Proposal for a preventive protocol for medication-related osteonecrosis of the jaw

e314 Med Oral Patol Oral Cir Bucal. 2021 May 1;26 (3):e314-26. Preventive protocol for MRONJ Journal section: Oral Medicine and Pathology Publication Types: Review Proposal for a preventive protocol for medication-related osteonecrosis of the jaw Manuel Mª Romero-Ruiz 1, Marta Romero-Serrano 1, Ascensión Serrano-González 2, María Ángeles SerreraFigallo 3, José Luis Gutiérrez-Pérez 4, Daniel Torres-Lagares 3 1 DDS. Dental School. University of Seville, Spain 2 MD, PhD. Hospital Puerta del Mar, Cádiz, Spain 3 DDS. PhD. Dental School. University of Seville, Spain 4 DMD, PhD. Dental School. University of Seville, Spain Correspondence: Dental School.University of Seville C/ Avicena s/n 41009 Sevilla, Spain [email protected] Received: 25/07/2020 Accepted: 03/09/2020 Abstract Background: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction experienced by some patients exposed to certain drugs (antiresorptives such as bisphosphonates or denosumab, and antiangiogenic drugs). From a review of the literature it appears that there is no uniform criterion when selecting preventive measures; these vary according to author. Likewise, the measures recommended are usually general, so that in few cases they result in specific actions to be applied depending on the different variables involved such as the type of drug used, the duration of its application, the underlying pathology, the presence or absence of risk factors, etc. The aim of this study has been to design a preventive protocol which can be easily applied in any clinic or by any dental care service. Material and Methods: We undertook an exhaustive literature review to find any articles related to the topic of study, namely, preventive measures for medication-related osteonecrosis of the jaw, on the one hand generically and on the other focusing on dental implant treatment. The most part the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. From 3946 items, we selected a total of 21 items. Results: From the analysis of the selected articles, several protocols have been developed that are easy to apply in a dental clinic.: Protocol 1. Before starting treatment with antiresorptives (Patients who are going to be treated for osteoporosis / Patients who are going to be treated for cancer). Protocol 2. Once treatment is initiated with antiresorptives (Patients being treated for osteoporosis / Patients being treated for cancer). Conclusions: The application of these protocols requires an interdisciplinary team which can handle the various treatments and apply the measures contained in them. Along with a team of well-educated and trained dentists, it is equally important to maintain contact with the medical team involved in the treatment of the underlying pathology, especially rheumatologists, oncologists, internists and gynaecologists. All the above requires a great staff learning and organization effort, continuous training and coordination of the whole team involved in the preventive management of these patients. Key words: Medication-related osteonecrosis of the jaw, clinical protocols, clinical guidelines, prevention. doi:10.4317/medoral.24197 MM Romero-Ruiz, M Romero-Serrano, A Serrano-González, MÁ Serrera-Figallo, JL Gutiérrez-Pérez, D Torres-Lagares. Proposal for a preventive protocol for medication-related osteonecrosis of the jaw. Med Oral Patol Oral Cir Bucal. 2021 May 1;26 (3):e314-26. Article Number:24197 http://www.medicinaoral.com/ © Medicina Oral S. L. C.I.F. B 96689336 - pISSN 1698-4447 - eISSN: 1698-6946 eMail: [email protected] Indexed in: Science Citation Index Expanded Journal Citation Reports Index Medicus, MEDLINE, PubMed Scopus, Embase and Emcare Indice Médico Español e315 Med Oral Patol Oral Cir Bucal. 2021 May 1;26 (3):e314-26. Preventive protocol for MRONJ Introduction Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction experienced by some patients exposed to certain drugs (antiresorptives such as bisphosphonates or denosumab, and antiangiogenic drugs), used in cases of osteoporosis or bone manifestations in different types of cancer, to reduce skeletal complications of these conditions, achieving a reduction in pain and typical pathological fractures, as well as an improvement in the life quality of these patients (1). According to the American Association of Oral and Maxillofacial Surgeons (AAOMS 2014), patients with MRONJ should be or have been in treatment with antiresorptive or antiangiogenic drugs, present exposed bone or bone which may be probed through an intraor extraoral fistula in the maxillofacial region, and the lesion must have persisted for more than 8 weeks with no history of radiotherapy in the region (2). The etiopathogenesis of this type of Osteonecrosis of the Jaw (ONJ) nowadays continues to be a challenge for researchers, being a constant topic of