The Incidence and Severity of Medication Related Osteonecrosis of the Jaws is Similar in Male and Female Mice.

BACKGROUND: Medication related osteonecrosis of the jaws (MRONJ), a rare side-effect of antiresorptive medications, is described as exposed bone in the oral cavity that lasts for at least 8 weeks. Most studies report a female predilection for MRONJ; these findings could be due to the increased use of antiresorptives in females, or due to inherent differences between male versus female patients. PURPOSE: The purpose of this study was to measure and compare the incidence and severity of osteonecrosis of the jaws (ONJ) between male and female mice. STUDY DESIGN, SETTING, SAMPLE: We designed a randomized in-vivo animal study utilizing male and female mice treated with zoledronic acid (ZA). Experimental periodontitis was induced in 24 male and 24 female mice using a silk ligature following administration of saline or a potent bisphosphonate. After 8 weeks, animals were evaluated radiographically and histologically. INDEPENDENT VARIABLE: The independent variables were sex (male vs female) and treatment group (ZA vs saline control). Treatment was randomly assigned with balanced distribution between male and female animals. MAIN OUTCOME VARIABLE: The main outcome variable was ONJ status coded as present or absent. ONJ was defined as present if there was histologic contact between the ligature and the alveolar bone. Secondary outcomes of interest were radiographic and histologic parameters. ANALYSIS: Statistical differences were analyzed using a two-way analysis of variance with Tukey's post hoc test using a P value of 0.05 for significance. RESULTS: The final sample was composed of 24 vehicle treated and 24 ZA treated animals. In vehicle treated animals, 8% of female and 8% of male animals developed ONJ. In ZA treated animals, 83% of female and 92% of male animals developed ONJ. Sex was not associated with the risk (measured as incidence of disease) for developing ONJ or in the radiographic or histologic parameters that were assessed (P values >.1). CONCLUSIONS: Sex does not appear to affect the incidence of MRONJ or the severity of the disease as assessed by the radiographic and histologic parameters.

Bone-Level Tapered Implants for Single Tooth Replacement: Immediate vs Delayed Placement-A Multicenter Randomized Controlled, 1-Year, Non-inferiority Clinical Study.

PURPOSE: To compare the outcomes of immediate and delayed implant placement with bone-level tapered implants. MATERIALS AND METHODS: In this post-market, multicenter prospective randomized controlled study with a primary endpoint of 1 year, 53 patients were randomized to receive either immediate implant placement (test group) or delayed implant placement (control group). The mean crestal bone level changes from implant loading to 12 months postloading were measured using standardized digital periapical radiographs. Changes in facial plate thickness (as measured on CBCT images), implant success and survival, implant stability, soft tissue changes, patient-centered outcomes, and adverse events were measured to assess outcomes between the test and control treatments at 12 months postloading. RESULTS: Of the original 53 patients, 46 patients completed the study (23 in each group). Mean bone changes from loading to the 12-month follow-up were recorded with no statistically significant difference (P = .950) between the groups. The hypothesis was confirmed that immediate implant placement (test) in extraction sockets produces in similar outcomes as delayed placement (control). The test group was found to be similar to the control group (P = .022) in terms of mean changes in facial plate thickness. Implant survival and success were 95.8% in the test group and 92% in the control group. Stability in the control group was superior at the time of surgery, but there was no difference between the groups at implant loading, producing a nonsignificant P value of .563). CONCLUSIONS: This randomized controlled multicenter study showed comparable outcomes 1 year after prosthetic loading in the immediate and delayed implant placement groups.

The Implant-borne Articulation Splint in Fibula Free Flap Mandibular Reconstruction: A Technical Note.

Computer-aided design and computer-aided manufacturing and digitally simulated surgeries have revolutionized maxillomandibular reconstruction. In particular, this technology has increased the accuracy and facilitated the process of dental implantation in fibula free flaps. Despite the efficacy of virtual planning, there is a minor degree of translational difference between digital and intraoperative measurements, which may affect the precision of implant and fibula orientations. This is especially concerning during the last stage of fibula insetting, where the graft segments have the potential to roll, yaw, or pitch. The objective of this study is to describe an advanced prosthodontic technique that ensures the fibula grafts and implants remain in a restorable position during final insetting. We describe the technique and workflow of the implant-borne articulation splint through a case presentation and demonstrate results at 4 months postoperative and postradiotherapy. Given the degree of investment placed in virtual planning, free flap reconstruction, and endosteal implants, a technique that ensures optimal restorability of each implant is pivotal. Larger studies are still required to fully elucidate the cost-effectiveness and long-term results of the implant-borne articulation splint.

ITI consensus report on zygomatic implants: indications, evaluation of surgical techniques and long-term treatment outcomes.

