Untreated Apical Periodontitis and the Risk of Medication-related Osteonecrosis of the Jaws (MRONJ): A Systematic Review with Mechanistic Insights from Preclinical Studies.

INTRODUCTION

Medication-related osteonecrosis of the jaws (MRONJ) is a condition that causes progressive bone destruction and compromises patients' function, aesthetics, and quality of life.

OBJECTIVES

This study aims to investigate the role of untreated apical periodontitis (AP) in the development of MRONJ.

METHODS

A comprehensive search was performed in PubMed/MEDLINE, Web of Science, Scopus, and Embase. Gray literature was assessed using the ProQuest database. The eligibility criteria consisted of (1) preclinical studies; (2) use of antiresorptive, antiangiogenics, or other drugs known to cause MRONJ; (3) studies evaluating the development of osteonecrosis in regions of AP lesions. The following studies were excluded: (1) non-animal studies. Two independent reviewers performed data extraction and the assessment of the risk of bias.

RESULTS

From an initial dataset of 239 records, we included 11 studies. Induction of periapical lesions was performed most often after the administration of bisphosphonates. Zoledronic acid was the most used drug. Histologic or clinical evidence of MRONJ in areas of untreated AP was reported in 72.72% of the studies. Furthermore, areas with AP presented MRONJ more frequently, with or without clinical signs.

CONCLUSIONS

This systematic review of preclinical studies indicates that untreated AP, in the context of antiresorptive therapy, may increase the risk of MRONJ. Our findings provide mechanistic insights that clarify how AP may contribute to MRONJ pathogenesis, offering a theoretical background to support clinical observations. While human studies suggest a potential pathogenic interaction, they remain limited by heterogeneous designs, variable definitions of oral infections, and frequent grouping of AP with other conditions. These limitations underscore the translational significance of our preclinical analysis. Overall, our results reinforce the importance of early diagnosis and management of endodontic infections in patients receiving antiresorptive particularly cancer patients exposed to higher cumulative doses and highlight the need for well-designed prospective clinical studies to determine whether AP constitutes an independent risk factor for MRONJ.