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applied sciences Review 18 Years of Medication-Related Osteonecrosis of the Jaw (MRONJ) Research: Where Are We Now?—An Umbrella Review 1 , 2 , 3 4 5 Roberto Sacco * , Monica Diuana Calasans-Maia , Julian Woolley , Oladapo Akintola , 3 3 1 6 Carlos Fernando de Almeida Barros Mourão , Vittorio Moraschini , Evgeny Kushnerev , Alessandro Acocella , 5 1 Olamide Obisesan and Julian Yates Oral Surgery Department, Division of Dentistry, School of Medical Sciences, The University of Manchester, Manchester M13 9PL, UK; evgeny.kushnerev@manchester.ac.uk (E.K.); julian.yates@manchester.ac.uk (J.Y.) Oral Surgery Department, King’s College London, London WC2R 2LS, UK Oral Surgery Department, Dental School, Fluminense Federal University, Rio de Janeiro 24020-140, Brazil; monicacalasansmaia@gmail.com (M.D.C.-M.); mouraocf@gmail.com (C.F.d.A.B.M.); vitt.mf@gmail.com (V.M.) Oral and Maxillofacial Surgery Department, Northwick Park Hospital–London North West University Healthcare NHS Trust, London HA1 3UJ, UK; julianwoolley@gmail.com Oral Surgery Department, King’s College Hospital, London SE5 9RS, UK; dapoakintola@nhs.net (O.A.); oobisesan@nhs.net (O.O.) Private Practice, 50129 Florence, Italy; alessandroacocella@yahoo.it * Correspondence: roberto.sacco@manchester.ac.uk; Tel.: +44-(0)20-3299-32496 Abstract: Background: Osteonecrosis of the jaw (ONJ) is a condition affecting patients exposed Citation: Sacco, R.; Calasans-Maia, to medications used to treat benign and malignant conditions of bone tissue. Many studies have M.D.; Woolley, J.; Akintola, O.; de highlighted that ONJ is a severe condition, which is very challenging to manage, especially in Almeida Barros Mourão, C.F.; individuals with oncologic disease. The aim of this umbrella review is to analyze all available inter- Moraschini, V.; Kushnerev, E.; ventional and non-interventional systematic reviews published on medication-related osteonecrosis Acocella, A.; Obisesan, O.; Yates, J. 18 of the jaw (MRONJ) and summarize this evidence. Material and methods: A multi-database search Years of Medication-Related (PubMed, MEDLINE, EMBASE and CINAHL) was performed to identify related multi-language Osteonecrosis of the Jaw (MRONJ) papers published from January 2003 until June 2021. An additional manual search was also per- Research: Where Are We Now?—An Umbrella Review. Appl. Sci. 2021, 11, formed in systematic review registries (PROSPERO, INPLASY, JBI and OFS) to identify possible 8818. https://doi.org/10.3390/ missing reviews. Data were extracted from relevant papers and analyzed according to the outcomes app11198818 selected in this review. Results: The search generated 25 systematic reviews eligible for the analysis. The total number of patients included in the analysis was 80,840. Of the reviews, 64% (n = 16) were Academic Editor: Gaetano Isola non-interventional and 36% (n = 9) were interventional. Study designs included case series 20.50% (n = 140), retrospective cohort studies 12.30% (n = 84) and case reports 12.20% (n = 83). It was unclear Received: 31 August 2021 what study design was used for 277 studies included in the 25 systematic reviews. Conclusions: The Accepted: 16 September 2021 data reviewed confirmed that the knowledge underpinning MRONJ in the last 20 years is still based Published: 23 September 2021 on weak evidence. This umbrella review highlighted a widespread low-level quality of studies and many poorly designed reviews. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Keywords: osteonecrosis; medication-related osteonecrosis of the jaw; systematic review; umbrella published maps and institutional affil- review; evidence-based medicine iations. 1. Introduction Copyright: © 2021 by the authors. Medication-related osteonecrosis of the jaw (MRONJ) is an irreversible adverse event Licensee MDPI, Basel, Switzerland. related principally to antiresorptive medications (e.g., bisphosphonates and receptor acti- This article is an open access article vator of nuclear factor Kappa-B ligand inhibitors) and angiogenesis inhibitors [1,2]. These distributed under the terms and conditions of the Creative Commons types of drug therapies are used for the treatment of the skeletal manifestation of malig- Attribution (CC BY) license (https:// nancies and/or bone metastases, and in the management of osteoporosis, Paget’s disease creativecommons.org/licenses/by/ or hypercalcaemia [3,4]. 4.0/). Appl. Sci. 2021, 11, 8818. https://doi.org/10.3390/app11198818 https://www.mdpi.com/journal/applsci Appl. Sci. 2021, 11, 8818 2 of 20 Since the first clinical study of bisphosphonate-related osteonecrosis 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- (TNF-) inhibitors drugs and recreational drugs [5–7]. Due to the number of medications linked with the development of ONJ, in a 2014 positional paper, the Ameri- can 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 po- tency 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 [10–14]. 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 [8,16–18]. Further- more, 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 [21–23]. 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 [21–24]. 