debate. From the data available it may be deduced that the aetiology would be multifactorial, there being on the one hand inhibition of the osteoclast function by the antiresorptive drugs, which would lead to disorders in the repairing, healing and bone remodelling mechanisms, essential in protecting against infection, and microfractures which take place as a result of physiological bone function (3). On the other hand, both the antiangiogenic drugs such as Bevacizumab or Sunitinib, and some bisphosphonates such as zoledronic acid are capable of inhibiting angiogenesis, by reducing the formation of blood vessels, which is fundamental for healing and bone remodelling (4). In recent years, the infectious/inflammatory theory has become increasingly important as a cause for the emergence of ONJ. Different studies on animal models support the theory that infection or local inflammation could trigger a condition of osteonecrosis in these patients (3). Although it is well known that the majority of cases of ONJ had a dental extraction history, it is also true that normally these extracted teeth had undergone prior periodontal or periapical pathological infection, which justified their extraction. Given that most teeth with a dental inflammatory disease are eventually extracted, there may be confusion on the true role of the surgical procedure itself as a direct trigger for ONJ (2,5,6). The basic role of infection in the pathogenesis of this condition is manifested by the fact that its incidence is reduced as soon as the dental hygiene of these patients improves (7). The mechanism by which microorganisms induce ONJ could be related to the production by the bacteria in certain substances such as lipopolysaccharides which would favour reabsorption, or Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL) in fibroblasts, having the same effect. Similarly, local acidosis induced by infection has also been related as a cause of the release of bisphosphonates, facilitating osteonecrosis (8,9). Treatment with dental implants in patients who take antiresorptives or antiangiogenic drugs has always been a controversial topic. As cases of MRONJ were being published, it was highlighted that in an elevated percentage, the precipitating factor was a dental extraction (54%-61%), such that although there was not much evidence, it was deemed that the risk of triggering an ONJ after dentoalveolar surgery would be similar to the one that existed after exodontia. In this sense, the surgical procedure of inserting an implant in these patients would involve a risk of ONJ similar to that of dental exodontia (2,10). Slowly publications began to appear which related implants with the emergence of ONJ, arousing controversy about the desirability of recommending implantological treatments in patients treated with antiresorptives, although the evidence in that respect is heterogeneous, incomplete and of low quality (11,12). There is sufficient evidence to state that the risk of implant failure due to ONJ is limited in patients undergoing treatment with antiresorptives for osteoporosis, although the risk must be assessed on an individual basis. However, in patients undergoing treatment with antiresorptives for cancer, the risk is much higher and there is a consensus that implants should be contraindicated in these cases (2,13,14). Notwithstanding, from the evidence published in recent years, it appears that the majority of cases of periimplant MRONJ develop as a late complication around previously osseointegrated and successfully loaded implants, such that the condition could not be attributed to the surgical procedure of implant insertion. Several publications have suggested that the presence of periimplantitis could be a more important risk factor for MRONJ than surgical insertion, which would reinforce the importance of the infectious/inflammatory theory in the etiopathogenesis of MRONJ in these cases (14-18). Treatment of MRONJ once established is complex, because it depends on the stage of the disease, there being several therapeutic approaches, sometimes conflicting, depending on the authors undertaking it. Bermúdez et al. (19) carried out a study on the different therapeutic approaches found in the literature and grouped them into seven protocols, each one of which covered different types of treatment, highlighting that the best results were obtained with a conservative protocol, with clinical and radiological follow-up, minimally invasive surgical treatment and various coadjuvant measures. This shows the enormous variety of existing proposals and the difficulty in tackling the process therapeutically. In part due to the above, when talking of therapeutic management of these patients, stress has been laid on the importance of a multi-disciplinary approach which e316 Med Oral Patol Oral Cir Bucal. 