Ozone therapy effect in medication-related osteonecrosis of the jaw as prevention or treatment: microtomographic, confocal laser microscopy and histomorphometric analysis.

OBJECTIVE: This study aimed to evaluate the efficacy of ozone therapy in the preoperative (prevention) and/or postoperative (treatment) of MRONJ. MATERIAL AND METHODS: Forty male Wistar rats were caudally treated with zoledronic acid (ZOL) and to ozone therapy before extraction (prevention, POG), after extraction (treatment, TOG), or both (prevention and treatment, TPOG), and treated with saline (SAL). The animals received intramuscular fluorochrome (calcein and alizarin), and 28 days postoperatively, they were euthanized, and the tissues were subjected to microtomographic computed tomography (microCT), LASER confocal, and histomorphometric analyses. RESULTS: Micro-CT showed a higher bone volume fraction average in all groups than that in the ZOL group (P < 0.001), the ZOL group showed high porosity (P = 0.03), and trabecular separation was greater in the TOG group than in the POG group (P < 0.05). The mineral apposition rate of the POG group was high (20.46 ± 6.31) (P < 0.001), followed by the TOG group (20.32 ± 7.4). The TOG group presented the highest mean newly formed bone area (68.322 ± 25.296) compared with the ZOL group (P < 0.05), followed by the SAL group (66.039 ± 28.379) and ZOL groups (60.856 ± 28.425). CONCLUSIONS: Ozone therapy modulated alveolar bone repair in animals treated with ZOL, mainly after surgery trauma, leading to bone formation as healing tissue. CLINICAL RELEVANCE: Osteonecrosis has been a challenge in dentistry, and owing to the lack of a consensus regarding therapy, studies presenting new therapies are important, and ozone has been one of the therapies explored empirically.

Navigating the complexities and controversies of medication-related osteonecrosis of the jaw (MRONJ): a critical update and consensus statement.

OBJECTIVES: To provide a critical update identifying the knowledge gaps and controversies in medication-related osteonecrosis of the jaw (MRONJ) within the Belgian healthcare context and outline opportunities for improvement and research in these areas. METHODS: A literature review was performed to identify guidelines from international clinical societies in oncology or oral and maxillofacial surgery on diagnosing, preventing, and treating MRONJ. The recommendations were critically assessed in light of recent developments in the field and confronted with the clinical experience of experts. RESULTS: Despite progress in the diagnostic criteria of MRONJ, the continued need for an 8-week timeout period should be reconsidered. Furthermore, 3D imaging techniques should be introduced to improve diagnosis and staging. The staging system remains ambiguous regarding Stage 0 MRONJ, and ongoing confusion exists regarding the term non-exposed MRONJ. The prevention of MRONJ should be tailored, considering the individual patient's risk of MRONJ, frailty, and life expectancy. More research seems needed into the efficacy and safety of drug holidays, considering the risks of rebound remodeling on fractures. With renewed interest in surgical and adjunct management techniques, adequately designed clinical studies are needed to help translate trial outcomes into universally applicable treatment guidelines taking into account individual patient characteristics. CONCLUSIONS: Important knowledge gaps remain and hamper the development of clinical guidelines. Several controversies were identified where consensus is lacking, and further harmonization between stakeholders is necessary. Finally, the need for randomized controlled comparative clinical trials in MRONJ resonates harder than ever to identify the best treatment for individual patients.

Medication-related osteonecrosis of the jaw (MRONJ): a review of pathogenesis hypothesis and therapy strategies.

Medication-related osteonecrosis of the jaw (MRONJ), a severe side effect caused by antiresorptive antiangiogenic medication, particularly bisphosphonates (BPs), has become a challenging disease with serious and profound effects on the physical and mental health of patients. Although it occurs with high frequency and is harmful, the exact mechanism of MRONJ remains unknown, and systematic and targeted approaches are still lacking. Maxillofacial surgeons focus on the etiology of osteonecrosis in the mandible and maxilla as well as the appropriate oral interventions for high-risk patients. Adequate nursing care and pharmacotherapy management are also crucial. This review provides a current overview of the clinicopathologic feature and research of MRONJ caused by BPs, with an emphasis on the potential mechanisms and current therapy and prevention strategies of the disease. We are of the opinion that an in-depth comprehension of the mechanisms underlying MRONJ will facilitate the development of more precise and efficacious therapeutic approaches, resulting in enhanced clinical outcomes for patients.