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. However, many guidelines have been issued in an attempt to improve the quality of care of patients at risk of MRONJ, Table 1 [1,8,26–36]. An umbrella review on MRONJ was published in 2020 [37]. However, this review presented deficiencies in many aspects, from the quality assessment strategy to the omis- sion of an analysis of the systematic reviews related to epidemiological, diagnostic and preventive strategies studies (non-interventional studies). Hence the aim of this umbrella review is to summarize and assess quality in a comprehensive and complete manner all Appl. Sci. 2021, 11, 8818 3 of 20 available evidence in published systematic reviews on MRONJ and report the strength and the deficiencies associated with studies included. Table 1. Chronologic summary of the most common published guidelines/position papers/recommendations. Guideline/Position Paper/Recommendation Country Year Canadian Consensus of Practice Guidelines for Bisphosphonate Associated Osteonecrosis of Canada 2008 the Jaw [26] Osteonecrosis of the Jaw Complicating Bisphosphonate Treatment for Bone Disease in Multiple Australia 2009 Myeloma: An Overview with Recommendations for Prevention and Treatment [27] The Use of Bisphosphonates in Multiple Myeloma: Recommendations of an Expert Panel on Europe 2009 Behalf of the European Myeloma Network [28] Management of Patients at Risk of Bisphosphonate Osteonecrosis in Maxillofacial Surgery Units UK 2009 in the UK [29] Managing the Care of Patients Receiving Antiresorptive Therapy for Prevention and Treatment of Osteonecrosis. Executive Summary of Recommendations from the American Dental Association USA 2011 Council on Scientific Affairs [30] Guidelines for Supportive Care in Multiple Myeloma 2011 [31] UK 2011 Medication-Related Osteonecrosis of the Jaw-2014 Update [8] USA 2014 Diagnosis and Management of Osteonecrosis of the Jaw: A Systematic Review and Canada 2014 International Consensus [32] Medication Related Osteonecrosis of the Jaw: 2015 Position Statement of the Korean Society for Korea 2015 Bone and Mineral Research and the Korean Association of Oral and Maxillofacial Surgeons [33] “Position paper on medication-related osteonecrosis of the jaw (MRONJ)” [34] Germany 2016 Antiresorptive Agent-Related Osteonecrosis of the Jaw: Position Paper 2017 of the Japanese Japan 2016 Allied Committee on Osteonecrosis of the Jaw [35] Case-Based Review of Osteonecrosis of the Jaw (ONJ) and Application of the International Canada 2017 Recommendations for Management from the International Task Force on ONJ [1] Oral Health Management of Patients at Risk of Medication-Related Osteonecrosis of the Jaw [36] Scotland 2017 2. Materials and Methods This umbrella review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [38]. The protocol of this review was registered in the International Platform of Regis- tered Systematic Review and Meta-analysis Protocols (INPLASY) under the number IN- PLASY202160061. The following four databases were explored: PubMed, MEDLINE, EMBASE and CINAHL. A three-stage screening approach was used to ensure precision and safeguard the quality of the search. The screening of titles and abstracts was carried out independently by five authors (RS, JW, OO, EK and OA) to eliminate any irrelevant materials (i.e., reviews, animal studies, non-clinical studies). Disagreements were resolved by discussion until a consensus was reached. A data screening and abstraction form was used to: Verify the study eligibility derived from the inclusion/exclusion criteria. Carry out the methodological quality assessment. Extract data on study characteristics and outcomes for the included studies (Figure 1). Appl. Sci. 2021, 11, 8818 4 of 20 Figure 1. PRISMA study flow diagram. The authors of any studies eligible for inclusion in the review with insufficient infor- mation were contacted directly to provide further information. The inclusion criteria was based on a PICO(S) strategy [39]. Focused question and PICO strategy What is the current state of evidence related to MRONJ after 18 years of study? - Population (P): any (no limits of age) patients with MRONJ; - Interventions (I): any types; - Comparison (C): any types; - Outcome (O): state of knowledge based on the type of studies included in the reviews; - Study (S): systematic review (SR) or meta-analysis (MA). A search strategy for all databases was developed as follows: 1. Osteonecrosis [MeSH Terms] OR Avascular osteonecrosis of the jaw [MeSH Terms] OR Osteonecrosis of the jaw [MeSH Terms] OR MRONJ [MeSH Terms] OR ONJ [MeSH Terms] OR BONJ [MeSH Terms] OR ARONJ [MeSH Terms] OR BRONJ Patients [MeSH Terms] OR Any patients [MeSH Terms] OR Oncology [MeSH Terms] OR Osteoporosis [MeSH Terms] OR Non-oncologic patients; 2. Systematic review [MeSH Terms] OR Review [MeSH Terms] OR Meta-analysis; 3. 1 and 2 and 3. Appl. Sci. 2021, 11, 8818 5 of 20 The search strategy included appropriate changes in the keywords and followed the syntax rules of each database. 2.1. Criteria for Inclusion in This Review 2.1.1. Types of Studies The authors of this umbrella review considered both interventional and non-interventional reviews. The search strategy for this study focused on published systematic reviews and/or meta-analysis. Articles were obtained from January 2003 to June 2021. No language re- strictions were imposed on the search. Narrative reviews, reviews not following PRISMA guidelines (after 2009), reviews without registration, animal reviews, and those reviews which included patients with a previous history of radiation therapy to the head and/or neck regions were excluded. 2.1.2. Types of Participants The review considered studies involving patients who developed MRONJ after having taken antiresorptive, antiangiogenic and/or any drug therapy associated with osteonecrosis of the jaw. No restriction of age, gender or ethnic origin was applied. There was also no restriction on the minimum number of studies or type of studies included in the systematic reviews and/or meta-analysis. 