Cases Of Medication-related Osteonecrosis Of The Jaw Research Articles

Medication-Related Osteonecrosis of the Jaw: A Cross-Sectional Survey among Urologists in Switzerland, Germany, and Austria.

Medication-related osteonecrosis of the jaw (MRONJ) is a potentially preventable adverse side effect of mainly antiresorptive drugs. MRONJ is expected to become a growing clinical problem due to the aging population and the increasing number of patients requiring antiresorptive agents. Knowledge and awareness about MRONJ and elimination of the oral and dental risk factors before starting antiresorptive therapy (AR) are fundamental to reducing the incidence of MRONJ. In urology, ARs are used primarily in patients suffering from bone metastases due to prostate cancer and to prevent cancer-treatment-induced bone loss (CTIBL) in prostate cancer patients receiving endocrine therapy. This postal survey aimed to evaluate disease-related knowledge and awareness about implementing oral examinations for patients starting AR among Swiss, German, and Austrian urologists. A total of 176 urologists returned the completed questionnaire, yielding a response rate of 11.7%. Of the respondents, 44.9% (n = 79) and 24.4% (n = 43) stated that they give more than five first-time prescriptions of denosumab and of intravenous or oral bisphosphonates per year, respectively. Only 14.8% (n = 26) of the participating urologists had never encountered MRONJ cases related to BPs. Of the participants, 89.8% (n = 158) had implemented referrals to dentists for oral examination before initiating AR. The mean percentage of correct answers regarding the knowledge about MRONJ was 70.9% ± 11.2%. In contrast to previous surveys on MRONJ among physicians, this study showed that the participating urologists were sufficiently informed about MRONJ, as reflected by the high number of participants implementing preventive dental screenings.

MEDICATION-RELATED OSTEONECROSIS OF THE JAW ASSOCIATED WITH PAZOPANIB AND ORAL BISPHOSPHONATES

The drugs most commonly associated with medication-related osteonecrosis of the jaw (MRONJ) are bisphosphonates (BPs), denosumab, as well as bevacizumab and sunitinib, among others. MRONJ prevalence among oral BP (OBP) users varies from 0.004% to 0.1%, reaching 0.21% after 4 years of use. Pazopanib is a multi-tyrosine kinase inhibitor used for the treatment of renal cell carcinoma (RCC). To date, about 12 cases of MRONJ associated with pazopanib have been reported. A 64-year-old woman was referred presenting bone exposure in the mandible 60 days ago. There was no history of local surgery or trauma. Her medications included pazopanib for RCC treatment 7 months ago and OBPs for osteoporosis treatment 8 years ago. Clinical, radiographic, and histopathologic findings were consistent with MRONJ. The potential risk due to the simultaneous use of 2 drugs known to be associated with MRONJ should be better clarified with the report of further cases.

Medication-Related Osteonecrosis of the Jaw: 14 Years' Retrospective Study on Pathogenetic Trigger Events.

Although events such as tooth extraction and oral surgery were considered for a while the sole triggering factor for Medication-Related Osteonecrosis of the Jaw (MRONJ), it is still unclear if trigger events may be precipitating factors that accelerate the onset of the disease that would have possibly occurred anyway. Therefore, this research aimed to retrospectively analyze MRONJ cases diagnosed in our tertiary referral hospital during the last 14 years, focusing on the onset of the disease, potential trigger events, and countermeasures to update the knowledge on their pathogenesis. An audit of patients diagnosed with MRONJ attending our department from 2008 to 2021was performed. χ2 test and Fisher exact test were employed to assess the relationship between the medications used and trigger events; χ2 test was also used to assess any relationship between MRONJ localization and drug, drug class, trigger, or trigger type. Seventy-six patients' records were identified. Fifty-two records were selected for analysis. Trigger events for the onset of the disease were found in 35 cases (67.3%). χ2 test showed a correlation between the drug used and trigger event occurrence (P=0.045) confirmed by Fisher exact test (P=0.34). Visual histogram analysis showed positive correlation when Alendronate (12 cases, 85.7%), Zoledronate (12 cases, 75%), and Risedronate (2 cases, 100%) were administered. Subgroup analysis per underlying disease, showed a significant correlation between the drug used and trigger event occurrence in the osteoporosis group (χ2 test, P=0.021; Fisher exact test, P=0.009).