Impact of beta-tricalcium phosphate on preventing tooth extraction-triggered bisphosphonate-related osteonecrosis of the jaw in rats.

Antiresorptive or antiangiogenic drugs can cause medication-related osteonecrosis of the jaw that is refractory. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) may be caused by procedures such as tooth extraction damage the alveolar bone, release bisphosphonates (BPs) and impede healing. This study investigated strategies for BRONJ prevention and molecular mechanisms of its onset. We assessed the effectiveness of filling extraction sockets with beta-tricalcium phosphate (ß-TCP). Rats were administered zoledronic acid (ZA) 1.2 mg/kg once per week for 2 weeks, and a molar was extracted. They were randomly assigned to the ß-TCP group (bone defects filled with 0.01 g of ß-TCP) or control group. Tissue content measurements indicated 2.2 ng of ZA per socket in the ß-TCP group and 4.9 ng in the control group, confirming BP distribution and BP adsorption by ß-TCP in vivo. At 4 weeks after extraction, the ß-TCP group had normal mucosal coverage without inflammation. Moreover, at 8 weeks after extraction, enhanced bone healing, socket coverage, and new bone formation were observed in the ß-TCP group. Connective tissue in the extraction sockets suggested that local increases in BP concentrations may suppress the local autophagy mechanisms involved in BRONJ. Filling extraction sockets with ß-TCP may prevent BRONJ.

Oral health conditions in patients under antiresorptive therapy are comparable to unexposed during supportive periodontal care.

OBJECTIVES: To investigate oral health and oral health-related quality of life (OHRQoL) of patients under antiresorptive therapy (ART) during supportive periodontal care (SPC) considering history of medication-related osteonecrosis of the jaw (MRONJ). MATERIALS AND METHODS: In this cross-sectional study, 100 patients (50 receiving ART (exposed) and 50 without ART (unexposed)) in regular SPC were enrolled for a clinical oral examination and the evaluation of OHRQoL using the OHIP-G14-questionnaire. History of MRONJ was assessed by anamnesis and reviewing patient records. RESULTS: There were no statistically significant group differences in age (exposed: 70.00 ± 9.07 versus unexposed: 71.02 ± 8.22 years), sex, distribution of systemic diseases and duration of SPC (on average 8.61 ± 5.73 years). Number of teeth (21.02 ± 5.84 versus 21.40 ± 5.42), DMFT (18.38 ± 3.85 versus 17.96 ± 4.08), probing pocket depth (2.31 ± 0.20 versus 2.38 ± 0.26), clinical attachment level (3.25 ± 0.76 versus 3.46 ± 0.58) and bleeding on probing (15.07 ± 11.53 versus 15.77 ± 13.08) were also not significantly different. The OHIP-G14 sum-score was significantly higher in exposed participants (6.10 ± 6.76 versus 3.62 ± 5.22, p = 0.043). History of MRONJ was prevalent in 8% of patients under ART. Periodontal/peri-implant-related MRONJ were reported in three participants with cancer (n = 1 before and n = 2 after active periodontal therapy). History of MRONJ due to endodontic/restorative reasons was reported in one patient with osteoporosis. CONCLUSIONS: Patients under ART in SPC demonstrated similar clinical periodontal and dental status but lower OHRQoL compared to unexposed (not statistically significant). Patient awareness of the MRONJ-risk and appropriate preventive measures should be ensured. CLINICAL RELEVANCE: SPC in osteoporotic patients under ART appeared safe regarding MRONJ, but further investigations on the MRONJ-risk in patients with different risk-profiles are necessary. STUDY REGISTRATION: clinicaltrials.gov (#NCT04192188).

Prevention and management of drug-induced osteonecrosis of the jaws using platelet-rich fibrin: A clinical feasibility study.

