Abstract
Osteonecrosis of the jaw (ONJ) is a rare but serious drug induced adverse event, mainly associated with the use of antiresorptive medications, such as intravenous (IV) bisphosphonates (BPs) in cancer patients. In this review, we evaluated all the pharmacogenomic association studies for ONJ published up to December 2018. To date, two SNPs (CYP2C8 rs1934951 and RBMS3 rs17024608) were identified to be associated with ONJ by two genome-wide association studies (GWAS). However, all six subsequent candidate gene studies failed to replicate these results. In addition, six discovery candidate gene studies tried to identify the genetic markers in several genes associated with bone remodeling, bone mineral density, or osteoporosis. After evaluating the results of these 6 studies, none of the SNPs was significantly associated with ONJ. Recently, two whole-exome sequencing (WES) analysis (including one from our group) were performed to identify variants associated with ONJ. So far, only our study successfully replicated discovery result indicating SIRT1 SNP rs7896005 to be associated with ONJ. However, this SNP also did not reach genome-wide significance. The major limitations of these studies include lack of replication phases and limited sample sizes. Even though some studies had larger sample sizes, they recruited healthy individuals as controls, not subjects treated with BPs. We conclude that a GWAS with a larger sample size followed by replication phase will be needed to fully investigate the pharmacogenomic markers of ONJ.
Highlights
Pharmacogenomics, or the genetic/genomic determinants of drug response and adverse effects, is a tool that has been useful in individualizing medication therapy in order to improve drug efficacy and minimize adverse effects [1,2]
Later in 2014, the term “Medication Related Osteonecrosis of the Jaw” (MRONJ) was introduced in light of the fact that antiangiogenic therapies were linked to this complication [6]
Given their non-proliferative action, BPs are important and effective medications for preventing bone loss in cancer patients [15,21,27] especially used for patients with multiple myeloma (MM) and other cancers which metastasize to the bone, to prevent skeletal related events (SREs) [28]
Summary
Pharmacogenomics, or the genetic/genomic determinants of drug response and adverse effects, is a tool that has been useful in individualizing medication therapy in order to improve drug efficacy and minimize adverse effects [1,2]. Osteonecrosis of the jaw (ONJ) is a rare but severe drug induced adverse event, which is defined as the exposure of jaw bone (mandible, maxilla, or both) with slow healing for > 8 weeks, or even no healing [3]. The term “Bisphosphonates Related Osteonecrosis of the Jaw” (BRONJ) was initially used by the American Association of Oral and Maxillofacial Surgeons (AAOMS) to describe this drug induced complication. In 2009, the term BRONJ was replaced with “Antiresorptive Related Osteonecrosis of the Jaw” (ARONJ) because another class of antiresorptive agents, receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor, denosumab (Prolia®, Xgeva®) was found to be associated with ONJ [5]. Later in 2014, the term “Medication Related Osteonecrosis of the Jaw” (MRONJ) was introduced in light of the fact that antiangiogenic therapies were linked to this complication [6].
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