RESUMEN
Bisphosphonates are used in the treatment of hypocalcaemia, mainly in cancer and osteoporosis. Some patients experience adverse events, such as BP-related osteonecrosis of the jaw (BRONJ). DNA methylation plays a key role in gene regulation in many tissues, but its involvement in bone homeostasis is not well characterized, and no information is available regarding altered methylation in BRONJ. Using the Illumina Infinium HumanMethylation27 BeadChip assay, we performed an epigenome-wide association study in peripheral blood samples from 68 patients treated with nitrogenous BP, including 35 with BRONJ. Analysis of the estimated cumulative BP exposure distribution indicated that the exposure of the case group to BP was slightly higher than that of the control group; more severely affected cases (i.e., with BRONJ in both mandible and maxilla) were significantly more exposed to BP than were those with BRONJ only in the mandible or maxilla (one-sided Wilcoxon rank sum test, p=0.002). Logistic regression analysis confirmed the positive association between cumulative bisphosphonates exposure and risk of BRONJ (OR 1.015 per mg of cumulative exposure, 95% CI 1.004-1.032, p=0.036). Although no statistically significant differences were observed between case and control groups, methylation levels of probes mapping on three genes, ERCC8, LEPREL1 and SDC2, were strongly associated with cumulative BP exposure levels (p<1.31E-007). Enrichment analysis, combining differentially methylated genes with genes involved in the mevalonate pathway, showed that BP treatment can affect the methylation pattern of genes involved in extracellular matrix organization and inflammatory responses, leading to more frequent adverse effects such as BRONJ. Differences in DNA methylation induced by BP treatment could be involved in the pathogenesis of the bone lesion.
Asunto(s)
Osteonecrosis de los Maxilares Asociada a Difosfonatos/metabolismo , Metilación de ADN/efectos de los fármacos , Difosfonatos/efectos adversos , Mandíbula/metabolismo , Maxilar/metabolismo , Adulto , Anciano , Osteonecrosis de los Maxilares Asociada a Difosfonatos/genética , Osteonecrosis de los Maxilares Asociada a Difosfonatos/patología , Metilación de ADN/genética , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Difosfonatos/administración & dosificación , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Femenino , Humanos , Técnicas In Vitro , Masculino , Mandíbula/patología , Maxilar/patología , Ácido Mevalónico/metabolismo , Persona de Mediana Edad , Procolágeno-Prolina Dioxigenasa/genética , Procolágeno-Prolina Dioxigenasa/metabolismo , Sindecano-2/genética , Sindecano-2/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
PURPOSE: The aim of this prospective hospital-based study was to refine a surgical protocol for tooth extractions in patients with a history of intravenous use of a potent bisphosphonate by modifying a previously reported protocol to produce a significantly shortened operating time. PATIENTS AND METHODS: Prospective patients with a follow-up of at least 4 months were included. Tooth extractions were performed without a vestibular split-thickness flap; healing was stimulated by filling the extraction site with autologous plasma rich in growth factors (PRGF System, BTI Biotechnology Institute, Vitoria, Spain). Local and systemic infection control was obtained with dental hygiene and antibiotic therapy. RESULTS: Sixty-three patients participated in the study. Two hundred two tooth extractions were performed. Differences between the present and previous protocols (the previous protocol used a vestibular flap) were analyzed and the surgical time proved significantly shorter for the present approach (P = .00). CONCLUSIONS: The proposed surgical protocol appears to be a better choice for patients treated with intravenous bisphosphonates who need tooth extraction, because it seems to be faster and simpler than the previously reported successful protocol.