Genetic Background of Medication-Related Osteonecrosis of the Jaw: Current Evidence and Future Perspectives.

1. Introduction

Osteonecrosis or avascular necrosis is a pathological condition defined by the death of bone tissue due to the disruption in blood supply. It can affect various areas such as the femoral head, humeral head, spine, or jaw (osteonecrosis of the jaw; ONJ). ONJ is mainly caused by various medications (MRONJ), radiation therapy, and trauma to the jaw [ 1 ]. Medication-related osteonecrosis of the jaw (MRONJ) is a significant adverse effect of mainly antiresorptive drugs [ 1 ]. Antiresorptive agents such as bisphosphonates (BPs) or denosumab inhibit bone resorption by reducing the activity of osteoclast cells. Bisphosphonates bind to hydroxyapatite in bone and inhibit osteoclast function as well as induce apoptosis in osteoclast cells [ 2 ]. Denosumab is a monoclonal antibody that targets the receptor activator of nuclear factor kappa-B ligand (RANKL), a molecule essential for osteoclast function [ 3 ]. These agents are effective in the treatment of osteoporosis and in reducing the risk of skeletal-related events (SREs) (e.g., hypercalcemia, pathologic fracture, spinal cord compression, palliative radiotherapy to bone) in cancer patients [ 4 , 5 ]. The first case of bisphosphonate-related osteonecrosis of the jaw (BRONJ) was described more than twenty years ago, in 2003 [ 6 ]. Since that time, several other agents have been linked to similar maxillary and mandibular osteonecrotic conditions. Due to these new findings, the American Association of Oral and Maxillofacial Surgeons updated the terminology from BRONJ to MRONJ in 2014 [ 7 ]. Based on the agent causing the osteonecrosis, MRONJ cases can be divided into two distinct groups. These groups are bisphosphonate-related osteonecrosis of the jaw (BRONJ) and non-bisphosphonate-related osteonecrosis of the jaw (non-BRONJ). Non-BRONJ instances are caused by numerous drugs such as the anti-receptor activator of nuclear factor kappa-Β ligand (anti-RANKL) antibody denosumab, an inhibitor of mammalian target of rapamycin (mTOR) everolimus, tyrosine kinase inhibitors, or antiangiogenic drugs (e.g., bevacizumab) [ 8 ]. Evidently, MRONJ is a heterogeneous disease, as several drugs and diverse pathophysiological factors contribute to its development. This heterogeneity might hinder the identification of universal genetic factors, as distinct genetic factors may be implicated in different cases.

MRONJ is defined as bone exposed or accessible through an extra or intraoral fistula in the maxillofacial region that has persisted for more than 8 weeks, current or previous treatment with antiresorptive agents alone or in combination with other drugs (e.g., antiangiogenic agents, immune modulators), and no history of metastatic disease or radiation exposure to the jaw [ 1 ]. MRONJ incidence is approximately a magnitude higher in cancer patients (0–18 percent) compared with the incidence in individuals treated with osteoporosis (0.02–0.3 percent) [ 1 ].

Affected patients might experience symptoms including odontalgia, dull pain in the jaw, intraoral and extraoral swelling, sinus pain, purulent discharge, and exposed and necrotic bone [ 1 , 9 ]. Due to these symptoms, predominantly the pain associated with the disease, MRONJ significantly hinders the quality of life of the affected patient [ 10 ]. Moreover, a more severe clinical stage of the disease is associated with even worse quality of life (QoL) indices [ 11 ]. A recent study showed that improvement in disease status potentially predicts the improvement in QoL indices [ 12 ].

The exact pathomechanism of MRONJ is still not clear. Several factors are thought to play a role in the disease. Bone remodeling imbalance, the inhibition of angiogenesis, immune system dysfunction, inflammation, and soft tissue toxicity might all be important factors in the development of the disease [ 13 ]. Risk factors include local factors such as dentoalveolar operations and systemic factors like diabetes mellitus or corticosteroid therapy [ 1 ]. Aside from these mechanisms, certain genetic factors, mainly SNPs, are also reported to play a consequential role in the development of MRONJ [ 14 ].

Single nucleotide polymorphisms (SNPs) in various genes have been investigated in MRONJ, primarily through candidate gene approaches, whole exome sequencing, and genome-wide association studies. The identified genes predominantly relate to bone metabolism, immune system function, or inflammatory processes. While disease-associated polymorphisms might have diagnostic value in the future, they also enhance our understanding of the pathomechanism of MRONJ.

Some studies have also aimed to discover the possible role of microRNAs in the pathophysiology of the disease [ 15 , 16 ]. Several microRNAs play an important role in bone biology [ 17 ], thus a better understanding of the microRNA landscape in MRONJ would help us further unveil the pathophysiology of the disease as well as help detect new therapeutic strategies.

Aside from detecting SNPs and microRNAs, gene expression studies have also been conducted in MRONJ [ 18 , 19 ]. Identifying differently expressed genes (DEGs) in tissues associated with the condition can help further understand the pathophysiology as well as detect novel therapeutic targets and biomarkers.

This paper aimed to describe the genetic factors associated with MRONJ susceptibility and identify potential avenues for progress in this scientific field.

2. Indications for Antiresorptive Therapy

Antiresorptive agents such as BPs (e.g., zoledronic acid, alendronate, ibandronate, risedronate) and denosumab are primarily used to treat osteoporosis, the most common metabolic bone disease [ 20 ]. Both BPs and denosumab are highly effective in the treatment of primary (e.g., postmenopausal osteoporosis) and secondary osteoporosis (e.g., glucocorticoid-induced osteoporosis) as well as increasing the bone mineral density and lowering fracture risk [ 4 , 21 ]. BPs are also the first-line therapeutic choice in Paget’s disease of the bone or osteitis deformans, another relatively common metabolic bone disease [ 22 ]. Moreover, antiresorptive therapy is also crucial in the management of SREs in patients with multiple myeloma (MM) and bone metastases. BPs significantly decrease skeletal morbidity and also effectively delay the first SRE [ 5 ]. Denosumab was detected to be even more effective in reducing the risk of SREs when compared to BPs [ 4 ]. Furthermore, denosumab also improved the pain outcomes and lowered the opioid needs of patients [ 4 ]. BPs are also the mainstay of treatment in osteogenesis imperfecta (OI), an inherited skeletal dysplasia [ 23 ]. The use of BPs is beneficial in OI, as they increase bone mass as well as reduce fracture incidence [ 23 ]. BPs are also used, alongside parathyroid hormone analogs, in the treatment of fibrous dysplasia (FD) [ 24 ]. FD is an uncommon monostotic or polyostotic fibro-osseous bone lesion, with the potential for malignant transformation, in which BPs are used to maintain bone density [ 24 ].

3. The Pathophysiology of MRONJ

Since the first case was reported in 2003 by Marx et al. [ 6 ], the pathomechanism of MRONJ has still not been exactly described. There are several proven factors contributing to the condition, however, none of them can describe the disease alone.

Bone remodeling inhibition is recognized as one of the key hypotheses of MRONJ pathophysiology [ 1 ]. Both BPs and denosumab (DMB) hinder bone remodeling by inhibiting osteoclast function, which is supported by the histological assessment of ONJ animal models [ 25 ]. Zoledronate-treated animals displayed atypical osteoclast cells, detached from the bone surface at the osteonecrosis site [ 25 ]. The parathyroid hormone (PTH) also rescued necrotic lesions and facilitated wound healing in a rat MRONJ model [ 26 ]. As PTH promotes bone remodeling, this further validates bone remodeling inhibition as an important factor in the development of the disease [ 27 ].

BPs, mainly zoledronate, have a direct cytotoxic effect on human gingival fibroblasts [ 28 ]. Zoledronate might hinder wound healing by inhibiting gingival fibroblast cell proliferation and migration [ 28 , 29 ]. These deficits in fibroblast function can attenuate MRONJ development. Despite having no cytotoxic effect on fibroblasts, DMB still results in an incidence similar to that of BPs [ 30 ]. Thus, direct soft tissue toxicity might be less important in the pathogenesis of the condition.

Local immune dysfunction has also been reported as an important factor in the development of MRONJ [ 31 ]. It is well-known that patients with immune disorders (e.g., diabetes, autoimmune disorders) have higher chances of MRONJ [ 1 ]. BPs mainly affect the innate immune system such as the dendritic cells, macrophages, and neutrophil granulocytes [ 31 ]. Soft tissue toxicity leads to easier infection of the gingival mucosa, while dysfunction of the innate immune system prolongs the infection and inflammation [ 31 ].

Inflammation is also thought to be a key factor in the development of the disease [ 32 ]. An animal model of the disease demonstrated that MRONJ susceptibility was increased in periradicular disease after tooth extraction [ 25 ]. In another study, the extraction of healthy teeth did not increase the chance of developing the condition, while on the other hand, preexisting periapicular disease increased the osteonecrotic susceptibility [ 33 ]. Furthermore, Nakamura et al. detected that MRONJ was more likely to develop from teeth with local infections [ 34 ].

