Functional in vivo strain data are examined in relation to bone material properties in an attempt to evaluate the relative importance of osteoporotic bone loss versus fatigue damage accumulation as factors underlying clinical bone fragility. Specifically, does the skeleton have a sufficiently large safety factor (ratio of bone failure strain to maximum functional strain) to require that fatigue damage accumulation is the main factor contributing to increased risk of fracture in the elderly? Existing methods limitin vivo strain measurements to the surfaces of cortical bone. Peak principal compressive strains measured at cortical sites during strenuous activity in various mammalian and avian species range from −1700 to −5200 με, averaging - 2500 με (−0.0025 strain). Much of this threefold variation reflects differences in the intensity of physical activity, as well as differences among species and bones that have been studied. Peak strains can also vary as much as tenfold at different cortical sites within the same bone. No data exist for cortical bone strain during strenuous activity in humans, but it is likely that human bones experience a similar range of peak strain levels. Compact bone fails in longitudinal compression at strains as high as −14,000 to −21,000 με, but begins to yield at strains between −6000 and −8000 με. Given that yielding involves rapid accumulation of microdamage within the bone, it seems prudent to base skeletal safety factors on the yield strain, rather than the ultimate failure strain of bone tissue. Safety factors to yield failure therefore range from 1.4 to 4.1. This safety factor range is likely diminished further by age-related increases in mineralization and secondary remodeling that reduce the strength and energy-absorbing capacity of bone. Although no one safety factor applies to all skeletal sites within an individual, it seems clear that osteoporotic bone loss of 40 to 50% of normal constitutes a causative factor of clinical bone fragility, particularly if bone loss is high at sites of high functional strain. Theoretical consideration of the statistical distribution of bone strength in relation to functional loading events within a population over a lifetime of use further supports this interpretation, by indicating an increased probability of fracture with increasing age. Fatigue damage accumulation will serve to exacerbate these trends. Bone loss and fatigue damage accumulation therefore, should be viewed as mutually reinforcing agents of bone fragility. Improved correlation of peak functional strain patterns with localized bone loss and bone turnover dynamics at sites of high fracture risk, together with assessment of microdamage, is needed to resolve the relative contribution of these factors to osteoporotic bone fragility.