MRONJ risk associated with combined antiresorptive and vascular endothelial growth factor receptor tyrosine kinase inhibitors.

Abstract

Concomitant use of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) and bone resorption inhibitors (BRIs) may increase the risk of medication-related osteonecrosis of the jaw (MRONJ). The relative contribution of VEGFR-TKI, BRI type, and patient-related risk factors remains unclear. We retrospectively reviewed patients treated with BRIs, with or without concomitant VEGFR-TKIs. The primary endpoint was MRONJ-free survival, defined as time from BRI initiation to MRONJ diagnosis. Secondary endpoints included MRONJ incidence and skeletal-related events (SREs). Overall, 233 patients received BRI/VEGFR-TKI combination (study group) and 986 received BRI alone (control group). Median MRONJ-free survival was shorter in the study group than in controls (79 vs 202 months). However, after adjustment for smoking status, age, sex, and BRI type, concomitant VEGFR-TKI use was not independently associated with MRONJ-free survival (HR 1.3, 95% CI 0.8-2.1; <i>p</i> = 0.2), whereas denosumab use and active smoking remained independent predictors. VEGFR-TKI therapy was associated with earlier MRONJ occurrence among BP-treated patients (adjusted HR 3.22, 95% CI 1.08-9.56; <i>p</i> = 0.03), but not among denosumab-treated patients. MRONJ-incidence did not differ between BRI/VEGFR-TKI and BRI groups (14.6% vs 12.0%; <i>p</i> = 0.3), but BRI-exposure was shorter in the combination group. SRE occurrence was 69.5%, similar between BP- and denosumab-treated patients; however, denosumab-treated patients had longer exposure, resulting in a lower SRE rate (0.13 vs 0.39 events/month). MRONJ risk depends on BRI type and individual patient profile. VEGFR-TKIs may accelerate MRONJ onset in BP-treated patients, whereas denosumab showed higher MRONJ risk independently of VEGFR-TKI use. Treatment choices should balance MRONJ risk against skeletal disease burden.