2.1.3. Outcomes Measured (a) Primary outcome Evaluate the current state of knowledge regarding the medication- related osteonecrosis of the jaw as it relates with non-interventional type of studies and interventional type of studies, as well as the trends (number of SR and MA) per year. (b) Secondary outcome Evaluate factors such as: Type of studies included in the reviews; Number of patients included in the review; Patients’ demographic; Type of patient groups (Oncology vs. Non-oncology). 2.1.4. Data Extracted All selected papers were carefully read by four independent review authors (RS, OA, JW and JY) and data were extracted using a research report form. The number of included studies, design of the studies, number of patients, results, quality of the evidence and recommendation was recorded. In case of missing information, authors were contacted and given 6 weeks to respond. If the information was not provided, the missing data was recorded as “Not Reported (NR)” in the text and in the tables. A total of 25 systematic reviews were included in this study [40–64]. 2.1.5. Review Quality Assessment Criteria Three independent review authors (RS, AA and MDCM) appraised the included studies. The methodological quality of each review was evaluated using the Confidence in Evidence from Reviews of Qualitative (CERQual) research tool recommended by the Grading of Recommendations Assessment, Development and Evaluation Working Group (GRADE). The CERQual evaluation tool enabled the authors to evaluate the included studies, according to four key domains: (1) The methodological limitations of the individual qualitative studies contributing to a review finding; (2) The coherence of the review finding; (3) The adequacy of data supporting a review finding; (4) The relevance of the data from the primary studies supporting a review finding to the context (perspective or population, phenomenon of interest and/or setting) specified in the review question [65]. Appl. Sci. 2021, 11, 8818 6 of 20 Any disagreements in risk of bias assessments were referred to the third author of the review team (JY) and subsequently resolved by discussion. 3. Results Initially considered to be potentially eligible for inclusion were 104 studies but after inspection of the full papers, 79 were excluded for not meeting the inclusion criteria for this umbrella review. Results were expressed as descriptive statistics because of the significant heterogeneity in the published data. A total of 25 systematic reviews were therefore included in this study. The included systematic reviews involved a total of 80,840 patients. All the published data described patients evaluated from 2006 to 2021 (Table 2). Table 2. Systematic reviews included within this analysis. Systematic review (SR); meta-analysis (MA). Authors Focused Question Type of Patients Type of Reviews What is the effect of ARDs on MRONJ development in osteoporosis patients? and what are the risk factors, Aljohani et al. (2017) [40] Osteoporosis SR demographical and clinical characteristics associated with MRONJ in this particular group of patients? What are the effects of different interventions to either prevent or treat medication-related osteonecrosis of the Mixed (Oncology & Beth-tasdogan et al. (2017) [41] MA jaw compared with each other or compared with no Non-Oncology) treatment or an inactive intervention (’placebo’)? In populations of patients treated with antiresorptive agents undergoing tooth extraction, which antibiotic is Mixed (Oncology & Cabras et al. (2021) [42] SR more effective in reducing risk of MRONJ, compared Non-Oncology) to other antibiotics or placebo? Is the C-terminal telopeptide test effective in predicting Mixed (Oncology & Dal Prá et al. (2017) [43] the development of bisphosphonate-related SR Non-Oncology) osteonecrosis of the jaw? Can children be affected by bisphosphonate-related Mixed (Oncology & Duarte et al. (2020) [44] SR osteonecrosis of the jaw? Non-Oncology) Is dental implant placement purposeful for patients Mixed (Oncology & Gelazius et al. (2018) [45] SR using bisphosphonates? Non-Oncology) Mixed (Oncology & Govaerts et al. (2020) [46] NR SR Non-Oncology) Osteogenesis Hennedige et al. (2014) [47] NR SR Imperfecta Hess et al. (2008) [48] NR Non-Oncology SR Mixed (Oncology & Lorenzo pouso et al. (2020) [49] NR MA Non-Oncology) What are the most effective biomarkers for the risk Mixed (Oncology & Lorenzo-pouso et al. (2019) [50] SR assessment of developing BRONJ? Non-Oncology) In patients on IV or orally administered BPs, what is the risk of developing BRONJ when dental implants Madrid & Sanz (2009) [51] Unclear SR are placed and what is the impact of BP therapy on implant outcome? Mauri et al. (2009) [52] NR Oncology MA Mixed (Oncology & McGowan et al. (2018) [53] NR SR Non-Oncology) Migliorati et al. (2010) [54] NR Oncology SR Is a high-dose AR drug holiday at the time of tooth extraction, or other dentoalveolar surgery, necessary to Mixed (Oncology & Ottesen et al. (2020) [55] SR prevent the development of MRONJ in patients with Non-Oncology) cancer? Mixed (Oncology & Palaska et al. (2009) [56] NR SR Non-Oncology) Are bisphosphonate-related ONJ and Mixed (Oncology & Querrer et al. (2021) [57] denosumab-related ONJ any different, regarding SR Non-Oncology) clinical and imaging aspects? Appl. Sci. 2021, 11, 8818 7 of 20 Table 2. Cont. Authors Focused Question Type of Patients Type of Reviews Rollason et al. (2016) [58] NR Oncology SR Is there any sufficient evidence that non-oncological Sacco et al. (2021a) [59] immunosuppressed patients are at higher risk of Non-Oncology SR developing ONJ due to antiresorptive drug therapy? Is