Fracture of the proximal humerus is one of the most frequent fractures attributable to osteoporosis; yet, it has seldom been studied. Two types of factors (related to bone fragility and falls) were evaluated to identify risk factors for proximal humerus fractures as well as to examine possible interactions between them. Subjects were 6901 white women aged > or =75 years and all participated in the EPIDOS study of risk factors for osteoporotic fractures (France, 1992-1998). The baseline examination included measurements of femoral neck bone mineral density (BMD) and calcaneal ultrasound parameters (speed of sound [SOS] and broadband ultrasound attenuation [BUA]), a functional clinical examination, and completing a questionnaire on health status and lifestyle. During a mean of 3.6 (0.8) years of follow-up, 165 women had a humeral fracture. Using multivariate Cox regression models, we identified three predictors related to bone fragility-low BMD (relative risk [RR] = 1.4; 95% CI, 1.1-1.7), low SOS (RR = 1.3; 95% CI, 1.0-1.6), and maternal history of hip fracture (RR = 1.8; 95% CI, 1.0-3.0)-and four fall-related predictors-a previous fall (RR = 3.0; 95% CI, 1.5-6.1), a low level of physical activity (RR = 2.2; 95% CI, 1.1-4.4), impaired balance (RR = 1.8; 95% CI, 1.1-2.9), and pain in lower limb extremity (RR = 1.4; 95% CI, 1.0-2.1). The effect of these fall-related predictors varied according to the BMD level; they were significantly associated with proximal humerus fractures in women with osteoporosis (BMD T score < -2.5) but not in nonosteoporotic women. The incidence of proximal humerus fracture in women with osteoporosis and a low fall risk score (5.1 per 1000 woman-years) was only slightly higher than in nonosteoporotic women (4.6 per 1000 woman-years) and similar to the incidence in women without osteoporosis but a high fall risk score (5.3 per 1000 woman-years). On the other hand, the incidence in women who had both types of risk factors was more than two times higher (12.1 per 1000 woman-years) than in women with only one of the two risk factors. These results suggest that women who have both types of risk factors should receive the highest priority for prevention.