OBJECTIVE: Although a standard treatment guideline has not been established to date, various treatment modalities have been described in the literature based on the staging of medication-related osteonecrosis of the jaw (MRONJ). The aim of this case series was to describe the outcomes of surgical intervention of MRONJ cases with the adjunctive use of platelet-rich fibrin (PRF). MATERIALS AND METHODS: Thirteen patients under therapy with zoledronic acid, seven of them underwent surgical removal of necrotic bone with debridement, followed by placement of three to four PRF membranes and achieving primary closure. In six patients, PRF was used preventively to avoid MRONJ. RESULTS: The surgical treatment outcomes were successful in all patients, with a follow-up range of 12-48 months. In the presented cases, the intraoral evaluation showed excellent soft tissue healing except for one patient secondary wound healing was reported. Additionally, there was no recurrence of bone exposure in all cases. PRF membranes were comparatively effective in postsurgical pain control. CONCLUSION: The use of PRF could represent a valuable adjunct in the surgical management for advanced stages of MRONJ cases. CLINICAL RELEVANCE: This clinical case series describes the use of PRF membranes as a valuable adjunct in the surgical management of MRONJ patients, especially when treating advanced MRONJ cases. Moreover, PRF demonstrates usefulness in preventing such difficult complications from occurring.

Sex difference in the morbidity and pain response with stage 0 of medication-related osteonecrosis of the jaws.

OBJECTIVE: Medication-related osteonecrosis of the jaws (MRONJ) is a potentially severe complication associated with antiresorptive or antiangiogenic therapies. Prior studies, including our own clinical data, have indicated a higher incidence of MRONJ among women compare to men. However, robust evidence establishing a relationship between sex and the prevalence of MRONJ is lacking. METHODS: We conducted a meta-analysis and utilized murine models to investigate potential sex-based differences in the morbidity associated with MRONJ. RESULTS: Our results revealed no significant difference in the incidence of MRONJ between the sexes when using exposed necrotic bone as a diagnostic criterion. However, a histological examination of the murine models identified the presence of stage 0 MRONJ. Notably, pain assessments across all groups revealed that male mice with stage 0 MRONJ displayed less severe pain symptoms than their female counterparts. CONCLUSIONS: Our findings suggested that sex does not contribute to the risk of developing MRONJ. However, considering that approximately 50% of stage 0 MRONJ cases progress to more advanced stages, the less pronounced pain in male patients might delay medical consultation and potentially lead to disease progression. Clinicians should be particularly vigilant about the subdued pain response in male patients with stage 0 MRONJ to prevent disease advancement.

Revisiting best practice guidelines and patient care workflow for managing the risk of medication-related osteonecrosis of the jaw: comparative summary and case studies.

OBJECTIVE: Patients taking antiresorptive medications in dental clinics are at risk of medication-related osteonecrosis of the jaw (MRONJ), which poses daily challenges for their clinicians. This paper aimed to summarize and revisit the three most recognized practice guidelines for the management and prevention of MRONJ, which were proposed by the American Association of Oral and Maxillofacial Surgeons (AAOMS), and presented by the Journal of Bone and Mineral Research (JBMR) and the Journal of Clinical Oncology (JCO). Results and case studies: The AAOMS position paper focused on risk stratification by different medications, management decision trees, risk factors, pathophysiology, and disease staging. The JBMR international consensus presented eight focused questions, which were addressed by systematic reviews. The JCO clinical practice guideline presented six clinical questions, and each concluded with practical recommendations. Practical information was summarized and converted into an adoptable patient care workflow for clinicians to follow and apply in daily practice. Three case studies presented were treated following these guidelines. Each patient underwent advanced surgeries including alveoloplasty, tooth extraction, implant placement, and particulate bone grafting. Some of the considerations not fully informed were discussed and illustrated in each step of the patient care workflow, which included specifics for risk communication, updates on the use of antibiotics, biomarkers, and drug holidays. CONCLUSION AND PRACTICAL IMPLICATIONS: Structured risk communication with official informed consent documentation should be considered before initiating invasive treatments. Disease control phase with home care therapy should be provided prior to staged reconstructive therapy. Drug holidays and antibiotics coverage can be customized based on individual conditions and related procedures with interprofessional coordination.

Pentoxifylline and tocopherol as prophylaxis for osteonecrosis of the jaw due to bone-modifying agents in patients with cancer submitted to tooth extraction: a case series.