BPs have been demonstrated to inhibit angiogenetic pathways in multiple studies [ 35 , 36 ]. Moreover, locally delivered VEGF into healing extraction sockets lowered the MRONJ incidence through a pro-angiogenetic mechanism [ 37 ]. At the margins of osteonecrotic lesions, microvascular changes such as hypo-vascularized edematous areas have been detected [ 38 ]. These results suggest that angiogenesis inhibition might also be a contributing factor to MRONJ development. Figure 1 displays the most important factors contributing to the development of MRONJ.

4. Single Nucleotide Polymorphisms (SNPs) in MRONJ

4.1. CYP2C8

One of the most researched genes in the context of MRONJ is the CYP2C8 gene, which encodes the cytochrome P4502C8 (CYP2C8) protein, a key member of the CYP2C family [ 39 ]. The cytochrome P450 proteins function as important enzymes in the oxidative metabolism of several drugs (e.g., paclitaxel, rosiglitazone, amodiaquine) [ 39 ]. Even though BPs are not directly metabolized by CYP2C8, this enzyme might have a functional role in periodontal fibroblast cells both in the metabolism of the drug and reactive oxygen species (ROS) [ 40 ]. Yamoune et al. found that zoledronic acid increased the ROS activity for certain genetic variants of the CYP2C8 protein [ 40 ]. Increased oxidative stress has been found to be a risk factor for developing MRONJ due to its ability to suppress bone turnover [ 41 ]. Moreover, CYP2C8 also alters the metabolic pathway involved in cholesterol production, which is crucial for osteoblast and osteoclast function [ 42 , 43 ].

In 2008, Sarasquete et al. conducted a genome-wide single nucleotide polymorphism analysis in MM patients [ 44 ]. In this study, 22 BRONJ cases and 65 matched BRONJ-free cases were compared. Four intronic SNPs, all in the CYP2C8 gene, were found to be associated with BRONJ, distinctly rs1934951, which is located at intron 8 in the CYP2C8 gene [ 44 ]. Some studies involving MM and prostate cancer patients were unable to detect an association between the genotype of rs1934951 and BRONJ [ 45 , 46 , 47 ]. Interestingly, Balla et al. found a significant correlation between rs1934951 and the anatomic localization of BRONJ [ 48 ]. In this study, AG carriers had a significantly higher chance of developing ONJ in mandibular localization [ 46 ]. Interestingly, Kastritis et al. found that the high-risk allele of rs1934951 SNP was associated with the earlier development of BRONJ [ 49 ]. Thus, carriers of the high-risk allele of rs1934951 are more likely to develop BRONJ earlier compared to non-high-risk allele carrier patients [ 49 ].

Due to the contradictory results regarding the relevance of CYP2C8 rs1934951 in BRONJ, Zhong et al. performed a meta-analysis to determine the association between the polymorphism and BRONJ susceptibility [ 50 ]. In the pooled analysis, there were 126 cases and 453 controls. This meta-analysis did not detect a significant correlation between the genotype of rs1934951 and BRONJ. However, a subgroup analysis only considering MM patients showed a significant correlation between the disease and the SNP [ 50 ].

Overall, there is still not enough evidence to conclude on the significance of the CYP2C8 gene in MRONJ. Studies with higher case numbers and matched control groups are needed to evaluate the role of CYP2C8 in the disease.

4.2. SIRT1

The SIRT1 gene encodes SIRT1, a member of the sirtuin (SIRT) protein family. Sirtuins are nicotine adenine dinucleotide + (NAD + ) dependent histone deacetylases that are involved in several crucial biological processes (e.g., inflammation, apoptosis, cell metabolism, cell proliferation) by epigenetically regulating numerous important genes in various biological pathways [ 51 ]. SIRT1 is involved in several age-related diseases such as different cancers, cardiac hypertrophy, and Alzheimer’s disease [ 51 ]. SIRT1 is also an important regulator in bone homeostasis, primarily promoting bone formation through various biological processes [ 52 ]. These include activating the Wnt/β-catenin pathway by preventing β-catenin degradation, inhibiting osteoblast apoptosis, and also promoting autophagy to resist external cellular stress [ 52 ].

A study found that in both ovariectomized female mice and aged male mice (models for post-menopausal and age-related osteoporosis, respectively), a significant improvement in bone mass could be achieved by administering a SIRT1 agonist [ 53 ]. Moreover, a randomized placebo-controlled trial detected that a first-generation SIRT1 agonist, resveratrol, increased the bone mineral density (BMD) in obese men [ 54 ]. Another study found that oncologic doses of zoledronic acid (ZA) caused SIRT1-dependent inflammation in human oral keratinocytes (HOKs), which is recognized as a major risk factor for mucosal nonunion in MRONJ [ 55 ]. Additionally, menaquinone-4 was found to prevent MRONJ by alleviating osteoblast apoptosis via a SIRT1-dependent pathway [ 56 ].

In 2018, an exome-wide association analysis detected an association between MRONJ and two SNPs on chromosome 10 in the SIRT1 and HERC4 genes [ 57 ]. In this study, SIRT1 rs7896005, an intronic SNP, was associated with lower odds of developing the condition. Furthermore, in silico analysis revealed that this SNP was an expression quantitative trait locus (eQTL) of the SIRT1 gene in whole blood, with the minor A allele increasing the gene expression, resulting in a lower risk for MRONJ [ 57 ]. In a follow-up study, Yang et al. aimed to identify causal SNPs explaining the association between rs7896005 and MRONJ susceptibility [ 58 ]. They found that rs932658, an SNP in the promoter region of the SIRT1 gene, was causally related to susceptibility to the disease [ 58 ]. In this study, a higher expression of the SIRT1 gene was detected with the minor A allele of the rs932658 SNP, which might act as a protective factor in MRONJ [ 58 ]. In a recent paper, Bojtor et al. further validated the association between rs932658 and disease incidence in a retrospective study involving 63 osteoporosis and cancer MRONJ patients [ 59 ]. Furthermore, patients with rs932658 minor allele A had better healing tendencies from MRONJ compared to patients with other allelic variants [ 59 ].

In conclusion, SIRT1 rs932658 is a promising SNP as a novel diagnostic tool to analyze disease susceptibility in patients at risk. Moreover, further validation of this polymorphism causal relationship with the disease might help better understand the pathomechanism of the disease as well as help to determine new SIRT1-associated drug targets in MRONJ therapy.

4.3. ESR1 and CYP19A1

Estrogen receptor and aromatase enzyme coding genes have also been researched in MRONJ, as estrogens are recognized as key regulators of bone remodeling in both sexes [ 55 ]. The effect of estrogens on bone cells is mediated by two nuclear receptors: ERα and ERß, encoded by the esr1 and esr2 genes, respectively [ 60 ]. Estrogens play a crucial role in maintaining BMD and mass via several pathways, which include repressing pro-osteoclastic cytokines (e.g., IL-1, IL-6) [ 61 , 62 ], anti-apoptotic effects in osteoblasts [ 63 ], and increasing the transcription of osteoprotegerin (OPG) [ 64 ]. Furthermore, both the ESR1 and ESR2 polymorphisms have been shown to affect the bone mass in humans [ 60 ]. Interestingly, ESR1 also regulates insulin-like growth factor-1 (IGF-1) activation, which is involved in re-epithelization and wound healing processes [ 65 , 66 ]. Based on these findings, ESR1 polymorphisms can affect MRONJ susceptibility through both bone-specific and wound-healing mechanisms.

A study from 2023 involving 125 bisphosphonate-taking postmenopausal women found two SNPs (rs4870056 and rs78177662) in the ESR1 gene that were significantly associated with MRONJ occurrence [ 67 ]. Both variants increased the risk of the condition by approximately 2.5-fold [ 67 ]. Rs4870056 is located in an intronic region, and has a strong link with another ESR1 SNP, rs2234693 (Pvull) [ 67 ]. ESR1 Pvull (rs2234693) is one of the most researched polymorphisms in the ESR1 gene, which is associated with numerous diseases (e.g., cardiovascular diseases, breast cancer) [ 68 , 69 ], and might also have an effect on BMD [ 70 ].

Aromatase, encoded by the CYP19A1 gene, is part of the cytochrome P450 enzyme family, responsible for transforming androgen precursors to estrogenic compounds [ 71 ]. The aromatase enzyme is expressed in several extraglandular sites such as adipose tissue or bone [ 72 ]. Moreover, aromatase activity is necessary for longitudinal bone growth and may significantly affect bone loss [ 71 ].

Aromatase polymorphism g.132810C>T was found to be significantly associated with BRONJ development in a study by [ 73 ], where patients with a TT homozygous genotype had a twofold higher risk for the development of BRONJ [ 73 ]. Interestingly, this genotype is associated with higher levels of local estrogens [ 74 ]. According to the author’s theory, locally higher estrogen levels and BPs inhibit bone remodeling more than BPs alone, leading to an increased risk for BRONJ [ 73 ].

To conclude, genes associated with estrogen pathways present a promising possibility for understanding and predicting MRONJ better in the future. However, there are only limited data available on these genes, so further studies are very much needed.