A 5-year retrospective cohort study of denosumab induced medication related osteonecrosis of the jaw in osteoporosis patients

Denosumab has been suggested as a first-line therapy for osteoporotic patients. However, a standardized protocol for the prevention of denosumab induced medication-related osteonecrosis of the jaw (MRONJ) has not yet been established. The purpose of this study was to report denosumab induced MRONJ cases, and investigate the factors affecting the occurrence of MRONJ in patients who underwent denosumab and invasive dental treatment (especially tooth extraction) between October 2016 and March 2020. Four of the 98 patients developed MRONJ before and after tooth extraction. The participants were divided into two groups: receiving only denosumab (n = 51) and receiving bisphosphonate as first treatment and denosumab as second treatment (n = 47). There was no significant difference between groups in the occurrence of MRONJ and factors affecting MRONJ. Two out of 4 patients developed MRONJ regardless of invasive treatment after denosumab administration and proceeded with extraction; one patient developed MRONJ after denosumab administration and extraction. The other patient underwent a tooth extraction without osteoporosis treatment, and non-identified MRONJ developed after denosumab administration. MRONJ cases reported in this study show that MRONJ can develop as chronic inflammation without invasive dental treatment; therefore, implementing preventive dental treatment before initiating denosumab treatment is necessary to reduce the occurrence of MRONJ.

Novel Cell Therapy Using Mesenchymal Stromal Cell Sheets for Medication-Related Osteonecrosis of the Jaw.

Despite medication-related osteonecrosis of the jaw (MRONJ) being first reported in 2003, the optimal treatment and prevention modalities for MRONJ are not clear. As a result, dentistry, oral surgery, and departments involved in the treatment of cancer and bone diseases are struggling with the management of MRONJ. Several cases of MRONJ cannot be managed by conventional treatment strategies recommended in various position papers. Therefore, studies have been conducted to investigate the efficacy of novel therapies for MRONJ. However, the optimal treatment is unknown. Several cell therapies including autologous cell transplantation have been reported for MRONJ. Although the efficacy of cell therapy for MRONJ has been demonstrated, large, statistically accurate clinical trials are lacking. We have been investigating the efficacy of MRONJ treatment using mesenchymal stromal cell (MSC) sheets since 2013 and confirmed its efficacy through various experiments, wherein MSC sheets were transplanted in model rats and beagle dogs with MRONJ-like lesions. Based on these results, we are planning to conduct a clinical trial of MRONJ therapy using periodontal ligament-derived MSC sheets.

Antimicrobial photodynamic and photobiomodulation adjuvant therapies for medication-related osteonecrosis of the jaw – Report of two cases with long-term follow-up

Medication-related osteonecrosis of the jaw (MRONJ) is a relatively rare condition with high morbidity. In this study, we report the management of two recalcitrant cases of MRONJ in the mandibles of two older women who received treatment with alendronate for osteoporosis. Sequestrectomies, combined with antimicrobial photodynamic therapy (aPDT) and photobiomodulation (PBMT), were performed in both patients. During perioperative and weekly postoperative aPDT sessions, a diode laser treated three anatomical points by emitting a continuous gallium-aluminum-arsenide wave at 660 nm (red laser), 0.028 cm2, 0.1 W, 3.57 W/cm2 for 90 s per point, 9 J per point, 321 J/cm2, and a total energy of 27 J. PBMT was applied weekly after surgery at 808 nm wavelength (other parameters being equal) for wound healing and pain relief. Both patients were followed-up for two years without any report of recurrence. Thus, aPDT and PBMT can be considered non-invasive adjuvant therapies for MRONJ without any adverse effects.

Does Drug Holiday Affect Jaw Trabeculation in Medication Related Osteonecrosis of the Jaw? - A Pilot Study.