PURPOSE: To assess the prophylaxis effect of pentoxifylline and tocopherol (PENTO) on the frequency and severity of medication-related osteonecrosis of the jaw (MRONJ) diagnosed at three months in patients with cancer submitted to tooth extractions during the treatment with bone-modifying agents. METHODS: This case series was conducted at the outpatient dental clinic of the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP) between April 2021 and April 2022. Patients ≥ 18 years old were included; those with maxillary metastasis or who performed head or neck radiotherapy were excluded. The PENTO protocol was prescribed two weeks before and two weeks after the tooth extraction, and patients were reassessed one week, one month, and three months after the extraction. The main outcome was the development of MRONJ. RESULTS: Of the 114 screened patients, 17 were included; they were aged between 43 and 73 years and were mostly female (88.2%). Thirty-two tooth extractions were performed (22 in the maxilla and 10 in the mandible). Breast cancer was the most predominant neoplasm (70.6%), being metastatic in 35.3% of patients. Also, all patients used intravenous bisphosphonates. Stage 1 MRONJ was diagnosed in three patients (17.6%), representing three (9.4%) of all tooth extractions. The repair of MRONJ was achieved 30 days after the PENTO protocol. CONCLUSION: The prophylaxis use of PENTO reduced the severity of injuries, was well-tolerated, and showed patient compliance.

Alterations in macrophage polarization in the craniofacial and extracranial skeleton after zoledronate application and surgical interventions - an in vivo experiment.

Purpose: Medication-related osteonecrosis occurs exclusively in the jaw bones. However, the exact pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) and the unique predisposition of the jaw bones have not been elucidated, making its treatment a challenge. Recent evidence indicates that macrophages might play a pivotal role in MRONJ pathogenesis. The aim of the present study was to compare the macrophage populations between the craniofacial and extracranial skeleton and to investigate the changes induced by zoledronate (Zol) application and surgical interventions. Materials and methods: An in vivo experiment was performed. 120 wistar rats were randomized to 4 groups (G1, G2, G3, G4). G1 served as an untreated control group. G2 and G4 received Zol injections for 8 weeks. Afterwards, the right lower molar of the animals from G3 and G4 was extracted and the right tibia osteotomized followed by osteosynthesis. Tissue samples were taken from the extraction socket and the tibia fracture at fixed time points. Immunohistochemistry was conducted to determine the labeling indexes of CD68+ and CD163+ macrophages. Results: Comparing the mandible and the tibia, we observed a significantly higher number of macrophages and a heightened pro-inflammatory environment in the mandible compared to the tibia. Tooth extraction caused an increase of the overall number of macrophages and a shift toward a more pro-inflammatory microenvironment in the mandible. Zol application amplified this effect. Conclusion: Our results indicate fundamental immunological differences between the jaw bone and the tibia, which might be a reason for the unique predisposition for MRONJ in the jaw bones. The more pro-inflammatory environment after Zol application and tooth extraction might contribute to the pathogenesis of MRONJ. Targeting macrophages might represent an attractive strategy to prevent MRONJ and improve therapy. In addition, our results support the hypothesis of an anti-tumoral and anti-metastatic effect induced by BPs. However, further studies are needed to delineate the mechanisms and specify the contributions of the various macrophage phenotypes.

Endodontic treatment of odontogenic infection in a patient at risk of medication-related osteonecrosis of the jaw: a case report and review of treatment criteria.

Medication-related osteonecrosis of the jaw (MRONJ) is an uncommon and severe condition in patients who are receiving treatment with antiresorptive and/or antiangiogenic drugs, which are frequently used to treat or prevent cancer metastases. The treatment of MRONJ is challenging because the choice of a specific dental treatment depends on several factors, including the systemic condition of the patient, type and dosage of medications, and clinical and radiographic characteristics of the dental lesions. This case report describes the conservative endodontic treatment of an odontogenic infection in a patient at risk of developing MRONJ owing to bisphosphonate treatment. Endodontic retreatment was performed to control the odontogenic infection and avoid tooth extraction. Certain factors favor the use of a conservative approach, such as a localized and small infection, the absence of systemic factors (such as metabolic disorders or medications) that can impair bone healing, and good oral hygiene.

[Preserving the oral health of patients on antiresorptive drugs]. / Préserver la santé orale des patients sous antirésorbeurs osseux.

