Search

Denosumab has been considered a treatment option for Central Giant Cell Granuloma (CGCG) a benign locally aggressive osteolytic lesion of the jaws. This study aimed to perform a scoping review of CGCG treated with Denosumab. The research question was: What is Denosumab's effectiveness in treating CGCG of the jaws? Studies that used Denosumab as a treatment for CGCGs in the jaws were selected following PRISMA-ScR guidelines, using Pubmed/Medline, Scopus, and Springer Link databases, among others. Demographics, clinical information, dosing, efficacy, adverse drug reactions (ADRs), and imaging tests used to assess the evolution of the lesions were extracted. Twenty-one studies were selected. Sixty patients with a mean age of 23.2 years were treated with Denosumab, 42% with 120 mg subcutaneously monthly, additional doses on days 1, 8, and 15 for month 1 in adults. In children, dosing was adjusted by weight to 60 or 70 mg. To avoid ADRs 500 mg of calcium and 400 IU of vitamin D orally were used. Initial effective response was reported after 1-3 months, with recurrence of 19.6% and ADRs in 74% of cases. Denosumab is effective for CGCG with monthly subcutaneous doses of 120 mg, 60 or 70 mg in patients < 45 or 50 kg for ≥ 12 months with calcium and vitamin D supplementation until remission changes are observed. Extensive or refractory lesions were the main indications. Common ADRs were hypo and hypercalcemia. Further studies are needed to define dose and supplementation protocols to avoid ADRs during and after therapy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The aim of the present study was to determine the methodological quality of systematic reviews that evaluated the effectiveness of pentoxifylline and tocopherol (PENTO) in the treatment of osteoradionecrosis of the jaw (ORNJ) and medication-related osteonecrosis of the jaw (MRONJ)., Methods: Searches were performed in Databases including PubMed, Scopus, LILACS, DARE, Cochrane Library, and SIGLE through OpenGrey until March 2024, were evaluated by two independent reviewers to answer the following question: Is the use of PENTO protocol effective in the treatment of ORNJ or for the treatment of MRONJ?, Results: A total of 256 articles were initially identified; however, following the use of appropriate inclusion and exclusion criteria, five systematic reviews were identified for detailed analysis. The final study sample comprised 588 patients: 397 patients with ORN and 197 patients with MRONJ who were treated with PENTO. The total recovery of individuals who used the PENTO protocol was 62,2 % for ORN and 100 % for MRONJ, with a follow-up period of 1 month to 10 years. The methodological quality of the studies was assessed using the AMSTAR 2 tool, in which four were of low quality and 1 moderate quality., Conclusion: The treatment of ORN and MRONJ with pentoxifylline and tocopherol has shown good results in the studies presented, with a partial or total reduction in bone exposure. However, the low quality of the relevant reports highlights the need for primary and secondary studies with better methodological rigor to reduce bias and provide reassurance for this treatment option., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The most common toxicities associated with cyclin-dependent kinase (CDK) 4/6 inhibitor therapy include decreased leukopenia and neutropenia due to the inhibition of CDK6 of leukocyte and neutrophil precursors in bone marrow. These hematological toxicities are more commonly observed with palbociclib administration than with abemaciclib administration, which is approximately 13 times more selective against CDK4 than CDK6. Thus, even though both successfully inhibit CDK4/6, the side effects of palbociclib and abemaciclib differ due to differences in selectivity. Recent reports have suggested an association between palbociclib and medication-related osteonecrosis of the jaw; however, reports on this association are inconsistent. This study investigated the potential association of palbociclib and abemaciclib with MRONJ using the FAERS. Signals of "Osteonecrosis of jaw" were detected only in females using palbociclib (cROR 025 : 2.08). Other signals detected included stomatitis-related adverse events with abemaciclib and intraoral soft tissue damage and infection with palbociclib. As previous exploratory studies have reported MRONJ signals for bisphosphonates and denosumab, we calculated the aROR for palbociclib-induced osteonecrosis of the jaw using concomitant bisphosphonates and denosumab as covariates. A signal was detected even after adjusting for sex, age, and concomitant medications as covariates (aROR0 025 : 5.74). A proper understanding of the differences in CDK selectivity is necessary for the appropriate use of CDK4/6 inhibitors. To the best of our knowledge, this is the first report on CDK4/6 inhibitors and drug-related osteonecrosis of the jaw. We believe that these results will offer new insights into adverse events related to the use of CDK4/6 inhibitors, and may aid in the proper use of CDK4/6 inhibitors., (© 2024 UICC.)

Bone-modifying agents (BMAs) are integral to managing patients with advanced cancer. They improve quality of survival by reducing skeletal-related events, treating hypercalcaemia and chemotherapy-induced bone loss (Coleman in Clin Cancer Res 12: 6243s-6249s, 2006), (Coleman in Ann Oncol 31: 1650-1663, 2020). Two decades ago, medication-related osteonecrosis of the jaw (MRONJ) was first reported following BMA therapy (Marx in J Oral Maxillofac Surg 61: 1115-1117, 2003). The risk of MRONJ extends over a decade following BMA treatment with bisphosphonates, complicating dental care such as extractions. In addition, MRONJ has been reported following additional therapies such as antiangiogenic agents, cytotoxic agents, immunotherapy, and targeted agents. The use of BMAs in the curative and adjuvant cancer setting is increasing, consequently the implication of MRONJ is growing. Over the past 20 years, the literature has consolidated major risk factors for MRONJ, the pathophysiology and management strategies for MRONJ. Our review aims to document the development of MRONJ preventative and management strategies in cancer patients receiving a BMA. The authors advocate the incorporation of dental oncology strategies into contemporary cancer care, to optimise long-term quality of survival after cancer treatment., (© 2024. The Author(s).)

The objective of this study was to identify the prevalence of osteonecrosis of the jaw in a pediatric population with systemic therapeutic exposure to an antiresorptive, anti-angiogenic, and/or immunomodulating drug (ARAID), and in particular in the subgroup of patients who had undergone invasive dental treatment. This was a retrospective cohort study performed at a single center. The investigation included pediatric patients who had undergone systemic therapy with ARAIDs and who began receiving ARAID therapy at ≤16 years of age. The study included 482 patients who received ARAIDs between January 2011 and January 2021. The most common medication class was bisphosphonates (45.0%), followed by mTOR inhibitors (30.1%) and anti-angiogenics (17.8%). No diagnosis of osteonecrosis of the jaw was observed. From this population, 26 patients were noted to have undergone invasive dental treatment. The duration from treatment to the invasive procedure ranged from 0 to 5.9 years. Medication-related osteonecrosis of the jaw is extremely rare among the pediatric population - much less common when compared to the adult population. Prospective cohort studies and continued evaluation will help determine the incidence and prevalence of medication-related osteonecrosis of the jaw in pediatric patients., (Copyright © 2023 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Osteonecrosis of the jaw is a recognized complication associated with bevacizumab. Here, we present a patient with squamous cell carcinoma of the tonsil who experienced minimal skin fibrosis following intensity-modulated radiation therapy. Subsequently, the patient developed rectal adenocarcinoma and encountered osteonecrosis of the jaw after receiving two cycles of bevacizumab. Close monitoring, accompanied by thorough examination to detect early signs of osteonecrosis of the jaw, should be considered for patients who have undergone radiation therapy in the head and neck region and are receiving bevacizumab or other medications known to be associated with osteonecrosis of the jaw.