2021 May 1;26 (3):e314-26. Preventive protocol for MRONJ sures published in the literature. As a result of the huge spread of the data in the published articles and the heterogeneous nature of these, we deemed it inappropriate to ask a specific PICO question because we ran the risk of leaving out articles relevant to our search. For this reason, likewise, we had to resort to review or expert opinion articles, which placed more emphasis on the specific preventive measures we wished to include in the protocol. The inclusion criteria were: (a) Studies published between January 2003 and 30 January 2019; (b) Human studies; (c) Any language; (d) case series, cohort studies, case-control studies, and controlled and/or randomized controlled clinical trials (CTs/RCTs); (e) retro or prospective studies; (f) studies including patients having undergone or undergoing oral or parenteral antiresorptive or antiangiogenic drugs, with or without implant treatment, to whom any type of protocol or preventive measure was being applied; (g) review articles, systematic reviews and meta-analysis on the application of preventive measures or protocols for MRONJ in patients having taken, taking or planning to take the drugs involved. The following exclusion criteria were applied: (a) that they did not meet the inclusion criteria; (b) animal studies; (c) case reports. - Search sources and strategy An electronic search was conducted using three databases, PubMed, (Medline), Embase (Ovid) and Cochrane database of systematic reviews. The review was completed with a manual search in scientific journals in this sector in the e-library of the University of Seville. Likewise lists of references in all the publications identified were reviewed. Search of the Medline (PubMed) database was carried out using MeSH (Medical Subjects Headings) terms and free terms, in different combinations using Boolean Operators “AND” and “OR”. The terms used were general terms; (“Dental” OR “Oral”). Terms related to drugs involved; (“Diphosphonates” OR “Bisphosphonates” OR “Alendronic Acid” OR “Alendronate” OR “Etidronic Acid” OR “Etidronate” OR “Ibandronic Acid” OR “Ibandronate” OR “Pamidronate” OR “Risedronic Acid” OR “Risedronate” OR “Zoledronic Acid” OR “Zoledronate” OR “Denosumab” OR “Human monoclonal antibody to RANKL” OR “RANK ligand” OR “RANK antibody” OR “Bevacizumab” or “Sunitinib” OR “Antiresorptive drugs” OR “Antiresorptive agents” OR “Angiogenesis inhibitor”. Terms related to Osteonecrosis of the jaw; “Bisphosphonate-associated osteonecrosis of the jaw” OR “Medication related osteonecrosis” OR “Jaw osteonecrosis” OR “Osteonecrosis” OR “MRONJ” OR” BRONJ”. Terms related to dental implants; “Dental implants” OR “Dental implant” OR “Dental implants adverse effects” OR “Implant treatment” OR “Implant therapy” OR “Implants” OR should include consulting qualified dental professionals, when deciding on treating a patient with antiresorptives or antiangiogenics. There is increasing evidence that early screening, the application of adequate preventive measures and correct dental care before initiating antiresorptive treatment, achieve a reduction in the incidence of MRONJ using guidelines covering educational aspects and ones aimed at motivating patients to take part in their dental healthcare, as well as measures targeted at eliminating or preventing infected dental, periodontal and peri-implant sites (2,10,20-22). Likewise, preventive protocols for performing surgical extractions with the least possible trauma have been described, using antibiotic prophylaxis, finding a reduction in the risk of osteonecrosis (23,24). However, from a review of the literature it appears that there is no uniform criterion when selecting preventive measures; these vary according to author. Likewise, the measures recommended are usually general, so that in few cases they result in specific actions to be applied depending on the different variables involved such as the type of drug used, the duration of its application, the underlying pathology, the presence or absence of risk factors, etc. A similar situation arises with follow-up times, when check-ups should be carried out, or with the drugs and preventive measures employed before an exodontia or any other surgical procedure in these patients. We have not found in the literature any clearly defined, wide-ranging protocol which outlines specifically and systematically the different preventive measures for MRONJ set out in published studies in the literature, and especially for patients who are carriers or who wish to receive treatment with dental implants. Therefore, the aim of this study has been to design a preventive protocol which can be easily applied in any clinic or by any dental care service; one which is systematic and detailed and which takes into consideration all the variables involved in those patients who have received or are receiving treatment with antiresorptive or antiangiogenic drugs, and who are wearers or are about to receive treatment with dental implants. Material and Methods - Protocols and eligibility criteria We undertook an exhaustive literature review to find any articles related to the topic of study, namely, preventive measures for medication-related osteonecrosis of the jaw, on the one hand generically and on the other focusing on dental implant treatment. Although for the most part the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, this review cannot be considered strictly systematic, due to the large number of variables involved in the search, given that our aim was to draw up a preventive protocol describing all the mea- e317 Med Oral Patol Oral Cir Bucal. 