Mechanistic insights into MRONJ from the role of type H vessels and bone density changes

This study investigated how ossification patterns influence type H vessel formation and bone mineral density in bisphosphonate (BIS)-treated bones, aiming to explain jawbones' heightened susceptibility to medication-related osteonecrosis (MRONJ). A cross-sectional analysis of mandibular bone radiodensity was conducted using cone-beam computed tomography (CBCT) in 68 MRONJ patients and 71 controls. An early-stage MRONJ murine model was established through alendronate sodium administration. Mandibular and tibial samples were subjected to micro-CT analysis and immunohistochemical staining of type H vessels (CD31^hi Endomucin^hi) to evaluate osteogenic angiogenesis patterns. MRONJ patients exhibited elevated alveolar (RDa: 591.79 ± 266.67 vs. 396.62 ± 196.64 HU) and mandibular body (RDb: 435.624 ± 329.64 vs. 207.97 ± 165.12 HU) radiodensities compared to controls, while condylar radiodensity remained comparable (RDc: 314.81 ± 140.38 vs. 353.77 ± 144.26 HU). The RDa/RDc ratio demonstrated a over two-fold increase in MRONJ cases (2.37 ± 1.83 vs. 1.32 ± 0.97). BIS treatment preserved type H vessel density in intramembranous ossification-derived alveolar bone but increased it in endochondral ossification-originating condyles and tibias. The RDa/RDc ratio may serve as a diagnostic biomarker for BIS-related mandibular changes. Differential MRONJ risk correlates with embryological ossification patterns and type H vessel responses to BIS.