The relevance of the study is associated with the widespread use of osteomodifying agents in patients with bone metastases and osteoporosis. Bisphosphonates and other osteo-modifying agents are widely used in oncology and prevention of age-related changes in the human bone system. The use, therapeutic effects and complications of therapy with osteo modifying agents are being investigated all over the world. However, the etiology and pathogenesis of drug-induced osteonecrosis of the jaws (MONCH) have not been fully studied, in this regard, the study of risk factors and mechanisms of its development remains relevant. New data on the etiology and pathogenesis of drug-induced osteonecrosis are presented. The literature review is carried out on the electronic resource PubMed.

The aim of this article is to stimulate interest and discussion on the pathogenesis of 'phossy jaw'. Historical evidence from newspapers and articles of the time is presented, as other scientific evidence is largely absent. It has stimulated considerable interest in present-day media due to the struggles of nineteenth century reformers to improve working conditions against an apathetic government and weak enforcement of regulation. Those afflicted were often young women who suffered severe pain, loss of segments of jaw, and disfigurement., (© 2023. The Author(s).)

Objectives: The study investigated the effect of soft tissue closure after tooth extraction on the prevention of medication-related osteonecrosis of the jaw in a rabbit model., Materials and Methods: Twenty female New Zealand white rabbits were randomly assigned into the experimental group administrated with zoledronic acid (ZA) and control groups treated with saline. Bilateral lower premolar extraction was performed 4 weeks after ZA/saline administration. Immediately after extraction, the wound on the right mandible was closed by suture while the other side was left open. Animals were sacrificed 4 weeks and 8 weeks after tooth extraction. Fluorochrome labeling solutions were injected subcutaneously to evaluate the bone growth rates. The mandibles were harvested and subjected for microcomputed tomography, confocal microscope, and histomorphological examinations., Results: All extraction sites healed well without any signs of infection. Trabecular thickness (Tb.Th) was significantly higher in the ZA-treated group than in the control group at both week 4 and week 8, while no significant difference was detected in the rest of the assessed parameters. The bone growth rate in mandibles showed gradual reduction in the ZA-treated group. Histological analysis showed that at week 8, the animals in the ZA-treated group had significantly higher incidence of osteonecrosis than that in the control group, while no significance was revealed between the sutured and nonsutured side., Conclusions: ZA treatment significantly reduces bone growth rates but does not reveal a significant effect on bone mineral density and bone microarchitecture. Soft tissue closure of the extraction socket does not reduce the incidence of ONJ in the ZA-treated rabbit model., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Ru Qing Yu et al.)

Osteonecrosis of the jaw (ONJ) is a rare but very serious disease that can affect both jaws. It is defined as exposed bone in the maxillofacial region that does not heal within 8 weeks after a health care provider identification. ONJ can occur spontaneously or can be due to drugs like bisphosphonates (BPS) and anti-RANK agents, in patients with no history of external radiation therapy in the craniofacial region. Although in phase 3 trials of tyrosine kinase inhibitors (TKIs) used in thyroid cancer (TC) the ONJ was not reported among the most common side effects, several papers reported the association between ONJ and TKIs, both when they are used alone and in combination with a bisphosphonate. The appearance of an ONJ in a patient with metastatic radio-iodine refractory differentiated TC, treated with zoledronic acid and sorafenib, has put us in front of an important clinical challenge: when a ONJ occurred during TKIs treatment, it really worsens the patients' quality of life. We should consider that in the case of ONJ a TKI discontinuation becomes necessary, and this could lead to a progression of neoplastic disease. The most important aim of this review is to aware the endocrinologists/oncologists dealing with TC to pay attention to this possible side effect of BPS and TKIs, especially when they are used in association. To significantly reduced the risk of ONJ, both preventive measures before initiating not only antiresorptive therapy but also antiangiogenic agents, and regular dental examinations during the treatment should always be proposed., (© 2021. The Author(s).)

With the progress and development of society, osteonecrosis of the jaw has appeared some new features and new problems in oral clinical work. The prevention, early diagnosis, and early treatments of osteonecrosis of the jaw are of great significance. This article describes the current clinical diagnosis and treatment status of osteoradionecrosis of the jaw and medication-related osteonecrosis of the jaw, and puts forward some thoughts on the prevention, clinical diagnosis and treatment and future research direction of osteonecrosis of the jaw.

Recognizing rare but clinically significant toxicity of immunotherapy is critical. Here we describe the first detailed case of severe osteonecrosis of the jaw due to anti-PD-1. A 75-year-old man with metastatic melanoma, with no prior radiation or treatment with bone-targeting agents, experienced jaw pain 1 week after his first dose of nivolumab. Imaging studies were negative, and treatment was resumed after pain was controlled. 4 months later, the patient experienced acute exacerbation of pain and malocclusion of the jaw. Imaging showed bilateral fractures of the angle of mandible with extensive disruption of the normal trabecular architecture, requiring total mandibulectomy. The patient's metastatic melanoma responded to treatment and remains controlled >20 months after treatment cessation without further therapy.

Introduction: Medication-related osteonecrosis of the jaw is a frequent collateral effect found in patients under antiresorptive treatments. Malignancies such as multiple myeloma, breast and prostate cancer as well as bone-metabolic disorders such as osteoporosis, lead the indications for these antiresorptive therapies. Even with a low frequency, myelodysplastic syndromes are also entities that have previously been associated with the development of jaw osteonecrosis., Objective: the aim of this study is to present a case of a 78-year-old male patient with myelodysplastic syndrome and secondary osteoporosis, treated with high-dose Zoledronic Acid and who developed a clinical scenario compatible with medication-related osteonecrosis of the jaw during its evolution., Methodology: : the case was recorded and treated in the Oral Medicine Department, Facultad de Odontología, Universidad Nacional de Córdoba, during a two-years period with a partial resolution, which recurred fourteen months later, where finally therapeutic success was achieved through a conservative management., Conclusion: Due to the increasingly use of antiresorptive drugs, the development of jaw osteonecrosis is possible associated with less frequent pathologies, such as myelodysplastic syndrome. Treatment success in these patients depends on interdisciplinary management and a rigorous clinical, medical and dental follow-up., (Universidad Nacional de Córdoba.)

