Polysacharide of Agaricus blazei gel mitigates bone necrosis in model of the jaws related to bisphosphonate via Wnt signaling.

To investigate de effect of PAb gel on the bone tissue of rats submitted to Bisphosphonate-related osteonecrosis of the jaws (BRONJ). Initially, 54 animals were submitted to BRONJ model by Zoledronic Acid (ZA) (0.1 mg/kg 3x/wk for 9 wk, ip), followed by the 1st upper left molar extraction at the 8th wk. After tooth removal, the animals were divided into 3 groups, ZA that received placebo gel or PAb gel that received 1% PAb gel, inside the dental alveolus. The control Group (CONTROL) received 0.1 mg/kg of 0.9% saline and then placebo gel. Three weeks after tooth extraction, the animals were euthanized, and maxillae were colleted for macroscopic, radiographic, histological and Raman spectomery assays. Additionally, GSK3b, beta-catenin, and Runx2 mRNA expressions were determined. Blood samples were collected for the analysis of Bone-specific alkaline phosphatase (BALP) levels. PAb gel improved mucosal healing, increased the number of viable osteocytes, while it reduced the number of empty lacunae, as well as the amount of bone sequestration. Furthermore, PAb gel positively influenced the number and functionality of osteoblasts by stimulating Wnt signaling, thereby inducing bone remodeling. Additionally, PAb gel contributed to improved bone quality, as evidenced by an increase in bone mineral content, a decrease in bone solubility, and an enhancement in the quality of collagen, particularly type I collagen. PAb gel mitigated bone necrosis by stimulating of bone remodeling through Wnt signaling and concurrently improved bone quality. PAb gel emerges as a promising pharmacological tool for aiding in BRONJ therapy or potentially preventing the development of BRONJ.

Dental Implant Failure in Post-Menopausal Women on Oral Bisphosphonates: A Systematic Review and Meta-Analysis.

A systematic review was designed to investigate the effect of treatment with oral bisphosphonate (BP) on osseointegration of dental implants and the incidence of BP-related osteonecrosis of the jaw (BRONJ) in post-menopausal women. Multiple electronic databases, including MEDLINE (PubMed), EMBASE, and SCOPUS, were searched to find all eligible articles published since 1990. All titles and abstracts retrieved by searching information sources were evaluated independently by two authors against the eligibility criteria. The number of cases ranged from 11 to 235, and the number of controls ranged from 14 to 343. Alendronate was used in all other studies. Risedronate was used in six studies, while ibandronate was used in four studies. The number of implants in cases ranged from 25 to 1267, while in controls, the number of implants ranged from 28 to 1450. The time between the placement of implant and the follow-up visit ranged from 4-6 months to 8 years. The results show that out of 2582 placed implants, 50 (1.94%) failed in BP-treated patients. This is while out of 4050 placed implants, 188 (4.6%) failed in the non-BP group. The results from the meta-analysis demonstrated that BP therapy is significantly associated with increased implant failure rates (RR (95% CI)=1.73 (1.03-2.83), p=0.04). Overall, the qualitative assessment of this review suggests that oral treatment with BPs in post-menopausal women does not increase the rate of dental implant failure. Thus, further studies with larger sample sizes should compare BP and non-BP groups in regard to dental implants.

Impact of Bisphosphonate Therapy on Oral Health in Patients with Breast and Prostate Cancer and Bone Metastases: A Comprehensive Study.

This study investigates the impact of bisphosphonate therapy on the stomatognathic system in 80 patients with cancer of the breast and prostate with bone metastases. Bisphosphonates are integral for managing skeletal complications in these malignancies but are associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ), affecting 0.8-18.5% of patients. BRONJ manifests with pain, neuropathy, tissue swelling, mucosal ulceration, tooth mobility, and abscesses, yet its pathogenesis remains elusive, complicating risk prediction. The research employed comprehensive dental and radiological evaluations. Dental status was assessed using DMFT and OHI-S indices, Eichner's classification, and clinical periodontal measurements like the pocket depth (PD), clinical attachment loss (CAL), and modified Sulcus Bleeding Index (mSBI). A radiological analysis included panoramic X-rays for radiomorphometric measurements and TMJ lateral radiographs. Results indicated a significant decline in oral hygiene in patients with cancer after bisphosphonate therapy, marked by increased DMFT and OHI-S scores. Periodontal health also showed deterioration, with increased PD and CAL readings. The incidence of BRONJ symptoms was noted, although exact figures are not quantified in this abstract. The study also revealed changes in radiomorphometric parameters, suggesting bisphosphonates' impact on bone density and structure. No substantial alterations were observed in TMJ function, indicating a need for extended observation to understand bisphosphonates' long-term effects on the stomatognathic system. These findings highlight the importance of continuous dental monitoring and prophylaxis in patients undergoing bisphosphonate therapy. Implementing meticulous oral care protocols is essential for mitigating BRONJ risk and managing the complex oral health challenges in patients with cancer.

