Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse effect of antiresorptive agents, including bisphosphonates (BPs) and denosumab (DMB). We conducted a case-control epigenome-wide association study (EWAS) of 24 cancer patients treated with BPs or BPs + DMB using the Infinium® MethylationEPIC v2.0 to explore epigenetic differences associated with MRONJ. Differentially methylated positions (DMPs) and regions (DMRs) were assessed across three analyses: MRONJ vs. controls (main), BPs-MRONJ vs. BPs-controls, and BPs/DMB-MRONJ vs. BPs/DMB-controls. Eight plasma bone biomarkers were quantified by Luminex and correlated with top methylation sites. We identified 10 DMPs and 4 DMRs at suggestive significance (p < 1 × 10-5). cg1913766 in the NOP56 promoter was hypomethylated in the main analysis (p = 2.19 × 10-7) and in BPs-MRONJ (p = 4.80 × 10-6), correlating with osteocalcin (p = 0.02 and 0.03, respectively). TNXB cg21289669 was hypermethylated in the main analyses (p = 6.31 × 10-6), and TNXB locus formed a DMR (p = 3.30 × 10-10) in the main and BPs-MRONJ analyses (p = 2.76 × 10-7). cg11392877 in PDE8A was hypomethylated in BPs/DMB-MRONJ (p = 5.35 × 10-7). TRIM15 was a significant DMR in BPs-MRONJ and the main analysis (p = 3.30 × 10-10). TRIM15, TNXB, and PDE8A regulate collagen I, while NOP56 supports ribosome biogenesis, potentially contributing to MRONJ. Given the small sample size, these findings are preliminary and validation in larger studies is warranted.
Keywords: DNA methylation; bone proteins biomarkers; bone remodeling; epigenetics; epigenome-wide association study (EWAS); medication-related osteonecrosis of the jaw (MRONJ).