Objective: Bone turnover suppression agents are widely used for prophylaxis of bone metastases from cancer and osteoporosis; the occurrence of their side effect, antiresorptive agent-related osteonecrosis of the jaw (ARONJ), has been increasing. We investigated the relationships between opacification in the nasal sinuses, rhinosinusitis, and ARONJ based on data obtained from oral surgeons., Methods: We examined 132 patients who had been clinically diagnosed with ARONJ based on clinical observations; all patients had undergone treatment at the Departments of Otorhinolaryngology and Oral Surgery. In 16 of the 132 patients, we confirmed a diagnosis of osteonecrosis of the upper jaw and the presence of ipsilateral opacification of the maxillary sinus. We analyzed the data of these 16 patients in detail., Results: Five of the 16 patients had some nasal symptoms and had been diagnosed with rhinosinusitis. The opacification of the rhinosinuses improved, partially improved, and remained unchanged after treatment in 10, three, and two patients, respectively; notably, imaging assessment could not be conducted after treatment in one case., Conclusions: Although there is no consensus regarding the treatment of sinusitis accompanying ARONJ, attempts to improve the causal foci and conservative treatment may offer favorable results; thorough investigation is necessary in refractory cases before determining the use of surgery., Competing Interests: Declaration of Competing Interest All authors confirm that they have no funding information, financial relationships, or other conflicts of interest that should be disclosed., (Copyright © 2020 Oto-Rhino-Laryngological Society of Japan Inc. Published by Elsevier B.V. All rights reserved.)

Objective: This study aims to explore the molecular mechanism of macrophages and γδ-T cells in the ZOL drug-induced osteonecrosis of jaws based on the IFN-γ involved osteoblast differentiation signaling pathway., Results: The number and apoptotic rate of CD11b+Gr1hi cells and γδ-T cells in the ONJ group were significantly higher. The TNF-α, IL-1β, IFN-γ, CCL3, CCL4, IL-12 and IL-13 levels were significantly higher in the ONJ group. The expression of CTSK and FGFR3 was lower in the ONJ group, but was higher in the NF-κB and ERBB2IP group., Conclusion: The proliferation of macrophages and γδ-T cells promote the inflammation in ZOL-induced jaw necrosis., Methods: A total of 20 patients with osteonecrosis of the jaw from January 2016 to March 2018 were collected and assigned into the observation group, while 20 healthy subjects were assigned into the control group. Furthermore, 40 SD rats were selected and assigned into observation group, while 10 non-treatment SD rats were selected and assigned as controls. The distribution and proportion of CD11b+Gr1hi cells and γδ-T cells in the necrotic tissues of the jaw were analyzed. Then, the TNF-α, IL-1β, IFN-γ, CCL3, CCL4, IL-12 and IL-13 levels were measured. Afterwards, the expression of CTSK, FGFR3, NF-κB and ERBB2IP in the necrotic tissues of the jaw in the animal models were analyzed.

Medication-related osteonecrosis of the jaw is a disease where there is necrotic bone exposed or that can be explored by means of a fistula in the maxillofacial region. It has been associated with the use Biphosphonates and denosumab for osteoporosis. Although its etiology is unclear, it may be related to a decrease in bone turnover produced by these drugs, rendering the bone more prone to generate cell necrosis during invasive dental procedures, especially in the posterior region of the jaw. There is no consensus about the prevention and treatment of this condition. The aim of this paper is to present a review of the literature with the main characteristics of osteonecrosis of the jaws associated with drugs, together with a proposal for prevention and treatment for these patients.

Objectives: Giant cell tumour of bone (GCTB) is a rare tumour, generally managed with surgery. Treatment of the very rare unresectable advanced/metastatic GCTB is challenging and denosumab is the only current available medical option, an anti-RANKL monoclonal antibody inhibiting osteolysis. An uncommon but severe and treatment-limiting adverse event of denosumab is the osteonecrosis of the jaw (ONJ). The clinical management of GCTB patients stopping denosumab for medication-related (MR)-ONJ and the possible reintroduction of denosumab after MR-ONJ resolution is matter of debate. We performed a retrospective study to describe the incidence, clinical features and outcome of MR-ONJ in unresectable GCTB patients treated with denosumab at our Institution., Design and Setting: Retrospective, single-institutional study., Participants: Adult patients receiving denosumab as antineoplastic therapy for GCTB and experiencing MR-ONJ at Fondazione IRCCS Istituto Nazionale Tumori of Milan between January 2008 and July 2019., Main Outcome Measures: Incidence, time of onset and clinical features of MR-ONJ., Results: 29 patients with locally advanced and/or metastatic GCTB treated with denosumab were identified. At a median follow-up of 70 months (range 1-125), 4 (13.8%) patients experienced MR-ONJ while on treatment, after 125, 119, 85 and 41 months of denosumab, respectively. All patients showed an ongoing tumour stabilisation with denosumab at the MR-ONJ onset and in all cases denosumab was stopped. All four patients were treated with ozone therapy. Two are waiting for surgery, two were already operated on. Both of them experienced disease progression and were thus rechallenged with denosumab. One is still on therapy after 25 months. The other had an MR-ONJ relapse after 39 months and was treated again with ozone therapy and surgery. She is under surveillance, GCTB being currently stable., Conclusion: A clinical algorithm of denosumab rechallenge after complete resolution of MR-ONJ in progressing GCTB patients should be prospectively validated., Competing Interests: Competing interests: SS, AMF, AR, NS: institutional research funding from Pfizer, Novartis, Glaxo. PGC: grants and personal fees from Bayer, Glaxo, Novartis., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background Signal generation through data mining algorithms is an innovative and emerging field in pharmacovigilance. Early detection of safety signals is important for public health safety. However, the possibility of generating pseudo signals should not be overlooked. Objective Our study aimed to identify potential signals of aromatase inhibitors associated Osteonecrosis of Jaw and assess the possibilities of the safety signal to be a pseudo signal/false positive in FDA Adverse Event Reporting System (FAERS). Setting Spontaneously reported data in FAERS database. Methods Data for this study were obtained from the public release of data in FAERS. OpenVigil, a pharmacovigilance analytical tool was used to access FAERS data. Reporting Odds Ratio (ROR) was used to assess the relation between the drug and adverse event. A value of ROR-1.96SE  > 1, (SE-standard error) was considered positive. Main outcome measure Signal strength. Results FAERS database had a total of 15,178 reports for Osteonecrosis of Jaw. Amongst which 617 reports were associated with aromatase inhibitors. Signal strength ROR (lower bound of the 95% CI) for letrozole, anastrozole and exemestane associated Osteonecrosis of Jaw without any background correction was 8.34, 6.64 and 15.14 respectively. Upon removing the reports of concomitantly administered drugs (bisphosphonates and denosumab), signal strength drastically decreased to 0.03, 0.36 and 0.47 for letrozole, anastrozole and exemestane respectively. The signal strength of bisphosphonates and denosumab associated Osteonecrosis of Jaw was not changed significantly upon removal of aromatase inhibitors. Conclusion Our study concluded that the signal generated for aromatase inhibitors associated Osteonecrosis of Jaw in FAERS database can be false positive. Careful background corrections with identification of those risk factors are imperative to exclude false positive results.