2021 May 1;26 (3):e314-26. Preventive protocol for MRONJ “Osseointegration” OR “Osseointegrated dental implantation” OR “Dental implantation, endosseus” OR “Implant loss” OR “Implant failure” OR “Periimplantitis” OR “Peri-implantitis” OR “Periimplant disease” OR “. Terms related to dental extraction or oral surgery as a risk factor; “Tooth extraction” OR “Tooth extractions” OR “Dental extraction” OR “Oral surgery” OR “Oral surgery procedure” OR “Oral surgery procedures” OR “Procedures, oral surgery”. Terms related to prevention or preventive measures for osteonecrosis; “Preventive dentistry” OR “Prophylaxis” OR “Dental Prophylaxis” OR “Prophylaxis, dental” OR “Preventive measures” OR “Preventive management” OR “Antibiotic Prophylaxis” OR “Antibiotic” OR “Bisphosphonates-associated osteonecrosis of the jaw therapy” OR “Bisphosphonates-associated osteonecrosis of the jaw prevention and control” OR “Bisphosphonates-associated osteonecrosis of the jaw preventive protocol” OR ”Preventive protocol” OR “Preventive” OR “Protocol”. For the other two databases, similar terms were used but adapted to the specific criteria of each of them. - Data gathering and extraction Two authors (MMRR and MRS) reviewed all the titles and abstracts independently. After ruling out all those which did not meet the eligibility criteria, the complete text of the remaining articles was reviewed. The complete text of those which offered little information in the title or abstract were also selected, to avoid missing out any relevant article. Any disagreements were resolved by discussion between the two reviewers. Results - Articles selected Fig. 1 shows the flowchart of the search process. Of the 3946 initial articles, after the various exclusion processes, 21 articles were selected which met the inclusion criteria. The articles included were grouped into: clinical articles (n=10, Table 1); (Dimopoulos et al., 2009 (20); Ripamonti et al., 2009 (25); Lodi et al., 2010 (26); Ferlito et al., 2011 (27); Kwon et al., 2012 (28); Vandone et al., 2012 (29); Bramati et al., 2014 (30); Troeltzsch et al., 2016 (31); Giovannacci et al., 2016 (13); Mücke et al., 2016 (32)). Review articles on MRONJ (n=6, Table 2); (Ruggiero et al., 2014 (2); Otto et al., 2015 (33); DinizFreitas et al. 2016 (34); Beth-Tasgodan et al., 2017 (35); Di Fede et al., 2018 (36); Karna et al., 2018 (37)). Review articles on relation between MRONJ and dental implants (n=5, Table 3); (Ata-Ali et al., 2016 (11); Freitas et al., 2016 (38); Walter et al., 2016 (18); Guazzo et al., 2017 (39); Stavropoulos et al., 2018 (1)). Fig. 1: Flowchart of the search and inclusion process for studies for review. e318 Med Oral Patol Oral Cir Bucal. 2021 May 1;26 (3):e314-26. Preventive protocol for MRONJ article N procedure underlying disease medication administration route treatment followup incidence type of study conclusions Dimopoulos et al, Ann Oncol. 2009. (20) 128 group A (38) and B (90) if treatment was initiated before or after implementation of the preventive measures. cancer (multiple myeloma) bisphosphonates (zolendronate) intravenous extraction, implant or spontaneous 2.5 to 55 months 16 patients (12.5%) developed ONJ: 10 in group A (26.3%) and 6 in group B (6.7%) prospective and retrospective The risk of developing ONJ after treatment with zoledronic acid is reduced (but not eliminated) by the implementation of preventive measures. Ripamonti et al, Annals of Oncology. 2009. (25) 966 patients undergoing oral reviews to detect possible dental disorders and dental care if necessary, thus estimating incidence of ONJ 903 cancer, 27 osteoporosis, 36 both bisphosphonates (zolendronate, pamidronate, clodronate) oral and intravenous prevention 6 years retrospective and 2 years prospective ONJ went from 3.2% to 1.3% after applying prevention prospective and retrospective There is an important reduction in ONJ in those patients receiving suitable preventive dental measures. Lodi et al, J Oral Maxillofac Surg. 2010 (26) 38 extractions protocol to reduce the risk of ONJ, based on controlling local and systemic infection using chemical and mechanical reduction of local bacterial load and antibiotic prophylaxis. 