Unraveling Jawbone Susceptibility: Distinctive Features Underlying Medication-Related Osteonecrosis

Medication-related osteonecrosis of the jaw (MRONJ) is a devastating complication arising primarily after invasive dentoalveolar procedures in patients treated with antiresorptive, antiangiogenic, or targeted therapies. Although recognized risk factors are established, the distinctive vulnerability of jawbones compared to long bones is not fully understood. This review comprehensively synthesizes recent advances regarding the embryological, anatomical, and physiological disparities that contribute to region-specific susceptibility to MRONJ. Recent evidence suggests that jawbones diverge significantly from long bones in embryonic origin, ossification pathways, vascular architecture, innervation patterns, and regenerative capacities. These differences affect bone metabolism, healing dynamics, response to pharmacologic agents, and local cellular activities, such as enhanced bisphosphonate uptake and specialized microcirculation. Experimental and clinical evidence reveals that mandibular periosteal cells exhibit superior osteogenic and angiogenic potentials, and the jaws respond differently to metabolic challenges, trauma, and medication-induced insults. Furthermore, site-specific pharmacologic and inflammatory interactions, including altered periosteal microcirculation and leukocyte-endothelial interactions, may explain the development of MRONJ, although rare cases of medication-related osteonecrosis have also been reported in long bones. Emerging research demonstrates that immune dysregulation, particularly M1 macrophage polarization with overexpression of matrix metalloproteinase-13 (MMP-13), plays a crucial role in early MRONJ development. Understanding these mechanisms highlights the critical need for region-specific preventive measures and therapeutic strategies targeting the unique biology of jawbones. This comparative perspective offers new translational insights for designing targeted interventions, developing tissue engineering solutions, and improving patient outcomes. Future research should focus on gene expression profiling and cellular responses across skeletal regions to further delineate MRONJ pathogenesis and advance personalized therapies for affected patients.