Introduction: The presumably multifactorial pathomechanisms of medication-related osteonecrosis of the jaws have not been fully elucidated so far. Management of this rare but serious side effect is a real challenge and requires a multidisciplinary approach. Aim: The aim of the authors was to take stock of our present knowledge about the pathogenesis, risk factors, clinical manifestations and the possibilities of prevention and treatment in the medication-related osteonecrosis of the jaws. In addition, the available international guidelines are compared and the evidence-based, stage-specific conservative and adjuvant therapeutic approaches are also reviewed, having regard to special aspects of medical and dental care. Method: In the last 5 years - due to the increasing number of disorder-oriented database - the number of available systematic reviews, recommendations and meta-analyses has escalated significantly which we reviewed and compared. Results: Since the last Position Paper published by the taskforce of the American Association of Oral and Maxillofacial Surgeons, novel pharmacological groups with the potential to induce osteonecrosis have come in the clinical scope, further elaborating the nomenclature of the disease and further specifying patient groups. The sphere of patients at risk has broadened and novel patient groups (rheumatologic-osteological, immunosuppressed, transplanted or oncological patients treated with monoclonal antibody, known as 'target therapy') are expected to develop this serious side effect. Conclusion: Although a number of issues are still open regarding the treatment of the disorder, evidence-based, individualized, stage-adapted therapeutic approaches have replaced the previous empirical treatment. Orv Hetil. 2020; 161(6): 214-223.

Objective: The usefulness of bone scan index (BSI), a quantitative metric of the area of uptake in computer-aided diagnosis in bone scintigraphy, has been reported for the diagnosis of anti-resorptive-agent-related osteonecrosis of the jaw (ARONJ). The aim of this study is to validate the diagnostic ability of BSI for the early detection of ARONJ. In addition, the Bone uptake value (BUV), another quantitative index obtained from bone scintigraphy that indicates the degree of radioisotope (RI) accumulation, was used to improve the diagnostic ability for early detection of ARONJ., Methods: A total of 34 patients (11 with ARONJ, 23 without ARONJ) who were administered anti-resorptive-agents for bone metastasis and had incidentally consulted a dental surgeon within 3 months after regular whole-body bone scintigraphy were retrospectively included in the study. The bone scintigraphy data were subjected to semiquantitative analysis of uptake in the jaw using BONENAVI (FUJIFILM Toyama Chemical, Co. Ltd., Tokyo, Japan; EXINI Diagnostics AB, Lund, Sweden) and BUV software (Technical Society for Quantitative Bone Scintigraphy and Fujifilm Toyama Chemical Co., Ltd. Tokyo, Japan). The ROI was set semi-automatically on mandibular hotspots, and the regional BSI was termed BSIJ. Planar anterior and posterior images were then sent to BUV software, with the ROI set manually as for BSI, and the regional BUV was termed BUVJ., Results: Mean BSIJ values for the ARONJ positive and ARONJ negative groups were 0.17 ± 0.83 and 0.03 ± 0.50%, respectively. Mean BUVJ values for the ARONJ positive and ARONJ negative groups were 0.47 ± 0.17 and 0.19 ± 0.11, respectively. BSIJ × BUVJ values for the ARONJ positive versus ARONJ negative groups were 0.088 ± 0.067 vs. 0.007 ± 0.010. The AUC for BSIJ, BUVJ and BSIJ × BUVJ was 0.949, 0.951 and 0.988, respectively., Conclusion: The BSI metric of a CAD system for bone scintigraphy was useful for the early detection of ARONJ. Accuracy was improved with the additional use of BUVJ data. We recommend that SPECT imaging be performed when bone scintigraphy reveals focal or diffuse uptake in the mandible with high BSIJ and BUVJ.

Background: We investigated the efficacy of hyperbaric oxygen (HBO), low-intensity laser (LIL), and platelet-rich plasma (PRP) in the management of medication-related osteonecrosis of the jaws (MRONJ)., Methods: A literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Two examiners independently assessed eligibility and risk of bias and extracted data., Results: There was improvement in 75.6% of the 41 patients submitted to HBO, with positive effects on pain relief and decreased size and number of lesions at a faster rate, with better effects when the drug was discontinued. For LIL, 158 (64.2%) of the 246 patients/sites improved the symptoms and 98 (39.8%) healed completely. Fourteen (17.3%) of the 81 patients treated with PRP significantly improved the symptoms and 65 (80.2%) completely healed., Conclusions: These therapies served as safe and effective adjuvant modalities for MRONJ treatment. The lack of randomized clinical trials evidences the need for more high-quality investigations on the subject., (© 2019 Wiley Periodicals, Inc.)

Background: Osteoradionecrosis (ORN) of the jaws is among the most serious oral complications of head and neck cancer radiotherapy, arising from radiation-induced fibro-atrophic tissue injury, manifested by necrosis of osseous tissues and failure to heal, often secondary to operative interventions in the oral cavity. It is associated with considerable morbidity and has important quality of life ramifications. Since ORN is very difficult to treat effectively, preventive measures to limit the onset of this disease are needed; however, the effects of various preventive interventions has not been adequately quantified., Objectives: To assess the effects of interventions for preventing ORN of the jaws in adult patients with head and neck cancer undergoing curative or adjuvant (i.e. non-palliative) radiotherapy., Search Methods: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 5 November 2019), the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 10) in the Cochrane Library (searched 5 November 2019), MEDLINE Ovid (1946 to 5 November 2019), Embase Ovid (1980 to 5 November 2019), Allied and Complementary Medicine (AMED) Ovid (1985 to 5 November 2019), Scopus (1966 to 5 November 2019), Proquest Dissertations and Theses International (1861 to 5 November 2019) and Web of Science Conference Proceedings (1990 to 5 November 2019). The US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases., Selection Criteria: We selected randomised controlled trials (RCTs) or quasi-RCTs of adult patients 18 years or older with head and neck cancer who had undergone curative or adjuvant radiotherapy to the head and neck, who had received an intervention to prevent the onset of ORN. Eligible patients were those subjected to pre- or post-irradiation dental evaluation. Management of these patients was to be with interventions independent of their cancer therapy, including but not limited to local, systemic, or behavioural interventions., Data Collection and Analysis: Two review authors independently selected trials from search results, assessed risk of bias, and extracted relevant data for inclusion in the review. Authors of included studies were contacted to request missing data. We used standard methodological procedures expected by Cochrane., Main Results: Four studies were identified that met pre-determined eligibility criteria, evaluating a total of 342 adults. From the four studies, all assessed as at high risk of bias, three broad interventions were identified that may potentially reduce the risk of ORN development: one study showed no reduction in ORN when using platelet-rich plasma placed in the extraction sockets of prophylactically removed healthy mandibular molar teeth prior to radiotherapy (odds ratio (OR) 3.32, 95% confidence interval (CI) 0.58 to 19.09; one trial, 44 participants; very low-certainty evidence). Another study involved comparing fluoride gel and high-content fluoride toothpaste (1350 parts per million (ppm)) in prevention of post-radiation caries, and found no difference between their use as no cases of ORN were reported (one trial, 220 participants; very low-certainty evidence). The other two studies involved the use of perioperative hyperbaric oxygen (HBO) therapy and antibiotics. One study showed that treatment with HBO caused a reduction in the development of ORN in comparison to patients treated with antibiotics following dental extractions (risk ratio (RR) 0.18, 95% CI 0.43 to 0.76; one trial, 74 participants; very low-certainty evidence). Another study found no difference between combined HBO and antibiotics compared to antibiotics alone prior to dental implant placement (RR 3.00, 95% CI 0.14 to 65.16; one trial, 26 participants; very low-certainty evidence). Adverse effects of the different interventions were not reported clearly or were not important., Authors' Conclusions: Given the suboptimal reporting and inadequate sample sizes of the included studies, evidence regarding the interventions evaluated by the trials included in this review is uncertain. More well-designed RCTs with larger samples are required to make conclusive statements regarding the efficacy of these interventions., (Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

