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.

Immediate loading of a fully tapered implant with deep apical threads placed in healed alveolar ridges vs. immediate extraction sockets.

OBJECTIVES: Immediate implant placement and loading is a practice that continues to gain traction in implant dentistry because it reduces treatment time and improves satisfaction. Novel implant designs that facilitate increased primary stability, while not compromising osseointegration and long-term survival are important to offer immediate solutions for missing teeth. Here, we hypothesize that fully tapered implants can obtain successful osseointegration with high survival rates after immediate loading in fresh extraction sockets and healed sites. MATERIALS AND METHODS: A total of 13 swine with 73 implants were evaluated. Fully tapered or apically tapered implants were placed in extraction sockets and healed sites. Insertion torque and resonance frequency analysis were determined at placement and euthanasia. Animals were evaluated at: placement, and 1-week and 12-weeks after placement. Bone to Implant Contact (BIC), Bone Area/Total Area (BA/TA), and first BIC (fBIC) analyses were conducted. RESULTS: The fully tapered implant achieved similar primary stability with lower insertion torque at placement. Apically and fully tapered implants had comparable BIC (50.1% vs 59.4%) and ISQ (82.5 vs 80.3) values by 12 weeks in healed sites. In extraction sockets, BIC and ISQ for the apically tapered implant was 35.8% and 73.2 and 37.8% and 79.2 for the fully tapered implants, respectively. CONCLUSIONS: In this short-term study, immediately loaded fully tapered implants obtained high survival with similar osseointegration ability as apically tapered implants when placed in healed sites and fresh extraction sockets. Fully tapered implants show promise for use in immediate loading and immediate placement.

Development of Medication-Related Osteonecrosis of the Jaw After Extraction of Teeth With Experimental Periapical Disease.

PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) is a rare but severe side effect of antiresorptive medications. Most animal models use tooth extraction as an instigating local factor to induce MRONJ, with varied results. However, these teeth are healthy and absent of dental disease, a rare finding that does not reflect clinical practices. The authors hypothesized that extraction of teeth with periapical inflammation would lead to MRONJ in rats treated with high-dose bisphosphonates. MATERIALS AND METHODS: Rats were pretreated with zoledronic acid (ZA) for 1 week. Pulp exposure (PE) was established by exposing the pulpal chamber of the first and second molars. Experimental periapical disease (EPD) was induced by PE and bacterial inoculation into pulp chambers of the first and second mandibular molars. The mandibular molars were extracted 4 weeks after PE or EPD, and animals were euthanized 4 weeks after tooth extraction. Extraction sockets were assessed clinically, radiographically, and histologically. RESULTS: Clinically, radiographically, and histologically, socket healing was observed in all vehicle-treated animals and in ZA-treated animals after extraction of healthy teeth or teeth with PE. In contrast, bone exposure, lack of socket healing, and osteonecrosis were present in most ZA-treated animals after extraction of teeth with EPD. Bacterial presence was noted in areas of osteonecrotic alveolar bone. CONCLUSION: These data support a synergistic contribution of severe dental disease and tooth extraction to MRONJ pathogenesis. Importantly, this model is amenable to manipulation of methodologic conditions for the dissection of parameters involved in MRONJ pathogenesis.

Nonsurgical Management of Medication-Related Osteonecrosis of the Jaws Using Local Wound Care.

PURPOSE: Medication-related osteonecrosis of the jaws (MRONJ) is a known complication of antiresorptive medications with surgical and nonsurgical treatment options. The aim of this study was to evaluate the effectiveness of nonsurgical therapy using local wound care on management of MRONJ lesions. MATERIALS AND METHODS: The authors conducted a retrospective cohort study of patients who presented to the University of California-Los Angeles School of Dentistry Oral and Maxillofacial Surgery Clinic for evaluation and treatment of MRONJ. The primary predictor variable was wound care score; secondary predictors were demographics (age, gender), anatomic location, primary condition, and type and time of antiresorptive treatment. Outcomes assessed were disease resolution and time to disease resolution. Statistical analysis was carried out using the Spearman correlation for continuous and ordinal variables or the χ2 test for categorical variables. Time-to-event statistics and Cox proportional hazards models were calculated; a Kaplan-Meier plot was generated to assess time to healing. RESULTS: One hundred six patients with 117 MRONJ lesions were treated using local wound care; complete disease resolution was observed 71% of lesions, with an additional 22% of lesions undergoing disease improvement. Wound care score was statistically associated with disease resolution and time to resolution, whereas demographics, anatomic site, condition, and type and time of antiresorptive treatment had no effect on resolution. CONCLUSION: Local wound care increased the likelihood of MRONJ resolution and decreased the time to disease resolution. This strategy can be used in patients who cannot undergo surgery and should be implemented in all patients with MRONJ lesions who are managed nonsurgically.