Medical and Dental Professions' Varying Levels of Awareness Regarding Medication-related Osteonecrosis of the Jaw in Saudi Arabia? A Cross-sectional Study.

AIMS: This study aimed to assess the awareness of the risk of medication-related osteonecrosis of the jaw (MRONJ) among general dental practitioners (GDPs) and primary care physicians (PCPs), focusing on the clinical implications and coordination of treating or identifying high-risk patients. MATERIALS AND METHODS: Two Google Forms electronic questionnaires were distributed to 724 GDPs and 617 PCPs in primary care settings. One for PCPs with eight multiple choice questions and the other for GDPs with 10 multiple choice questions. A clinical case scenario and a section on open-ended comments were included in both questionnaires. The data obtained from each group were statistically analyzed and compared. RESULTS: A total of 239 GDPs and 220 PCPs participated in the study, with a response rate of 34.23%. The mean age of participants was 29.5 years and 54.35% were females (51.2% and 57.5% in the GDPs and PCPs group, respectively). Most participants had graduated from Saudi Arabia. Almost all dentists were aware of osteonecrosis of the jaw (95.1%), 68.3% of them were aware of the guidelines regarding bisphosphonate-related osteonecrosis of the jaw (BRONJ) and MRONJ, 60.5% rated their general knowledge about MRONJ as very poor to poor, and 91.8% did not know any guidelines regarding BRONJ or MRONJ. Among the participants, 75.3% did not know how MRONJ was present in the oral cavity. A total of 69.9% of participants were unaware of other factors associated with an increased risk of MRONJ. CONCLUSION: MRONJ risk awareness varies greatly between dentists who diagnose and manage patients in dental clinics and physicians who write about medicines and therapies. Counseling sessions and greater coordination between dental and medical specialists are strongly suggested while prescribing antiresorptive drugs to prevent the consequent development of MRONJ. CLINICAL SIGNIFICANCE: This study shows a significant lack of knowledge regarding MRONJ among GDPs and PCPs, which may affect the prevention and treatment of patients. Therefore, we urge GDPS and PCPs to take more information from scientific sources on this topic and more cooperation from specialties for the benefit of patients. How to cite this article: Aljohani MH, Aljohani AS, Aljohani RM, et al. Medical and Dental Professions' Varying Levels of Awareness Regarding Medication-related Osteonecrosis of the Jaw in Saudi Arabia? A Cross-sectional Study. J Contemp Dent Pract 2024;25(1):62-67.

Zoledronic Acid Accelerates ER Stress-Mediated Inflammation by Increasing PDE4B Expression in Bisphosphonate-Related Osteonecrosis of the Jaw.

Long-term administration of bisphosphonates can lead to a significant side effect known as bisphosphonate-related osteonecrosis of the jaw (BRONJ). Although macrophage-mediated inflammation has been established as an important factor in BRONJ, the underlying mechanism remains elusive. In the current study, the roles of endoplasmic reticulum (ER) stress in zoledronic acid (ZOL)-induced inflammation were analyzed in macrophages, and the regulatory mechanism of ER stress activation was next investigated. An in vitro model of BRONJ was established by treating RAW264.7 cells with ZOL. The activation of ER stress was analyzed by western blotting and transmission electron microscopy, and inflammation was assessed by quantitative real-time PCR and enzyme-linked immunosorbent assay. ER stress was significantly activated in ZOL-treated macrophages, and inhibition of ER stress by TUDCA, an ER stress inhibitor, suppressed ZOL-induced inflammation in macrophages. Mechanistically, phosphodiesterase 4B (PDE4B) was significantly increased in ZOL-treated macrophages. Forced expression of PDE4B promoted ER stress and inflammation, whereas PDE4B knockdown decreased ZOL-induced ER stress and inflammation in macrophages. More importantly, PDE4B inhibitor could improve ZOL-induced BRONJ in vivo. These data suggest that ZOL accelerates ER stress-mediated inflammation in BRONJ by increasing PDE4B expression. PDE4B inhibition may represent a potential therapeutic strategy for BRONJ. Subsequent research should concentrate on formulating medications that selectively target PDE4B, thereby mitigating the risk of BRONJ in patients undergoing bisphosphonate treatment.