To establish the profile of patients who developed antiangiogenic agent-related osteonecrosis of the jaws, and identify the treatments currently used in dental management. We searched the PubMed®/Medline® and Scopus databases using the words "osteonecrosis AND antiangiogenic therapy", with the following inclusion criteria: articles published in English, case reports, available online, and for an unlimited period. Of the 209 articles retrieved, 18 were selected, for a total of 19 case reports, since one article included two cases that met the inclusion criteria for this study. Medication-related osteonecrosis of the jaws is characterized by exposure of necrotic bone in the oral cavity that does not heal over a period of 8 weeks in patients with no previous history of radiation therapy. Antiangiogenic drugs are indicated in the treatment of certain tumors, since they stop the formation of new blood vessels, controlling tumor growth and the chance of metastasis. Dental prevention is essential in patients who will be put on antiangiogenic agents, to minimize the risk for osteonecrosis.

The link between medication-related osteonecrosis of the jaw (MRONJ) and bone modulating drugs, such as bisphosphonates and denosumab, is well established, and the number of reported cases is increasing. The development of novel medications used in the treatment of cancer, as well as autoimmune and bone conditions, has led to more cases of MRONJ being reported. However, in addition to this group of medications, increasing numbers of new agents in cancer therapy, such as antiangiogenic agents, have also been implicated in the development of MRONJ. As these newer agents with similar mechanisms are routinely used, the numbers of reported cases will likely rise further. This article aims to identify and summarize the drugs implicated in MRONJ, besides bisphosphonates and denosumab. A wide range of medications classified as tyrosine kinase inhibitors, monoclonal antibodies, mammalian target of rapamycin inhibitors, radiopharmaceuticals, selective estrogen receptor modulators, and immunosuppressants have been implicated in MRONJ. It remains crucial that oral health care providers are aware of these new medications and their associated risks to manage their patients appropriately., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The association of the high blood pressure D variant of the angiotensin-converting enzyme (ACE) gene with medication-related jaw osteonecrosis (MRONJ) is described in two Greek patients. The first patient, a 73-year-old man, took zolendronate, 4 mg/100 ml IV once per month for two years for prostate cancer and bone metastases. Three months after drug discontinuation, extraction of the first premolar was performed. After the intervention, he suffered from osteonecrosis of the mandible. He presented with hypertension and genetic testing revealed that he was homozygous for the high blood pressure D variant of the ACE gene. The second patient, a 65 years old woman, took denosumab, 120 mg subcutaneously once per month for 6 months for possible bone metastases from breast cancer. Three months after extraction of the first molar, she suffered from MRONJ. He also presented with hypertension and genetic testing revealed that she had the high blood pressure D variant of the ACE gene in a heterozygous state, which moderately predisposes to hypertension. To our knowledge, this is the first report indicating that genetic predisposition to hypertension may increase risk for MRONJ., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Medication-related osteonecrosis of the jaw may appear as adverse effect in antiresorptive therapy. Its successful treatment is challenging. We aimed to gather the systemic and local factors playing a role in etiology, published after its recognition. Risk factors were collected from the PubMed database 1998-2018. The three main groups of risk patients are: patients starting, patients having antiresorptive therapy, osteonecrosis diagnosed patients. The dentist must recognize risk factors, determine appropriate treatment plan and frequency of check-ups. Oncological disease treated intravenously means the greatest risk. Further systemic risk factors are: supportive therapies, concomitant disease, way of life, individual factors. Local risk factors may be: dentoalveolar surgery, periapical and periodontal inflammation, ill-fitting denture, presence of some anatomical structures. The accumulation of risk factors determines the probability of the manifestation of osteonecrosis. The most favorable case is patient starting antiresorptive therapy with a dental status needing no treatment. Orv hetil. 2019; 160(7): 243-251.

Objective: Osteonecrosis of the jaw (ONJ) is commonly associated with antiresorptive therapy. There have been numerous reports of ONJ unrelated to antiresorptive therapy (ONJ uat ), confounding risk assessment. This study aimed to determine if ONJ uat is associated with one or more particular comorbidities., Study Design: This was a retrospective case-control study of patients with ONJ uat and delayed healing (DH). Each case was matched for patient age and gender, as well as location of ONJ uat or DH lesion to a control patient who had a history of dentoalveolar surgery with uneventful healing and no history of antiresorptive therapy. Comorbidity data included medical conditions and smoking., Results: Of the 92 patients identified, 67 (73%) met the criteria for ONJ uat and 25 (27%) for DH. The most common trigger for ONJ and DH was extraction (50%). The presence of any comorbidity (i.e., at least 1) was more prevalent in ONJ uat than among controls (P = .04), and there were more comorbidities in patients with ONJ uat and DH than in controls [M(SD) = 1.94 (1.2) and 2.0 (1.3) vs 1.26 (0.89); both P < .001]., Conclusions: ONJ and DH are not limited to patients with a history of antiresorptive therapy. More comorbidities may signal increased risk for ONJ uat and DH., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In patients with drag-induced jaw osteonecrosis which developed in cancer patients due to administration of bisphosphonates for metastases, the microflora of the oral cavity was examined by chromatography-mass spectrometry (HMS). The method of HMS can be used as an additional method of diagnostics in complex clinical cases with ineffective treatment.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse drug effect consisting of bone destruction of the maxilla and/or mandible. The most common precipitating event described in the literature is the extraction of a tooth followed by "spontaneous" occurrence with no clear predisposing event. Current studies are investigating methods of managing dental extractions in patients at risk of MRONJ; however, no studies to date examine the aetiology and management of "spontaneous" MRONJ. This paper describes two cases of "spontaneous" MRONJ seen at the Dental Unit in the Alfred Hospital and systematically reviews the current literature. No significant interactions (P > 0.05) were detected between variables: age, sex, bone disease, antiresorptive, antiresorptive duration, jaw, location and stage. "Spontaneous" cases were commonly associated with the mylohyoid ridge, palatal tori and other anatomical sites, and tended to occur in those generally considered at low risk of developing MRONJ. The review suggests that perhaps the term "spontaneous" is a misnomer and thorough history taking is critical in establishing a precipitating event., (© 2018 Australian Dental Association.)

