Background: Antiresorptive therapy with bisphosphonates or denosumab is standard care for patients with primary or secondary osseous metastasized breast cancer. The most important toxicity of this class of drugs is medication-related osteonecrosis of the jaw (MRONJ). MRONJ represents a major medical burden and impairs quality of life. Based on recent studies, the risk of MRONJ occurrence ranges from 1% to 3%. The objective of this study was to assess the population-based incidence of MRONJ in breast cancer patients with bone metastases in Tyrol, Austria. Methods: This retrospective multicenter study was conducted between 2000 and 2020 at nine centers across Tyrol, Austria, including 8,860 patients with breast cancer. Depending on whether patients with bone metastases received denosumab, bisphosphonates or denosumab following bisphosphonates they were allocated to one of three groups. Data was collected using an electronic case report form (e-CRF) and managed via the web-based database AskiMed. MRONJ incidences with 95% confidence intervals and the differences between the median of cumulative incidences were calculated in patients treated with bisphosphonates and/or denosumab. Results: A total of 639 patients had bone metastasis and received antiresorptive therapy. MRONJ was diagnosed in 56 (8.8%) patients. Regarding the 292 (45.7%) patients treated with denosumab alone, the MRONJ incidence was 11.6% (95%CI 8.2%-15.9%). The group of patients treated with only bisphosphonates included 255 (39.9%) patients; their MRONJ incidence was 2.7% (95%CI 1.1%-5.6%). Of the 92 (14.4%) patients receiving both antiresorptive therapies consecutively, the MRONJ incidence was 16.3% (95%CI 9.4%-25.5%). Thus, a total of 49 (12.8%) MRONJ cases were detected in patients using denosumab alone as well as using the combination of denosumab following bisphosphonates. Patients treated with denosumab developed a MRONJ in median 60 months earlier than with bisphosphonates alone or followed by denosumab. The hazard ratio for MRONJ from start of therapy of denosumab compared to bisphosphonates alone or followed by denosumab was 7.9 (3.8-16.2; p-value < 0.0001). Conclusions: This study showed a substantially higher MRONJ incidence for denosumab alone or bisphosphonates followed by denosumab in the tyrolean cohort when compared to other recent studies. Future comparative real-world-evidence research provide explicit benefit-harm tradeoffs to inform treatment decision making.