# Denosumab Dosage and Tooth Extraction Predict Medication-Related Osteonecrosis of the Jaw in Patients with Breast Cancer and Bone Metastases

## TL;DR

This study identifies that receiving 32 or more doses of denosumab and having a history of tooth extraction increases the risk of jaw osteonecrosis in breast cancer patients with bone metastases.

## Contribution

The study establishes a specific cumulative dose threshold (32 doses) for denosumab that significantly increases MRONJ risk in breast cancer patients.

## Key findings

- Receiving 32 or more denosumab doses significantly increases the likelihood of MRONJ.
- A history of tooth extraction independently elevates the risk of MRONJ.
- The optimal cutoff of 32 cumulative doses was determined using ROC analysis with high predictive accuracy.

## Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication in breast cancer patients treated with denosumab for bone metastases. However, the cumulative dose at which MRONJ risk rises is unknown. In this retrospective cohort study of patients treated from 2012 to 2024, we found that receiving 32 or more denosumab doses significantly increased MRONJ likelihood. A history of tooth extraction also independently elevated risk. Establishing 32 cumulative doses as a threshold allows clinicians to identify high-risk patients and coordinate timely dental evaluations. These findings support improved risk stratification and proactive management to reduce MRONJ incidence in this population.

Background/Objectives: Prolonged use of denosumab in patients with metastatic breast cancer has raised concerns about the development of medication-related osteonecrosis of the jaw (MRONJ). However, the threshold at which the risk increases remains unclear. Methods: This retrospective cohort study analyzed patients with breast cancer and bone metastases who received denosumab between May 2012 and August 2024. Associations between cumulative denosumab administration and MRONJ were evaluated using univariate and multivariate logistic regression analyses. A receiver operating characteristic (ROC) analysis was used to determine the optimal cutoff for cumulative doses. Results: MRONJ developed in 101 patients (31.2%). Multivariate analysis identified cumulative denosumab administration (odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.03–1.06; p < 0.001) and a history of tooth extraction (OR: 4.40, 95% CI: 2.23–8.71; p < 0.001) as independent risk factors for MRONJ. ROC analysis determined an optimal cutoff of 32 cumulative doses, with an area under the curve of 0.83 (95% CI: 0.78–0.88; p < 0.0001). Conclusions: Cumulative denosumab administration and history of tooth extraction were independent risk factors for MRONJ in patients with breast cancer and bone metastases. The risk of MRONJ increased after 32 cumulative doses, providing a clinically actionable threshold for risk assessment and patient monitoring.