BackgroundThe role of drug holiday in long term antiresorptive drug users to prevent MRONJ is debated for quite some time. We aimed to compare jawbone trabeculation between patients on drug holiday with those not on drug holiday among Medication Related Osteonecrosis of the Jaw (MRONJ) cases using fractal analysis and to estimate the frequency of MRONJ despite being on drug holiday. Material and MethodsThe sample of 18 MRONJ cases were divided into drug holiday, and non-drug holiday groups. Non-drug holiday group was further divided into pre- and post- drug holiday groups. Jawbone trabeculation was assessed utilizing fractal analysis method (ImageJ software) by two observers. ANOVA was used to compare the fractal dimension (FD) values between the groups. A ‘p’ value of less than 0.05 was considered significant. Results8 patients developed MRONJ despite being on drug holiday (44.44%). There was no significant difference in the FD values between drug holiday and pre-drug holiday groups. When pre- and post-drug holiday FD values were compared, the difference was significant only on the right maxilla with observer 2. Also, no significant difference was noted between the two observers. ConclusionsBone trabeculation remained unaltered following drug holiday from anti-resorptive drugs. This study serves as a preliminary proof for the argument against drug holiday which portrays the necessity for a detailed prospective study in this arena. Key words:Osteonecrosis, bisphosphonates, Bisphosphonate-Associated Osteonecrosis of the Jaw, anti-resorptive drugs, osteoporosis, jaw.

Preclinical models of medication-related osteonecrosis of the jaw (MRONJ).

Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse event affecting patients with cancer and patients with osteoporosis who have been treated with powerful antiresorptives (pARs) or angiogenesis inhibitors (AgIs). pARs, including nitrogen-containing bisphosphonates (N-BPs; e.g., zoledronic acid, alendronate) and anti-RANKL antibodies (e.g., denosumab), are used to manage bone metastases in patients with cancer or to prevent fragility fractures in patients with osteoporosis. Though significant advances have been made in understanding MRONJ, its pathophysiology is still not fully elucidated. Multiple species have been used in preclinical MRONJ research, including the rat, mouse, rice rat, rabbit, dog, sheep, and pig. Animal research has contributed immensely to advancing the MRONJ field, particularly, but not limited to, in developing models and investigating risk factors that were first observed in humans. MRONJ models have been developed using clinically relevant doses of systemic risk factors, like N-BPs, anti-RANKL antibodies, or AgIs. Specific local oral risk factors first noted in humans, including tooth extraction and inflammatory dental disease (e.g., periodontitis, periapical infection, etc.), were then added. Research in rodents, particularly the rat, and, to some extent, the mouse, across multiple laboratories, has contributed to establishing multiple relevant and complementary preclinical models. Models in larger species produced accurate clinical and histopathologic outcomes suggesting a potential role for confirming specific crucial findings from rodent research. We view the current state of animal models for MRONJ as good. The rodent models are now reliable enough to produce large numbers of MRONJ cases that could be applied in experiments testing treatment modalities. The course of MRONJ, including stage 0 MRONJ, is characterized well enough that basic studies of the molecular or enzyme-level findings in different MRONJ stages are possible. This review provides a current overview of the existing models of MRONJ, their more significant features and findings, and important instances of their application in preclinical research.

Vitamin D Deficiency Investigation in Oncologic Patient Undergoing Surgical Management of Medication Related Osteonecrosis of the Jaw: A Clinical Prospective Study