PRESERVING THE ORAL HEALTH OF PATIENTS ON ANTIRESORPTIVE DRUGS. For many years, antiresorptive medication have proven their effectiveness in reducing the risk of pathological fractures in osteoporotic or tumoral bone. However, bisphosphonates and denosumab may, in rare cases, induce osteonecrosis of the jaw, especially when prescribed for malignant disease (bone metastases or multiple myeloma). The presence of oral infections and the performance of invasive procedures, particularly dental avulsions, increase the risk of this complication. The management of osteonecrosis of the jaw is complex, and the prescribing physician and the dental surgeon must implement preventive measures. There are numerous recommendations published by national and international scientific societies that guide practitioners in the oral management of these patients. An oral check-up and oral cavity restoration are strongly recommended before treatment, as well as the implementation of rigorous oral hygiene and regular visits to the dental surgeon. During and after treatment with antiresorptive medication, oral care protocols are used to reduce the risk of osteonecrosis of the jaws and, when it occurs, to manage it.

PRÉSERVER LA SANTÉ ORALE DES PATIENTS SOUS ANTIRÉSORBEURS OSSEUX. Depuis de nombreuses années, les antirésorbeurs osseux ont prouvé leur efficacité dans la diminution du risque de fracture pathologique sur os ostéoporotique ou tumoral. Parmi eux, les bisphosphonates et le dénosumab sont cependant susceptibles d'induire, dans de rares cas, une ostéonécrose des maxillaires, notamment lorsqu'ils sont prescrits pour une pathologie maligne (métastases osseuses ou myélome multiple). La présence de foyers infectieux bucco- dentaires et la réalisation de gestes invasifs, notamment des avulsions dentaires, augmentent le risque de cette complication. La prise en charge de l'ostéonécrose des maxillaires étant complexe, le médecin prescripteur et le chirurgien-dentiste doivent mettre en place des mesures préventives. Il existe de nombreuses recommandations éditées par des sociétés scientifiques nationales et internationales qui guident les praticiens dans la prise en charge bucco- dentaire de ces patients. Un bilan bucco-dentaire et une remise en état de la cavité buccale sont fortement recommandés avant la mise en place du traitement, ainsi que l'instauration d'une hygiène orale rigoureuse et de consultations régulières chez le chirurgien-dentiste. Pendant et après le traitement par antirésorbeurs osseux, des protocoles de soins bucco-dentaires permettent de diminuer le risque d'ostéonécrose des maxillaires et, lorsqu'elle survient, de la prendre en charge.

Osteonecrosis of the jaws in patients under osteoporosis treatment: a nine-year experience report.

Objective: This study aimed to report the experience of medication-related osteonecrosis of the jaws (MRONJ) in osteoporotic patients for nine years, and their associated initiating factors. Materials and methods: The numbers of invasive oral procedures (IOP) (tooth extraction, dental implant placement, and periodontal procedures) and removable prostheses performed from January 2012 to January 2021 were obtained from the digital records of a large public dental center. There were an estimated 6,742 procedures performed in patients under osteoporosis treatment. Results: Two cases (0.03%) of MRONJ were registered in nine years amongst patients with osteoporosis who had dental treatment at the center. From the 1,568 tooth extractions, one patient (0.06%) developed MRONJ. There was also one case from the 2,139 removable prostheses delivered (0.05%). Conclusion: The prevalence of MRONJ associated with osteoporosis treatment was very low. The protocols adopted seem to be adequate for the prevention of this complication. The findings of this study reinforce the rare frequency of MRONJ associated with dental procedures in patients submitted to the pharmacological management of osteoporosis. An integral analysis of systemic risk factors and oral preventive strategies may be considered regularly in the dental treatment of these patients.

Laser Devices and Autologous Platelet Concentrates in Prevention and Treatment of Medication-Related Osteonecrosis of the Jaws: A Systematic Review.

