Purpose: Vertebral fragility fractures are often treated by injecting bone cement into the collapsed vertebral bodies (vertebroplasty). The mechanisms by which vertebroplasty induces pain relief are not completely understood yet and recent debates cast doubt over the outcome of the procedure. The controversy is intensified by inconsistent results of randomized clinical trials and biomechanical studies that have investigated the effectiveness or the change in biomechanical response due to the reinforcement. The purpose of this study was to evaluate the effectiveness of vertebroplasty, by varying the relevant treatment parameters and (a) computationally predicting the improvement of the fracture risk depending on the chosen treatment strategy, and (b) identifying the determinants of a successful treatment. Methods: A Finite Element model with a patient-specific failure criterion and direct simulation of PMMA infiltration in four lumbar vertebrae was used to assess the condition of the bone under compressive load before and after the virtual treatment, simulating in a total of 12000 virtual treatments. Results: The results showed that vertebroplasty is capable of reducing the fracture risk by magnitudes, but can also have a detrimental effect. Effectiveness was strongly influenced by interactions between local bone quality, cement volume and injection location. However, only a moderate number of the investigated treatment strategies were able to achieve the necessary improvement for preventing a fracture. Conclusions: We conclude that the effectiveness of vertebroplasty is sensitive to the patient's condition and the treatment strategy.