Osteonecrosis of the Jaw in the Absence of Antiresorptive or Antiangiogenic Exposure: A Series of 6 Cases.

PURPOSE: Medication-related osteonecrosis of the jaws (MRONJ) is a well-described complication of antiresorptive and antiangiogenic medications. Although osteonecrosis can be associated with other inciting events and medications, such as trauma, infection, steroids, chemotherapy, and coagulation disorders, these are rarely reported in the literature. MATERIALS AND METHODS: This is a six case series of MRONJ associated with medications other than antiresorptive or antiangiogenic drugs. RESULTS: Patient demographics, inciting event, location, stage, imaging findings, and outcome are reported. CONCLUSION: With the continued development and clinical use of new biologic medications for diseases such as cancer and rheumatoid arthritis, it is important to continue to evaluate their effects on the oral cavity. The degree of risk for osteonecrosis in patients taking these new classes of drugs is uncertain but warrants awareness and monitoring.

Stage 0 osteonecrosis of the jaw in a patient on denosumab.

Osteonecrosis of the jaws (ONJ) is a complex disease involving multiple tissue and cell-type responses to wound healing or infection. AAOMS defines bisphosphonate related ONJ (BRONJ) as exposed, necrotic bone in the maxillofacial region that has persisted for more than 8 weeks in a patient with current or previous antiresorptive treatment, without a history of radiation therapy to the jaws. Since the first reported ONJ cases in 2003 and 2004, there has been little advancement in understanding the etiology and pathophysiology of ONJ. Many hypotheses have been proposed, including bisphosphonate (BP) toxicity to oral epithelium, altered wound healing after tooth extraction, high turnover of the mandible and maxilla, oral biofilm formation, infection and inflammation, and suppression of angiogenesis and bone turnover. The current classification system of ONJ involves stages 0 to 3 and is based on patient clinical presentation. This report describes a case of stage 0 ONJ in a patient on denosumab and indicates the full-spectrum similarities between BP- and denosumab-associated ONJ clinically, radiographically, and histologically.

Bisphosphonate uptake in areas of tooth extraction or periapical disease.

PURPOSE: Bisphosphonates (BPs) are widely used for the management of bone diseases such as osteoporosis and bone malignancy. However, osteonecrosis of the jaws (ONJ) is a serious complication of BP treatment. ONJ lesions mainly occur after extraction of teeth deemed unrestorable or around teeth with active periodontal or periapical disease. Because socket healing or dental disease shows higher bone turnover, the authors hypothesized that preferentially high BP accumulation would be observed in these areas. MATERIALS AND METHODS: The authors tested the uptake of fluorescein-labeled zoledronic acid (5-FAM-ZOL) in sites of tooth extraction or experimental periapical disease in mice. Maxillary molars were extracted or the crowns of mandibular molars were drilled to induce pulp exposure. Animals were injected with 5-FAM-ZOL 200 µg/kg at various times after intervention and fluorescence was measured at healthy versus intervention sites. Fluorescein injections were used as controls. Data were analyzed by t test and mixed effects linear models were constructed because the animals had repeated measurements over time and at the 2 sites. RESULTS: A statistically significant (P≤.001 to .002) time-dependent uptake of 5-FAM-ZOL was detected in the areas of extraction socket and in the alveolar ridge around teeth with periapical disease compared with the healthy contralateral sites of the same animals. For the 2 conditions, the uptake reached a maximum 3 days after experimental intervention and decreased thereafter. CONCLUSIONS: These data suggest that sites with increased bone turnover, such as extraction sites or areas of periapical inflammation, are exposed to higher BP doses than the remaining alveolar ridge and could explain, at least in part, the susceptibility of such areas to ONJ.

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.

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.

Trb3 controls mesenchymal stem cell lineage fate and enhances bone regeneration by scaffold-mediated local gene delivery.