Rodents as an animal model for studying tooth extraction-related medication-related osteonecrosis of the jaw: assessment of outcomes.

OBJECTIVE: To assess the outcomes of several rodent animal models for studying tooth extraction-related medication-related osteonecrosis of the jaw (MRONJ). DESIGN: After a search of the databases, 2004 articles were located, and 118 corroborated the inclusion factors (in vivo studies in rodents evaluating tooth extraction as a risk factor for the development of MRONJ). RESULTS: Numerous studies attempting to establish an optimal protocol to induce MRONJ were found. Zoledronic acid (ZA) was the most used drug, followed by alendronate (ALN). Even when ZA did not lead to the development of MRONJ, its effect compromised the homeostasis of the bone and soft tissue. The association of other risk factors (dexamethasone, diabetes, and tooth-related inflammatory dental disease) besides tooth extraction also played a role in the development of MRONJ. In addition, studies demonstrated a relationship between cumulative dose and MRONJ. CONCLUSIONS: Both ZA and ALN can lead to MRONJ in rodents when equivalent human doses (in osteoporosis or cancer treatment) are used. Local oral risk factors and tooth-related inflammatory dental disease increase the incidence of MRONJ in a tooth extraction-related rodent model.

Enhancing the Oral Rehabilitation and Quality of Life of Bisphosphonate-Treated Patients: The Role of Dental Implants.

The purpose of this review is to examine the literature on the topic of bisphosphonate-related osteonecrosis of the jaw (BRONJ) and dental implant failure in patients undergoing bisphosphonate (BP) therapy who also received dental implants before, during, or after BP treatment, as compared to healthy patients. This research followed the guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. The "PICO" or population, intervention, comparison, and outcome clinical question was as follows: does the insertion of dental implants in patients receiving bisphosphonate therapy increase the failure and loss of implants or the incidence of bisphosphonate-related osteonecrosis of the jaw compared to healthy patients? The articles published in PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE) up to July 1, 2023, were retrieved using a mix of Medical Subject Heading (MeSH) words and their entry terms. The absence of randomized clinical trials examining this issue underscores the need for additional studies with extended follow-ups to answer outstanding questions. Because of the potential for BRONJ and implant failure, patients receiving bisphosphonate medication should exercise caution when planning dental implant surgery. In addition, when such procedures are carried out, the patient's entire systemic condition must be considered.

Clinical Impact on Dental Implant Survival in Patients Taking Antiresorptive Medications: A Systematic Review and Meta-Analysis.

Dental implants are a predictable option to replace missing teeth. Patients on antiresorptive medications used to treat disorders associated with bone resorption may need dental implants to replace missing teeth. The data on implant failure in patients on antiresorptive medication requiring dental implants, is conflicting and limited. This systematic review aims to investigate if antiresorptive medications have any clinical impact on dental implant survival. Electronic databases were searched until May 2020. The focus question (PICOS): Participants: humans, Interventions: implant placement surgery in patients on antiresorptive medication, Comparisons: patients on antiresorptive medication vs control (patients not on antiresorptive medication), Outcomes: implant survival, and Study design: clinical studies. The protocol of this systematic review was registered in PROSPERO (CRD42020209083). Fourteen nonrandomized studies were selected for data extraction and risk of bias assessment using the ROBINS-1 tool. Only studies with a control were included for the meta-analysis, 8 articles were included in the meta-analysis using implant-level data, and 5 articles were included in the meta-analysis using patient-level data. There was no statistical significance between the 2 groups at the patient level based on 265 patients. However, there was a statistically significant difference at the implant level based on 2697 implants. Therefore, antiresorptive medications, mainly bisphosphonates (BPs), may significantly contribute to implant failure. Antiresorptive medications, especially BPs may reduce implant survival and impair the osseointegration of dental implants. Failed implants in patients on BPs may not lead to osteonecrosis and may be replaced with success.