OBJECTIVES: The aim of the ITI Consensus Workshop on zygomatic implants was to provide Consensus Statements and Clinical Recommendations for the use of zygomatic implants. MATERIALS AND METHODS: Three systematic reviews and one narrative review were written to address focused questions on (1) the indications for the use of zygomatic implants; (2) the survival rates and complications associated with surgery in zygomatic implant placement; (3) long-term survival rates of zygomatic implants and (4) the biomechanical principles involved when zygoma implants are placed under functional loads. Based on the reviews, three working groups then developed Consensus Statements and Clinical Recommendations. These were discussed in a plenary and finalized in Delphi rounds. RESULTS: A total of 21 Consensus Statements were developed from the systematic reviews. Additionally, the group developed 17 Clinical Recommendations based on the Consensus Statements and the combined expertise of the participants. CONCLUSIONS: Zygomatic implants are mainly indicated in cases with maxillary bone atrophy or deficiency. Long-term mean zygomatic implant survival was 96.2% [95% CI 93.8; 97.7] over a mean follow-up of 75.4 months (6.3 years) with a follow-up range of 36-141.6 months (3-11.8 years). Immediate loading showed a statistically significant increase in survival over delayed loading. Sinusitis presented with a total prevalence of 14.2% [95% CI 8.8; 22.0] over a mean 65.4 months follow-up, representing the most common complication which may lead to zygomatic implant loss. The international experts suggested clinical recommendations regarding planning, surgery, restoration, outcomes, and the patient's perspective.

Complementary modulation of BMP signaling improves bone healing efficiency.

The bone morphogenetic protein (BMP) signaling pathway plays a crucial role in bone development and regeneration. While BMP-2 is widely used as an alternative to autograft, its clinical application has raised concerns about adverse side effects and deteriorated bone quality. Therefore, there is a need to develop more sophisticated approaches to regulate BMP signaling and promote bone regeneration. Here, we present a novel complementary strategy that targets both BMP antagonist noggin and agonist Trb3 to enhance bone defect repair without the application of exogenous BMP-2. In vitro studies showed that overexpression of Trb3 with simultaneous noggin suppression significantly promotes osteogenic differentiation of mesenchymal stem cells. This was accompanied by increased BMP/Smad signaling. We also developed sterosome nanocarriers, a non-phospholipid liposomal system, to achieve non-viral mediated noggin suppression and Trb3 overexpression. The gene-loaded sterosomes were integrated onto an apatite-coated polymer scaffold for in vivo calvarial defect implantation, resulting in robust bone healing compared to BMP-2 treatments. Our work provides a promising alternative for high-quality bone formation by regulating expression of BMP agonists and antagonists.

Guided and Navigation Implant Surgery: A Systematic Review.

Purpose: To evaluate how guided and navigation surgical approaches for implant placement affect survival and accuracy. Materials and Methods: An electronic literature search was conducted in PubMed/Medline and the Cochrane Library. The reviews were refereed by two independent investigators using the following PICO question: population-patients with missing maxillary or mandibular teeth; intervention-dental implant guided surgery, dental implant navigation surgery; comparison-conventional implant surgery or historical control; outcome-implant survival, implant accuracy. Single-arm, weighted meta-analyses were performed on navigational and static guided surgery groups for cumulative survival rate and accuracy of implant placement (ie, angular, depth, and horizontal deviation). Group metrics with less than five reports were not synthesized. The study was compiled under PRISMA 2020 guidelines. Results: A total of 3,930 articles were screened. Full-text review of 93 articles resulted in a total of 56 articles included for quantitative synthesis and analysis. Implant placement with a fully guided approach resulted in the following means and 95% CI: cumulative survival rate of 97% (96%, 98%), angular deviation of 3.8 degrees (3.4 degrees, 4.2 degrees), depth deviation of 0.5 mm (0.4 mm, 0.6 mm), and horizontal deviation at the implant neck of 1.2 mm (1.0 mm, 1.3 mm). Implant placement with a navigation approach resulted in an angular deviation of 3.4 degrees (3.0 degrees, 3.9 degrees), horizontal deviation at the implant neck of 0.9 mm (0.8 mm, 1.0 mm), and horizontal deviation at the implant apex of 1.2 mm (0.8 mm, 1.5 mm). Conclusion: Static guided and navigation surgical approaches for dental implant placement have survival rates comparable to historical controls. Accuracy of implant placement does not differ markedly between these two approaches.

Does American Society of Anesthesiologist classification effect hospital course and postoperative complications following oral and maxillofacial surgical procedures?

OBJECTIVE: The purpose of the present study was to assess the duration of operative time and outcomes related to patients with an increased American Society of Anesthesiologists (ASA) Physical Status classification in the setting of hospital-based maxillofacial surgical procedures. STUDY DESIGN: The study was a retrospective multi-institutional cohort study using the American College of Surgeons National Surgical Quality Improvement Program database to enroll patients who underwent maxillofacial procedures between 2012 and 2019. The primary independent variable was ASA Physical Status Classification (I, II, III, IV). Descriptive, univariate, and multiple logistic regression statistics were used to evaluate the relationship between ASA classification, body mass index (BMI), operative time, and perioperative complications. RESULTS: The study cohort was comprised of 1807 patients, with 946 males and 861 females. The ASA Physical Status Classification ranged from class I to IV. On bivariate analysis, patients classified as ASA III (286 [IQR 152-503], P < .001) and ASA IV (412 [IQR 156.5-547.5], P = .003) were associated with longer operative times. The risk of perioperative complications was 2.6% for ASA I patients (n = 19), 6.3% for ASA II (n = 48; P = .005), 24.5% for ASA III (n = 76; P < .001), and 55.0% for ASA IV (n = 11; P < .001). On multivariate-adjusted analysis, using ASA I as the reference, ASA III (ß +53.2 minutes, 95% CI +28.6 to +77.8, P < .001) and ASA IV (ß +81.5 minutes, 95% CI +21.0 to +141.9, P = .008) were variables associated with longer operative time. CONCLUSIONS: Increased ASA Physical Status Classification was associated with increased operative time and perioperative complications.

