{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T14:16:13Z","timestamp":1789395373659,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R56DE030538"],"award-info":[{"award-number":["R56DE030538"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2013control epigenome-wide association study (EWAS) of 24 cancer patients treated with BPs or BPs + DMB using the Infinium\u00ae 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 &lt; 1 \u00d7 10\u22125). cg1913766 in the NOP56 promoter was hypomethylated in the main analysis (p = 2.19 \u00d7 10\u22127) and in BPs-MRONJ (p = 4.80 \u00d7 10\u22126), correlating with osteocalcin (p = 0.02 and 0.03, respectively). TNXB cg21289669 was hypermethylated in the main analyses (p = 6.31 \u00d7 10\u22126), and TNXB locus formed a DMR (p = 3.30 \u00d7 10\u221210) in the main and BPs-MRONJ analyses (p = 2.76 \u00d7 10\u22127). cg11392877 in PDE8A was hypomethylated in BPs\/DMB-MRONJ (p = 5.35 \u00d7 10\u22127). TRIM15 was a significant DMR in BPs-MRONJ and the main analysis (p = 3.30 \u00d7 10\u221210). 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.<\/jats:p>","DOI":"10.3390\/ijms262211208","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T09:44:53Z","timestamp":1763631893000},"page":"11208","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrative Epigenomic and Targeted Protein Analysis in MRONJ: Correlating DNA Methylation with Bone Biomarkers"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5165-2190","authenticated-orcid":false,"given":"Raed Awadh","family":"Alshammari","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"},{"name":"Department of Clinical Pharmacy, College of Pharmacy, University of Ha\u2019il, Ha\u2019il 55473, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa","family":"Tantawy","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7134-3065","authenticated-orcid":false,"given":"Danxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elysse","family":"Castro-Hall","sequence":"additional","affiliation":[{"name":"Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Abreu","sequence":"additional","affiliation":[{"name":"Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1966-6000","authenticated-orcid":false,"given":"Alessandro","family":"Villa","sequence":"additional","affiliation":[{"name":"Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Katz","sequence":"additional","affiliation":[{"name":"Department of Oral Medicine, College of Dentistry, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0844-1965","authenticated-orcid":false,"given":"Lexie Shannon","family":"Holliday","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8218-1620","authenticated-orcid":false,"given":"Yan","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"},{"name":"Cardio-Oncology Working Group, University of Florida Health Cancer Institute, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.joms.2022.02.008","article-title":"American Association of Oral and Maxillofacial Surgeons\u2019 Position Paper on Medication-Related Osteonecrosis of the Jaws-2022 Update","volume":"80","author":"Ruggiero","year":"2022","journal-title":"J. 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