Background and Objectives: Medication-related osteonecrosis of the jaws (MRONJ) is a disease that affects many patients taking anti-angiogenic and antiresorptive medicines. Since the pathogenetic mechanism is still partially unknown, preventive strategies, as well as treatment alternatives, are needed. Therefore, the aim of this research is to describe the main evidence from the last 10 years of clinical trials regarding the use of auxiliary devices such as autologous platelet concentrates (APCs) and laser, other than their effects against MRONJ disease onset or therapy. Advantages in the healing process and recurrence rates were also analyzed. Materials and Methods: A systematic search of the electronic databases of PubMed and Scopus was carried out. Data from the studies were analyzed, and the risk of bias was evaluated. Results: Nineteen studies between interventional studies, observational studies, and cohort studies have been considered in this review. Conclusions: Based on the studies included, the literature analysis shows that APCs could be a beneficial alternative in preventing and treating MRONJ. Laser technology, as a surgical tool or used on the antimicrobial photodynamic or photobiomodulation side, has been becoming increasingly popular in the last few years. The latest proposal concerning the combination of both auxiliary tools suggests interesting effects, but more studies should be conducted to evaluate eventual relapses and long-term consequences.

Osteonecrosis maxilar inferior asociado a bifosfonatos / Lower jaw osteonecrosis associated with bisphosphonates / Osteonecrose do maxilar inferior associada a bisfosfonatos

Introducción: dada la alta prescripción de bifosfonatos, presentamos sus efectos adversos en la esfera odontológica, siendo una complicación poco frecuente, pero de difícil tratamiento. Sin necesidad de suspender el tratamiento, dado el importante beneficio en cuanto a la prevención de fractura por fragilidad. Estas fracturas causan una alta morbimortalidad en contraposición al bajo riesgo que conlleva la Osteonecrosis mandibular asociada a bifosfonatos. Objetivo: orientar al personal de salud que maneja estos fármacos y quien asiste dichas complicaciones a poseer conocimientos para la prevención de osteonecrosis. Identificar y diferenciar los pacientes con mayor riesgo, de acuerdo con la dosis de bifosfonatos y la frecuencia del tratamiento. Materiales y Método: se realizó una revisión bibliográfica en las siguientes fuentes: Scielo, Google académico, Medline/Pubmed, Biblioteca Virtual en Salud (Brasil), desde el año 2005 a la fecha, idiomas español, portugués e inglés. Los descriptores utilizados son bifosfonatos, mandíbula, maxilar, odontología, osteonecrosis, osteonecrosis de los maxilares asociada a bifosfonatos. Resultados: las últimas pautas de tratamiento fueron modificadas en 2014, por consenso de la Asociación Americana de cirugía Oral y Maxilofacial. La patogénesis de la osteonecrosis maxilar asociada a bifosfonatos no está completamente definida, aunque las publicaciones tratan de explicarla. El riesgo de desarrollarla por terapia oral es menor que por su administración vía intravenosa. Discusión: el médico que prescribe el antirresortivo debe conocer el estado de salud dental de su paciente y, en lo posible, remitirlo a examen con el odontólogo antes de iniciar la terapia con bifosfonatos.

Introduction: Given the high prescription of bisphosphonates, we present their adverse effects in the dental sphere, being an infrequent complication, but difficult to treat. There is no need to suspend treatment, given the important benefit in terms of prevention of fragility fractures. These fractures cause high morbimortality as opposed to the low risk associated with bisphosphonate-associated osteonecrosis of the jaw. Objective: To orient the health personnel who handle these drugs and who assist these complications to have knowledge for the prevention of osteonecrosis. To identify and differentiate patients at higher risk, according to the dose of bisphosphonates and frequency of treatment. Materials and Method: A literature review was performed in the following sources: Scielo, Google academic, Medline/Pubmed, Virtual Health Library (Brazil), from 2005 to date, Spanish, Portuguese and English languages. The descriptors used were bisphosphonates, mandible, maxilla, dentistry, osteonecrosis, osteonecrosis of the jaws associated with bisphosphonates. Results: The latest treatment guidelines were modified in 2014, by consensus of the American Association of Oral and Maxillofacial Surgery. The pathogenesis of bisphosphonate-associated maxillary osteonecrosis is not completely defined, although publications try to explain it. The risk of developing it by oral therapy is lower than by intravenous administration. Discussion: The physician who prescribes the antiresorptive drug should know the dental health status of his patient and, if possible, refer him for examination by a dentist before initiating bisphosphonate therapy.