Medication-related osteonecrosis of the jaw (MRONJ) is defined as an area of exposed bone, or bone that can be probed through an intraoral or extraoral fistula persisted for greater than 8 weeks in patient with current or previous treatment with bisphosphonates, denosumab, or antiangiogenic therapy without history of radiation therapy to the jaw or obvious metastatic disease of the jaw. The physiopathology remains a controversial subject including the possible involvement of vitamin D deficiency. Purpose: discuss the involvement of vitamin D deficiency in MRONJ development. This through a series of five clinical cases and a review of the literature. Observations: A series of 5 clinical cases of MRONJ associated with vitamin D deficiency whose management was medico-surgical were included. The series included 2 women and 3 men of average age 54,8 years who were treated for malignant diseases and whose average serum vitamin D level was 10 ng / ml. Remission was complete in 4 cases and partial in 1 case. Discussion: Several epidemiological studies have shown a high prevalence of hypovitaminosis D in different apparently healthy populations. Moreover, Vitamin D deficiency has recently been incriminated as an added risk factor for MRONJ. It has been postulated through experimental and control case studies that systemic conditions associated with cancer patients with a vitamin D deficiency combined with tooth extraction may increase the risk of MRONJ. Conclusion: MRONJ is a known complication of Bisphosphonate. Additional processes would be involved in the genesis of MRONJ including the possible role of a vitamin D deficiency but the scientific evidence of their involvement is not yet fully characterized.

Genome-wide Association Study Identified Chromosome 8 Locus Associated with Medication-Related Osteonecrosis of the Jaw.

Medication‐related osteonecrosis of the jaw (MRONJ) is a rare but serious drug‐related adverse event. To identify pharmacogenomic markers of MRONJ associated with bisphosphonate therapy, we conducted a genomewide association study (GWAS) meta‐analysis followed by functional analysis of 5,008 individuals of European ancestry treated with bisphosphonates, which includes the largest number of MRONJ cases to date (444 cases and 4,564 controls). Discovery GWAS was performed in randomly selected 70% of the patients with cancer and replication GWAS was performed in the remaining 30% of the patients with cancer treated with intravenous bisphosphonates followed by meta‐analysis of all 3,639 patients with cancer. GWAS was also performed in 1,369 patients with osteoporosis treated with oral bisphosphonates. The lead single‐nucleotide polymorphism (SNP), rs2736308 on chromosome 8, was associated with an increased risk of MRONJ with an odds ratio (OR) of 2.71 and 95% confidence interval (CI) of 1.90–3.86 (P = 3.57*10−8) in the meta‐analysis of patients with cancer. This SNP was validated in the MRONJ GWAS in patients with osteoporosis (OR: 2.82, 95% CI: 1.55–4.09, P = 6.84*10−4). The meta‐analysis combining patients with cancer and patients with osteoporosis yielded the same lead SNP rs2736308 on chromosome 8 as the top SNP (OR: 2.74, 95% CI: 2.09–3.39, P = 9.65*10−11). This locus is associated with regulation of the BLK, CTSB, and FDFT1 genes, which had been associated with bone mineral density. FDFT1 encodes a membrane‐associated enzyme, which is implicated in the bisphosphonate pathway. This study provides insights into the potential mechanism of MRONJ.

What is the Risk of Developing Medication-Related Osteonecrosis in Patients With Extraction Sockets Left to Heal by Secondary Intention? A Retrospective Case Series Study

Tooth and root extractions represent trigger factors for medication-related osteonecrosis of the jaw (MRONJ). The best healing modality for postextraction sockets is still debated. The aim of the study was to estimate the incidence of MRONJ after extractions whose sockets were left to heal by secondary intention. A retrospective case series study was performed at the Department of Odontostomatological and Maxillofacial Sciences, Sapienza University of Rome. Only patients who underwent nonsurgical extractions, healed by secondary intention, were included in the study. The following parameters were considered: age, sex, pathologies for which bisphosphonates or other drugs related to MRONJ were prescribed, any local or systemic risk factors, type of drug used, route of administration, number of extractions performed, and number of sessions required to complete the extraction program. The main outcome variable was the occurrence of MRONJ. Statistical analysis was performed with SPSS statistical software. Two hundred twenty-one patients were treated from 2007 to 2020 with 639 tooth/root extractions. All patients were treated under antibiotic prophylaxis and with anesthesia without vasoconstrictors. No cases of MRONJ occurred. The mean age of patients was 68.02 ± 11.17. Most of the study sample was represented by women (201=90.95%) undergoing treatment for osteometabolic pathologies, most frequently postmenopausal osteoporosis. Alendronate was the most frequently prescribed drug, taken mainly orally. Most patients had local and/or systemic risk factors. Each patient had from 1 to 17 tooth/root extractions (mean=2.87 ± 2.59) during 1 to 4 sessions (mean=1.41 ± 0.64). Extractions mainly involved single-rooted teeth/roots, equally distributed between the maxilla and mandible. Secondary intention healing after nonsurgical tooth extraction does not seem to predispose to MRONJ. It can be advisable to perform extractions under antibiotic prophylaxis using anesthetics without vasoconstrictors and chlorhexidine mouth rinses in the 7 following days.