Purpose of Review: Osteonecrosis of the jaw (ONJ) is a rare and severe necrotic bone disease reflecting a compromise in the body's osseous healing mechanisms and unique to the craniofacial region. Antiresorptive and antiangiogenic medications have been suggested to be associated with the occurrence of ONJ; yet, the pathophysiology of this disease has not been fully elucidated. This article raises the current theories underlying the pathophysiology of ONJ., Recent Findings: The proposed mechanisms highlight the unique localization of ONJ. The evidence-based mechanisms of ONJ pathogenesis include disturbed bone remodeling, inflammation or infection, altered immunity, soft tissue toxicity, and angiogenesis inhibition. The role of dental infections and the oral microbiome is central to ONJ, and systemic conditions such as rheumatoid arthritis and diabetes mellitus contribute through their impact on immune resiliency. Current experimental studies on mechanisms of ONJ are summarized. The definitive pathophysiology is as yet unclear. Recent studies are beginning to clarify the relative importance of the proposed mechanisms. A better understanding of osteoimmunology and the relationship of angiogenesis to the development of ONJ is needed along with detailed studies of the impact of drug holidays on the clinical condition of ONJ.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but detrimental intraoral lesion that predominantly occurs in patients with long-term use of antiresorptive agents, such as bisphosphonate and denosumab, a human anti-receptor activator of NF-κB ligand (RANKL) monoclonal antibody (Ab). Surgical intervention, such as tooth extraction, is a known risk factor for MRONJ, which is often performed to eliminate preexiting pathologic inflammatory conditions, such as periodontal diseases. Nonetheless, it remains unknown whether pre-existing periodontal disease condition exacerbates, or removal of such condition ameliorates, MRONJ development after tooth extraction. In this study, we combined the ligature-induced periodontitis and the tooth extraction mouse models under the administration of zoledronic acid (ZOL) or anti-RANKL Ab, and provide experimental evidence that a pre-existing pathologic inflammatory condition exacerbates MRONJ development after tooth extraction in mice. Under ZOL administration, tooth extraction alone induced ONJ lesions; however, extraction of a ligature-placed tooth further exacerbated ONJ development. When the ligature was removed and the inflammatory condition was deescalated, ONJ development was ameliorated. Anti-RANKL Ab administration resulted in similar outcomes. Interestingly, unlike ZOL-administered mice, anti-RANKL Ab-administered mice exhibited complete absence of osteoclasts, suggesting that physical presence of osteoclasts is not directly involved in ONJ development. Collectively, our study demonstrated that periodontal disease is a functionally linked risk factor that predisposes ONJ development after tooth extraction in the presence of bisphosphonate and denosumab., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to investigate the relationship between type of antiresorptive medication and medication-related osteonecrosis of the jaw (MRONJ) onset and the role of premedication dental evaluation (PMDE) in the prevention of MRONJ., Study Design: Our database of patients with MRONJ was reviewed. The Kruskal-Wallis test was used to analyze the onset dose of the 3 frequent medication types associated with MRONJ. To evaluate the role of PMDE in the prevention of MRONJ, all patients on antiresorptive and/or antiangiogenic medications seen in the Dental Service of Memorial Sloan Kettering Cancer Center during a 10-year period were subclassified into 2 groups. Group I comprised patients seen for PMDE before the commencement of A/A and group II patients seen after prior exposure to antiresorptive and/or antiangiogenic medications. Fischer's exact test was used to compare the incidence of MRONJ in both groups., Results: Patients on denosumab developed MRONJ earlier compared with zoledronate and pamidronate (P = .003). Group I had a significantly reduced incidence of MRONJ (0.9%) compared with group II (10.5%) (P < .0001). Dentoalveolar trauma as a precipitating factor between groups I and II was not statistically significant., Conclusions: Denosumab was associated with an earlier occurrence of MRONJ compared with zoledronate and pamidronate. The role of PMDE may be an effective preventive strategy in reducing the incidence of MRONJ., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The aim of this retrospective study was to compare the morphological features of neurovascular canals and foramina of patients with medication-related osteonecrosis of the jaws (MRONJ) and healthy individuals by using cone beam computed tomography (CBCT)., Material and Methods: The CBCT images of 58 patients under bisphosphonate therapy diagnosed with MRONJ and age gender- matched controls were retrospectively evaluated. The diameter of mandibular and nasopalatine canal and mandibular, mental and lingual foramina were measured on several sections of CBCT. The value of mental index (MI) and panoramic mandibular index (PMI) were also assessed., Results: The mean value of diametric measurements for all neurovascular canals and foramina in MRONJ patients were narrower than controls. Left mandibular foramen was the most affected area (p<0.001). There were significantly difference in all measurements of mental foramen, lingual foramen and mandibular incisive canal between two groups (p<0.05). PMI of MRONJ subjects were also significantly differences in both sides (p<0.05)., Conclusion: In MRONJ patient, neurovascular canals and foramina are affected due to the alterations in bone remodeling. Therefore, the diametric measurement of neurovascular canals and assessment of MI and PMI on CBCT, is a potentially useful method for detection of early changes associated with bisphosphonate therapy and for predict areas where new necrosis may occur.

Purpose: The appearance of osteoradionecrosis (ORN) and medication-related osteonecrosis of the jaw (MRONJ) is similar, but clinically important differences between ORN and MRONJ exist. The aim of this study was to compare the clinical data between ORN and MRONJ and to reveal the critical differences between these diseases., Methods: We retrospectively reviewed the epidemiological data, clinical findings, and treatment in 27 ORN and 61 MRONJ patients. Radiographic signs before the initiation of treatment were also assessed., Results: The median age (P = 0.0474) and the ratio of female to male patients (P < 0.0001) were significantly higher in MRONJ patients. There were significantly more MRONJ patients who reported a history of pain when compared with ORN patients (P = 0.0263). As an aetiological factor, tooth extraction was significantly more relevant to MRONJ than ORN (P = 0.0352). When assessing the radiographic signs on computed tomographic images, periosteal reaction was found only in MRONJ patients (P = 0.0158). Minimal debridement was performed significantly more frequently for MRONJ (P = 0.0093), and by contrast, surgical resection was performed more frequently for ORN (P = 0.0002)., Conclusions: Understanding the clinical and underlying pathological differences between ORN and MRONJ probably contributes to the selection of appropriate treatment for each patient.