Aberrant lineage commitment of mesenchymal stem cells (MSCs) in marrow contributes to abnormal bone formation due to reduced osteogenic and increased adipogenic potency. While several major transcriptional factors associated with lineage differentiation have been found during the last few decades, the molecular switch for MSC fate determination and its role in skeletal regeneration remains largely unknown, limiting creation of effective therapeutic approaches. Tribbles homolog 3 (Trb3), a member of tribbles family pseudokinases, is known to exert diverse roles in cellular differentiation. Here, we investigated the reciprocal role of Trb3 in the regulation of osteogenic and adipogenic differentiation of MSCs in the context of bone formation, and examined the mechanisms by which Trb3 controls the adipo-osteogenic balance. Trb3 promoted osteoblastic commitment of MSCs at the expense of adipocyte differentiation. Mechanistically, Trb3 regulated cell-fate choice of MSCs through BMP/Smad and Wnt/ß-catenin signals. Importantly, in vivo local delivery of Trb3 using a novel gelatin-conjugated caffeic acid-coated apatite/PLGA (GelCA-PLGA) scaffold stimulated robust bone regeneration and inhibited fat-filled cyst formation in rodent non-healing mandibular defect models. These findings demonstrate Trb3-based therapeutic strategies that favor osteoblastogenesis over adipogenesis for improved skeletal regeneration and future treatment of bone-loss disease. The distinctive approach implementing a scaffold-mediated local gene transfer may further broaden the translational use of targeting specific therapeutic gene related to lineage commitment for clinical bone treatment.

Management of odontogenic sinusitis: multidisciplinary consensus statement.

BACKGROUND: Odontogenic sinusitis (ODS) can present a therapeutic dilemma because multiple treatment strategies have been reported. ODS review articles have been published, but they have lacked multidisciplinary collaboration and an evidence-based methodology. The purpose of this article was to perform an evidence-based review of ODS management options, and develop a multidisciplinary consensus statement on ODS management options. METHODS: An evidence-based review of dental and medical literature on ODS management was performed using PubMed, EMBASE, and Cochrane Review Databases up to December 2019. Exclusion criteria included non-English-language articles, case series with fewer than 10 patients, fungal sinusitis, and studies that did not report treatment success rates. Because aggregate levels of evidence for recommendations were no higher than level C, a clinical consensus statement was conducted using a modified Delphi method. RESULTS: Sixteen articles met inclusion criteria for the evidence-based review on the following ODS management options: dental treatment alone or combined with ESS for various dental pathologies, and endoscopic sinus surgery (ESS) alone for dental implant-related ODS. Strong consensus was achieved for 9 of the 10 clinical statements, the strongest being the use of shared decision-making for selecting management strategies. No consensus was reached for determining the extent of ESS necessary for uncomplicated ODS. CONCLUSION: Strong consensus was reached that ODS management should involve shared decision-making between the otolaryngologist, dental provider, and patient, where the benefits and risks of dental treatment and ESS are discussed. Higher-quality studies are necessary to develop evidence-based treatment recommendations for ODS.

Biomimetic Enhancement of Bone Graft Reconstruction.

With aging populations and increasing oral rehabilitation, use of dental implants for oral reconstruction is increasing. Adequate hard/soft tissue are required to support use of titanium implants. Bone augmentation is sometimes a necessary procedure to supplement existing alveolar bone. With a wide variety of biomaterials available for clinical use, we focus on the enhancement of bone graft materials, targeting new technologies with potential clinical use. Clinical indications supported by research studies are provided for platelet-rich fibrin, various growth factors, and newly emerging scaffolds. Interestingly, modified biomaterials are being developed and have potential clinical use as more data become available.

Medication related osteonecrosis of the jaw in osteoporotic vs oncologic patients-quantifying radiographic appearance and relationship to clinical findings.

OBJECTIVES: To explore whether differences exist in the clinical and radiographic presentation of oncologic vs osteoporotic patients with medication-related osteonecrosis of the jaw (MRONJ). METHODS: We retrospectively assessed panoramic radiographs and CBCT examinations of 70 MRONJ patients receiving antiresorptive medications for the management of either osteoporosis or bone malignancy. Radiographic features of MRONJ were documented and categorized according to severity. A composite radiographic index (CRI) was constructed to account for the heterogeneity in radiographic manifestations of MRONJ and further stratify extent of osseous changes. RESULTS: Patients with osteoporosis were mostly older females and presented more frequently with Stage 2 MRONJ, while patients with malignancy were equally distributed between males and females, and presented mostly with Stage 1 MRONJ. Most MRONJ lesions in oncologic patients occurred in the mandible, whereas the maxilla and mandible were equally affected in osteoporotic patients. Patients with minimal radiographic changes (low CRI score) often presented with MRONJ in dentate areas, while most patients in medium and high CRI groups presented with MRONJ after recent tooth extraction. The low CRI group consisted of primarily oncologic patients, while osteoporotic vs oncologic patients were divided more evenly in the other CRI groups (p = 0.083). While CRI scores increased with clinical staging, a Spearman's rank correlation coefficient of 0.49 suggests that clinical appearance does not reliably predict osseous changes. CONCLUSIONS: Our data identify differences in the MRONJ appearance of patients with osteoporosis vs malignancy and emphasize the significance of detailed radiographic assessment, in addition to the clinical appearance, in characterizing the osseous changes of the disease.