Impaired Callus Formation in Pathological Mandibular Fractures in Medication-Related Osteonecrosis of the Jaw and Osteoradionecrosis

Nonsurgical treatment of mandibular fractures secondary to medication-related osteonecrosis of the jaw (MRONJ) or osteoradionecrosis (ORN) mostly results in nonunion, whereas nonsurgical fracture treatment of atrophic fractures can achieve favorable results in selected cases. The aim of this study was to compare callus formation in pathological mandibular fractures due to MRONJ, ORN, or extreme mandibular atrophy. A retrospective cohort study reviewing the medical records of all MRONJ-, ORN-, or atrophy-related fractures treated at the departments of maxillofacial surgery in the Leuven or Lille university hospitals between 2010 and 2019 was undertaken. The primary predictor variable in this study was disease state (MRONJ, ORN, or extreme mandibular atrophy). The primary outcome variable was callus formation after 1 month of follow-up (present, absent). Additional study variables measured included patient age and gender. T-tests, Fisher exact tests, and multiple logistic regression were used for statistical analysis. The significance level was set at P < .05. Seventy patients were analyzed (12 MRONJ cases, 54 ORN fractures, 4 atrophic fractures). The callus formation prevalence in nonsurgically approached fractures secondary to ORN and MRONJ after 1 month of follow-up was 3.03% (2/66 cases). In contrast, callus was detected in all patients in the mandibular atrophy-related fracture group. Osteonecrosis was statistically correlated with impaired callus formation (P=.0121). Whereas one would expect indirect fracture healing and thus callus formation to occur in all non-surgically treated fractures, our data demonstrate its absence in the majority of MRONJ- and ORN-related fractures. Multiple plausible explanations for this phenomenon were identified: periosteal damage with loss of callus-forming cells, compromised vasculature, and bacterial colonization.

Cell therapy for medication-related osteonecrosis of the jaw: update on treatment strategies.

Bioactive glasses (BAG) are used as bone-graft substitutes in orthopaedic surgery. A specific BAG scaffold was developed by sintering BAG-S53P4 granules. It is hypothesised that this scaffold can be used as a bone substitute to fill bone defects and induce a bioactive membrane (IM) around the defect site. Beyond providing the scaffold increased mechanical strength, that the initial inflammatory reaction and subsequent IM formation can be enhanced by coating the scaffolds with poly(DL-lactide-co-glycolide) (PLGA) is also hypothesised. To study the immunomodulatory effects, BAG-S53P4 (± PLGA) scaffolds were placed on monolayers of primary human macrophage cultures and the production of various pro- and anti-inflammatory cytokines was assessed using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and ELISA. To study the osteogenic effects, BAG-S53P4 (± PLGA) scaffolds were cultured with rabbit mesenchymal stem cells and osteogenic differentiation was evaluated by RT-qPCR and matrix mineralisation assays. The scaffold ion release was quantified and the BAG surface reactivity visualised. Furthermore, the pH of culture media was measured. BAG-S53P4 scaffolds had both anti-inflammatory and osteogenic properties that were likely attributable to alkalinisation of the media and ion release from the scaffold. pH change, ion release, and immunomodulatory properties of the scaffold could be modulated by the PLGA coating. Contrary to the hypothesis, the coating functioned by attenuating the BAG surface reactions and subsequent anti-inflammatory properties, rather than inducing an elevated inflammatory response compared to BAG-S53P4 alone. These results further validated the use of BAG-S53P4 (± PLGA) scaffolds as bone substitutes and indicate that scaffold properties can be tailored to a specific clinical need.

