Bisphosphonate-Related Osteonecrosis of the Jaw and Oral Microbiome: Clinical Risk Factors, Pathophysiology and Treatment Options.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) represents a serious health condition, impacting the lives of many patients worldwide. The condition challenges clinical care due to its complex etiology and limited therapeutic options. A thorough understanding of the pathophysiological and patient-related factors that promote disease development is essential. Recently, the oral microbiome has been implicated as a potential driver and modulating factor of BRONJ by several studies. Modern genomic sequencing methods have provided a wealth of data on the microbial composition of BRONJ lesions; however, the role of individual species in the process of disease development remains elusive. A comprehensive PubMed search was conducted to identify relevant studies on the microbiome of BRONJ patients using the terms "microbiome", "osteonecrosis of the jaws", and "bisphosphonates". Studies focusing on symptoms, epidemiology, pathophysiology, risk factors, and treatment options were included. The principal risk factors for BRONJ are tooth extraction, surgical procedures, and the administration of high doses of bisphosphonates. Importantly, the oral microbiome plays a significant role in the progression of the disease. Several studies have identified alterations of microbial composition in BRONJ lesions. However, there is no consensus regarding bacterial species that are associated with BRONJ across studies. The bacterial genera typically found include Actinomyces, Fusobacterium, and Streptococcus. It is postulated that these microbes contribute to the pathogenesis of BRONJ by promoting inflammation and disrupting normal bone remodeling processes. Current therapeutic approaches are disease-stage-specific and the necessity for more effective treatment strategies remains. This review examines the potential causes of and therapeutic approaches to BRONJ, highlighting the link between microbial colonization and BRONJ development. Future research should seek to more thoroughly investigate the interactions between bisphosphonates, the oral microbiome, and the immune system in order to develop targeted therapies.

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.

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.

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.

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.

A retrospective study on the incidence of medication-related osteonecrosis of the jaws (MRONJ) associated with different preventive dental care modalities.

PURPOSE: To assess the efficacy of different preventive dental visits and treatments in reducing the risk of medication-related osteonecrosis of the jaws (MRONJ). METHODS: In this retrospective study, patients diagnosed with MRONJ were divided into 5 groups based on available data: no preventive dental visits (group 0); dental visits and compliance with recommended treatments, at the university hospital's dental clinic (group 1) or maxillofacial surgery unit (group 2), or at a private dentist's (group 3); dental visits at one of the above and noncompliance with proposed treatments (group 4); patients judged eligible by the oncologist on panoramic radiography (group 5). Patients were classified on severity of MRONJ according to the Italian SIPMO/SICMF 2.0 staging system. A descriptive analysis was performed on the results. Fisher's exact test was applied (p < 0.05). RESULTS: Ninety-three patients diagnosed with MRONJ were considered for the study, but 22 were excluded due to a lack of data, leaving a sample of 71 cases. MRONJ staging was only 0 for some patients (26.92%) in group 0. In all groups, the majority of patients had stage 2 MRONJ. The proportions of cases in stage 3 were 7.69% in group 0, 18.18% in group 3, and 43.48% in group 5. Groups 0 and 3 were somewhat similar as regard MRONJ staging. Most patients in group 5 had MRONJ stage 2 or 3. No statistically significant differences emerged between the groups. CONCLUSIONS: Preventive dental care can reduce the risk of MRONJ providing patients comply with the specialist's recommendations.

Titanium implant alters the effect of zoledronic acid on the behaviour of endothelial cells.

OBJECTIVES: To evaluate the effect of zoledronic acid (ZA) on human umbilical vein endothelial cells (HUVECs) attached to different surfaces. MATERIALS AND METHODS: A total of three groups were evaluated in this study: sandblasting and acid etching (SLA) + HUVECs; mechanically polished (MP) + HUVECs; and plastic cell culture plates + HUVECs. Scanning electron microscopy, energy-dispersive X-ray spectroscopy, surface roughness and water contact angle were tested for titanium surface characterisation. ZA was added at different concentrations (0, 1, 10, 50 and 100 µM). Cell adhesion, proliferation, viability, apoptosis and gene expression were evaluated. RESULTS: Mechanically polished and SLA surfaces showed negative effects on cell adhesion and proliferation and promoted cell apoptosis with 100 µM ZA (p < .05). The highest expression of intercellular adhesion molecule-1 (ICAM-1) and angiopoietin-1 was found on SLA surfaces (p < .01). The lowest expression of platelet-endothelial cell adhesion molecule-1 and ICAM-1 was found on MP surfaces (p < .05). A significant decrease in von Willebrand factor was detected on MP and SLA surfaces (p < .001). CONCLUSIONS: Zoledronic acid has an anti-angiogenic effect on HUVECs attached to titanium implants, while the SLA surface might stimulate HUVECs to express angiogenic and adhesive factor genes despite ZA treatment.