Objective: To evaluate the effects of different doses and durations of teriparatide therapy on MRONJ resolution in rats., Subjects and Methods: A total of 120 rats that had been affected with MRONJ (after six weekly zoledronate injections and tooth extraction) were randomly divided into eight subgroups: 2, 10, and 20 μg/kg/day teriparatide were administered to L4, M4, and H4 for 4 weeks, and to L8, M8, and H8 for 8 weeks, respectively. C4 and C8 received saline for 4 and 8 weeks, respectively. One week after the final injection, rats were sacrificed and assessed clinically (bone exposure/fistula) and histologically (number of osteocytes in extraction socket and empty lacunae in alveolar bone)., Results: MRONJ was clinically improved in 72.2%, 61.5%, and 40% of stage I, II, and III experimental rats, respectively. In the control rats, the results were 20.8% for stage I and no improvement for stages II and III. Aside from L4 and L8, the experimental subgroups had a significantly higher rate of clinical and histological improvement compared with their corresponding controls. There was a significantly higher number of osteocytes and lower number of empty lacunae in M4 and H4 compared with C4, in H4 compared with L4, in M8 and H8 compared with C8, and in H8 compared with L8., Conclusion: Teriparatide therapy improved clinical and histological features of MRONJ in a dose-dependent manner, but clinically relevant doses of teriparatide might not be sufficient for MRONJ resolution in rats. Extending the duration of teriparatide therapy from 4 to 8 weeks did not affect treatment outcomes., (Copyright © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Osteoporosis is a major, growing healthcare issue. This is especially of concern in an ageing population like that of Singapore. Osteoporotic patients are at risk of fractures, which can result in increased morbidity and mortality. The use of antiresorptive therapy with bisphosphonates or denosumab has been proven to reduce fracture risk. However, the use of these medications has rarely been associated with the development of osteonecrosis of the jaw, a potentially debilitating condition affecting one or both jaws. Appropriate understanding of the patient's antiresorptive therapy regime, as well as early institution of preventive dental measures, can play an important role in preventing medication-related osteonecrosis of the jaw (MRONJ). Regular monitoring and prompt referral to specialist care is warranted for patients with established MRONJ., (Copyright: © Singapore Medical Association.)

Antiresorptives and antiangiogenics are treatments that have proven effective in oncology and the treatment of osteoporosis and they are increasingly prescribed. The care of these patients requires collaboration between the prescriber and the oral health professional to establish an optimized treatment plan. Therapeutic education of the patient is essential for him to understand the issues of good oral health and the adverse effects that can be caused by these treatments. The management is essentially based on the individual benefit/risk balance resulting from the general, local and inherent of the molecule risk factors. Management of drug-related osteonecrosis of the jaw should be as early as possible., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Osteonecrosis of the jaw (ONJ) is a rare but potentially severe condition that can be induced by specific treatments. We report the case of a 69-year-old male kidney transplant recipient who presented with ONJ 5 years after transplantation. The patient presented with ulcerations of the oral mucosa related to post-transplantation lymphoproliferative disorder, which was treated with rituximab. Subsequently, ONJ developed. Although rituximab treatment cannot be firmly established as the cause of this condition, similar cases of ONJ have been reported after treatment with this monoclonal antibody. This case raises a potential link between rituximab treatment and ONJ and prompts further studies to investigate the potential impact of rituximab on bone angiogenesis., (Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Osteonecrosis of the jaw (ONJ) is a severe complication of antiresorptive medication (AM) in the treatment of bone-affecting cancer-related conditions and osteoporosis. Aim of this study was to reveal whether patients treated with AM and show Medication Related OsteoNecrosis of the Jaw (MRONJ) are vitamin D deficient or not., Materials and Methods: A 2 year retrospective study evaluated hospital records of 63 patients who received AM. Patients were divided into two groups. One group (n = 45) consisted of patients who presented a stage 2 ONJ (eb+ = exposed bone). Second group patients (n = 18) (eb- = no exposed bone) presented for extraction of teeth. Serum levels of vitamin D (25-OHD) were analysed. P values ≤ 0.05 in t-test were regarded as statistically significant., Results: Serum levels of 25-OHD were significantly higher in the eb(-) group (29.5 ng/ml), than in the eb(+) group (20.49 ng/ml). Blood levels of calcium were also significantly higher in eb(-) group (2.25 mmol/L; 0.11 SD) than in eb(+) group (2.175 mmol/L; 0.16 SD)., Conclusion: Prevalence of MRONJ in AM treated patients seems to be increased by low serum 25-OHD. A measurable tendency in the role of 25-OHD for the development of MRONJ was recorded and leads to the recommendation for a sufficient vitamin D substitution in patients treated with AM., (Copyright © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Purpose: The aim of this experimental study was to investigate the prophylactic effect of pentoxifylline (PTX) on medication-related osteonecrosis of the jaw (MRONJ)., Materials and Methods: Female Sprague-Dawley rats (n = 33) received zoledronic acid (ZA) for 8 weeks to create an osteonecrosis model. The left mandibular second molars were extracted and the recovery period lasted 8 weeks before sacrifice. PTX was intraperitoneally administered to prevent MRONJ. The specimens were histopathologically and histomorphometrically evaluated., Results: Histomorphometrically, between the control and ZA groups, there was no statistically significant difference in total bone volume (P = .999), but there was a statistically significant difference in bone ratio in the extraction sockets (P < .001). A comparison of the bone ratio of the ZA group with the ZA/PTX group (PTX administered after extraction) showed no statistically significant difference (P = .69), but there was a statistically significant difference with the ZA/PTX/PTX group (PTX administered before and after extraction; P = .008). Histopathologically, between the control and ZA groups, there were statistically significant differences for inflammation (P = .013), vascularization (P = .022), hemorrhage (P = .025), and regeneration (P = .008). Between the ZA and ZA/PTX groups, there were no statistically significant differences for inflammation (P = .536), vascularization (P = .642), hemorrhage (P = .765), and regeneration (P = .127). Between the ZA and ZA/PTX/PTX groups, there were statistically significant differences for inflammation (P = .017), vascularization (P = .04), hemorrhage (P = .044), and regeneration (P = .04)., Conclusion: In this experimental model of MRONJ, it might be concluded that although PTX, given after tooth extraction, improves new bone formation that positively affects bone healing, it is not prophylactic. However, PTX given before tooth extraction is prophylactic. Therefore, PTX might affect healing in a positive way by optimizing the inflammatory response., (Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Non-surgical treatment has generally been recommended for stage II medication-related osteonecrosis of the jaw (MRONJ) in preference to surgery. However, non-surgical treatment is not empirically effective. The aim of this study was to evaluate whether surgical or non-surgical treatment leads to better outcomes for stage II MRONJ., Material and Methods: In this retrospective study, surgery was performed in a total of 28 patients while 24 patients underwent non-surgical treatment. The outcomes of both treatment approaches after 6 months were evaluated and statistically compared. In addition, risk factors for surgical and non-surgical treatments were assessed for each., Results: Surgical treatment in 25 patients (89.3%) resulted in success, with failure in 3 patients (10.7%). Non-surgical treatment was successful for 8 patients (33.3%) and failed in 16 patients (66.7%). There was therefore a significant difference between surgical and non-surgical treatment outcomes (P<0.01). Regarding risk factors, in non-surgical treatment primary diseases, medications, and drug holiday had a significant effect on outcomes (P<0.01). Risk factors for surgical treatment could not be clarified., Conclusions: Surgical treatment is more effective than non-surgical treatment for stage II MRONJ, and drug holiday, primary disease, and medication constitute risk factors in non-surgical treatment.