4.4. Genes Associated with Osteoclast Function and Bone Remodeling (COLIA1, RANK, OPG, MMP2, OPN)

In 2011, Katz et al. conducted a cohort study on 78 MM patients taking intravenous BP therapy [ 46 ]. This paper reported that, over the 1-year study period, 12 patients developed BRONJ. The authors compared ten SNPs in seven genes ( CYP2C8 , COL1A1 , RANK , OPN , MMP2 , OPG , and TNF ) in a candidate-gene study style. In this study, a combined genotype score of five SNPs ( COL1A1 rs1800012, RANK rs12458117, MMP2 rs243865, OPN rs11730582, and OPG rs2073618) was able to significantly predict an 11-fold increase in MRONJ risk with a cutoff score of 5 [ 46 ].

COL1A1 encodes an important part of type 1 collagen and its mutations are associated with osteogenesis imperfecta [ 75 ]. COL1A1 rs1800012 may also be associated with ligament and tendon injuries [ 76 ]. RANK (receptor activator of the NF-kB) is a transmembrane protein expressed on osteoclasts and several other cells. It functions as the receptor of RANKL, and its activation is very important in osteoclast differentiation, activation, and survival [ 77 ]. Another very important molecule involved in osteoclastogenesis is osteoprotegerin (OPG), which functions as a decay receptor of RANKL [ 78 ]. RANK and OPG genetic polymorphisms have been previously linked to BMD [ 79 ]. MMP2 encodes an important matrix metalloproteinase (matrix metallopeptidase 2, MMP2) that is involved in the cleavage of several extracellular and non-extracellular matrix molecules [ 80 ]. MMP2 has previously been suggested as a candidate gene in MRONJ, as BPs are associated with atrial fibrillation, and MMP2 is associated with both bone and cardiovascular abnormalities [ 81 ].

These results support the role of bone remodeling abnormalities as a key factor in the pathogenesis of MRONJ and also suggest that genetic testing might be an effective tool for risk screening in the future. However, the small sample size poses a major limitation when interpreting these findings.

4.5. VEGFA

As abnormal and inhibited angiogenesis is a leading hypothesis in the possible pathophysiological mechanisms, it is logical that multiple papers have reported on SNPs in the VEGFA gene in MRONJ patients. VEGFA encodes the vascular endothelial growth factor (VEGF) protein, a key regulator of physiological (e.g., embryonic development) and pathological (e.g., solid tumors or intraocular neovascular syndromes) angiogenesis [ 82 ]. Moreover, VEGF is also an important molecule in inflammatory disorders and wound healing [ 82 ], and plays a crucial role in bone angiogenesis [ 83 ]. VEGFA polymorphisms have been linked to several diseases such as diabetic retinopathy, age-related macular degeneration, and different solid tumors [ 84 , 85 , 86 , 87 ]. VEGF also plays an important role in skeletal development [ 88 ]. Furthermore, postnatally osteoblast-derived VEGF regulates osteoblastogenesis and adipogenesis in bone marrow by stimulating RUNX2 and repressing PPARG2 [ 88 ]. It is hypothesized that polymorphisms associated with lower VEGF expression might have a pathophysiological role in the development of the condition.

In 2011, Arduino et al. were the first to analyze VEGFA polymorphisms in Italian female breast cancer patients with MRONJ [ 89 ]. The authors analyzed three SNPs (rs3025039, +936 C>T; rs699947, −2578 C>A; rs2010963, −634 G>C) in the VEGFA gene. The combined haplotype of CAC (+936/−2578/−634) was associated with MRONJ susceptibility [ 89 ]. All three of these polymorphisms have previously been reported to correlate with VEGFA expression [ 90 , 91 , 92 ], with two of them being associated with a lower expression level of VEGF (−2578/−634), and one of them with a higher expression level (+936). Analyzing only the two SNPs (−2578/−634) resulting in lower expression levels remained significantly associated with a higher incidence of MRONJ [ 89 ]. Another study conducted in the Korean population also evaluated these SNPs (rs3025039, rs699947, rs2010963), and further affirmed the association between VEGFA and the disease, finding that the CC genotype of both rs3025039 and rs2010963 was associated with a higher chance of developing the condition [ 93 ]. These results are partially consistent with a metanalysis in both polymorphisms of allele C being associated with MRONJ susceptibility, but not entirely identical, as there were some differences in the allele frequencies and the significant polymorphisms between the two studies, likely due to the different populations (Italian vs. Korean) studied. However, a more recent case–control study involving osteoporosis patients exclusively found no significant associations between rs2010963, rs3025039, and rs699947 and disease susceptibility [ 94 ]. On the other hand, two SNPs (rs881858 and rs10434) were found to be associated with MRONJ. The authors argue that rs10434 might also have an effect on VEGF expression based on different alleles being associated with different diseases, however, there is no direct proof of this in the literature [ 94 ]. A meta-analysis from 2020 involving 105 MRONJ cases found that rs3025039 was significantly associated with a risk for the condition [ 14 ].

Overall, there are some contradictions in the results considering VEGFA in MRONJ, which could have been caused by the different populations and different patients (e.g., osteoporosis vs. cancer patients) screened in the different studies. However, polymorphisms in VEGFA , which are associated with a lower level of VEGF expression, might pose a promising target for future investigation. Table 1 summarizes the studies investigating SNPs in the CYP2C8 , SIRT1 , and VEGF genes, which are among the most studied genes in MRONJ.

4.6. Other Genes Researched in MRONJ

In a 2022 study, 24 potentially pathogenic variants were identified using whole exome sequencing, with allele frequencies significantly different between the MRONJ-affected and control groups [ 95 ]. Nine of the polymorphisms clustered in only two genes. These genes are KRT18 and PABPC3 . The KRT18 gene encodes a type 1 intermediate filament protein called keratin 18 [ 95 ]. It is interesting to note that the role of genes encoding other keratin proteins has been suggested in oral mucosal diseases [ 96 ]. Furthermore, KRT18 plays an important role in cytoskeleton organization and in various estrogen signaling pathways [ 95 ]. Malfunction of the KRT18 protein can lead to cytoskeletal dysfunction of the oral mucosal cells, which may predispose one to oral mucosal diseases and MRONJ. The PABPC3 gene encodes a poly-A binding protein, whose functional role in the pathogenesis of the disease needs to be elucidated by further experimental and clinical studies.

A genome-wide association study identified a polymorphism (rs17024608) in the RBMS3 gene, which was significantly associated with BRONJ incidence [ 97 ]. Variations of this gene have previously been linked to bone mass and osteoporotic fracture risk [ 97 ].

In another study, the PPARG (peroxisome proliferator-activated receptor gamma) SNP rs1152003 was also found to be associated with MRONJ in MM patients as well as SNPs in ABP1 (amiloride binding protein 1), CHST11 (carbohydrate sulfotransferase 11), and CROT (carnitine O-octanoyltransferase) genes [ 98 ]. PPARG polymorphisms have also been associated with bone remodeling and bone mineral density [ 98 ]. Interestingly, a study from 2017 found that the high-risk allele of PPARG rs1152003, together with CYP2C8 rs1934951, was associated with early-onset of the disease [ 49 ]. Thus, these SNPs might be useful to assess the risk of early MRONJ development. Moreover, Poznak et al. found that PPARG rs1152003 had a significant association with MRONJ risk in an univariate analysis, however, after covariate adjustment, this SNP did not remain significantly associated [ 99 ].

A case–control study identified farnesyl pyrophosphate synthase ( FDPS ) rs2297480 allele A to be associated with MRONJ susceptibility [ 100 ]. FDPS functions as an important enzyme of the mevalonate pathway, and it is targeted by several amino-bisphosphonates [ 101 , 102 ]. Interestingly, FDPS rs2297480 allele A was also detected to be associated with an increased response to long-term amino-bisphosphonate therapy [ 102 ].

SNPs in genes encoding interleukins 1A and 1B have also been suggested to play a potential role in the pathogenesis of the disease [ 103 ].

Infection and immune system dysfunction are regularly mentioned as a major morbidity factor in MRONJ. In a case–control study of 204 patients, several variants of Human Leukocyte Antigen Class II (HLA Class II) (DRB1*15, DQB1*06:02, DRB1*01, and DQB1*05:01) were significantly more prevalent in MRONJ patients [ 104 ]. These HLA antigens are involved in immune cell differentiation and antigen presentation [ 104 ]. Figure 2 highlights some studies on the genetic background of the disease.

5. Gene Expression Studies in MRONJ

By analyzing the mRNA pattern of MRONJ tissue samples, we can obtain a snapshot of its gene expression pattern. Such studies will not only provide a better understanding of the pathomechanism of the disease, but also identify potential drug targets.

One study found differential expression of defensins, a family of antimicrobial proteins, in MRONJ bone tissue samples [ 18 ]. Two types of defensin molecules (DEFA3, DEFB3) were also more highly expressed in denosumab-induced osteonecrosis of the jaw than in the control tissues [ 18 ]. This result further confirms the role of chronic infection in the pathophysiology of the disease.

The expression of factors promoting vascular remodeling was also investigated in a rat model [ 107 ]. Increased expression of factors promoting angiogenesis (e.g., VEGFA, VEGFR-2) was observed in this experiment. However, it has been suggested that a compensatory mechanism due to the inhibitory effect of zoledronic acid on vascularization may underlie this. Further studies with a larger number of human cases are needed to explain this precisely.