[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.

Persistent bone resorption lacunae on necrotic bone distinguish bisphosphonate-related osteonecrosis of jaw from denosumab-related osteonecrosis.

BACKGROUND: Bisphosphonate and denosumab are widely used for the treatment of osteoporosis and bone metastasis of cancer to prevent excessive bone resorption. Osteonecrosis of the jaw is a serious adverse effect of bisphosphonate or denosumab referred to as bisphosphonate-related osteonecrosis of the jaw (BRONJ) or denosumab-related osteonecrosis of the jaw (DRONJ), respectively. Since bisphosphonate and denosumab inhibit bone resorption by different mechanism, we evaluated whether these drug types result in different histopathological characteristics related to bone resorption. MATERIALS AND METHODS: We histopathologically investigated 10 cases of BRONJ, DRONJ, and suppurative osteomyelitis. Paraffin sections prepared from decalcified dissected jaw bones were used for histopathological observation, second harmonic generation imaging, and bone histomorphometry. The samples were also observed by a scanning electron microscope. RESULTS: Numerous bone resorption lacunae were observed on the necrotic bone surface in almost all cases of BRONJ; however, such resorption lacunae were limited in DRONJ and suppurative osteomyelitis. Prominent bone resorption lacunae were also confirmed by second harmonic generation imaging and scanning electron microscopy in BRONJ, but not in DRONJ or suppurative osteomyelitis. As determined by bone histomorphometry, the number of bone resorption lacunae and the length of the erosion surface of resorption lacunae were significantly higher in BRONJ group than in the DRONJ and suppurative osteomyelitis groups. These parameters were correlated between the necrotic bones and the vital bones in BRONJ. CONCLUSIONS: Persistent bone resorption lacunae on the necrotic bone surface are unique to BRONJ, providing a basis for distinguishing BRONJ from DRONJ and OM in histopathological diagnosis.

Qualitative and quantitative analysis of the CTX in relation to the period of intake of bisphosphonates: A systematic review.

The aim of this systematic review was to determinate the true value of C-terminal crosslinking telopeptide test (CTX) in patient who takes Bisphosphonate. A comprehensive search of studies published up to March 2020 and listed in the PubMed/MEDLINE and Cochrane Library databases, was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines. The search identified 99 publications; 6 studies were finally deemed eligible for inclusion according to the study criteria. These studies included a total 104 patients and was selected 101. The CTX value in the various study groups is less than 150 pg/ml. There is a difference between the age of the patient and the period of taking the drug. This systematic review indicates that the CTX test has diffent predictive value in determining the risk of osteonecrosis in patients taking bisphosphonate compared to previus standard.

Wound closure and alveoplasty after preventive tooth extractions in patients with antiresorptive intake-A randomized pilot trial.

OBJECTIVES: To compare success rates between the sub-periosteal prepared (SPP) muco-periosteal flap and the epi-periosteal prepared (EPP) mucosa flap and the feasibility of alveoplasty after surgical tooth extractions in patients undergoing/after antiresorptive treatment. SUBJECTS: Patients with an indication for preventive tooth extraction undergoing/after antiresorptive treatment were enrolled over a 24-month period in a parallel-group randomized clinical pilot trial and randomly assigned for primary wound closure to either the SPP or the EPP group. The primary outcome was treatment failure 8 weeks after surgery. To assess the feasibility of alveoplasty, necrotic bone changes at the time point of tooth extraction were evaluated. RESULTS: One hundred and sixty patients were randomized to the SSP (n = 82) or the EPP (n = 78) group. One hundred and fifty-seven patients met the primary endpoint 8 weeks after surgery with five treatment failures for the SPP group (6.3%) and 18 (23.4%) for the EPP group (p = .004). A significant relationship (p < .0001) was observed between symptomatic teeth and non-vital bone found in 54.8% of all biopsies. CONCLUSIONS: The strong superiority of the muco-periosteal flap as primary wound closure revealed the feasibility and effectiveness of the study. The large number of necrotic biopsies emphasizes the importance of alveoplasty as a preventive measure.