Depletion of macrophages deteriorates bisphosphonate-related osteonecrosis of the jaw-like lesions in mice.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a potentially intractable disease with no definitive pathophysiology and no treatment and prevention strategies. This study aimed to investigate whether time-selective depletion of macrophages worsens BRONJ-like lesions in mice. A murine model of high-prevalence BRONJ-like lesions in combination with zoledronate/chemotherapeutic drug administration and tooth extraction was created according to the methods of our previous studies. Daily intra-oral submucosal administration of clodronate-loaded liposomes, which temporarily depletes systemic macrophages, was performed immediately after tooth extraction. Spleens, femora, tibiae, and maxillae were dissected 2 weeks after extraction to evaluate BRONJ-like lesions and systemic conditions by micro-computed tomography analysis, histomorphometric and immunofluorescent analyses, and serum chemistry with ELISA. Depletion of macrophages significantly decreased the numbers of local and systemic macrophages and osteoclasts on the bone surface, which markedly worsened osseous healing, with increased necrotic bone and empty lacunae in the existing alveolar bone and newly formed bone in the extraction sockets, and soft tissue healing, with decreased collagen production and increased infiltration of polymorphonuclear cells. Interestingly, the depletion of macrophages significantly shifted macrophage polarization to M1 macrophages through an increase in F4/80+CD38+ M1 macrophages and a decrease in F4/80+CD163+ M2 macrophages, with decreases in the total number of F4/80+ macrophages. These data demonstrated that severe inhibition of osteoclasts in bone tissue and polarization shifting of macrophages in soft tissue are essential factors associated with BRONJ.

Outcomes of a Pharmacological Protocol with Pentoxifylline and Tocopherol for the Management of Medication-Related Osteonecrosis of the Jaws (MRONJ): A Randomized Study on 202 Osteoporosis Patients.

Medication-related osteonecrosis of the jaws (MRONJ) is a challenging situation in clinics. Previous studies have shown that pentoxifylline combined with tocopherol proved to be beneficial in patients with osteoradionecrosis, due to their antioxidant and antifibrotic properties. The aim of this randomized study was to evaluate the effect of pentoxifylline and tocopherol in patients that had developed MRONJ after tooth extractions. The study population consisted of 202 Stage I MRONJ female patients with an average age of 66.4 ± 8.3 years, who were divided into two groups. The test group (n = 108) received a pharmacological protocol with pentoxifylline and tocopherol (2 months pre-operatively and 6 months post-operatively). The control group (n = 94) had sequestrectomy operations without any pharmacological preparation. The main outcomes were clinical healing of the mucosa after 1 month, and clinical and radiographic healing of the bone lesion at 6 months. In the test group all patients had mucosal healing and there was only one relapse within 6 months. In the control group, in 17% of the patients the mucosa did not heal, 71% of the patients relapsed within two months, and 7% developed infectious complications (such as abscess or phlegmon). After 6 months, the control group patients with persisting issues were prescribed pentoxifylline and tocopherol, as in the test group. At a subsequent follow-up, all those patients healed completely. Patients were monitored for a period of 7.8 ± 0.3 years, during which no relapse or additional problems were reported. As a conclusion, pentoxifylline and tocopherol protocol seems to be beneficial in the management of MRONJ patients.

Comparison of Different Antibiotic Regimes for Preventive Tooth Extractions in Patients with Antiresorptive Intake-A Retrospective Cohort Study.

In the present study, the impacts on success rates between three different antibiotic regimes in patients receiving preventive tooth extraction during/after antiresorptive treatment were compared. For the retrospective analysis, we enrolled patients who had undergone tooth extraction from 2009 to 2019 according to the specified preventive conditions under antiresorptive therapy. Three antibiotic regimens were distinguished: (Group 1) intravenous for 7 days, (Group 2) oral for 14 days, and (Group 3) oral for 7 days of application. The primary endpoint was the occurrence of medication-related osteonecrosis of the jaw at 12 weeks after surgery. A total of 760 patients and 1143 extraction regions were evaluated (Group 1 n = 719; Group 2 n = 126; Group 3 n = 298). The primary endpoint showed no significant difference in the development of medication-related osteonecrosis of the jaw between the groups studied (Group 1 n = 50/669 (7%); Group 2 n = 9/117 (7%); Group 3 n = 17/281 (6%); p = 0.746). Overall, the success rate was 93% after intervention when preventive measures were followed. With the same success rate, a reduced, oral administration of antibiotics seems to be sufficient regarding the possible spectrum of side effects, the development of resistance and the health economic point of view.