An in vitro study demonstrated that low-dose BPs such as zoledronate, alendronate, and clodronate could alter the expression of vital genes (e.g., TGF-B1 , TGF-BR1 , TGF-BR2 , RUNX-2 , Col-1 ) in osteoblast growth and differentiation and osteoblast–osteoclast interactions [ 108 ]. Wehrhan et al. found that Msx-1, an important transcription factor promoting cellular plasticity and differentiation in the periodontal ligaments, was significantly underexpressed in BRONJ tissue [ 109 ]. The underexpression of Msx-1 can explain the common clinical finding of sclerotic remodeling of the periodontal ligaments in MRONJ cases [ 109 ].

By examining the transcriptional pattern of genes involved in immunological processes, the locally altered immune environment of MRONJ tissue can be determined [ 19 ]. Moreover, individuals who were more susceptible to BRONJ had lower gene expression levels for several important factors (RANK, AHR, FGF9), determining immune resilience and normal barrier function [ 110 ]. In these individuals, the added stress of BP administration might cause BRONJ development [ 110 ]. A bioinformatic analysis, conducted on samples from MM patients with or without BRONJ, revealed that differently expressed genes (DEGs) in BRONJ cases were mainly enriched in pathways that are important in immune functions and RNA splicing such as TNF, ILB1, and DDX5 [ 111 , 112 ].

In conclusion, gene expression studies can provide information on the current state of the transcriptome of tissue affected by osteonecrosis of the jaw, which may provide valuable insights into the pathomechanism of MRONJ, and may also identify potential new therapeutic targets. Moreover, the evaluation of combined gene expression panels might provide new biomarkers in the disease [ 113 ]. Table 2 summarizes studies analyzing gene expression in connection with MRONJ.

6. MicroRNAs and Other Noncoding RNAs in MRONJ

MicroRNAs (miRNAs) are small noncoding RNA molecules that play a crucial role in the regulation of gene expression at the messenger RNA (mRNA) level [ 116 ]. They primarily exert their repression of gene translation by selectively binding to the 3′UTR (untranslated region) of their target mRNA [ 117 ]. Altered miRNA expression patterns have been linked to several diseases including cardiovascular abnormalities (e.g., cardiac hypertrophy, cardiac failure), metabolic diseases (e.g., diabetes mellitus), and different cancers [ 116 ]. MiRNAs have also been described as crucial regulators in bone formation and homeostasis including osteogenesis, osteoclastogenesis, and the regulation of osteoblasts [ 17 ]. Due to their cardinal role in bone biology, some miRNAs have been examined in both human and animal MRONJ studies.

In 2018, Musolino et al. investigated 18 different miRNAs expressed in peripheral lymphocytes in 10 MM patients (5 cases and 5 controls) with or without MRONJ [ 15 ]. In this study, 14 miRNAs were found to have a significant difference in expression between the groups, all of them being overexpressed. Six of these miRNAs (miR-16-1, miR-149, miR-23-a, miR-145, miR-129-1, miR-221) displayed strong overexpression (4-fold to 11-fold) [ 15 ]. Notably, all of them regulate pathways that are important in bone homeostasis and inflammatory processes [ 15 ]. Another study compared 6 BRONJ cases and 11 healthy controls [ 16 ]. In this study, miR-21 and miR-23-a were found to be overexpressed, while miR-145 was found to be underexpressed in the sera of BRONJ patients [ 16 ].

There are also some preliminary data available regarding other noncoding RNAs that might be potential contributors to the disease. Allegra et al. found distinct expression profiles of long noncoding RNAs (lncRNAs) in MM patients with MRONJ compared with MRONJ-free MM patients [ 118 ].

These possible new findings might help better understand the pathophysiology of MRONJ as well as identify new targets for therapy. For example, the inhibition of miR-23-a improved femoral head osteonecrosis in rat models [ 119 ]. Another study found that the local administration of miR-149-5p loaded vesicles promoted better wound healing in a BRONJ mouse model [ 120 ]. Despite these promising results, further studies are needed to better understand the role of noncoding RNAs in MRONJ.

7. Conclusions and Future Perspectives

A review of the literature showed that several genes and gene variants have been implicated in the pathogenesis of MRONJ. The initial candidate gene studies have been complemented by whole exome and genome-wide sequence analyses with the introduction of high-throughput NGS technology, which has significantly expanded our knowledge of the complex genetic background of MRONJ. The role of some gene variants (e.g., SIRT1 , VEGF in genes) has been confirmed by several independent studies. In addition, there are newly described potential genes that need further validation (e.g., KRT18 ), which may bring us closer to a deeper understanding of the background of MRONJ. The heterogeneous nature of MRONJ might complicate the identification of universal genetic factors, however, in the future, in addition to the methods presented in this summary, which primarily detect sequence divergences, for example, by epigenetic or DNA methylation or mRNA or microRNA expression studies, we may gain a more complete picture of the diverse genetic background of the disease.

MRONJ is a complex, multifactorial disease in which the genetic factors described above also play a key role. Despite the major negative impact of the disease on quality of life, there is currently no clinical risk assessment system that can provide a good approximation of which patients should be expected to develop this adverse side effect.

Several clinical trials have been conducted on patients with this condition to find novel therapeutical modalities to tackle this disease. For instance, a study found that teriparatide had a beneficial effect on bone healing in MRONJ without any additional adverse effects [ 121 ]. Another study detected that the addition of bone morphogenic protein-2 (BMP-2) to leukocyte-rich and platelet-rich fibrin improved postoperative outcomes in MRONJ patients [ 122 ]. The integration of emerging therapeutic strategies complemented by novel prognostic biomarkers can help further enhance the management of this condition.

Known risk factors, combined with newly identified genetic predisposing factors, could be used to develop a personalized algorithm including genetic diagnostics to screen patients at high risk for MRONJ. Greater therapeutic attention to them (e.g., performing necessary dental procedures prior to antiresorptive therapy) could reduce the incidence of osteonecrotic side effects when administering antiresorptive agents. This could improve the quality of life of patients as well as improve the success of the treatment of the often malignant underlying disease. This will require further large case–control studies in the future to confirm the role of known genetic factors and identify new genetic risk factors. The introduction of novel scientific approaches can help further improve the knowledge of MRONJ genetics. For instance, the founding of a biobank of MRONJ samples and related genetic data could facilitate large-scale studies on multi-centered study groups. Longitudinal genetic studies would also be beneficial to better understand the development of this disease. Furthermore, analyzing epigenomic data could help understand the effects of environmental factors on gene expression and genetic susceptibility. Finally, the implementation of polygenic risk scores (PRSs) based on GWAS data can provide an overview of the genetic effects in MRONJ by aggregating the combined effect of several lower-impact polymorphisms. By calculating the PRSs, high-risk individuals can be identified, which could lower the MRONJ incidence in patients at risk.

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Author Contributions

Conceptualization, B.B. (Bence Bojtor), B.B. (Bernadett Balla), J.P.K. and P.L.; Writing—original draft preparation, B.B. (Bence Bojtor); Writing—review and editing, J.P.K., B.B. (Bernadett Balla), Z.P., S.S., M.V. and P.L. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

References

1. Ruggiero S.L. Dodson T.B. Aghaloo T. Carlson E.R. Ward B.B. Kademani D. American Association of Oral and Maxillofacial Surgeons’ Position Paper on Medication-Related Osteonecrosis of the Jaws—2022 Update J. Oral Maxillofac. Surg. 2022 80 920 943 10.1016/j.joms.2022.02.008 35300956

2. Russell R.G. Watts N.B. Ebetino F.H. Rogers M.J. Mechanisms of action of bisphosphonates: Similarities and differences and their potential influence on clinical efficacy Osteoporos. Int. 2008 19 733 759 10.1007/s00198-007-0540-8 18214569

3. Hanley D.A. Adachi J.D. Bell A. Brown V. Denosumab: Mechanism of action and clinical outcomes Int. J. Clin. Pract. 2012 66 1139 1146 10.1111/ijcp.12022 22967310 PMC3549483

4. Cadieux B. Coleman R. Jafarinasabian P. Lipton A. Orlowski R.Z. Saad F. Scagliotti G.V. Shimizu K. Stopeck A. Experience with denosumab (XGEVA(R)) for prevention of skeletal-related events in the 10 years after approval J. Bone Oncol. 2022 33 100416 10.1016/j.jbo.2022.100416 35242510 PMC8857591

5. Ross J.R. Saunders Y. Edmonds P.M. Patel S. Broadley K.E. Johnston S.R. Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer BMJ 2003 327 469 10.1136/bmj.327.7413.469 12946966 PMC188427

6. Marx R.E. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic J. Oral Maxillofac. Surg. 2003 61 1115 1117 10.1016/S0278-2391(03)00720-1 12966493

7. Ruggiero S.L. Dodson T.B. Fantasia J. Goodday R. Aghaloo T. Mehrotra B. O’Ryan F. American Association of Oral and Maxillofacial Surgeons American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update J. Oral Maxillofac. Surg. 2014 72 1938 1956 10.1016/j.joms.2014.04.031 25234529