Introdução: dada a alta prescrição de bisfosfonatos, apresentamos seus efeitos adversos na esfera odontológica, uma complicação rara, mas de difícil tratamento. Sem a necessidade de suspender o tratamento, dado o importante benefício em termos de prevenção de fraturas por fragilidade. Essas fraturas causam alta morbidade e mortalidade, em contraste com o baixo risco associado à osteonecrose da mandíbula associada aos bisfosfonatos. Objetivo: orientar a equipe de saúde que manipula esses medicamentos e que atende a essas complicações para que tenham conhecimento sobre a prevenção da osteonecrose. Identificar e diferenciar os pacientes de maior risco, de acordo com a dose de bisfosfonatos e a frequência do tratamento. Materiais e Método: foi realizada uma revisão da literatura nas seguintes fontes: Scielo, Google acadêmico, Medline/Pubmed, Biblioteca Virtual em Saúde (Brasil), de 2005 até a presente data, idiomas espanhol, português e inglês. Os descritores utilizados foram: bisfosfonatos, mandíbula, maxila, odontologia, osteonecrose, osteonecrose dos maxilares associada a bisfosfonatos. Resultados: as diretrizes de tratamento mais recentes foram modificadas em 2014, por consenso da Associação Americana de Cirurgia Oral e Maxilofacial. A patogênese da osteonecrose da mandíbula associada a bisfosfonatos não está totalmente definida, embora a literatura tente explicá-la. O risco de desenvolvê-la com a terapia oral é menor do que com a administração intravenosa. Discussão: o médico que prescreve o medicamento deve estar ciente do estado de saúde bucal do paciente e, se possível, encaminhar o paciente para ser examinado por um dentista antes de iniciar a terapia com bisfosfonatos.

Clinical values of serum Semaphorin 4D (Sema4D) in medication­related osteonecrosis of the jaw.

BACKGROUND: Bisphosphonates (BPs) are widely used in clinical practice to prevent and treat bone metabolism-related diseases. Medication-related osteonecrosis of the jaw (MRONJ) is one of the major sequelae of BPs use. Early prediction and intervention of MRONJ are of great significance. METHODS: Ninety-seven patients currently on treatment with BPs or with a history of BPs usage and 45 healthy volunteers undergoing dentoalveolar surgery were included in this study. Participants' serum Semaphorin 4D (Sema4D) levels were measured and analyzed before participants underwent surgery (T0) and after a 12-month follow-up (T1). Kruskal-Wallis test and ROC analysis were used to examine the predictive effect of Sema4D on MRONJ. RESULTS: Sema4D levels in serum of patients corresponding to confirmed MRONJ were significantly lower at both T0 and T1 time points compared to non-MRONJ and healthy controls. Sema4D has a statistically predictive effect on the occurrence and diagnosis of MRONJ. Serum Sema4D levels were significantly reduced in MRONJ class 3 patients. MRONJ patients who received intravenous BPs had significantly lower Sema4D levels than those who received oral BPs. CONCLUSION: Serum Sema4D level has predictive value for the onset of MRONJ in BPs users within 12 weeks after dentoalveolar surgery.

Incidence and trend of antiresorptive agent-related osteonecrosis of the jaw from 2016 to 2020 in Kure, Japan.

We investigated the incidence/trend of osteonecrosis of the jaw by antiresorptive agent dose over a 5-year period in Kure city, Japan. The incidence was 24 times higher among osteoporosis patients with low-dose agents and 421 times higher among cancer patients with high-dose agents than in the population without agents. PURPOSE: We launched the registry system of osteonecrosis of the jaw (ONJ) cases in 2015 to investigate the trend in ONJ incidence. The purpose of our study was to estimate the ONJ incidence among patients with antiresorptive agent use by dosage and people without antiresorptive agent use in Kure and its trend from 2016 to 2020. METHODS: From 2016 to 2021, 98 eligible ONJ patients were enrolled. Medication-related ONJ (MRONJ) was diagnosed based on the American Association of Oral and Maxillofacial Surgeons criteria. The annual number of those with and without antiresorptive agents was obtained from the claims database. Antiresorptive agents used for cancer and osteoporosis patients were defined as high- and low-dose medications, respectively. RESULTS: The annual incidence of high-dose MRONJ was 2305.8 per 100,000 and that of low-dose MRONJ was 132.5 per 100,000, while the ONJ incidence among people without antiresorptive agents was 5.1 per 100,000. The incidence ratio was 23.6 (p < 0.001, 95% confidence interval (CI) 13.3-41.8) among osteoporosis patients who used low-dose antiresorptive agents and 420.6 (p < 0.001, 95% CI 220.8-801.4) among cancer patients who used high-dose agents compared with people who did not use these agents. MRONJ incidence increased from 2016 to 2020, but the incidence of high-dose MRONJ decreased, although this was nonsignificant. CONCLUSION: We demonstrated the incidence and trend of ONJ by antiresorptive agent dose over a 5-year period in Kure after launching the multiprofession study. This collaborative study for the early detection and prevention of ONJ will continue.