Ghost Cell Odontogenic Carcinoma: A Case Report and Literature Review.

Ghost cell odontogenic carcinoma (GCOC) is an exceptionally rare malignant odontogenic neoplasm with a significant potential for aggressive growth. Although the literature on this tumor is limited, its high recurrence rates suggest that early and multimodal intervention may be beneficial. This study reports a case of GCOC of the mandible that was successfully treated with surgical resection, reconstruction, and radiation. A comprehensive literature review was performed, and the relevant genomic and histopathological characteristics of this malignancy were determined. Laryngoscope, 133:830-833, 2023.

Inhibition of HMGB1/RAGE Signaling Reduces the Incidence of Medication-Related Osteonecrosis of the Jaw (MRONJ) in Mice.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of antiresorptive or antiangiogenic medications, used in the treatment of bone malignancy or osteoporosis. Bone necrosis, mainly represented by osteocytic death, is always present in MRONJ sites; however, the role of osteocyte death in MRONJ pathogenesis is unknown. High mobility group box 1 (HMGB1) is a non-histone nucleoprotein that in its acetylated form accumulates in the cytoplasm, whereas non-acetylated HMGB1 localizes in the nucleus. SIRT1 deacetylase regulates cellular localization of HMGB1. Interestingly, HMGB1 is released during cell necrosis and promotes inflammation through signaling cascades, including activation of the RAGE receptor. Here, we utilized a well-established mouse MRONJ model that utilizes ligature-induced experimental periodontitis (EP) and treatment with either vehicle or zolendronic acid (ZA). Initially, we evaluated HMGB1-SIRT1 expression in osteocytes at 1, 2, and 4 weeks of treatment. Significantly increased cytoplasmic and perilacunar HMGB1 expression was observed at EP sites of ZA versus vehicle (Veh) animals at all time points. SIRT1 colocalized with cytoplasmic HMGB1 and presented a statistically significant increased expression at the EP sites of ZA animals for all time points. RAGE expression was significantly higher in the submucosal tissues EP sites of ZA animals compared with those in vehicle group. To explore the significance of increased cytoplasmic and extracellular HMGB1 and increased RAGE expression in MRONJ pathogenesis, we used pharmacologic inhibitors of these molecules. Combined HMGB1/RAGE inhibition resulted in lower MRONJ incidence with statistically significant decrease in osteonecrotic areas and bone exposure versus non-inhibitor treated ZA animals. Together, our data point to the role of HMGB1 as a central alarmin, overexpressed at early phase of MRONJ pathogenesis during osteocytic death. Moreover, HMGB1-RAGE pathway may represent a new promising therapeutic target in patients at high risk of MRONJ. © 2022 American Society for Bone and Mineral Research (ASBMR).

Epigenetic Regulation of NGF-Mediated Osteogenic Differentiation in Human Dental Mesenchymal Stem Cells.

Nerve growth factor (NGF) is the best-characterized neurotrophin and is primarily recognized for its key role in the embryonic development of the nervous system and neuronal cell survival/differentiation. Recently, unexpected actions of NGF in bone regeneration have emerged as NGF is able to enhance the osteogenic differentiation of mesenchymal stem cells. However, little is known regarding how NGF signaling regulates osteogenic differentiation through epigenetic mechanisms. In this study, using human dental mesenchymal stem cells (DMSCs), we demonstrated that NGF mediates osteogenic differentiation through p75NTR, a low-affinity NGF receptor. P75NTR-mediated NGF signaling activates the JNK cascade and the expression of KDM4B, an activating histone demethylase, by removing repressive H3K9me3 epigenetic marks. Mechanistically, NGF-activated c-Jun binds to the KDM4B promoter region and directly upregulates KDM4B expression. Subsequently, KDM4B directly and epigenetically activates DLX5, a master osteogenic gene, by demethylating H3K9me3 marks. Furthermore, we revealed that KDM4B and c-Jun from the JNK signaling pathway work in concert to regulate NGF-mediated osteogenic differentiation through simultaneous recruitment to the promoter region of DLX5. We identified KDM4B as a key epigenetic regulator during the NGF-mediated osteogenesis both in vitro and in vivo using the calvarial defect regeneration mouse model. In conclusion, our study thoroughly elucidated the molecular and epigenetic mechanisms during NGF-mediated osteogenesis.