Jaw osteonecrosis in patients treated with denosumab 120 mg with regular dental monitoring: 4-year retrospective study

Background: Medication-related osteonecrosis of the jaw (MRONJ) is an expected, but rare adverse effect of denosumab. There are few data denosumab 120 mg related MRONJ occurrence when regular dental monitoring is planned. International and French recommendations do not detail the schedule of the follow-up visits, allowing local interpretations. Methods: The aim of this retrospective study was to describe our local experience of regular dental monitoring in patients receiving denosumab 120 mg. We included all ≥18-year-old patients exposed to denosumab 120 mg, bisphosphonate- and denosumab-naive, and with regular dental monitoring (pre-treatment and every 4 months after denosumab initiation) at the University Hospital Center, France, from 2015 to 2019. The crude incidence of denosumab-related osteonecrosis of the jaw was estimated per 100 person-years (95% confidence interval). Results: During the study period, 251 patients were included, of whom 77 did not attend the 1st follow-up visit at 4 months. Almost all patients had osteonecrosis of the jaw risk factors. Ten MRONJ cases were reported (four stage 0 and six stage 1). The crude incidence rate was 5.1 per 100 person-years (95% CI: 1.9–8.2). Denosumab was stopped in all patients who developed MRONJ, with favorable outcome for 3 cases and stabilization in 4 cases after osteonecrosis of the jaw management. Conclusion: This study suggested that a regular dental follow-up every 4 months may be a suitable option for prevention and early detection/treatment of MRONJ. A randomized study should be performed to determine the best dental monitoring schedule.

A multicenter observational study on Medication-Related Osteonecrosis of the Jaw (MRONJ) in advanced cancer and myeloma patients of a cancer network in North-Western Italy.

Background Incidence of Medication-Related Osteonecrosis of the Jaw (MRONJ) related to cancer and myeloma treatments is undetermined, with scarce data varying from 2 to 7.8/million/year in limited investigated populations. A 9-years [2009-2018] regional-wide survey was conducted, deploying the North-Western Italy Cancer Network (“Rete Oncologica Piemonte e Valle d’Aosta”), to assess number and main characteristics of MRONJ cases among myeloma/cancer patients, within a population of 4.5 million inhabitants. Material and Methods MRONJ cases were collected retrospectively from January 2009 to June 2015; from July 2015 to December 2018, data were collected prospectively. Number of new MRONJ cases per year, underlying disorder, drug(s) administered, treatment duration, site and onset timing of MRONJ were detailed. Results 459 MRONJ cases were identified. Primary diseases were breast cancer (46%), prostate cancer (21%), myeloma (19%), and other types of carcinoma (14%). Patients received antiresorptive treatment either alone (399; 88.47%) or in combination with biological agents (52; 11.53%); 8 patients (1.7%) received only antiangiogenic drugs. Zoledronic acid [388] and denosumab [59] were the most frequently administered drugs. Mandible was involved in 296 (64,5%) cases. Number of new MRONJ cases was stable from 2009 to 2015, with a mean of 51.3 cases per year (raw incidence: 11.6/million/year), declining in the 2016-2018 years to 33.3 cases per year (raw incidence: 7.5/million/year). Conclusions With such discrepancy of cases overtime being partially explicable, number of new MRONJ cases per year are consistent with those observed in a previous study [2003-2008] in the same region, being instead higher than those reported in other populations. Key words:Osteonecrosis of the jaw, bisphosphonates, zoledronic acid, denosumab, antiangiogenic drug, incidence.

Medication-Related Osteonecrosis of the Jaws and CDK4/6 Inhibitors: A Recent Association.

