## 5 Discussion  
Medication-related osteonecrosis of the jaw (MRONJ) is a rare but disabling disease [1,8,66]. Currently, the aetiopathogenesis of MRONJ has not been well explained despite a large number of patients suffering from this severe adverse event [8]. At present there are three key theories proposed for the pathogenesis of MRONJ; bone turnover suppression, cellular toxicity and infection. Whereas circumstantial studies underpin the hypothesis that antiresorptive drugs reduce bone formation and promote necrosis, physiological and radiological research suggest different findings. The hypotheses of drug-related cellular toxicity affecting epithelial cells and macrophages causing limited immune defence as a result of impaired functions has been purported by many ex vivo and in vivo studies. Infection is believed to be an important contributing factor to the disease as it can encourage extreme bone resorption. Whether it is the generating factor or the result of the disease process still remains unclear [67]. Additional studies are necessary to confirm the exact pathological process of anti-angiogenic drugs as their drug actions are different from bisphosphonates and denosumab. Despite the great collaborative effort in the past decades in investigating MRONJ, there are many unanswered questions and a lack of a common agreement among researchers and investigators. Although there are many systematic reviews on the subject, there is still no unanimous consensus on many aspects of MRONJ from preventive strategy, to the management of the disease [41]. Despite the limited evidence available, many countries have established guidelines in the attempt to improve the care of these vulnerable patients. Using the Oxford Centre for Evidence-Based Medicine (1a, 2a and 3a), the present umbrella review looked at the current highest available evidence published in the last 20 years on drug-induced ONJ in the attempt to highlight the current state of the quality of research [68]. Among the systematic reviews and meta-analysis included in this study, we noticed a very broad inclusion criteria adopted by authors of the many reviews. This is evident from the study numbers included in the reviews, which varied from 1 article [58] to 219 articles [53]. Except for the few meta-analyses included in this review, most of the included articles were often weak, low ranked and demonstrated a high risk of bias [41; 52]. These methodological inadequacies have undoubtedly increased the risk of inconsistency of the general guidelines worldwide, resulting in lack of effectiveness in handling patients at risk or affected by MRONJ. The authors have discovered that the majority of the reviews feature predominantly case reports, case series, and observational studies. For this reason, the findings of these reviews should be interpreted cautiously [48; 56; 59; 60; 61; 64]. This review also revealed that a large number of systematic reviews in the literature (excluded in this article) do not follow the recognized PRISMA checklist guidance, which inevitably increases the chances of methodological errors and reporting bias. In the future, systematic reviews or meta-analysis should outline a clear protocol before conducting the study; with the foresight that these pieces of research are often fundamental tools used to implement clinical practice in the form of guidelines. Unusually, systematic reviews have clear protocols. However, we have noticed that many of the 24 included reviews did not perform a comprehensive search for studies, report funding for included studies or conduct a satisfactory risk bias analysis [56; 63]. These shortcomings are likely to have increased the issues surrounding the adequacy of their results, resulting in low strength of evidence in the published conclusions. Despite the large number of systematic reviews on MRONJ, there is still discordant thought without a unanimous consensus on many aspects of MRONJ, from preventive strategy to the management of the disease.