21 cancer and 2 osteoporosis bisphosphonates (zolendronate, pamidronate, clodronate) intravenous extraction 1 year 0% developed ONJ prospective The proposed preventive protocol seems to reduce the risk of ONJ after dental extraction in a group of subjects treated with intravenous bisphosphonates. Ferlito et al, J Oral Maxillofac Surg. 2011 (27) 102 extractions preventive protocol for patients receiving zolendronate and requiring simple or multiple dental extractions cancer bisphosphonates (zolendronate) intravenous extraction 12 months 0% developed ONJ Uncontrolled longitudinal observational. extraction of alveolar bone after extraction of teeth and correct antimicrobial prophylaxis Kwon et al, Clin Oral Implants Res. 2012 (28) 19 analysis of clinical, radiological and histological findings in patients diagnosed and treated for ONJ associated with implant placement osteoporosis bisphosphonates oral and intravenous implants 3 years 3 patients developed ONJ after implant placement and 9 patients developed ONJ on average within 35 months. prospective already osseointegrated dental implants may also cause osteonecrosis Vandone et al, Ann Oncol. 2012 (29) 269 comparison between a retrospective group without prevention and a prospective group with prevention cancer bisphosphonates (zolendronate, pamidronate) intravenous prevention 47 months ONJ went from 5.5% to 2.8% after applying prevention prospective and retrospective implementation of a preventive dental programme can reduce the risk of ONJ in metastatic patients treated with i.v. Bramati et al, J Bone Miner Metab. 2015 (30) 212 Strict prevention programme and comparison with a prior cohort study without dental prevention cancer bisphosphonates (zolendronate, pamidronate) Intravenous prevention 5 years 100% efficient prevention prospective ONJ could be effectively prevented. Recommendation of an obligatory preventive programme including a multidisciplinary team for all patients starting BP. Troeltzsch et al J Craniomaxillofac Surg. 2016 (31) 117 analyses of periimplant parameters are associated with peri-implant ONJ. 29 cancer, 5 osteoporosis bisphosphonates or denosumab oral and intravenous Implants 6 years ONJ 44%. Signs of periimplantitis (39%): seemed to be associated with ONJ. retrospective Patients receiving high doses of antiresorptives have risk of developing periimplant ONJ Giovannacci et al, J Craniofac Surg. 2016 (13) 15 G1: necrosis immediately after placement of the implant (from 2 to 10 months). G2: distant necrosis (from 1 to 15 years) 9 cancer and 6 osteoporosis bisphosphonates (alendronate, ibandronate, zolendronate) oral and intravenous implants 15 years ** retrospective information to patients taking BP and wanting placement of IOI; but also those going to start treatment with BP and have IOI Mücke et al, J Craniomaxillofac Surg. 2016 (32) 253 Group A monitored and treated when the dentist deemed it necessary and was reassessed once a year. Group B, patients monitored and treated by the authors when necessary at 12-week intervals. cancer (prostate metastasis) bisphosphonates (zolendronate) intravenous prevention between 1 and 7 years 22.3% ONJ in control group and 2.2% ONJ in study group prospective Preventive oral and maxillofacial treatment before the application of bisphosphonate combined with dental follow-ups at 3 months significantly reduces the emergence and risk of ONJ Table 1: Clinical articles. e319 Med Oral Patol Oral Cir Bucal. 2021 May 1;26 (3):e314-26. Preventive protocol for MRONJ Article no. articles reviewed type of articles reviewed key words aims conclusions Ruggiero et al, J Oral Maxillofac Surg. 2014 (2) 184 Controlled clinical trials, cases and controls, ECA and cohorts. X 1. Estimates of risk of ONJ. 2. Comparisons of risks and benefits of drugs related to ONJ to facilitate decision making. 3. Guidance to clinics on: a. differential diagnosis of ONJ in patients with a history of exposure to antiresorptive and / or antiangiogenic agents. b. Prevention measures and management strategies for ONJ. The Special Committee recommends changing the nomenclature of bisphosphonate-related osteonecrosis of the jaw. The Special Committee favours the term medication-related osteonecrosis of the jaw. Otto et al, J Craniomaxillofac Surg. 2018 (33) 30 Prospective and retrospective Bisphosphonates, Bisphosphonaterelated osteonecrosis of the jaw, Medication-related osteonecrosis of the jaw, MRONJ, Prophylaxis, Risk factors, Tooth extractions To investigate the result of tooth extractions in patients receiving bisphosphonate therapy. Tooth extraction can be performed safely and predictably, even in high risk patients, when it is undertaken in accordance with established guidelines. It is not tooth extraction itself but rather the prevailing infectious conditions which may be a key risk factor for the development of ONJ. Diniz-Freitas et al, Med Oral Patol Oral Cir Bucal. 