The effects of different doses of teriparatide on bisphosphonate-related osteonecrosis of the jaw in mice.

OBJECTIVES: This study aimed to investigate the therapeutic effect of different doses of teriparatide (TPTD) on bisphosphonate-related osteonecrosis of the jaw (BRONJ). MATERIALS AND METHODS: To establish the BRONJ model, 20 mice were randomly divided into two groups: a group that received tail vein administration of zoledronic acid with dexamethasone (ZA-125 µg/kg, DEX 5 mg/kg) and a group that received saline weekly. The mice subsequently underwent bilateral maxillary first molar extraction. After 8 weeks of modelling administration, the maxilla samples were examined by micro-computed tomography and histological staining (haematoxylin and eosin, Masson's trichrome and tartrate-resistant acid phosphatase) and the cytokine level was measured (enzyme-linked immunosorbent assay and Western blot). To determine the role of TPTD in BRONJ, the same protocol as previously described was applied in 100 mice (80 received ZA + DEX, and 20 received saline). After 8 weeks of modelling administration, 80 ZA + DEX mice were randomly divided into four groups: three groups with subcutaneous administration of TPTD (i.e. T1-3, T2-10 and T3-30 µg kg-1  day-1 ) and one group with saline daily for the next 8 weeks. The other 20 saline mice continued to receive saline daily. RESULTS: In Part 1, the level of receptor activator of nuclear factor-kappa Β ligand and the numbers of osteoclasts differed between the model and control groups. In Part 2, we found that TPTD had a positive effect on BRONJ in a mouse model based on clinical and histomorphological observations. Among the three treatment groups, the T1 and T2 groups significantly differed from the model group, whereas the T3 group showed no statistical differences. CONCLUSION: Subcutaneous administration of TPTD has a beneficial effect on BRONJ in mice. Nevertheless, further studies are needed to determine whether the therapeutic effect on BRONJ is dose-dependent.

The feasibility of locating the affected bone of BRONJ with indocyanine green.

The morbidity of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is also increasing with the use of bisphosphonates (BPs). Removing affected bone accurately is the most effective treatment. This study aimed to explore the feasibility of Indocyanine green (ICG)-based Near-Infrared fluorescence (NIF) imaging to remove BRONJ affected bone. Firstly, the rat model of BRONJ was constructed. And 5 mg/kg ICG were injected via tail vein, after 12 hr, the affected and healthy bone were dissected for ICG-based NIF imaging and quantification detection of fluorescence intensity. Finally, all the bone samples were sent for further pathological examination. All the affected bone tissues in rat BRONJ model were fluorescence developed with ICG. And the fluorescence developed regions were further confirmed as affected bone tissues with pathological examination. The fluorescence intensity in affected bone tissues, adjacent, and opposite bone tissues was 1.93*107 ± 2.08*106, 1.19*106 ± 2.33*105, and 1.24*106 ± 1.57*105, respectively (p < .05). Conclusions It was feasible that the extent of affected bone in rat model with BRONJ could be estimated intraoperative via ICG-based NIF imaging. This novel approach would become an auxiliary method in the treatment of patients with BRONJ in the future.

Differences between auto-fluorescence and tetracycline-fluorescence in medication-related osteonecrosis of the jaw-a preclinical proof of concept study in the mini-pig.

