Macrophage dysregulation in medication-related osteonecrosis of the jaw: jaw-specific osteoimmune mechanisms and therapeutic perspectives
Year: 2026
Type: review
Abstract: Medication-related osteonecrosis of the jaw (MRONJ) is a refractory complication of antiresorptive and antiangiogenic therapies. Its jaw-specific susceptibility and persistent inflammatory features are not fully explained by traditional hypotheses centered on suppressed bone remodeling or impaired angiogenesis. From an osteoimmunological perspective, this review proposes that MRONJ may be more accurately understood as an immune-mediated failure of healing within a jaw-specific osteoimmune niche, in which pathological macrophage reprogramming arises from the interplay between pharmacological exposure and the local microenvironment. Mechanistically, nitrogen-containing bisphosphonates inhibit the mevalonate pathway and disrupt the isoprenylation of small GTPases, including Rac1 and RhoA, resulting in cytoskeletal dysfunction that may impair macrophage efferocytosis. Consequently, persistent necrotic and apoptotic debris may provide ongoing danger signals that sustain NLRP3 inflammasome activation in susceptible lesions, thereby disrupting reparative coupling among bone, vasculature, and mucosa. In parallel, the unique jaw microenvironment, characterized by high local drug accumulation, biofilm colonization, and hypoxia, creates a high-burden inflammatory niche that further impairs the macrophage clearance-resolution program. Finally, this review highlights potential translational strategies, including metabolic rescue, specialized pro-resolving mediators (SPMs), and targeted local delivery of immunomodulatory biomaterials. Together, these approaches support a therapeutic roadmap centered on inflammation resolution and mucosal sealing as key clinical endpoints.
Source: Frontiers in Immunology
Institution: Guiyang Medical University
Language: English
Topic: Bone health and treatments
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7222993644