2016 (34) 13 Systematic review and metaanalysis Bisphosphonates, angiogenesis inhibitors, antiresorptive drugs, extraction, osteonecrosis. To identify the most relevant protocols and the best measures for preventing ONJ secondary to dental extraction. no scientific evidence is available on the effectiveness of prevention protocols for ONJ in patients treated with antiresorptive or antiangiogenic drugs who undergo dental extraction. Beth-Tasdogan et al, Cochrane library. 2017(35) 5Randomized controlled trials X 1. To assess the effects of operations vs. no treatment, placebo or active control for prophylaxis of ONJ in patients exposed to antiresorptive or antiangiogenic drugs. 2. To assess the effects of non-surgical or surgical procedures vs. no treatment, placebo or active control for the treatment of persons with ONJ. Dental examinations at three monthly intervals and preventive treatments can be more effective than standard care for reducing the incidence of ONJ. The certainty of the evidence was assessed as low. There are insufficient tests to claim or refute a benefit from operations tested for ONJ prophylaxis Di Fede et al, Biomed Res Int. 2018 (36) 64 descriptive X To describe the new paradigm on preventive dental management in patients at risk of ONJ, before and during / after the administration of medication The need for a standardized multidisciplinary approach, with sustained dialogue between specialists, to improve the effectiveness of preventive strategies and enhance patient quality of life. Karna et al, J Oral Oncol. 2018 (37) 6 Controlled clinical trials, cases and controls, ECA and cohorts. X To assess the effectiveness of dental procedures to prevent or reduce the incidence of ONJ in patients with cancer receiving antiresorptive treatment, compared to similar control groups not receiving any procedures No conclusive proof was evinced. Therefore, further large-scale prospective studies are required with well-defined procedures and control groups, and consistent measurement of results in both groups. Table 2: Review articles on osteonecrosis. e320 Med Oral Patol Oral Cir Bucal. 2021 May 1;26 (3):e314-26. Preventive protocol for MRONJ Article No. articles reviewed Type of articles reviewed Key words Aims Conclusions Ata-Ali et al, Clin Oral Implant Res. 2014 (11) 15 (i) Studies including patients with a history of systemic BP therapy (via the oral and/or intravenous route) and receiving at least one dental implant before or after BP administration; (ii) Prospective or retrospective studies and cases series; (iii) Studies specifying implant success rate. Dental implants, bisphosphonate(s), etidronate, clodronate, risedronate, alendronate, ibandronate, pamidronate, zoledronic acid. To assess the scientific evidence that bisphosphonate therapy can reduce the success rate of dental implants. Placement of dental implants in patients receiving bisphosphonates does not reduce the success rate of dental implants. These patients are not exempt from complications and, therefore, risk assessment must be established on an individual basis De Freitas et al, Med Oral Patol Oral Cir Bucal. 2016 (38) 15 Articles included in patients undergoing bisphosphonate therapy (oral and intravenous) and undergoing dental implant procedure; cases series; retrospective studies; prospective studies. Bisphosphonates, diphosphonates, dental implants, osteonecrosis. To analyse articles studying patients who underwent bisphosphonate therapy and receiving dental implants before, during or after bisphosphonate treatment. Care must be taken when planning dental implant surgery in patients receiving bisphosphonate treatment due to the risk of developing ONJ and implant failure. Furthermore, the overall systemic condition of the patient should be taken into consideration when undertaking such procedures. Walter et al, Int J Implant Dent. 2016 (18) 50 Prospective (controlled randomized, non-randomized controlled studies, cohort studies) and retrospective (control, case control, single cohort) and case series treating dental implants in patients with antiresorptive therapy. Bisphosphonate associated osteonecrosis of the jaw, Bisphosphonate, Dental implant, Denture, Augmentation, Sinus lift, Antibiotics, Quality of life To ascertain which patients with antiresorptive therapy (BP, denosumab) benefit from dental implants without being exposed to an unreasonably high risk of developing osteonecrosis. Successful implant therapy is possible in patients receiving antiresorptive therapy. The possibility of developing osteonecrosis should be explained to the patient. Individual risk assessment is essential, bearing in mind the primary disease with the medication and other diseases and medications which compromise wound healing. Whenever possible, bone augmentation should be avoided, and in these patients perioperative antimicrobiological prophylaxis is recommended. Guazzo