Background: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction experienced by some individuals to certain medicines commonly used in the treatment of cancer and osteoporosis (e.g. bisphosphonates, denosumab and antiangiogenic agents) and involves the progressive destruction of bone in the mandible or maxilla. Depending on the drug, its dosage, and the duration of exposure, the occurrence of this adverse drug reaction may be rare (e.g. following the oral administration of bisphosphonate or denosumab treatments for osteoporosis, or antiangiogenic agent-targeted cancer treatment) or common (e.g. following intravenous bisphosphonate for cancer treatment). MRONJ is associated with significant morbidity, adversely affects quality of life (QoL), and is challenging to treat., Objectives: To assess the effects of interventions versus no treatment, placebo, or an active control for the prophylaxis of MRONJ in people exposed to antiresorptive or antiangiogenic drugs.To assess the effects of non-surgical or surgical interventions (either singly or in combination) versus no treatment, placebo, or an active control for the treatment of people with manifest MRONJ., Search Methods: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 23 November 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 10), MEDLINE Ovid (1946 to 23 November 2016), and Embase Ovid (23 May 2016 to 23 November 2016). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on language or publication status when searching the electronic databases; however, the search of Embase was restricted to the last six months due to the Cochrane Embase Project to identify all clinical trials and add them to CENTRAL., Selection Criteria: We included randomised controlled trials (RCTs) comparing one modality of intervention with another for the prevention or treatment of MRONJ. For 'prophylaxis of MRONJ', the primary outcome of interest was the incidence of MRONJ; secondary outcomes were QoL, time-to-event, and rate of complications and side effects of the intervention. For 'treatment of established MRONJ', the primary outcome of interest was healing of MRONJ; secondary outcomes were QoL, recurrence, and rate of complications and side effects of the intervention., Data Collection and Analysis: Two review authors independently screened the search results, extracted the data, and assessed the risk of bias in the included studies. For dichotomous outcomes, we reported the risk ratio (RR) (or rate ratio) and 95% confidence intervals (CI)., Main Results: We included five RCTs (1218 participants) in the review. Three trials focused on the prophylaxis of MRONJ. Two trials investigated options for the treatment of established MRONJ. The RCTs included only participants treated with bisphosphonates and, thus, did not cover the entire spectrum of medications associated with MRONJ. Prophylaxis of MRONJOne trial compared standard care with regular dental examinations in three-month intervals and preventive treatments (including antibiotics before dental extractions and the use of techniques for wound closure that avoid exposure and contamination of bone) in men with metastatic prostate cancer treated with zoledronic acid. The intervention seemed to lower the risk of MRONJ: RR 0.10; 95% CI 0.02 to 0.39 (253 participants; low-quality evidence). Secondary outcomes were not evaluated.As dentoalveolar surgery is considered a common predisposing event for developing MRONJ, one trial investigated the effect of plasma rich in growth factors (PRGF) for preventing MRONJ in people with cancer undergoing dental extractions. There was insufficient evidence to support or refute a benefit of PRGF on MRONJ incidence when compared with standard treatment (RR 0.08, 95% CI 0.00 to 1.51; 176 participants; very low-quality evidence). Secondary outcomes were not reported. In another trial comparing wound closure by primary intention with wound closure by secondary intention after dental extractions in people treated with oral bisphosphonates (700 participants), no cases of intraoperative complications or postoperative MRONJ were observed. QoL was not investigated. Treatment of MRONJOne trial analysed hyperbaric oxygen (HBO) treatment used in addition to standard care (antiseptic rinses, antibiotics, and surgery) compared with standard care alone. HBO in addition to standard care did not significantly improve healing from MRONJ compared with standard care alone (at last follow-up: RR 1.56; 95% CI 0.77 to 3.18; 46 participants included in the analysis; very low-quality evidence). QoL data were presented qualitatively as intragroup comparisons; hence, an effect estimate of treatment on QoL was not possible. Other secondary outcomes were not reported.The other RCT found no significant difference between autofluorescence- and tetracycline fluorescence-guided sequestrectomy for the surgical treatment of MRONJ at any timepoint (at one-year follow-up: RR 1.05; 95% CI 0.86 to 1.30; 34 participants included in the analysis; very low-quality evidence). Secondary outcomes were not reported., Authors' Conclusions: Prophylaxis of MRONJOne open-label RCT provided some evidence that dental examinations in three-month intervals and preventive treatments may be more effective than standard care for reducing the incidence of MRONJ in individuals taking intravenous bisphosphonates for advanced cancer. We assessed the certainty of the evidence to be low.There is insufficient evidence to either claim or refute a benefit of either of the interventions tested for prophylaxis of MRONJ (i.e. PRGF inserted into the postextraction alveolus during dental extractions, and wound closure by primary or secondary intention after dental extractions). Treatment of MRONJAvailable 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 fluorescence-guided bone surgery.

The anti-receptor activator of nuclear factor kappa-B ligand (RANKL) antibody, Denosumab (DEN), was approved in April 2012 in Japan, but a Dear Healthcare Professional Letter of Rapid Safety Communication was released in September, 2012 by the regulatory authority because of the severe hypocalcemia risks. Currently, the effectiveness of this regulatory action has not been evaluated and, therefore, this study aimed to assess its impact on DEN-induced hypocalcemia using the Japanese Adverse Drug Event Report database (JADER). The case reports from April 2012 to September 2014 were collected from the JADER, which included 151642 adverse events for the primary suspected drugs. The reporting odds ratio (ROR) of hypocalcemia as a signal of the target adverse event was analyzed for DEN and zoledronic acid (ZOL, a reference drug). Changes in RORs were compared between the pre- (Pre, April 2012 to September 2012) and post- (Post 1, October 2012 to September 2013 and Post 2, October 2013 to September 2014) periods of the regulatory action. A decrease in the hypocalcemia ROR was observed for DEN in the post-periods, especially Post 2. Multivariate logistic regression analysis showed a significant decrease in hypocalcemia signal in Post 1 (p=0.0306 vs. Pre) and Post 2 (p=0.0054 vs. Pre). ZOL caused no significant changes in ROR of hypocalcemia, and none of the drugs caused ROR changes in jaw osteonecrosis (a reference adverse event). This study suggests that the regulatory action against hypocalcemia in DEN effectively decreased hypocalcemia signal. Further studies using medical information databases are needed to confirm this result.