Chronic Periodontal Infection and Not Iatrogenic Interference Is the Trigger of Medication-Related Osteonecrosis of the Jaw: Insights from a Large Animal Study (PerioBRONJ Pig Model).

Background and Objectives: Antiresorptive drugs are widely used in osteology and oncology. An important adverse effect of these drugs is medication-induced osteonecrosis of the jaw (MRONJ). There is scientific uncertainty about the underlying pathomechanism of MRONJ. A promising theory suspects infectious stimuli and local acidification with adverse effects on osteoclastic activity as crucial steps of MRONJ etiology. Clinical evidence showing a direct association between MRONJ and oral infections, such as periodontitis, without preceding surgical interventions is limited. Large animal models investigating the relationship between periodontitis and MRONJ have not been implemented. It is unclear whether the presence of infectious processes without surgical manipulation can trigger MRONJ. The following research question was formulated: is there a link between chronic oral infectious processes (periodontitis) and the occurrence of MRONJ in the absence of oral surgical procedures? Materials and Methods: A minipig large animal model for bisphosphonate-related ONJ (BRONJ) using 16 Göttingen minipigs divided into 2 groups (intervention/control) was designed and implemented. The intervention group included animals receiving i.v. bisphosphonates (zoledronate, n = 8, 0.05 mg/kg/week: ZOL group). The control group received no antiresorptive drug (n = 8: NON-ZOL group). Periodontitis lesions were induced by established procedures after 3 months of pretreatment (for the maxilla: the creation of an artificial gingival crevice and placement of a periodontal silk suture; for the mandible: the placement of a periodontal silk suture only). The outcomes were evaluated clinically and radiologically for 3 months postoperatively. After euthanasia a detailed histological evaluation was performed. Results: Periodontitis lesions could be induced successfully in all animals (both ZOL and NON-ZOL animals). MRONJ lesions of various stages developed around all periodontitis induction sites in the ZOL animals. The presence of MRONJ and periodontitis was proven clinically, radiologically and histologically. Conclusions: The results of this study provide further evidence that the infectious processes without prior dentoalveolar surgical interventions can trigger MRONJ. Therefore, iatrogenic disruption of the oral mucosa cannot be the decisive step in the pathogenesis of MRONJ.

Location and Gender Differences in Osteonecrosis of the Jaws in Patients Treated with Antiresorptive and Antineoplastic Drugs Undergoing Dentoalveolar Surgical, Systematic Review with Meta-Analysis and Trial Sequential Analysis.

In the treatment and prevention of osteoporosis and more generally of neoplastic and metabolic pathologies affecting bone tissues, antiresorption drugs such as bisphosphonates and monoclonal antibody are used. Bisphosphonates have been linked to cases of osteonecrosis of the jaws since 2003 by Marx, with more and more evidence over the next two decades; together with bisphosphonate drugs, cases relating to the use of monoclonal drugs have been subsequently added. Among the main independent risk factors, we have extraction procedures in oral surgery that can affect both the mandible and the maxilla and the anterior or posterior sectors. The incidence of MRONJ treated with oral bisphosphonates ranges from 0.5% to 3% according to studies; this incidence would appear to be higher in patients treated with antiresorptive agents with neoplastic diseases. Many pathologies including those in which antiresorptive drugs are used show differences in prevalence in relation to sex; similarly, there could be differences in the incidence of cases of osteonecrosis based on gender in patients undergoing dentoalveolar surgery. Therefore, the objective of this systematic review and trial sequential analysis was to identify and quantify whether there is a proportionally greater risk of MRONJ in male or female subjects and whether there is evidence of greater involvement of osteonecrosis at several extraction sites, differentiating them into mandibular or maxilla and in the anterior or posterior sector. The revision protocol followed the indications of the Cochrane Handbook, and were recorded in Prospero, while the drafting of the manuscript was based on PRISMA. The results of the systematic review, after the study identification and selection process, included a total of 24 studies. The results of the meta-analysis reports: odds ratio (random effects model): 1.476 (0.684, 3.184) between male and female; odds ratio (random effects model): 1.390 (0.801, 2.412) between mandible and maxillary, and an odds ratio value of 0.730 (0.250, 2.137) between the anterior and posterior extraction sites. In conclusion, we can see that there was a trend in the onset of MRONJ as a complication of dentoalveolar surgical procedures, which proportionally mostly involved the male sex and the posterior mandibular sectors, however, this trend must be further confirmed by additional studies.

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.

