There are still many unknowns in the physiological response of human beings to space, but compelling evidence indicates that accelerated bone loss will be a consequence of long-duration spaceflight. Lacking phenomenological data on fracture risk in space, we have developed a predictive tool based on biomechanical and bone loading models at any gravitational level of interest. The tool is a statistical model that forecasts fracture risk, bounds the associated uncertainties, and performs sensitivity analysis. In this paper, we focused on events that represent severe consequences for an exploration mission, specifically that of spinal fracture resulting from a routine task (lifting a heavy object up to 60 kg), or a spinal, femoral or wrist fracture due to an accidental fall or an intentional jump from 1 to 2 m. We validated the biomechanical and bone fracture models against terrestrial studies of ground reaction forces, skeletal loading, fracture risk, and fracture incidence. Finally, we predicted fracture risk associated with reference missions to the moon and Mars that represented crew activities on the surface. Fracture was much more likely on Mars due to compromised bone integrity. No statistically significant gender-dependent differences emerged. Wrist fracture was the most likely type of fracture, followed by spinal and hip fracture.