The purpose of the present study was to estimate the prevalence of cyclin-dependent kinase (CDK) 4/6 inhibitors use among cancer patients from the medication-related osteonecrosis of the jaw (MRONJ) cohort of the University of Messina. We retrospectively reviewed the records of all patients with either intravenous bisphosphonates or denosumab-related MRONJ reported in the electronic health records of the Unit of Oral Surgery, School of Dentistry, University of Messina between the first quarter of 2018 and the first quarter 2020 to identify eligible patients. We observed six cases of MRONJ associated with CDK4/6 inhibitors concomitantly with intravenous bisphosphonates and/or denosumab in breast cancer patients. The CDK4/6 inhibitors registered were palbociclib (n = 5) and abemaciclib (n = 1). Data of cancer patients diagnosed with MRONJ in the same period (n = 10) were extracted for comparison. The comparative assessment with this group of patients showed a similar distribution of MRONJ stage ranged and clinical course after treatment. The degree of risk for osteonecrosis in patients taking these new classes of drugs is uncertain but warrants awareness and close monitoring. The role of premedication dental evaluation as a prevention strategy has been acknowledged for cancer patients about to initiate intravenous bisphosphonates and/or denosumab for treatment of bone metastasis, but additional attention should be paid to whom are assuming CDK4/6 inhibitors because of their oral adverse events.

Shotgun metagenome sequencing identification of a set of genes encoded by Actinomyces associated with medication-related osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is intractable and severely affects a patient's quality of life. Although many cases of MRONJ have been reported in the past decade, the disease pathophysiology is unclear and there are no evidence-based therapeutic strategies. MRONJ usually features bone inflammation and infection. Prior studies that explored the association between MRONJ and microbial infection used the culture-based approach, which is not applicable to hundreds of unculturable taxa in the human oral microbiome, or 16S ribosomal RNA gene sequencing, which does not provide quantitative information of the abundance of specific taxa, and information of the presence, abundance, and function of specific genes in the microbiome. Here, deep shotgun metagenome sequencing (>10 Gb per sample) of bulk DNA extracted from saliva of MRONJ patients and healthy controls was performed to overcome these limitations. Comparative quantitative analyses of taxonomic and functional composition of these deep metagenomes (initially of 5 patients and 5 healthy controls) revealed an average 10.1% increase of genus Actinomyces and a 33.2% decrease in genus Streptococcus normally predominant in the human oral microbiota. Pan-genome analysis identified genes present exclusively in the MRONJ samples. Further analysis of the reads mapping to the genes in the extended dataset comprising five additional MRONJ samples and publicly available dataset of nine healthy controls resulted in the identification of 31 genes significantly associated with MRONJ. All these genes were encoded by Actinomyces genomic regions. Of these, the top two abundant genes were almost exclusively encoded by Actinomyces among usual taxa in the human oral microbiota. The potential relationships of these key genes with the disease are discussed at molecular level based on the literature. Although the sample size was small, this study will aid future studies to verify the data and characterize these genes in vitro and in vivo to understand the disease mechanisms, develop molecular targeted drugs, and for early stage screening and prognosis prediction.

A Survey of Medication-Related Osteonecrosis of the Jaw Reporting and Risk Assessment by Oral and Maxillofacial Surgeons