Diagnostic accuracy comparing OPT and CBCT in the detection of non-vital bone changes before tooth extractions in patients with antiresorptive intake.

OBJECTIVES: To compare the diagnostic accuracy in detecting early non-vital bone changes between orthopantomography (OPT) and cone-beam computed tomography (CBCT) in correlation with histopathological findings before tooth extractions in patients with antiresorptive (AR) intake. SUBJECTS: Patients with an indication tooth extraction who had received OPT and CBCT preoperatively while or after undergoing AR treatment were prospectively enrolled over a 24-month period in the progesterone in spontaneous miscarriage (PRISM) trial. Imaging studies were randomly analyzed by three examiners for early non-vital bone changes using specific predefined characteristics and a 5-level scale (1 definite absence of criteria to 5 definite presence of criteria). Sensitivity and specificity values were calculated in correlation with the histopathologically evaluated bone samples at the time point of tooth extraction. RESULTS: One hundred thirty patients with 237 treated extraction sites met the inclusion criteria. For all images evaluated by all examiners, CBCT (430/492; 87.4%; receiver operating characteristic [ROC]: area under the curve [AUC] = 0.88; p < 0.001) was more likely to detect histopathologically confirmed non-vital bone than the OPT (132/492; 26.8%; ROC: AUC = 0.562; p = 0.115). CONCLUSIONS: In the detection of non-vital bone changes, CBCT is superior to OPT in both sensitivity and specificity. Specific imaging characteristics allow for the prediction of early non-vital bone changes already at the time before tooth extractions.

[Bisphosphonate-related osteonecrosis of the jaws]. / Bisfosfonatnye osteonekrozy chelyustei.

The number of patients with metabolic osteopathies and oncological diseases occurring with the formation of bone metastases is constantly growing and requires special attention not only of oncologists, but also maxillofacial surgeons, dental surgeons and periodontists, due to severe complications from the oral cavity, against the background of antiresorptive therapy with bisphosphonates. These drugs are associated with the development of necrotic processes of the jaw bones and surrounding tissues. It is worth noting the fact that the development of complications after taking these drugs leads to a significant increase in the suffering of patients. The importance of an integrated approach to the treatment and prevention of such complications is extremely important, as it reduces the risk of possible complications and improves the quality of life of this group of patients.

Structural insights into the binding of zoledronic acid with RANKL via computational simulations.

Zoledronic acid (ZOL) inhibits receptor activator of nuclear factor-κB ligand (RANKL) and reduces bone turnover. This plays an important role in the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Previous reports have shown that ZOL binds to the enzyme farnesyl pyrophosphate synthase (FPPS) to block its activity. However, the mechanism of action of ZOL and its interaction with RANKL is still unclear. In this study, we confirmed that ZOL significantly suppressed the bone remodeling in ZOL-treated rats, investigated whether ZOL could bind to RANKL and examined the interactions between these molecules at the atomic level. Surface plasmon resonance (SPR) assay was performed to validate that ZOL could directly bind to RANKL in a dose dependent manner, and the equilibrium constant was calculated (KD = 2.28 × 10-4 M). Then, we used molecular docking simulation to predict the binding site and analyze the binding characteristics of ZOL and RANKL. Through molecular dynamics simulation, we confirmed the stable binding between ZOL and RANKL and observed their dynamic interactions over time. Binding free energy calculations and its decomposition were conducted to obtain the binding free energy -70.67 ± 2.62 kJ/mol for the RANKL-ZOL complex. We identified the key residues of RANKL in the binding region, and these included Tyr217(A), Val277(A), Gly278(A), Val277(B), Gly278(B), and Tyr215(C). Taken together, our results demonstrated the direct interaction between ZOL and RANKL, indicating that the pharmacological action of ZOL might be closely related to RANKL. The design of novel small molecules targeting RANKL might reduce the occurrence of BRONJ.

aPDT associated with sequestrectomy in the treatment of osteonecrosis in cancer patients with metastasis: Case report.

