Distal radius (Colles’) fractures are a common fall-related injury in older adults and frequently result in long-term pain and reduced ability to perform activities of daily living. Because the occurrence of a fracture during a fall depends on both the strength of the bone and upon the kinematics and kinetics of the impact itself, we sought to understand how changes in bone mineral density (BMD) and loading direction affect the fracture strength and fracture initiation location in the distal radius. A three-dimensional finite element model of the radius, scaphoid, and lunate was used to examine changes of ±2% and ±4% BMD, and both axial and physiologically relevant off-axis loads on the radius. Changes in BMD resulted in similar percent changes in fracture strength. However, modifying the applied load to include dorsal and lateral components (assuming a dorsal view of the wrist, rather than an anatomic view) resulted in a 47% decrease in fracture strength (axial failure load:​ 2752 N, off-axis:​ 1448 N). Loading direction also influenced the fracture initiation site. Axially loaded radii failed on the medial surface immediately proximal to the styloid process. In contrast, off-axis loads, containing dorsal and lateral components, caused failure on the dorsal–lateral surface. Because the radius appears to be very sensitive to loading direction, the results suggest that much of the variability in fracture strength seen in cadaver studies may be attributed to varying boundary conditions. The results further suggest that interventions focused on reducing the incidence of Colles’ fractures when falls onto the upper extremities are unavoidable may benefit from increasing the extent to which the radius is loaded along its axis.