there any evidence that malignant cells or metastatic cancer is present within osteonecrosis of the jaws in Sacco et al. (2021b) [60] Oncology SR patients treated with antiresorptive and/or antiangiogenic medications? Which is the best available treatment option for Sacco et al. (2021c) [61] managing antiangiogenic related MRONJ in Oncology SR oncology patients? Does hyperbaric oxygenation have positive effects in the treatment of medication-related osteonecrosis of the jaws? Does low-intensity laser therapy have de Souza Tolentino et al. positive effects in the treatment of medication-related Mixed (Oncology & MA (2019) [62] osteonecrosis of the jaws? Additionally, does Non-Oncology) platelet-rich plasma (PRP) have positive effects in the treatment of medication-related osteonecrosis of the jaws? Mixed (Oncology & Woo et al. (2006) [63] NR SR Non-Oncology) Is there any evidence that orthodontic treatment Woolley et al. (2021) [64] induces ONJ or other adverse outcomes inpatients Non-Oncology SR treated with antiresorptive drug therapy? The types of systematic review included in this research were: systematic reviews (n = 21; 84%) and meta-analysis reviews (n = 4; 16%). Of these reviews n = 16 (64%) were non-interventional and n = 9 (36%) were interventional. The general characteristics of the studies included are shown in Tables 2 and 3. Table 3. Type of studies and patients included within respective systematic reviews. Randomized controlled trial (RCT); prospective (PR); retrospective (RE); case series (CS); case report (CR); prospective case-controlled study (P-CCS); retrospec- tive case-controlled study (R-CCS); case-controlled study (CCS); cross-sectional study (CSS); letter to the editor (LE). Number and Study Types Number of Patients Type of Drug Authors Included in the Analysis Included in the Research Therapy Used Antiresorptive (including Aljohani et al. (2017) [40] 1 PR; 20 RE; 20 CS; 3 CR 587 denosumab) Antiresorptive (including Beth-tasdogan et al. (2017) [41] 5 RCT 1218 denosumab) Antiresorptive (including Cabras et al. (2021) [42] 1 RCT; 7 PR; 4 RE; 5 CS 1888 denosumab) Antiresorptive (including Dal Prá et al. (2017) [43] 8 PR 1442 denosumab) Duarte et al. (2020) [44] 2 PR; 5 RE 538 Bisphosphonate Gelazius et al. (2018) [45] 1 RCT; 1 PR; 2 RE; 2 CS; 3 CR 514 Bisphosphonate 4 RCT; 4 P-CCS; 7 R-CCS; 7 Antiresorptive (including Govaerts et al. (2020) [46] 1513 PR; 7 RE denosumab) Hennedige et al. (2014) [47] 4 RE; 1 CS 501 Bisphosphonate Hess et al. (2008) [48] 1 RCT; 8 RE; 18 CS; 3 CR 99 Bisphosphonate Lorenzo pouso et al. (2020) [49] 7 CCS; 5 RE 2995 Bisphosphonate Lorenzo-pouso et al. (2019) [50] 6 P-CCS; 1 LE 2623 Bisphosphonate Appl. Sci. 2021, 11, 8818 8 of 20 Table 3. Cont. Number and Study Types Number of Patients Type of Drug Authors Included in the Analysis Included in the Research Therapy Used Madrid & Sanz (2009) [51] 1 P-CCS; 3 RE 1561 Bisphosphonate Mauri et al. (2009) [52] 15 RCT 10,707 Bisphosphonate Antiresorptive (including McGowan et al. (2018) [53] Unclear 4106 denosumab) Migliorati et al. (2010) [54] Unclear 39,124 Bisphosphonate Antiresorptive (including Ottesen et al. (2020) [55] 3 PR; 10 RE; 1 CS 2100 denosumab) Palaska et al. (2009) [56] 72 CS; 33 CR 656 Bisphosphonate Querrer et al. (2021) [57] 2 RCT; 5 CSS 7755 Antiresorptive Rollason et al. (2016) [58] 1 RCT 49 Bisphosphonate Bisphosphonate and Sacco et al. (2021a) [59] 9 RE; 8 CS; 10 CR 206 anti-TNF inhibitors Sacco et al. (2021b) [60] 3 PR; 2 RE; 2 CS; 6 CR 37 Bisphosphonate Sacco et al. (2021c) [61] 1 RCT; 7 CS; 20 CR 36 Antiangiogenic de Souza Tolentino et al. 1 RCT; 5 PR; 4 RE; 3 CS 188 Antiresorptive (2019) [62] Woo et al. 2006 [63] Unclear 368 Bisphosphonate Woolley et al. (2021) [64] 1 RE; 1 CS; 5 CR 29 Bisphosphonate The most common design of review was a non-interventional epidemiological de- sign (n = 13; 52%) (incidence, frequency and associated risks of MRONJ) followed by an interventional design n = 6 (24%). The most common drug type therapy investigated in the reviews included in this study were bisphosphonates 60%, while antiangiogenic drug therapy was investigated in 4% of the studies. The most frequent type of articles included in the reviews included in this study were case series (n = 140; 20.5%) followed by retrospective cohort studies (n = 84; 12.3%) and case report (n = 83; 12.2%). Regarding their study design, 277 articles (40.5%) were unable to be categorized. The reviews included in the study predominantly analyzed the evidence related to MRONJ in both oncology and non-oncologic patients (n = 14; 56%). A small number considered only oncologic patients (n = 5; 20%) (Table 3 and Figure 2). A number of reviews included in this study did not report a formal risk of bias quality analysis (n = 5; 20%), likely due to the year of article publications (antecedent to the PRISMA checklist guidance methodology). All the results presented in the reviews included in this study were highlighted as having a lack of evidence or providing any conclusive suggestions (Table 4). Appl. Sci. 2021, 11, 8818 9 of 20 Figure 2. Overview of the study characteristics: (a) type of the disease analyzed in the reviews included in the study; (b) type of drugs analyzed in the reviews included in the study; (c) type of studies analyzed in the reviews included in the study; (d) type of reviews included in the study. Table 4. Results from included reviews. Non-Interventional Reviews Author Result The mean age of MRONJ osteoporosis patients in our study was 69.7 5.2 years. The mandible was the most common site (394, 70.6%), followed by maxilla (152 case, 27.2%) and then in