INTRODUCTION AND IMPORTANCE: Bisphosphonates are drugs that have demonstrated effectiveness in the prevention and treatment of bone metastases from malignant neoplasms and other diseases of bone metabolism and although they represent a risk factor for osteonecrosis. PRESENTATION OF CASE: The present case depicts a patient with prostate neoplasia and metastases, referred to the dental department because he presented severe periodontal infection in the previous incisors of the mandible and was under treatment by intravenous zoledronic acid. A panoramic x-ray showed a marked bone loss with a periodontal infection that indicated the tooth exodontia of the affected teeth. However, 2 months after the removal of the dental elements, bone sequestration was detected a CT scan confirmed that. Surgery was then performed to remove mandibular bone sequestration and photodynamic therapy (aPDT) treatment for decontamination of the affected area. DISCUSSION: There was a tissue reconstitution of the site in 3 weeks and total eradication of bone necrosis with aPDT treatment associated with bone sequestration. CONCLUSION: aPDT has proven to be an effective complementary treatment for the process of tissue decontamination and photostimulation in cases of BRONJ.

Porphyromonas gingivalis Induces Bisphosphonate-Related Osteonecrosis of the Femur in Mice.

One of the most prominent characteristics of bisphosphonate-related osteonecrosis of the jaw(BRONJ) is its site-specificity. Osteonecrosis tends to occur specifically in maxillofacial bones, in spite of a systemic administration of the medicine. Previous studies suggested rich blood supply and fast bone turnover might be reasons for BRONJ. Yet, a sound scientific basis explaining its occurrence is still lacking. The present study aimed to explore the role of Porphyromonas gingivalis (P. gingivalis), an important oral pathogen, on the site-specificity of bisphosphonate-induced osteonecrosis and to elucidate its underlying mechanism. Mice were intraperitoneally injected with zoledronic acid (ZA) or saline for 3 weeks. In the third week, the right mandibular first molars were extracted and circular bone defects with a diameter of 1 mm were created in right femurs. After the operation, drug administration was continued, and P. gingivalis suspension was applied to the oral cavities and femur defects. The mice were killed after four or eight weeks postoperatively. The right mandibles and femurs were harvested for micro-CT and histological analyses. A poor healing of bone defects of both jaws and femurs was noted in mice injected with both ZA and P. gingivalis. Micro-CT analysis showed a decreased bone volume, and histological staining showed an increased number of empty osteocyte lacunae, a decreased collagen regeneration, an increased inflammatory infiltration and a decreased number of osteoclasts. In addition, the left femurs were collected for isolation of osteoclast precursors (OCPs). The osteoclastogenesis potential of OCPs was analyzed in vitro. OCPs extracted from mice of ZA-treated groups were shown to have a lower osteoclast differentiation potential and the expression level of related genes and proteins was declined. In conclusion, we established a mouse model of bisphosphonate-related osteonecrosis of both the jaw and femur. P. gingivalis could inhibit the healing of femur defects under the administration of ZA. These findings suggest that P. gingivalis in the oral cavity might be one of the steering compounds for BRONJ to occur.

Incidence and risk factors associated to Medication-Related Osteo Necrosis of the Jaw (MRONJ) in patients with osteoporosis after tooth extractions. A 12-months observational cohort study.

OBJECTIVE: To evaluate the 12-months incidence of MRONJ after tooth extractions and possible related risk factors in patients with osteoporosis treated by means of oral bisphosphonates. MATERIAL AND METHODS: Forty-five records of osteoporotic patients on therapy with oral bisphosphonates and treated with at least one dental extraction at the Department of Oral Surgery of University of Naples Federico II were selected. All patients were treated using a standardized surgical extraction protocol. At baseline and after 12-months follow-up, the following variables were recorded: "mucosal healing", "gender", "type of drug"; "duration of therapy"; "drug holiday". The collected data were analyzed and a linear regression analysis was performed to assess a possible correlation with onset MRONJ. RESULTS: A total of 159 tooth extraction in 43 females (95.6%) and in 2 males (4.4%) with a mean age of 67.5 ± 3 years were available for the analysis. The majority part of patients was on therapy with alendronate (23; 51.2%), 11 patients (24.4%) were treated with risedronate and 11 (24.4%) with ibandronate. Before oral surgery, 84% of the patients showed a low-medium risk of MRONJ, while in 16% of the patients a medium-high risk was recorded. After 12-months follow-up, osteonecrosis was observed in 1 patient, with an overall incidence of MRONJ of 0.6%. The linear regression showed a significant correlation with MRONJ onset only for "gender" variable, with a R2 of 0.489. CONCLUSIONS: Within their limitations, the outcomes of the study indicate that the risk of MRONJ after tooth extraction in osteoporotic patients taking bisphosphonates for OS is very low. A prolonged and specific antibiotic and antiseptic therapy, in addition to a surgical procedure as little traumatic as possible, will allow to perform oral surgery safely.