8. De Cicco D. Boschetti C.E. Santagata M. Colella G. Stagliano S. Gaggl A. Bottini G.B. Vitagliano R. D’Amato S. Medication-Related Osteonecrosis of the Jaws: A Comparison of SICMF-SIPMO and AAOMS Guidelines Diagnostics 2023 13 2137 10.3390/diagnostics13132137 37443531 PMC10340476

9. Bedogni A. Mauceri R. Fusco V. Bertoldo F. Bettini G. Di Fede O. Casto A.L. Marchetti C. Panzarella V. Saia G. Italian position paper (SIPMO-SICMF) on medication-related osteonecrosis of the jaw (MRONJ) Oral Dis. 2024 30 3679 3709 10.1111/odi.14887 38317291

10. Bensi C. Giovacchini F. Lomurno G. Eramo S. Barraco G. Tullio A. Quality of life in patients affected by medication-related osteonecrosis of the jaws: A systematic review Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2021 132 182 189 10.1016/j.oooo.2021.03.006 33934955

11. Miksad R.A. Lai K.C. Dodson T.B. Woo S.B. Treister N.S. Akinyemi O. Bihrle M. Maytal G. August M. Gazelle G.S. Quality of life implications of bisphosphonate-associated osteonecrosis of the jaw Oncologist 2011 16 121 132 10.1634/theoncologist.2010-0183 21212433 PMC3228058

12. Munakata K. Miyashita H. Yamada Y. Soma T. Iwasaki R. Nakagawa T. Asoda S. Factors affecting the quality of life of patients with medication-related osteonecrosis of the jaw during treatment: A quality-of-life survey and causal analysis J. Cranio-Maxillofac. Surg. 2024 52 715 721 10.1016/j.jcms.2024.03.021 38582669

13. Kalita F. Gupta D.S. Gehlot N. Mitra S. Singh S. Pillai S.S. Osteonecrosis of the Jaws: An Update and Review of Literature J. Oral Maxillofac. Surg. 2023 22 344 351 10.1007/s12663-023-01876-w PMC10130280 37122785

14. Guo Z. Cui W. Que L. Li C. Tang X. Liu J. Pharmacogenetics of medication-related osteonecrosis of the jaw: A systematic review and meta-analysis Int. J. Oral Maxillofac. Surg. 2020 49 298 309 10.1016/j.ijom.2019.07.016 31445964

15. Musolino C. Oteri G. Allegra A. Mania M. D’Ascola A. Avenoso A. Innao V. Allegra A.G. Campo S. Altered microRNA expression profile in the peripheral lymphoid compartment of multiple myeloma patients with bisphosphonate-induced osteonecrosis of the jaw Ann. Hematol. 2018 97 1259 1269 10.1007/s00277-018-3296-7 29546453

16. Yang R. Tao Y. Wang C. Shuai Y. Jin L. Circulating microRNA Panel as a Novel Biomarker to Diagnose Bisphosphonate-Related Osteonecrosis of the Jaw Int. J. Med. Sci. 2018 15 1694 1701 10.7150/ijms.27593 30588193 PMC6299413

17. Lian J.B. Stein G.S. van Wijnen A.J. Stein J.L. Hassan M.Q. Gaur T. Zhang Y. MicroRNA control of bone formation and homeostasis Nat. Rev. Endocrinol. 2012 8 212 227 10.1038/nrendo.2011.234 22290358 PMC3589914

18. Thiel Y. Ghayor C. Lindhorst D. Essig H. Weber F. Rucker M. Schumann P. Antimicrobial peptide gene expression in medication-related osteonecrosis of the jaw Pathol. Res. Pract. 2020 216 153245 10.1016/j.prp.2020.153245 33065485

19. He J. Zhou Q. Jia X. Zhou P. Chen L. Immune-related expression profiles of bisphosphonates-related osteonecrosis of the jaw in multiple myeloma Pharmazie 2021 76 159 164 33849701 10.1691/ph.2021.01013

20. Aibar-Almazan A. Voltes-Martinez A. Castellote-Caballero Y. Afanador-Restrepo D.F. Carcelen-Fraile M.D.C. Lopez-Ruiz E. Current Status of the Diagnosis and Management of Osteoporosis Int. J. Mol. Sci. 2022 23 9465 10.3390/ijms23169465 36012730 PMC9408932

21. Lyu H. Jundi B. Xu C. Tedeschi S.K. Yoshida K. Zhao S. Nigwekar S.U. Leder B.Z. Solomon D.H. Comparison of Denosumab and Bisphosphonates in Patients With Osteoporosis: A Meta-Analysis of Randomized Controlled Trials J. Clin. Endocrinol. Metab. 2019 104 1753 1765 10.1210/jc.2018-02236 30535289 PMC6447951

22. Kravets I. Paget’s Disease of Bone: Diagnosis and Treatment Am. J. Med. 2018 131 1298 1303 10.1016/j.amjmed.2018.04.028 29752905

23. Marom R. Rabenhorst B.M. Morello R. Osteogenesis imperfecta: An update on clinical features and therapies Eur. J. Endocrinol. 2020 183 R95 R106 10.1530/EJE-20-0299 32621590 PMC7694877

24. Riddle N.D. Bui M.M. Fibrous dysplasia Arch. Pathol. Lab. Med. 2013 137 134 138 10.5858/arpa.2012.0013-RS 23276185

25. Soundia A. Hadaya D. Esfandi N. de Molon R.S. Bezouglaia O. Dry S.M. Pirih F.Q. Aghaloo T. Tetradis S. Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease Bone 2016 90 133 141 10.1016/j.bone.2016.06.011 27327410 PMC5471352

26. Kuroshima S. Entezami P. McCauley L.K. Yamashita J. Early effects of parathyroid hormone on bisphosphonate/steroid-associated compromised osseous wound healing Osteoporos. Int. 2014 25 1141 1150 10.1007/s00198-013-2570-8 24301537 PMC3923117

27. Wein M.N. Kronenberg H.M. Regulation of Bone Remodeling by Parathyroid Hormone Cold Spring Harb Perspect. Med. 2018 8 a031237 10.1101/cshperspect.a031237 29358318 PMC6071549

28. Anitua E. Zalduendo M. Troya M. Orive G. PRGF exerts a cytoprotective role in zoledronic acid-treated oral cells Clin. Oral Investig. 2016 20 513 521 10.1007/s00784-015-1528-y 26201455

29. Ohlrich E.J. Coates D.E. Cullinan M.P. Milne T.J. Zafar S. Zhao Y. Duncan W.D. Seymour G.J. The bisphosphonate zoledronic acid regulates key angiogenesis-related genes in primary human gingival fibroblasts Arch. Oral Biol. 2016 63 7 14 10.1016/j.archoralbio.2015.11.013 26658366

30. Chang J. Hakam A.E. McCauley L.K. Current Understanding of the Pathophysiology of Osteonecrosis of the Jaw Curr. Osteoporos. Rep. 2018 16 584 595 10.1007/s11914-018-0474-4 30155844

31. Zhang W. Gao L. Ren W. Li S. Zheng J. Li S. Jiang C. Yang S. Zhi K. The Role of the Immune Response in the Development of Medication-Related Osteonecrosis of the Jaw Front. Immunol. 2021 12 606043 10.3389/fimmu.2021.606043 33717086 PMC7947359

32. Bassan Marinho Maciel G. Maciel R.M. Ferrazzo K.L. Danesi C.C. Etiopathogenesis of medication-related osteonecrosis of the jaws: A review J. Mol. Med. 2024 102 353 364 10.1007/s00109-024-02425-9 38302741

33. Hadaya D. Soundia A. Gkouveris I. Dry S.M. Aghaloo T.L. Tetradis S. Development of Medication-Related Osteonecrosis of the Jaw After Extraction of Teeth With Experimental Periapical Disease J. Oral Maxillofac. Surg. 2019 77 71 86 10.1016/j.joms.2018.08.010 30218655 PMC6312738

34. Nakamura N. Otsuru M. Miyoshi T. Suyama K. Omori K. Morishita K. Soutome S. Rokutanda S. Miura K.I. Umeda M. Risk factors for the development of medication-related osteonecrosis of the jaw and effects of tooth extraction with local infection J. Dent. Sci. 2024 19 1770 1782 10.1016/j.jds.2023.10.006 39035297 PMC11259623

35. Wood J. Bonjean K. Ruetz S. Bellahcene A. Devy L. Foidart J.M. Castronovo V. Green J.R. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid J. Pharmacol. Exp. Ther. 2002 302 1055 1061 10.1124/jpet.102.035295 12183663

36. Kun-Darbois J.D. Libouban H. Mabilleau G. Pascaretti-Grizon F. Chappard D. Bone mineralization and vascularization in bisphosphonate-related osteonecrosis of the jaw: An experimental study in the rat Clin. Oral Investig. 2018 22 2997 3006 10.1007/s00784-018-2385-2 29453497

37. Sharma D. Hamlet S. Vaquette C. Petcu E.B. Ramamurthy P. Ivanovski S. Local delivery of hydrogel encapsulated vascular endothelial growth factor for the prevention of medication-related osteonecrosis of the jaw Sci. Rep. 2021 11 23371 10.1038/s41598-021-02637-w 34862395 PMC8642483