both of them (only 12 cases, 2.2%). The ratio of mandible to maxilla Aljohani et al. (2017) [40] and both jaws involvement was 2.4:1. There was variability in the duration of BPs therapy, which ranged from 2 weeks to 93 months, with a mean duration of 51.9 18 months. Extraction was the most frequently reported preceding event (244 patients, 48.5%). The data acquired from the moderate/high risk of bias studies suggested that 2–3 g of amoxicillin daily, either alone or in combination with clavulanate, for 6–7 days is the Cabras et al. (2021) [42] most commonly used antibiotic treatment to minimize risk of MRONJ in patients requiring a dental extraction, which could provide reduction of MRONJ risk. All eight of the selected studies found that CTX levels were not predictive of the development of BRONJ. In conclusion, this systematic review indicates that the CTX Dal Prá et al. (2017) [43] test has no predictive value in determining the risk of osteonecrosis in patients taking bisphosphonates. Although no cases of osteonecrosis were identified, all studies had weaknesses such as a limited sample size or the absence of risk factors for the development of Duarte et al. (2020) [44] osteonecrosis. However, it is believed that patients with secondary osteoporosis who use bisphosphonates continuously should be followed up during adulthood, since bone turnover decreases over the years. Appl. Sci. 2021, 11, 8818 10 of 20 Table 4. Cont. Non-Interventional Reviews Author Result Currently, osteogenesis imperfecta patients are treated as high-risk candidates for developing osteonecrosis of the jaw after dental extractions. However, there is no Hennedige et al. (2014) [47] evidence to support hypothesis of causal relationship between bisphosphonates and osteonecrosis of the jaw in children and adolescents with osteogenesis imperfecta. Common risk factors, which were associated with 88.9% of all non-cancer cases of osteonecrosis of the jaw among bisphosphonate users were: Dental procedures were most common among osteoporosis patients (92.5%) and less common among Paget’s disease patients (67%) before onset of osteonecrosis of the jaw. A longer duration of bisphosphonate use in osteoporotic patients (93.5% more than 1 year of use) compared with Paget’s disease (60% more than Hess et al. (2008) [48] 1 year of use) or other patients (33.3% more than 1 year of use). Underlying medical conditions (81.3%) and reported concomitant use of medications that affect bone turnover (70.9%). The most common concomitant medical conditions included hypertension, hyperlipidemia, and hypercholesterolemia (22.6%). Patient taking medications that affect bone turnover, the most commonly used medication affecting bone metabolism included steroids (52.2%). MRONJ appears to be associated with an increase in prevalence of periodontal disease. Lorenzo pouso et al. (2020) [49] However, the lack of scientific evidence in this matter does not allow clear conclusions to be drawn. A total of seven biomarkers were identified and classified into three groups: bone turnover, angiogenesis and endocrine markers. Conflicting results were found in Lorenzo-pouso et al. (2019) [50] relation to most biomarkers, which suggest that no useful markers are currently available to evaluate BRONJ risk. Overall, osteonecrosis of the jaw was a rare event, occurring in 13 (0.24%) of the 5312 patients receiving bisphosphonates. Treatment with zoledronic acid was Mauri et al. (2009) [52] significantly associated with the occurrence of osteonecrosis of the jaw (OR = 3.23, 95% CI = 1.7–8) compared with no use. A total of 4106 patients with MRONJ were identified, 39 different systemic diseases were implicated, and 14 medical and 11 dental risk factors were reported, although no McGowan et al. (2018) [53] statistical analysis of the significance of each of these factors was possible. However, the most reported dental risk factor was tooth extraction (45%), followed by periodontal disease (10%). The prevalence results observed were different depending on the type of study design. The overall weighted prevalence of BON included a sample of 39,124 patients with a mean weighted prevalence of 6.1%. The weighted prevalence was 13.3% for studies with documented follow-up. The overall Migliorati et al. (2010) [54] prevalence for patients using zoledronic acid only was 8.6%, for pamidronate 7.3%, and 21% for patients who used both. There were no studies evaluating the economic impact of BON. The poor reporting of outcomes of treatment did not allow us to determine success or failure rates of the treatment strategies. The weighted mean time to event was estimated to be 21.9 months (1.8 years), with a median minimum time of 10 months. The weighted mean time to event for pamidronate was found to be 33.8 months (2.8 years), whereas the median value for the minimum duration was estimated Palaska et al. (2009) [56] to be 18 months. The majority of the oral BP users were treated for osteoporosis, weighted mean time to event to be 4.6 years, whereas the median minimum time to event was 3 years. Appl. Sci. 2021, 11, 8818 11 of 20 Table 4. Cont. Non-Interventional Reviews Author Result An increase in bone sequestra, cortical bone lysis, and bone density was observed in Querrer et al. (2021) [57] bisphosphonate-related ONJ, while larger bone sequestra, more frequent periosteal reactions, and mandibular canal enhancement were noted in denosumab-related ONJ. The data reviewed have confirmed that an invasive procedure is the most common trigger of MRONJ with relatively high frequency of postoperative complications or Sacco et al. (2021a) [59] recurrence