Medication-related osteonecrosis of the jaw (MRONJ) is a well-known pathologic entity in the field of oral and maxillofacial surgery. Whether evaluating patients initiating bisphosphonate therapy, diagnosing patients with osteonecrosis, or surgically managing long-term sequelae, oral and maxillofacial surgeons (OMSs) will invariably encounter this disease. There are few studies investigating the incidence of MRONJ, and many of these studies were found to have limitations that may lead to underestimation of MRONJ prevalence. The purpose of this survey was to determine if MRONJ is being reported to any central agency by practicing OMSs, and if OMSs are reporting cases to physicians prescribing antiresorptive medications. Furthermore, the authors seek to determine if the risk of MRONJ quoted to patients is similar to the incidence reported in the literature. Using SurveyMonkey, a 26-part questionnaire (Figure 1) designed to help gain information about MRONJ and how it is approached and reported was sent via email to 6409 OMSs listed in the 2015 AAOMS directory using an automated collection system. The questions addressed practice demographics, risk stratification, number of MRONJ cases experienced, if/where OMSs reported these incidents, and how OMSs learned about reporting cases. In total, 3,172 OMSs opened the email, 879 opened the questionnaire, 170 completed part of the survey, and 602 completed the entire survey. Of the 602, only 2% have never diagnosed a patient with MRONJ. For patients undergoing a dental extraction while taking alendronate for more than 4 years to treat osteoporosis, 53.63% of OMSs quote them a risk > 1% even after a recommended 2-month drug holiday (Damm 2013). This is a complete disparity from the values quoted by studies in the AAOMS position paper that cite a disease incidence of 0.004% and prevalence of 0.1%. Using weighted averages from literature in the position paper, estimated incidence of disease with zoledronate and denosumab are 0.87% and 0.93%, respectively (Ruggiero 2014). In this survey, OMSs quoted higher levels of risk with extractions than expected when compared to the literature, including 63% quoting a risk > 1% when taking zoledronate yearly for osteoporosis when the last dose was given more than 1 year ago, 95% quoting a risk > 1% for zoledronate when used as a chemotherapeutic adjuvant, 57% quoting a risk > 1% when taking denosumab for osteoporosis when the last dose was given over 6 months ago, and 94% quoting a risk > 1% when denosumab is used as a chemotherapeutic adjuvant. Of OMSs who have either diagnosed or treated a patient with MRONJ, 85% reported the case to the prescribing physician. However, 95.2% of OMSs have never reported a case to a drug manufacturer, and 97.6% have never reported a case to the FDA. The results of this questionnaire demonstrate that OMSs are quoting a risk of MRONJ to this patient population that is at least 10-fold higher than the values reported by the current literature. These findings suggest that most OMSs believe MRONJ is a larger risk to patients taking specific medications than is demonstrated by the current literature. Furthermore, approximately 96% of OMSs are not reporting cases of MRONJ to the FDA or drug manufacturers. This lack of reporting may contribute to the gross underestimation the authors of this survey have observed in clinical practice. A retrospective cohort study could be a valuable next step in determining the risks of invasive dental surgery to this patient population.

Actinomyces and MRONJ: A retrospective study and a literature review

The AAOMS in 2014 changed from BRONJ to the term Medication-Related Osteonecrosis of the Jaw (MRONJ), because of the growing number of osteonecrosis cases associated with other antiresorptive and antiangiogenic therapies. Even if the drugs involved are different, the histopathological findings are the same. Colonies of Actinomyces are encountered in most cases. The aim of the present study is to report on Actinomyces prevalence among the cases of MRONJ, taking into consideration also antiresorptive and antiangiogenic therapies in the literature and in our sample between 2005 and 2020.The review was performed using the database Medline the linkage between Actinomyces infection and MRONJ. The retrospective study was conducted on patients between with clinical and radiological manifestations of MRONJ May 2005 and February 2020.A total of 42 articles were found, 30 publications have been taken into consideration for the review. A total of 114 patients have been examined at the Padua Hospital. A total of 101 oncological patients presented the histological confirmation of MRONJ. 83 specimens revealed the presence of Actinomyces infection (82.18%).Actinomyces-associated lesions are frequent and present a wide spectrum of clinical manifestation.

Medication-Related Osteonecrosis of The Jaw treatment Modalities, A review Article

Introduction: Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction of antiresorptive and antiangiogenic agents. Management of MRONJ has remained a controversial topic within the oral and maxillofacial surgery community. Methods: Articles from 2010 to 2020 were selected. We determined that all review studies evaluated the effectiveness of various MRONJ therapies to resolve the condition were eligible for this study. We determined that all review studies evaluated the effectiveness of various MRONJ therapies to resolve the condition were eligible for this study. Results: Antibiotic therapy such as penicillin-based antibiotics plus β-lactamase inhibitor or metronidazole could decrease disease progression and may prevent super infection of the bone. Surgery should be considered in all stages of MRONJ as it confirms the histology. fluorescence-guided surgery is helpful for MRONJ cases under Denosumab and it is recommended to use Low Level Laser and PDT as adjuvant treatment of MRONJ. Conclusion: It seems that conservative treatment, minimally traumatic extraction technique, removal of bone edges and mucosal wound closure may prevent the occurrence of MRONJ