Years of Medication-Related Osteonecrosis of the Jaw (MRONJ) Research: Where Are We Now?--An Umbrella Review  
[PERSON]  
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Since the first clinical study of bisphosphonate-related osteeoncrosis of the jaw (BRONJ) was published in 2003, a growing number of scientific articles have documented similar complications connected with other medications, such as monoclonal antibodies, tumor necrosis factor-\(\alpha\) (TNF-\(\alpha\)) inhibitors drugs and recreational drugs [5; 6; 7]. Due to the number of medications linked with the development of ONJ, in a 2014 positional paper, the American Association of Oral and Maxillofacial Surgeons (AAOMS) developed and defined the medical term MRONJ [8]. This AAOMS position paper outlined that patients should be considered to have MRONJ if all of the following three characteristics are present:  
1. Current or previous treatment with antiresorptive or antiangiogenic agents; exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for longer than 8 weeks;
2. No history of radiation therapy to the jaws or obvious metastatic disease to the jaws [8]. Patients often present with exposed bone associated with a sequela of symptoms: pain, swelling, infection, tooth/teeth mobility, neuropathic pain and in some cases, pathological fracture [8]. Interestingly, approximately 25% of patients present with the aforementioned catalogue of symptoms without frank bone exposure [9]. The pathogenesis of MRONJ remains unclear, however a number of risk factors have been identified that are associated with an increased likelihood of MRONJ development. These risk factors have been recognized in multiple independent studies and include the potency and route of administration of the antiresorptive agent (intravenous bisphosphonate vs. oral), the underlying disease (cancer vs. osteoporosis), the duration and cumulative dosage of antiresorptive therapy, dentoalveolar surgery and dental infections [10; 11; 12; 13; 14]. The incidence of MRONJ can also vary based on other factors such as medical history, drug therapy, duration of therapy and type of dental treatments [8]. Researches have reported that for cancer patients treated with intravenous bisphosphonates the incidence of MRONJ following tooth extraction is expected to range from 1.6-14.8% with a mean incidence of 7% [8; 15]. This compares to a 1.8% incidence for oncology patients receiving denosumab and an incidence of MRONJ of 0.5% for patients taking oral bisphosphonates [8; 16; 17; 18]. Furthermore, the use of antiangiogenic agents in combination with antiresorptive drugs is known to increase the risk of MRONJ development with an estimate of 16% of recurrent rates [17]. Studies have reported that dental extractions are the most common cause of MRONJ with figures ranging from 48.5% to up to 80% [19]. In a recent study, the trigger of MRONJ was found to be independent of the administration routes, with 61.7% caused by tooth extraction, 14.8% by spontaneous onset and 7.4% by ill-fitting dentures [20]. There is however, limited information about the generating factors for denosumab-related MRONJ. Many additional factors have been reported in the literature as being associated with accelerated development and/or increased severity of the condition, but for most of these it remains unclear whether or not they are causative factors [21; 22; 23]. These include the use of corticosteroids, the presence of concomitant diseases or conditions (e.g., pre-existing dental infections, anemia, diabetes-mellitus and immunosuppression or renal failure), poor oral hygiene and smoking [21; 22; 23; 24]. The role of genetic factors in MRONJ is also being investigated in order to help to identify patients at increased risk of MRONJ; however, a robust association between MRONJ risk and a specific genetic variant has not yet been identified [25]. After almost 20 years of research there is still lack of consensus regarding the MRONJ diagnostic, preventive and treatment strategies.