following management. However, due to low-quality research available in the literature, it is difficult to ascertain quantitatively the susceptibility of immunosuppressed patients in the development of MRONJ in non-oncology patients. Based on the limited data available in literature, it is plausible that not histologically Sacco et al. (2021b) [60] analyzing all ONJ specimens could result in a small amount of undiagnosed and untreated malignant diseases (4.64% based on large cohort studies). Lack of evidence whether orthodontic treatment can precipitate MRONJ. Moreover, antiresorptive drug therapy has been associated with a sub-optimal treatment outcome. The review reported adverse outcomes including: difficulty achieving root Woolley et al. (2021) [64] parallelism, difficulty achieving complete space closure, exaggerated mobility post-debond, increased duration of orthodontic treatment beyond expected completion, sclerotic alveolar bone changes seen on post-op radiographic images, an increased amount of root resorption and one case of ONJ. Interventional Reviews Author Result Available evidence is insufficient to either claim or refute a benefit for hyperbaric oxygen therapy as an adjunct to conventional therapy. There is also insufficient evidence to draw conclusions about autofluorescence-guided versus tetracycline Beth-tasdogan et al. (2017) [41] fluorescence-guided bone surgery. Moreover, there is insufficient evidence to conclude that the use of the other interventions investigated would reduce the risk of MRONJ or would improve healing of MRONJ. Patients with intraoral therapy appeared to have a better implant survival (5 implants Gelazius et al. (2018) [45] failed out of 423) rate at 98.8% vs. patients treated intravenously (6 implants failed out of 68) at 91%. Laser ablation had a success of 60–95% for complete healing. The controlled trials of Govaerts et al. (2020) [46] leukocyte- and platelet-rich fibrin (LPRF) showed 60–100% success for the same outcome. Fluorescence-guided surgery had a complete healing percentage of 85–90%. From the analysis yield in this study, the placement of an implant may be considered a Madrid & Sanz (2009) [51] safe procedure in patients taking oral BPs for 5 years with regard to the occurrence of BRONJ since in these studies no BRONJ has been reported. There is no evidence for using a drug holiday, but it is also clear that caused by a limited numbers of eligible patients, and a great variation in between these patients, Ottesen et al. (2020) [55] high-level evidence for using an AR drug holiday is almost impossible to obtain this data. There is a lack of evidence from randomized controlled trials to guide treatment of Rollason et al. (2016) [58] bisphosphonate-related osteonecrosis of the jaw (BRONJ). The data reviewed confirmed that an invasive procedure is the most common trigger of MRONJ. The overall MRONJ disease recurrence was identified in n = 6 (16.6%) cases. Two (n = 2) recurrences were observed in the conservative treatment group, n = 3 recurrences were recognized in the conservative and antibiotics treatment group Sacco et al. (2021c) [61] of patients and n = 1 was observed in the surgical treatment group. However, due to the low quality of available research in literature, it is difficult to draw a definitive conclusion on the validity of the presented treatment to manage patients affected by MRONJ associated with angiogenic therapy. Appl. Sci. 2021, 11, 8818 12 of 20 Table 4. Cont. Interventional Reviews Author Result Adjuvant therapies hyperbaric oxygen (HBO), low-intensity laser (LIL), and platelet-rich plasma (PRP) have positive effects on MRONJ treatment, being safe and well-tolerated. de Souza Tolentino et al. (2019) [62] There was improvement in 75.6% of the patients submitted to HBO. For LIL, 64.2% of the patients/sites improved the symptoms and 39.8% healed completely. For PRP, 17.3% of the 81 patients treated, had significantly improved the symptoms and 80.2% completely healed. Over suppression of bone turnover is probably the primary mechanism for the development of this condition, although there may be contributing comorbid factors. All sites of potential jaw infection should be eliminated before bisphosphonate therapy Woo et al. (2006) [63] is initiated in these patients to reduce the necessity of subsequent dentoalveolar surgery. Conservative debridement of necrotic bone, pain control, infection management, use of antimicrobial oral rinses, and withdrawal of bisphosphonates are preferable to aggressive surgical measures for treating this condition. 4. Review Quality Assessment The assessment of each CERQual component was based on judgements by the re- view authors and these judgements were described and detailed in CERQual Qualitative Evidence Profile (Table 5). Methodological limitations: The extent to which there are problems in the design or conduct of the primary studies that contributed evidence to a review finding. Relevance: The extent to which the body of evidence from the primary studies sup- porting a review finding is applicable to the context (perspective or population, phe- nomenon of interest, setting) specified in the review question. Coherence: The extent to which the review finding is well grounded in data from the contributing primary studies and provides a convincing explanation for the patterns found in these data. Adequacy of data: An overall determination of the degree of richness and quantity of data supporting a review finding. ** The CERQual approach—Definitions of levels of confidence in a review finding High confidence: It is highly likely that the review finding is a