et al, J Oral Implant 2017(39) 10 Retrospective studies, cross-sectional studies and prospective studies antiresorptive drugs, bisphosphonates, dental implants, implant failure, ONJ To assess the scientific literature relating to implant placement in users of antiresorptive agents and the risk related to implant failure and the development of ONJ. Antiresorptive therapy must be considered a risk factor until further prospective testing is carried out. Stavropoulos et al Clin Oral Implants Res. 2018 (1) 36 Case series, cohort studies, case–control studies, and controlled and/or randomized controlled clinical trials; retro‐ or prospective design; and ≥10 patients with systemic intake of ARDs Antiresorptive drugs, bisphosphonates, dental implants, hormone replacement therapy, medication‐related osteonecrosis of the jaw, systematic review To assess the possible side effects of taking antiresorptive drugs in relation to various aspects of implant therapy Taking low-dosage oral bisphosphonates for the treatment of osteoporosis, in general, does not compromise implant therapy. There is almost no information available about the possible effect on implant therapy of high dosages, or the success or safety of bone graft procedures. Table 3: Review articles on osteonecrosis and implants. e321 Med Oral Patol Oral Cir Bucal. 2021 May 1;26 (3):e314-26. Preventive protocol for MRONJ - Preventive protocols The different variables involved were grouped into two preventive protocols; one for patients who had not yet begun treatment with antiresorptive drugs and the other for those who were already being treated with said drugs. Each group comprised in turn two subgroups depending on whether they were patients treated for osteoporosis or for cancer. Protocols, for patients already treated or who wished to be treated with dental implants, are outlined below. PROTOCOL 1. BEFORE STARTING TREATMENT WITH ANTIRESORPTIVES (Fig. 2) A. PATIENTS WHO ARE GOING TO BE TREATED FOR OSTEOPOROSIS. B. PATIENTS WHO ARE GOING TO BE TREATED FOR CANCER. PROTOCOL 2. ONCE TREATMENT IS INITIATED WITH ANTIRESORPTIVES (Fig. 3) A. PATIENTS BEING TREATED FOR OSTEOPOROSIS B. PATIENTS BEING TREATED FOR CANCER Fig. 2: Protocols 1A and 1B. e322 Med Oral Patol Oral Cir Bucal. 2021 May 1;26 (3):e314-26. Preventive protocol for MRONJ Discussion Antiresorptive drugs have begun to cover an important therapeutic field in two broad groups of patients, those affected by osteoporosis from various sources and those who suffer from oncological osteolytic processes. These conditions have in common the loss of bone density and the possibility of pathological fractures emerging which considerably compromise quality of life and entail high morbidity and elevated therapeutic costs, amongst other problems. These drugs have demonstrated their capacity for reducing bone symptoms although in certain cases they can induce osteonecrotic lesions of the jaw as an undesired effect of their use, possibly leading to serious consequences for the patient (2). Even though the risk of suffering an ONJ in patients with osteoporosis is very low (between 0.1 and 0.21 according to different series), in recent years alerts have been raised about how misleading this data is, since the number of persons undergoing treatment for osteoporosis is very elevated, it is a chronic treatment, and the risk of ONJ increases over the time the drug is taken, these being reasons why some authors point to the frequency of ONJ in these patients being greater than initially suspected (33). Warnings have been issued about the fact that many patients treated with antiresorptives for osteoporosis, do not meet the criteria established for prescribing said medication, which is why the prevention of ONJ should start by unifying criteria across different medical professionals for proper prescription of the drugs which produce it and thus avoid cases of unnecessary treatment. Otherwise, the risk of ONJ in patients with certain cancers is much greater (0.7% - 7.7 % according to series) so although it is advisable to apply preventive measures in all cases, in these patients it is important to maximize them. Etiopathogenetic mechanisms are still controversial, different etiopathogenetic theories having been postulated to explain the emergence of ONJ (9,34). It is clear that dentoalveolar surgery involves an aggression to a bone depleted of its remodelling functions by the lack of osteoclasts, which would prevent it from coping with demands, which together with antiangiogenesis caused by drugs could justify osteonecrosis. However, data exist that contradict this theory such as the fact that the significant reduction in osteoclastic activity mediated by these drugs would induce a predominance of osteoblastic activity and therefore would lead more towards osteopetrosis than towards osteonecrosis. Likewise, in Fig. 3: Protocols 2A and 2B.