and sex differences in vertebral body (VB) fragility. VB bone mineral content (BMC), cross-sectional area (CSA), and volumetric bone mineral density (vBMD) of the third lumbar vertebrae were measured using dual-energy X-ray absorptiometry. Using engineering principles, we calculated the load per unit CSA (stress), VB strength estimated from vBMD and the ratio of stress to strength (fracture risk index, FRI). Young adult Chinese women and men had a smaller VB with a higher vBMD than their Caucasian counterparts. In each race, women had a smaller VB than men but similar vBMD. From young adulthood ( approximately 30 years) to old age ( approximately 70 years), VB CSA increased more in Chinese than Caucasian women (8.6% vs. 5.8%) and increased less in Chinese than Caucasian men (8.7% vs. 11.8%). Estimated periosteal bone deposited was similar in Chinese and Caucasian women (2.64 vs. 2.63 g, 46% vs. 40% of peak BMC). Estimated endosteal bone lost was similar (3.94 vs. 4.05 g or 68% vs. 62% of peak BMC). As endosteal bone loss exceeded periosteal bone gain, net bone was lost from the VB, but this was similar in Chinese and Caucasian women (1.30 vs. 1.42 g or both lost 22% of peak BMC). For men, Chinese gained less periosteal bone than Caucasians (2.73 vs. 5.05 g or 34% vs. 56% of peak BMC) and lost less endosteal bone (3.07 vs. 5.49 g or 38% vs. 61% of peak BMC), so net bone loss was similar in Chinese and Caucasian men (0.34 vs. 0.44 g, both lost 5% of peak BMC). Comparing sexes, in Chinese, net bone loss was greater in women than in men because of greater endosteal bone loss in women (68% of peak BMC) than men (38% of peak BMC); periosteal bone gain was similar in women and men. In Caucasians, net bone loss was greater in women than men because periosteal bone gain was less in women (40%) than men (56%), endosteal bone loss was similar. The age-related increase in VB CSA reduced VB stress but vBMD decreased so the FRI increased; approximately 25% of elderly Chinese and Caucasian women and approximately 5% of elderly Chinese and Caucasian men had an FRI above unity. The structural basis of bone fragility differs by race and sex. Periosteal apposition plays a pivotal role in determining racial and sex differences in net bone loss, geometry, and strength.