Biodegradable Dual-Function Nanocomposite Hydrogels for Prevention of Bisphosphonate-Related Osteonecrosis of the Jaw.

This study presents the development of composite hydrogels, comprising a biodegradable polymer (carboxymethyl chitosan (CMCS or CM)) and a mixture of plasma-treated mesoporous silica nanoparticles (PMCM-41 or PM) and amine-functionalized mesoporous silica nanoparticles (NMCM-41 or NM), coloaded with a hydrophilic antibiotic (clindamycin hydrochloride (CDM or C)) and a poorly water-soluble compound (geranylgeraniol (GGOH or G)) for prevention of bisphosphonate-related osteonecrosis of the jaw (BRONJ). The CG-loaded hydrogel stabilities were better maintained when CDM-preloaded PMCM-41 and NMCM-41 were initially used and governed by weight ratios of CDM-loaded PMCM-41 to NMCM-41 and CDM quantity utilized. 5PM240C-1NM-CM demonstrated the best CDM-loaded hydrogel for GGOH postloading. The scanning electron microscopy (SEM) and X-ray microcomputer-tomography (µCT) images of 5PM240C-1NM-CM revealed a porous structure with homogeneously distributed nanoparticles. Two GGOH-loaded 5PM240C-1NM-CM hydrogels were generated after GGOH loadings. Their biphasic drug release profiles were fitted by Ritger-Peppas and Hixson-Crowell models. The copresence of GGOH could hinder CDM releases, while GGOH was released with a slower rate. The hydrogels prolonged the CDM and GGOH releases up to 9 days. They possessed antibacterial activities against Streptococcus sanguinis for up to 14 days and satisfactorily provided good cytoprotection against zoledronic acid for osteoclastic and osteoblastic progenitors, thus preserving a pool of viable progenitor cells that had the capacity to differentiate into mature osteoclasts and osteoblasts in vitro, suggesting their potential local application for prevention of BRONJ.

Risk of medication-related osteonecrosis of the jaw after dental extractions in patients receiving antiresorptive agents - A retrospective study of 240 patients.

This study investigated the incidence, risk factors, and outcome of medication-related osteonecrosis of the jaw after dental extractions in patients receiving antiresorptive agents for osteoporosis or bone metastases. 240 patients with a median drug exposure of 43 months were retrospectively studied. The incidence of MRONJ after dental extraction in the osteoporosis cohort was 2.7 % per person-year (95 % CI 1.6-4.6 %) (n = 13/126), and for the bone metastases cohort 26.4 % per person-year (95 % CI 20.4-34.2 %) (n = 58/114). 92 % of MRONJ cases were stage 1. Dental infection as the reason for extraction increased the osteonecrosis risk in the osteoporosis (OR 22.77; 95 % CI 2.85-181.62; p = 0.003) and bone metastases cohorts (OR 2.72; 95 % CI 1.28-5.81; p = 0.010). Using leukocyte and platelet-rich fibrin reduced this risk by 84 % (p = 0.003), as did antibiotics use by 86-93 % (p = 0.013). Within the bone metastases cohort, an interval since last administration of at least 3 months reduced risk of MRONJ (OR 0.83; 95 % CI 0.72-0.97; p = 0.018). Mucosal healing occurred in 11/13 patients (84.6 %; 95 % CI 54.5-98.1 %) with osteoporosis and 31/58 patients (53.4 %; 95 % CI 40.0-66.7 %) with bone metastases. In conclusion, though the MRONJ risk in this selected population taking antiresorptive agents and presenting to the Oral Maxillofacial Surgery clinic for a dental extraction is considerable and higher in those with dental infections, preventive measures such as antibiotics and use of LRPF membranes may significantly reduce that risk.