Although the continued periosteal apposition that accompanies age-related bone loss is a biomechanically critical target for prophylactic treatment of bone fragility, the magnitude of periosteal expansion required to maintain strength during aging has not been established. A new model for predicting periosteal apposition rate for men and women was developed to better understand the complex, nonlinear interactions that exist among bone morphology, tissue-modulus, and aging. Periosteal apposition rate varied up to eightfold across bone sizes, and this depended on the relationship between cortical area and total area, which varies with external size and among anatomical sites. Increasing tissue-modulus degradation rate from 0% to −4%/decade resulted in 65% to 145% increases in periosteal apposition rate beyond that expected for bone loss alone. Periosteal apposition rate had to increase as much as 350% over time to maintain stiffness for slender diaphyses, whereas robust bones required less than a 32% increase over time. Small changes in the amount of bone accrued during growth (ie, adult cortical area) affected periosteal apposition rate of slender bones to a much greater extent compared to robust bones. This outcome suggested that impaired bone growth places a heavy burden on the biological activity required to maintain stiffness with aging. Finally, sex-specific differences in periosteal apposition were attributable in part to differences in bone size between the two populations. The results indicated that a substantial proportion of the variation in periosteal expansion required to maintain bone strength during aging can be attributed to the natural variation in adult bone width. Efforts to identify factors contributing to variation in periosteal expansion will benefit from developing a better understanding of how to adjust clinical data to differentiate the biological responses attributable to size-effects from other genetic and environmental factors. © 2012 American Society for Bone and Mineral Research.