38. Bastos P. Patel V. Festy F. Hosny N. Cook R.J. In-vivo imaging of the microvasculature of the soft tissue margins of osteonecrotic jaw lesions Br. Dent. J. 2017 223 699 705 10.1038/sj.bdj.2017.888 29123273

39. Lai X.S. Yang L.P. Li X.T. Liu J.P. Zhou Z.W. Zhou S.F. Human CYP2C8: Structure, substrate specificity, inhibitor selectivity, inducers and polymorphisms Curr. Drug Metab. 2009 10 1009 1047 10.2174/138920009790711832 20214592

40. Yamoune S. Wintz K. Niederau C. Craveiro R.B. Wolf M. Stingl J. Role of cytochrome P450 2C8 genetic polymorphism and epoxygenase uncoupling in periodontal remodelling affecting orthodontic treatment Basic Clin. Pharmacol. Toxicol. 2022 130 132 140 10.1111/bcpt.13681 34740282

41. Tamaoka J. Takaoka K. Hattori H. Ueta M. Maeda H. Yamamura M. Yamanegi K. Noguchi K. Kishimoto H. Osteonecrosis of the jaws caused by bisphosphonate treatment and oxidative stress in mice Exp. Ther. Med. 2019 17 1440 1448 10.3892/etm.2018.7076 30680026 PMC6327453

42. Capdevila J.H. Falck J.R. Harris R.C. Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase J. Lipid Res. 2000 41 163 181 10681399

43. Viccica G. Vignali E. Marcocci C. Role of the cholesterol biosynthetic pathway in osteoblastic differentiation J. Endocrinol. Investig. 2007 30 (Suppl. S6) 8 12 17721067

44. Sarasquete M.E. Garcia-Sanz R. Marin L. Alcoceba M. Chillon M.C. Balanzategui A. Santamaria C. Rosinol L. de la Rubia J. Hernandez M.T. Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: A genome-wide single nucleotide polymorphism analysis Blood 2008 112 2709 2712 10.1182/blood-2008-04-147884 18594024

45. English B.C. Baum C.E. Adelberg D.E. Sissung T.M. Kluetz P.G. Dahut W.L. Price D.K. Figg W.D. A SNP in CYP2C8 is not associated with the development of bisphosphonate-related osteonecrosis of the jaw in men with castrate-resistant prostate cancer Ther. Clin. Risk Manag. 2010 6 579 583 21151627 10.2147/TCRM.S14303 PMC2999510

46. Katz J. Gong Y. Salmasinia D. Hou W. Burkley B. Ferreira P. Casanova O. Langaee T.Y. Moreb J.S. Genetic polymorphisms and other risk factors associated with bisphosphonate induced osteonecrosis of the jaw Int. J. Oral Maxillofac. Surg. 2011 40 605 611 10.1016/j.ijom.2011.02.002 21396799

47. Such E. Cervera J. Terpos E. Bagan J.V. Avaria A. Gomez I. Margaix M. Ibanez M. Luna I. Cordon L. CYP2C8 gene polymorphism and bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma Haematologica 2011 96 1557 1559 10.3324/haematol.2011.042572 21685474 PMC3186320

48. Balla B. Vaszilko M. Kosa J.P. Podani J. Takacs I. Tobias B. Nagy Z. Lazary A. Lakatos P. New approach to analyze genetic and clinical data in bisphosphonate-induced osteonecrosis of the jaw Oral Dis. 2012 18 580 585 10.1111/j.1601-0825.2012.01912.x 22339777

49. Kastritis E. Melea P. Bagratuni T. Melakopoulos I. Gavriatopoulou M. Roussou M. Migkou M. Eleutherakis-Papaiakovou E. Terpos E. Dimopoulos M.A. Genetic factors related with early onset of osteonecrosis of the jaw in patients with multiple myeloma under zoledronic acid therapy Leuk. Lymphoma 2017 58 2304 2309 10.1080/10428194.2017.1300889 28604257

50. Zhong D.N. Wu J.Z. Li G.J. Association between CYP2C8 (rs1934951) polymorphism and bisphosphonate-related osteonecrosis of the jaws in patients on bisphosphonate therapy: A meta-analysis Acta Haematol. 2013 129 90 95 10.1159/000342120 23171856

51. Wu Q.J. Zhang T.N. Chen H.H. Yu X.F. Lv J.L. Liu Y.Y. Liu Y.S. Zheng G. Zhao J.Q. Wei Y.F. The sirtuin family in health and disease Signal Transduct. Target. Ther. 2022 7 402 36581622 10.1038/s41392-022-01257-8 PMC9797940

52. Chen Y. Zhou F. Liu H. Li J. Che H. Shen J. Luo E. SIRT1, a promising regulator of bone homeostasis Life Sci. 2021 269 119041 10.1016/j.lfs.2021.119041 33453243

53. Zainabadi K. Liu C.J. Caldwell A.L.M. Guarente L. SIRT1 is a positive regulator of in vivo bone mass and a therapeutic target for osteoporosis PLoS ONE 2017 12 e01852362017 10.1371/journal.pone.0185236 PMC5609767 28937996

54. Ornstrup M.J. Harslof T. Kjaer T.N. Langdahl B.L. Pedersen S.B. Resveratrol increases bone mineral density and bone alkaline phosphatase in obese men: A randomized placebo-controlled trial J. Clin. Endocrinol. Metab. 2014 99 4720 4729 10.1210/jc.2014-2799 25322274

55. Zhu S. Cui Y. Zhang W. Ji Y. Li L. Luo S. Cui J. Li M. Inflammation Can Be a High-Risk Factor for Mucosal Nonunion of MRONJ by Regulating SIRT1 Signaling When Treated with an Oncologic Dose of Zoledronate Drug Des. Dev. Ther. 2024 18 2793 2812 10.2147/DDDT.S456811 PMC11229984 38979400

56. Cui Y. Zhang W. Yang P. Zhu S. Luo S. Li M. Menaquinone-4 prevents medication-related osteonecrosis of the jaw through the SIRT1 signaling-mediated inhibition of cellular metabolic stresses-induced osteoblast apoptosis Free Radic. Biol. Med. 2023 206 33 49 10.1016/j.freeradbiomed.2023.06.022 37364692

57. Yang G. Hamadeh I.S. Katz J. Riva A. Lakatos P. Balla B. Kosa J. Vaszilko M. Pelliccioni G.A. Davis N. SIRT1/HERC4 Locus Associated With Bisphosphonate-Induced Osteonecrosis of the Jaw: An Exome-Wide Association Analysis J. Bone Miner. Res. 2018 33 91 98 10.1002/jbmr.3285 28856724

58. Yang G. Collins J.M. Rafiee R. Singh S. Langaee T. McDonough C.W. Holliday L.S. Wang D. Lamba J.K. Kim Y.S. SIRT1 Gene SNP rs932658 Is Associated With Medication-Related Osteonecrosis of the Jaw J. Bone Miner. Res. 2021 36 347 356 10.1002/jbmr.4185 32967053 PMC8733933

59. Bojtor B. Vaszilko M. Armos R. Tobias B. Podani J. Szentpeteri S. Balla B. Lengyel B. Piko H. Illes A. Analysis of SIRT1 Gene SNPs and Clinical Characteristics in Medication-Related Osteonecrosis of the Jaw Int. J. Mol. Sci. 2024 25 3646 10.3390/ijms25073646 38612458 PMC11011248

60. Emmanuelle N.E. Marie-Cecile V. Florence T. Jean-Francois A. Francoise L. Coralie F. Alexia V. Critical Role of Estrogens on Bone Homeostasis in Both Male and Female: From Physiology to Medical Implications Int. J. Mol. Sci. 2021 22 1568 10.3390/ijms22041568 33557249 PMC7913980

61. Pacifici R. Rifas L. McCracken R. Vered I. McMurtry C. Avioli L.V. Peck W.A. Ovarian steroid treatment blocks a postmenopausal increase in blood monocyte interleukin 1 release Proc. Natl. Acad. Sci. USA 1989 86 2398 2402 10.1073/pnas.86.7.2398 2522659 PMC286920

62. Jilka R.L. Hangoc G. Girasole G. Passeri G. Williams D.C. Abrams J.S. Boyce B. Broxmeyer H. Manolagas S.C. Increased osteoclast development after estrogen loss: Mediation by interleukin-6 Science 1992 257 88 91 10.1126/science.1621100 1621100

63. Kousteni S. Bellido T. Plotkin L.I. O’Brien C.A. Bodenner D.L. Han L. Han K. DiGregorio G.B. Katzenellenbogen J.A. Katzenellenbogen B.S. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: Dissociation from transcriptional activity Cell 2001 104 719 730 10.1016/S0092-8674(02)08100-X 11257226

64. Bord S. Ireland D.C. Beavan S.R. Compston J.E. The effects of estrogen on osteoprotegerin, RANKL, and estrogen receptor expression in human osteoblasts Bone 2003 32 136 141 10.1016/S8756-3282(02)00953-5 12633785

65. Kahlert S. Nuedling S. van Eickels M. Vetter H. Meyer R. Grohe C. Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway J. Biol. Chem. 2000 275 18447 18453 10.1074/jbc.M910345199 10749889