reasonable representa- tion of the phenomenon of interest. Moderate confidence: It is likely that the review finding is a reasonable representation of the phenomenon of interest. Low confidence: It is possible that the review finding is a reasonable representation of the phenomenon of interest. Very low confidence: It is not clear whether the review finding is a reasonable repre- sentation of the phenomenon of interest. Appl. Sci. 2021, 11, 8818 13 of 20 Table 5. Quality assessment. Assessment of Overall CERQual Systematic Review Assessment of Assessment of Assessment of Study/Studies Methodological Assessment of Explanation of Judgement Category Relevance * Coherence * Adequacy * Limitations * Confidence ** Aljohani et al. (2017) [40]; Duarte et al. (2020) [44]; This finding was graded as: Hennedige et al. (2014) [47]; minor concerns for Hess et al. (2008) [48]; relevance and coherence in Lorenzo pouso et al. (2020) [49]; Serious concerns regarding all studies, moderate Mauri et al. (2009) [52]; methodological limitations Minor concerns Epidemiological type Minor concerns Serious Concerns concerns regarding McGowan et al. (2018) [53]; in four studies and regarding of reviews regarding relevance regarding adequacy Very low confidence methodological limitations Migliorati et al. (2010) [54]; moderate concerns coherence in all (non-interventional) in all studies in all studies in eight studies and serious Palaska et al. (2009) [56]; regarding methodological studies concerns regarding Sacco et al. (2021a) [59]; limitations in eight studies methodological limitations Sacco et al. (2021b) [60]; four studies and adequacy de Souza Tolentino et al. of data results in all studies (2019) [62]; Woolley et al. (2021) [64] This finding was graded as: Serious concerns regarding minor concerns for methodological limitations relevance and coherence, Beth-tasdogan et al. (2017) [41]; in one study, moderate Minor concerns moderate concerns Management type of Govaerts et al. (2020) [46]; concerns regarding Minor concerns Serious concerns regarding regarding methodological reviews Rollason et al. (2016) [58]; methodological limitations regarding relevance regarding adequacy Very low confidence coherence in all limitations in three studies (interventional) Sacco et al. (2021c) [61]; in three studies and minor in all studies in all studies studies and serious concerns Woo et al. 2006 [63] concerns regarding regarding methodological methodological limitations limitations (one study) and in two studies and adequacy of data results This finding was graded as: minor concerns for Serious concerns regarding relevance and coherence, methodological limitations moderate concerns Predicting biomarkers Minor concerns Serious concerns Dal Prá et al. (2017) [43]; in one study and moderate Minor concerns regarding methodological type of reviews about coherence in regarding adequacy Very low confidence Lorenzo-pouso et al. (2019) [50] concerns regarding about relevance limitations and serious (non-interventional) both studies in both studies methodological limitations concerns regarding in one study methodological limitations (one study) and adequacy of data results Appl. Sci. 2021, 11, 8818 14 of 20 Table 5. Cont. Assessment of Overall CERQual Systematic Review Assessment of Assessment of Assessment of Study/Studies Methodological Assessment of Explanation of Judgement Category Relevance * Coherence * Adequacy * Limitations * Confidence ** This finding was graded as: Serious concerns regarding minor concerns for methodological limitations Moderate concerns relevance, moderate Serious concerns Dental rehabilitation Gelazius et al. (2018) [45]; in one study and moderate Minor concerns regarding concerns regarding regarding adequacy Very low confidence (interventional) Madrid & Sanz (2009) [51] concerns regarding regarding relevance coherence in both methodological limitations in both studies methodological limitations studies and coherence, and serious in one study concerns regarding adequacy of data results This finding was graded as: minor concerns for relevance and coherence, Preventive strategy Moderate concerns Minor concerns Minor concerns Serious concerns moderate concerns type of review Ottesen et al. (2020) [55] regarding methodological regarding Very low confidence regarding relevance regarding adequacy regarding methodological (interventional) limitations coherence limitations and serious concerns regarding adequacy of data results This finding was graded as: minor concerns for relevance, moderate Preventive strategy Minor concerns Serious concerns Serious concerns regarding Minor concerns concerns regarding type of review Cabras et al. (2021) [42] regarding regarding Very low confidence methodological regarding relevance methodological limitations (non-interventional) coherence Adequacy and coherence, and serious concerns regarding adequacy of data results This finding was graded as: minor concerns for relevance and coherence, Diagnostic type of Moderate concerns Minor concerns Minor concerns Serious concerns moderate concerns review Querrer et al. (2021) [56] regarding methodological regarding Very low confidence regarding relevance regarding adequacy regarding methodological (non-interventional) limitations coherence limitations and serious concerns regarding adequacy of data results * Components of the CERQual approach. Appl. Sci. 2021, 11, 8818 15 of 20 In summary the authors found that: There were minor concerns with respect to the relevance and coherence of the epidemi- ological type of reviews in all studies. Moderate concerns were noted regarding the methodological limitations