Clinically Relevant Doses of Sclerostin Antibody Do Not Induce Osteonecrosis of the Jaw (ONJ) in Rats with Experimental Periodontitis.

Antiresorptive agents, such as bisphosphonates and denosumab, are frequently used for the management of osteoporosis. Indeed, both medications decrease the risk of osteoporotic fractures; however, these medications are associated with rare but potentially severe side effects, such as osteonecrosis of the jaw (ONJ). ONJ, defined as an area of exposed bone in the maxillofacial region that lasts for 8 weeks, often presents with significant pain and infection and can lead to serious complications. Interestingly, other treatments for osteoporosis have been developed, such as antibodies against the osteocyte-secreted protein, sclerostin. Sclerostin functions to inhibit the Wnt signaling cascade, leading to inhibition of bone formation. In clinical trials, a sclerostin antibody (romosozumab, Amgen Inc., UCB Brussels) increases bone formation and lowers the risk of osteoporotic fractures. However, in conjunction with increased osteoblastic activity, a reduction in bone resorption markers is observed. This antiresorptive effect raises the concern of possible ONJ development in patients treated with sclerostin antibodies. Here, utilizing ligature-induced experimental periodontitis (EP), we evaluated the effects of sclerostin inhibition on the development of ONJ-like lesions in ovariectomized rats. Beginning 8 weeks post-ovariectomy, rats were treated for 22 weeks with weekly injections of vehicle (Veh), 200 µg/kg zoledronic acid (ZA), a potent bisphosphonate at 100-fold the osteoporosis dose, or 5 mg/kg sclerostin antibody (Scl-Ab) at the osteoporotic dose. EP was initiated at week 12 and maintained for the remainder of the study. Scl-Ab treatment transiently increased serum P1NP, a bone formation marker, increased BV/TV, and decreased eroded surfaces in lumbar vertebrae. ZA-treated rats developed histologic features of ONJ, whereas Veh-treated controls did not. Scl-Ab animals lost less periodontal bone in sites with EP. However, these animals presented with no histologic signs of ONJ. In conclusion, sclerostin inhibition enhanced structural bone parameters, without inducing ONJ-like lesions, in ovariectomized rats with EP. © 2018 American Society for Bone and Mineral Research.

Vasculature submucosal changes at early stages of osteonecrosis of the jaw (ONJ).

Osteonecrosis of the jaw (ONJ), a rare, but potentially severe side effect of anti-resorptive medications, presents as exposed bone in the maxillofacial region lasting for at least 8 weeks. While clinical experience and animal models concur in finding that systemic antiresorptive treatment in conjunction with local risk factors, such as tooth extraction or dental disease may lead to ONJ development, the subclinical molecular changes that precede bone exposure remain poorly understood. The identification of these changes is not only important in understanding disease pathophysiology, but could provide potential for treatment development. Here, we evaluated the early stages of ONJ utilizing a model of experimental periodontitis (EP) in mice treated with two different types of antiresorptives, targeting potential changes in vasculature, hypoxia, oxidative stress, and apoptosis. Antiresorptive treatment in animals with EP increased levels of empty osteocytic lacunae and increased ONJ prevalence compared to Veh animals. The arteriole and venule network seen around EP areas was diminished in animals treated with antiresorptives. Higher levels of vascular endothelial growth factor A (VEGF-A) and vascular cell adhesion protein-1 (VCAM-1) were observed 1-week following EP in treated animals. Finally, levels of hypoxia, oxidative stress, and apoptosis remained high in antiresorptive treated animals with EP through the duration of the experiment. Together, our data point to subclinical vasculature organizational disturbances that subsequently affect levels of hypoxia, oxidative stress, and apoptosis in the area of developing ONJ.