66. Emmerson E. Campbell L. Davies F.C. Ross N.L. Ashcroft G.S. Krust A. Chambon P. Hardman M.J. Insulin-like growth factor-1 promotes wound healing in estrogen-deprived mice: New insights into cutaneous IGF-1R/ERalpha cross talk J. Investig. Dermatol. 2012 132 2838 2848 10.1038/jid.2012.228 22810305

67. Choi S.Y. Kim J.W. Oh S.H. Cheon S. Yee J. Kim S.J. Gwak H.S. Chung J.E. Prediction of medication-related osteonecrosis of the jaws using machine learning methods from estrogen receptor 1 polymorphisms and clinical information Front. Med. 2023 10 1140620 10.3389/fmed.2023.1140620 37415765 PMC10321771

68. Liu X. Huang J. Lin H. Xiong L. Ma Y. Lao H. ESR1 PvuII (rs2234693 T>C) polymorphism and cancer susceptibility: Evidence from 80 studies J. Cancer 2018 9 2963 2972 10.7150/jca.25638 30123365 PMC6096366

69. Casazza K. Page G.P. Fernandez J.R. The association between the rs2234693 and rs9340799 estrogen receptor alpha gene polymorphisms and risk factors for cardiovascular disease: A review Biol. Res. Nurs. 2010 12 84 97 10.1177/1099800410371118 20702456

70. Boot A.M. van der Sluis I.M. de Muinck Keizer-Schrama S.M. van Meurs J.B. Krenning E.P. Pols H.A. Uitterlinden A.G. Estrogen receptor alpha gene polymorphisms and bone mineral density in healthy children and young adults Calcif. Tissue Int. 2004 74 495 500 10.1007/s00223-003-0168-4 15354856

71. Gennari L. Merlotti D. Nuti R. Aromatase activity and bone loss Adv. Clin. Chem. 2011 54 129 164 21874760 10.1016/b978-0-12-387025-4.00006-6

72. Hernandez J.L. Garces C.M. Sumillera M. Fernandez-Aldasoro E.V. Garcia-Ibarbia C. Ortiz-Gomez J.A. Arozamena J. Alonso M.A. Riancho J.A. Aromatase expression in osteoarthritic and osteoporotic bone Arthritis Rheumatol. 2008 58 1696 1700 10.1002/art.23500 18512790

73. La Ferla F. Paolicchi E. Crea F. Cei S. Graziani F. Gabriele M. Danesi R. An aromatase polymorphism (g.132810C>T) predicts risk of bisphosphonate-related osteonecrosis of the jaw Biomark. Med. 2012 6 201 209 22448795 10.2217/bmm.12.14

74. Dunning A.M. Dowsett M. Healey C.S. Tee L. Luben R.N. Folkerd E. Novik K.L. Kelemen L. Ogata S. Pharoah P.D. Polymorphisms associated with circulating sex hormone levels in postmenopausal women J. Natl. Cancer Inst. 2004 96 936 945 10.1093/jnci/djh167 15199113

75. Steiner R.D. Basel D. COL1A1/2 Osteogenesis Imperfecta GeneReviews ® Adam M.P. University of Washington Seattle, WA, USA 1993 20301472

76. Wang C. Li H. Chen K. Wu B. Liu H. Association of polymorphisms rs1800012 in COL1A1 with sports-related tendon and ligament injuries: A meta-analysis Oncotarget 2017 8 27627 27634 10.18632/oncotarget.15271 28206959 PMC5432363

77. Liu C. Walter T.S. Huang P. Zhang S. Zhu X. Wu Y. Wedderburn L.R. Tang P. Owens R.J. Stuart D.I. Structural and functional insights of RANKL-RANK interaction and signaling J. Immunol. 2010 184 6910 6919 10.4049/jimmunol.0904033 20483727

78. Boyce B.F. Xing L. Biology of RANK, RANKL, and osteoprotegerin Arthritis Res. Ther. 2007 9 (Suppl. S1) S1 10.1186/ar2165 17634140 PMC1924516

79. Tu P. Duan P. Zhang R.S. Xu D.B. Wang Y. Wu H.P. Liu Y.H. Si L. Polymorphisms in genes in the RANKL/RANK/OPG pathway are associated with bone mineral density at different skeletal sites in post-menopausal women Osteoporos. Int. 2015 26 179 185 10.1007/s00198-014-2854-7 25138264

80. Koo B.H. Kim Y.H. Han J.H. Kim D.S. Dimerization of matrix metalloproteinase-2 (MMP-2): Functional implication in MMP-2 activation J. Biol. Chem. 2012 287 22643 22653 10.1074/jbc.M111.337949 22577146 PMC3391158

81. Lehrer S. Montazem A. Ramanathan L. Pessin-Minsley M. Pfail J. Stock R.G. Kogan R. Bisphosphonate-induced osteonecrosis of the jaws, bone markers, and a hypothesized candidate gene J. Oral Maxillofac. Surg. 2009 67 159 161 10.1016/j.joms.2008.09.015 19070762

82. Ferrara N. Gerber H.P. LeCouter J. The biology of VEGF and its receptors Nat. Med. 2003 9 669 676 10.1038/nm0603-669 12778165

83. Yao Z. Lafage-Proust M.H. Plouet J. Bloomfield S. Alexandre C. Vico L. Increase of both angiogenesis and bone mass in response to exercise depends on VEGF J. Bone Miner. Res. 2004 19 1471 1480 10.1359/JBMR.040517 15312247

84. Yang Q. Zhang Y. Zhang X. Li X. Liu J. Association of VEGF Gene Polymorphisms with Susceptibility to Diabetic Retinopathy: A Systematic Review and Meta-Analysis Horm. Metab. Res. 2020 52 264 279 32403142 10.1055/a-1143-6024

85. Wu M. Xiong H. Xu Y. Xiong X. Zou H. Zheng M. Wang X. Zhou X. Association between VEGF-A and VEGFR-2 polymorphisms and response to treatment of neovascular AMD with anti-VEGF agents: A meta-analysis Br. J. Ophthalmol. 2017 101 976 984 10.1136/bjophthalmol-2016-309418 28400373 PMC5530807

86. Koutras A. Kotoula V. Fountzilas G. Prognostic and predictive role of vascular endothelial growth factor polymorphisms in breast cancer Pharmacogenomics 2015 16 79 94 10.2217/pgs.14.148 25560472

87. Tang J. Qin Z. Li X. Han P. Wang F. Yang C. Li R. Wang K. Tang M. Wang W. Association between vascular endothelial growth factor gene polymorphisms and the risk and prognosis of renal cell carcinoma: A systematic review and meta-analysis Oncotarget 2017 8 50034 50050 10.18632/oncotarget.17293 28489583 PMC5564826

88. Liu Y. Olsen B.R. Distinct VEGF functions during bone development and homeostasis Arch. Immunol. Ther. Exp. 2014 62 363 368 10.1007/s00005-014-0285-y 24699630

89. Arduino P.G. Menegatti E. Scoletta M. Battaglio C. Mozzati M. Chiecchio A. Berardi D. Vandone A.M. Donadio M. Gandolfo S. Vascular endothelial growth factor genetic polymorphisms and haplotypes in female patients with bisphosphonate-related osteonecrosis of the jaws J. Oral Pathol. Med. 2011 40 510 515 10.1111/j.1600-0714.2010.01004.x 21251073

90. Renner W. Kotschan S. Hoffmann C. Obermayer-Pietsch B. Pilger E. A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels J. Vasc. Res. 2000 37 443 448 10.1159/000054076 11146397

91. Awata T. Inoue K. Kurihara S. Ohkubo T. Watanabe M. Inukai K. Inoue I. Katayama S. A common polymorphism in the 5’-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes Diabetes 2002 51 1635 1639 10.2337/diabetes.51.5.1635 11978667

92. Shahbazi M. Fryer A.A. Pravica V. Brogan I.J. Ramsay H.M. Hutchinson I.V. Harden P.N. Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection J. Am. Soc. Nephrol. 2002 13 260 264 10.1681/ASN.V131260 11752046

93. Choi H. Lee J.H. Kim H.J. Park W. Lee J.H. Kim J.H. Genetic association between VEGF polymorphisms and BRONJ in the Korean population Oral Dis. 2015 21 866 871 10.1111/odi.12355 26086871

94. Kim J.W. Yee J. Oh S.H. Kim S.H. Kim S.J. Chung J.E. Gwak H.S. Machine Learning Approaches for Predicting Bisphosphonate-Related Osteonecrosis in Women with Osteoporosis Using VEGFA Gene Polymorphisms J. Pers. Med. 2021 11 541 10.3390/jpm11060541 34200782 PMC8230421

95. Kim S. Mun S. Shin W. Han K. Kim M.Y. Identification of Potentially Pathogenic Variants Associated with Recurrence in Medication-Related Osteonecrosis of the Jaw (MRONJ) Patients Using Whole-Exome Sequencing J. Clin. Med. 2022 11 2145 10.3390/jcm11082145 35456240 PMC9030961

96. Kimura M. Nagao T. Machida J. Warnakulasuriya S. Mutation of keratin 4 gene causing white sponge nevus in a Japanese family Int. J. Oral Maxillofac. Surg. 2013 42 615 618 10.1016/j.ijom.2012.10.030 23182699