in eight studies and serious concerns were highlighted for similar limitations in four studies. Serious concerns were also noted for the adequacy of data of their results in all of the included studies. Due to the high number of serious concerns, particularly regarding methodology and result data, the overall assessment was assessed as very low confidence (lack of clarity whether the review finding is a reasonable representation of the phenomenon of interest). Minor concerns were highlighted with respect to the relevance and coherence of man- agement types of reviews. Moderate concerns were raised regarding methodological limitations in three studies and serious concerns in methodological limitations in one study. Serious concerns were raised for one study regarding the adequacy of data in the results. Due to these concerns, the overall assessment regarding the management type was graded as very low confidence (lack of clarity whether the review finding is a reasonable representation of the phenomenon of interest). With respect to predicting markers, the reviews were graded as having minor concerns for relevance and coherence, moderate concerns regarding methodological limitations and serious concerns regarding methodological limitations and adequacy of the result data. Due to these concerns, the overall assessment regarding predicting markers was rated as having very low confidence (lack of clarity whether the review finding is a reasonable representation of the phenomenon of interest). Relating to dental rehabilitation, reviews were graded with minor concerns for rele- vance, moderate concerns regarding methodological limitations and coherence, and serious concerns regarding adequacy of result data. This domain again was graded as having very low confidence (lack of clarity whether the review finding is a reasonable representation of the phenomenon of interest). Regarding preventive strategy, reviews demonstrated minor concerns for relevance and coherence, moderate concerns regarding methodological limitations and serious concerns regarding adequacy of data results. The overall assessment for preventative strategy was rated as very low confidence (lack of clarity whether the review finding is a reasonable representation of the phenomenon of interest). Finally, when assessing the diagnostic investigations within the reviews, this review identified minor concerns regarding relevance and coherence, moderate concerns regarding methodological limitations and serious concerns regarding adequacy of the data results. Therefore, with regard to the overall assessment, this domain was graded as very low confidence (lack of clarity whether the reviews found a reasonable representation of the phenomenon of interest). 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. Appl. Sci. 2021, 11, 8818 16 of 20 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 [48,56,59–61,64]. 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. In the future, it is essential to conduct studies with improved quality, including randomized-controlled trials that support evidence-based treatment protocols. In gen- eral, the authors advocate that the following rules should be applied for future MRONJ research studies: Sample size calculation should be established and employed for all the RCTs. Large RCTs should be carried out and described in sufficient detail to allow precise assess- ment, management and/or epidemiological findings. Risk stratification should be applied for any clinical studies in order to minimize the effect modification and/or confounding factors that could potentially affect the final result/s. Common, quantifiable and clinically relevant endpoints (time to complete wound healing, pain, specific investigations, treatment acceptability and participant satisfac- tion) should be described in sufficient detail particularly in patients undergoing to any type of intervention including preventive strategies. An adequate follow-up period is essential if MRONJ treatment or preventive strategy is studied in order to evaluate the long-term effects on this group of patients. A predictable special investigation, such as CT, CBCT or MRI should be used for any of the observational and interventional studies at diagnosis and during the follow-up. Appl. Sci. 2021, 11, 8818 17 of 20 6. Conclusions Through this umbrella review, it has become clear that there is limited high strength evidence to support many of the current recommendations surrounding medication-related osteonecrosis of the jaw. The low quality systematic reviews and meta-analyses highlighted by this study show no insightful therapeutic recommendations, preventive strategies, risk reduction or standards that can be applied for this debilitating disease. A number of higher quality clinical studies are necessary to make evidence-based decisions on MRONJ therapies. Author Contributions: R.S. conceived the presented systematic review idea and the design of the study; R.S., C.F.d.A.B.M., J.W., O.A., V.M., E.K., A.A., O.O. and J.Y. contributed to the acquisition, analysis, and the interpretation of data for the work; R.S., M.D.C.-M., J.W. and J.Y. drafted the paper and revised it critically; R.S., M.D.C.-M., J.W., O.A., C.F.d.A.B.M., V.M., E.K., A.A., O.O. and J.Y. approved the final version to be published. 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Applied Sciences – Multidisciplinary Digital Publishing Institute
Published: Sep 23, 2021
Keywords: osteonecrosis; medication-related osteonecrosis of the jaw; systematic review; umbrella review; evidence-based medicine
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