Vitamin D Deficiency as a Context-Dependent Modifier of Osteonecrosis of the Jaw.

Osteonecrosis of the jaw (ONJ) is a multifactorial disorder characterized by impaired bone remodeling, vascular compromise, immune dysregulation, and mucosal barrier disruption. Although these mechanisms have been extensively investigated, they are often discussed separately, limiting an integrated understanding of ONJ pathogenesis. Vitamin D has emerged as a biologically relevant factor across these interconnected pathways, yet its role in ONJ remains incompletely defined. This narrative and hypothesis-generating review synthesizes current mechanistic, preclinical, observational, and clinical evidence regarding vitamin D biology and ONJ and proposes a vitamin D-centered vulnerability model in which vitamin D deficiency acts as a context-dependent modifier rather than a primary causal driver. Mechanistically, vitamin D deficiency may impair osteoblast function and mineralization, disrupt angiogenic responses, promote pro-inflammatory immune signaling, and compromise mucosal integrity, collectively creating a microenvironment susceptible to impaired healing and osteonecrosis. These effects are likely to vary across clinical settings, particularly in patients receiving antiresorptive or antiangiogenic therapies. Clinical and epidemiological studies have reported associations between low vitamin D status and increased ONJ risk or severity, while some observational studies suggest that vitamin D supplementation may be associated with improved outcomes in selected populations. However, current human evidence remains predominantly observational and subject to substantial heterogeneity and residual confounding, and direct randomized evidence is lacking. Overall, this framework provides an integrated perspective linking vitamin D biology to ONJ-related pathogenic processes and may support future mechanistic research, risk stratification, and supportive multidisciplinary management strategies. Nevertheless, the proposed model should be interpreted cautiously as hypothesis-generating and requires further validation in well-designed prospective studies and randomized controlled trials.