97. Nicoletti P. Cartsos V.M. Palaska P.K. Shen Y. Floratos A. Zavras A.I. Genomewide pharmacogenetics of bisphosphonate-induced osteonecrosis of the jaw: The role of RBMS3 Oncologist 2012 17 279 287 10.1634/theoncologist.2011-0202 22267851 PMC3286178

98. Di Martino M.T. Arbitrio M. Guzzi P.H. Leone E. Baudi F. Piro E. Prantera T. Cucinotto I. Calimeri T. Rossi M. A peroxisome proliferator-activated receptor gamma (PPARG) polymorphism is associated with zoledronic acid-related osteonecrosis of the jaw in multiple myeloma patients: Analysis by DMET microarray profiling Br. J. Haematol. 2011 154 529 533 10.1111/j.1365-2141.2011.08622.x 21517810 PMC3638364

99. Van Poznak C. Reynolds E.L. Estilo C.L. Hu M. Schneider B.P. Hertz D.L. Gersch C. Thibert J. Thomas D. Banerjee M. Osteonecrosis of the jaw risk factors in bisphosphonate-treated patients with metastatic cancer Oral Dis. 2022 28 193 201 10.1111/odi.13746 33274559 PMC8284838

100. Marini F. Tonelli P. Cavalli L. Cavalli T. Masi L. Falchetti A. Brandi M.L. Pharmacogenetics of bisphosphonate-associated osteonecrosis of the jaw Front. Biosci. 2011 3 364 370 10.2741/e251 21196316

101. Coxon F.P. Thompson K. Rogers M.J. Recent advances in understanding the mechanism of action of bisphosphonates Curr. Opin. Pharmacol. 2006 6 307 312 10.1016/j.coph.2006.03.005 16650801

102. Marini F. Falchetti A. Silvestri S. Bagger Y. Luzi E. Tanini A. Christiansen C. Brandi M.L. Modulatory effect of farnesyl pyrophosphate synthase (FDPS) rs2297480 polymorphism on the response to long-term amino-bisphosphonate treatment in postmenopausal osteoporosis Curr. Med. Res. Opin. 2008 24 2609 2615 10.1185/03007990802352894 18687167

103. Szentpeteri S. Kosa J. Juhasz H.D. Deak G. Nemeth Z. Lakatos P. Vaszilko M. Examination of certain single-nucleotide polymorphisms of interleukins 1A and 1B in medication-related osteonecrosis of the jaw—An ambirectional cohort study J. Cranio-Maxillofac. Surg. 2024 10.1016/j.jcms.2024.06.007 39033051

104. Stockmann P. Nkenke E. Englbrecht M. Schlittenbauer T. Wehrhan F. Rauh C. Beckmann M.W. Fasching P.A. Kreusch T. Mackensen A. Major histocompatibility complex class II polymorphisms are associated with the development of anti-resorptive agent-induced osteonecrosis of the jaw J. Cranio-Maxillofac. Surg. 2013 41 71 75 10.1016/j.jcms.2012.10.018 23218978

105. Lee K.H. Kim S.H. Kim C.H. Min B.J. Kim G.J. Lim Y. Kim H.S. Ahn K.M. Kim J.H. Identifying genetic variants underlying medication-induced osteonecrosis of the jaw in cancer and osteoporosis: A case control study J. Transl. Med. 2019 17 381 10.1186/s12967-019-2129-3 31747953 PMC6868688

106. Sacco R. Olate S. Calasans-Maia M.D. Sacco N. Acocella A. De Almeida Barros Mourão C.F. Moraschini V. Akintola O. Guerra R.C. Yates J. A Comprehensive Quality Meta-Review of Genetic and Pharmacogenomic Aspects of Medication-Related Osteonecrosis of The Jaw (MRONJ) Appl. Sci. 2022 12 12289 10.3390/app122312289

107. Li J.W. Wang J.Y. Yu R.Q. Huo L. Zheng L.W. Expression of angiogenic markers in jawbones and femur in a rat model treated with zoledronic acid BMC Res. Notes 2022 15 12 10.1186/s13104-021-05900-5 35012647 PMC8751108

108. Manzano-Moreno F.J. Ramos-Torrecillas J. Melguizo-Rodriguez L. Illescas-Montes R. Ruiz C. Garcia-Martinez O. Bisphosphonate Modulation of the Gene Expression of Different Markers Involved in Osteoblast Physiology: Possible Implications in Bisphosphonate-Related Osteonecrosis of the Jaw Int. J. Med. Sci. 2018 15 359 367 10.7150/ijms.22627 29511371 PMC5835706

109. Wehrhan F. Hyckel P. Ries J. Stockmann P. Nkenke E. Schlegel K.A. Neukam F.W. Amann K. Expression of Msx-1 is suppressed in bisphosphonate associated osteonecrosis related jaw tissue-etiopathology considerations respecting jaw developmental biology-related unique features J. Transl. Med. 2010 8 96 10.1186/1479-5876-8-96 20942943 PMC2973937

110. Kalyan S. Wang J. Quabius E.S. Huck J. Wiltfang J. Baines J.F. Kabelitz D. Systemic immunity shapes the oral microbiome and susceptibility to bisphosphonate-associated osteonecrosis of the jaw J. Transl. Med. 2015 13 212 10.1186/s12967-015-0568-z 26141514 PMC4490596

111. Sun J. Wen X. Jin F. Li Y. Hu J. Sun Y. Bioinformatics analyses of differentially expressed genes associated with bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma Onco Targets Ther. 2015 8 2681 2688 10.2147/OTT.S88463 26445550 PMC4590669

112. Raje N. Woo S.B. Hande K. Yap J.T. Richardson P.G. Vallet S. Treister N. Hideshima T. Sheehy N. Chhetri S. Clinical, radiographic, and biochemical characterization of multiple myeloma patients with osteonecrosis of the jaw Clin. Cancer Res. 2008 14 2387 2395 10.1158/1078-0432.CCR-07-1430 18413829

113. Kim K.Y. Zhang X. Cha I.H. Identifying a combined biomarker for bisphosphonate-related osteonecrosis of the jaw Clin. Implant Dent. Relat. Res. 2018 20 191 198 10.1111/cid.12569 29266738

114. Shi Y. Li M. Yu Y. Zhou Y. Zhang W. Hua H. Wang S. Stress response in periodontal ligament stem cells may contribute to bisphosphonate-associated osteonecrosis of the jaw: A gene expression array analysis Mol. Med. Rep. 2020 22 2043 2051 10.3892/mmr.2020.11276 32705175 PMC7411417

115. Kuroshima S. Nakajima K. Sasaki M. Hayano H. Inoue M. Kozutsumi R. Sawase T. Gene expression analysis of fresh extraction wounds prior to onset of bisphosphonate-related osteonecrosis of the jaw-like lesions in mice: A preliminary animal study J. Prosthodont. Res. 2021 65 546 553 10.2186/jpr.JPR_D_20_00027 33840704

116. Saliminejad K. Khorshid H.R.K. Fard S.S. Ghaffari S.H. An overview of microRNAs: Biology, functions, therapeutics, and analysis methods J. Cell. Physiol. 2019 234 5451 5465 10.1002/jcp.27486 30471116

117. O’Brien J. Hayder H. Zayed Y. Peng C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation Front. Endocrinol. 2018 9 402 10.3389/fendo.2018.00402 30123182 PMC6085463

118. Allegra A. Mania M. D’Ascola A. Oteri G. Siniscalchi E.N. Avenoso A. Innao V. Scuruchi M. Allegra A.G. Musolino C. Altered Long Noncoding RNA Expression Profile in Multiple Myeloma Patients with Bisphosphonate-Induced Osteonecrosis of the Jaw BioMed Res. Int. 2020 2020 9879876 10.1155/2020/9879876 32714991 PMC7354644

119. Dong Y. Li T. Li Y. Ren S. Fan J. Weng X. MicroRNA-23a-3p inhibitor decreases osteonecrosis incidence in a rat model Mol. Med. Rep. 2017 16 9331 9336 10.3892/mmr.2017.7808 29039554 PMC5779994

120. Shen X. Zhu W. Zhang P. Fu Y. Cheng J. Liu L. Xu R. Jiang H. Macrophage miR-149-5p induction is a key driver and therapeutic target for BRONJ JCI Insight 2022 7 e159865 10.1172/jci.insight.159865 35993364 PMC9462481

121. Sim I.W. Borromeo G.L. Tsao C. Hardiman R. Hofman M.S. Hjelle C.P. Siddique M. Cook G.J.R. Seymour J.F. Ebeling P.R. Teriparatide Promotes Bone Healing in Medication-Related Osteonecrosis of the Jaw: A Placebo-Controlled, Randomized Trial J. Clin. Oncol. 2020 38 2971 2980 10.1200/JCO.19.02192 32614699

122. Park J.H. Kim J.W. Kim S.J. Does the Addition of Bone Morphogenetic Protein 2 to Platelet-Rich Fibrin Improve Healing After Treatment for Medication-Related Osteonecrosis of the Jaw? J. Oral Maxillofac. Surg. 2017 75 1176 1184 10.1016/j.joms.2016.12.005 28042979