Bulk properties of cortical bone have been well characterized experimentally, and potent toughening mechanisms, e.g., crack defections, have been identifed at the microscale. However, it is currently difcult to experimentally measure local damage properties and isolate their efect on the tissue fracture resistance. Instead, computer models can be used to analyze the impact of local characteristics and structures, but material parameters required in computer models are not well established. The aim of this study was therefore to identify the material parameters that are important for crack propagation in cortical bone and to elucidate what parameters need to be better defned experimentally. A comprehensive material parameter study was performed using an XFEM interface damage model in 2D to simulate crack propagation around an osteon at the microscale. The importance of 14 factors (material parameters) on four diferent outcome criteria (maximum force, fracture energy, crack length and crack trajectory) was evaluated using ANOVA for three diferent osteon orientations. The results identifed factors related to the cement line to infuence the crack propagation, where the interface strength was important for the ability to defect cracks. Crack defection was also favored by low interface stifness. However, the cement line properties are not well determined experimentally and need to be better characterized. The matrix and osteon stifness had no or low impact on the crack pattern. Furthermore, the results illustrated how reduced matrix toughness promoted crack penetration of the cement line. This efect is highly relevant for the understanding of the infuence of aging on crack propagation and fracture resistance in cortical bone.