Currently, the onset of bone damage and the interaction of cracks with the surrounding micro-architecture are still black boxes. With the motivation to address this issue, our research targets isolating lacunar morphological and densitometric effects on crack advancement under both static and cyclic loading conditions by implementing static extended finite element models (XFEM) and fatigue analyses. The effect of lacunar pathological alterations on damage initiation and progression is evaluated; the results indicate that high lacunar density considerably reduces the mechanical strength of the specimens, resulting as the most influencing parameter among the studied ones. Lacunar size has a lower effect on mechanical strength, reducing it by 2%. Additionally, specific lacunar alignments play a key role in deviating the crack path, eventually slowing its progression. This could shed some light on evaluating the effects of lacunar alterations on fracture evolution in the presence of pathologies.