Incidence of medication-related osteonecrosis of the jaw in patients treated with both bone resorption inhibitors and vascular endothelial growth factor receptor tyrosine kinase inhibitors
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Several case reports and small case series have suggested a higher incidence of medication-related osteonecrosis of the jaw (MRONJ) in patients treated concomitantly with bone resorption inhibitors (BRIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), as compared to patients treated with BRIs alone. We aimed to assess ONJ-incidence in patients exposed concomitantly to BRIs and VEGFR-TKIs.
Patients and methods
We reviewed the records of all patients who received VEGFR-TKIs concomitantly with BRIs. Patients, who were treated with BRIs without VEGFR-TKI, served as a control group. Endpoints of the study were total MRONJ-incidence, MRONJ-incidence during the first and second year of exposure, and time-to-ONJ-incidence.
Ninety patients were treated concomitantly with BRIs and VEGFR-TKIs with a median BRI-exposure of 5.0 months. Total MRONJ-incidence was 11.1%. During the first year of BRI-exposure (with a median concomitant exposure of 4.0 months), 6 out of 90 patients (6.7%) developed a MRONJ, compared to 1.1% in the control group (odds ratio 5.9; 95%CI 2.0–18.0; p = 0.0035). In Kaplan-Meier estimates, time-to-ONJ-incidence was significantly shorter in patients treated with BRIs and VEGFR-TKIs compared to BRIs alone (hazard ratio 9.5; 95%CI 3.1–29.6; p < 0.0001). MRONJs occurred earlier in patients treated concomitantly compared to patients treated with BRIs only (after a median exposure of 4.5 and 25.0 months, respectively; p = 0.0033).
With a global MRONJ-incidence of 11%, patients receiving concomitant treatment with VEGFR-TKIs and BRIs have a five to ten times higher risk for development of MRONJ compared to patients treated with BRIs alone.
KeywordsBone metastases Denosumab Bisphosphonates VEGFR-TKIs Medication-related osteonecrosis of the jaw
Benoit Beuselinck received a grant from Fonds voor Wetenschappelijk Onderzoek Vlaanderen (Belgium). Tom Van Cann and Annelies Verbiest both received a grant “Emmanuel Vanderschueren” from “Kom op tegen Kanker” (Belgium).
Compliance with ethical standards
The study was approved by the Ethics Board of both institutions, the University Hospitals Leuven and General Hospital Groeninge (B322201112522 and AZGS2014077).
Conflict of interest
Benoit Beuselinck is an investigator of the EudraCT: 2011-006085-40/MetaSun trial supported by Pfizer. Hans Wildiers received speaker’s fee and attended an advisory board from Amgen and Novartis. Kristiaan Nackaerts received individual honoraria for participation in an Amgen Advisory Board on osteonecrosis of the jaw. The other authors have no conflicts of interest to declare.
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