OBJECTIVES: Fluorescence-guided bone surgery is a well-established technique in the treatment of medication-related osteonecrosis of the jaw. No histopathological evidence for bone auto-fluorescence is currently available, and thus, any differences from tetracycline-fluorescence remain unclear. Therefore, the goals of this study were to find out if macroscopic and histological differences occur between the auto- and tetracycline-fluorescence in the delineation of viable and necrotic jawbone in the mini-pig. MATERIALS AND METHODS: According to the proof of concept, osteonecrosis was provoked in eight Göttingen minipigs. Pigs were divided into two groups (AF group: no fluorochrome label; TF group: tetracycline label). Delineation of necrosis and viable bone was evaluated in vivo and in vitro macro-/microscopically, correlated to fluorescence properties and compared between the two study groups. RESULTS: No macroscopic and microscopic clinical differences were seen in fluorescence between the AF and TF groups. Macroscopic and microscopic viable bone fluoresced green, whereas necrotic bone showed no or only pale fluorescence in both groups. The auto-fluorescence was attributable to the arrangements and structure of collagen and the cell-filled bone lacunae. CONCLUSION: Neither in vivo nor in vitro macroscopically differences are apparent between the auto-fluorescence and the tetracycline-fluorescence of bone. The auto-fluorescence is attributable to the arrangements and structure of collagen and the cell-filled bone lacunae. Tetracycline-fluorescence is a mixture of tetracycline (at the bone edges with increased bone formation) and large components of auto-fluorescence. CLINICAL RELEVANCE: Because auto-fluorescence is easy to apply, reproducible, and does not rely on the subjective impression of the surgeon, it promises to be an important standardized alternative to tetracycline-labeled MRONJ therapy.

Osteoclastic expression of higher-level regulators NFATc1 and BCL6 in medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis.

BACKGROUND: With an increasing indication spectrum of antiresorptive drugs, the medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy [MRONJ (BP)] is continuously gaining clinical relevance. Impaired osteoclast function, accompanied by altered cell morphology and expression of osteoclastic effector proteins, contributes to the pathogenesis of MRONJ (BP). However, the underlying regulatory mechanisms at a transcriptional level are unaddressed so far. These mechanisms are crucial to the development of disease-characteristic osteoclastic anomalies, that contribute to the pathogenesis of MRONJ (BP). NFATc1 is considered a master upstream osteoclastic activator, whereas BCL6 acts as osteoclastic suppressor. The present study aimed to elucidate the NFATc1 and BCL6 mediated osteoclastic regulation and activity in MRONJ (BP) compared to osteoradionecrosis (ORN) and osteomyelitis (OM) and normal jaw bone. METHODS: Formalin-fixed jaw bone specimens from 70 patients [MRONJ (BP) n = 30; OM: n = 15, ORN: n = 15, control: n = 10] were analyzed retrospectively for osteoclast expression of NFATc1 and BCL6. The specimens were processed for H&E staining and immunohistochemistry. The histological sections were digitalized and analyzed by virtual microscopy. RESULTS: Osteoclastic expression of NFATc1 and BCL6 was significantly higher in MRONJ (BP) specimens compared to OM and control specimens. NFATc1 and BCL6 labeling indices revealed no significant differences between MRONJ (BP) and ORN. The ratio of nuclear BCL6+ osteoclasts to cytoplasmic BCL6+ osteoclasts revealed significantly higher values for MRONJ (BP) specimens compared to OM and controls. CONCLUSION: This study displays that osteoclasts in MRONJ (BP) tissues feature increased expression of the higher-level regulators, paradoxically of both NFATc1 and BCL6. These observations can help to explain the genesis of morphologically altered and resorptive inactive osteoclasts in MRONJ (BP) tissues by outlining the transcriptional regulation of the pathomechanically relevant osteoclastic effector proteins. Furthermore, they strengthen the etiological delineation of MRONJ (BP) from OM and extend the osteoclast profiles of MRONJ (BP), OM and ORN and thus could lead to a better histopathological differentiation that can improve treatment decision and motivate new therapeutic concepts.

Long-term oral bisphosphonates delay healing after tooth extraction: a single institutional prospective study.

Tooth extraction in patients receiving bisphosphonates is thought to be a risk factor for osteonecrosis of the jaw (ONJ); however, ONJ did not develop, even when tooth extraction was performed with continued oral bisphosphonate therapy. A drug holiday from bisphosphonates before tooth extraction may not be necessary. INTRODUCTION: It is controversial whether bisphosphonate withdrawal is necessary prior to invasive procedures such as tooth extraction in order to prevent bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study aimed to evaluate the clinical safety of continuing oral bisphosphonate therapy in patients undergoing tooth extraction. METHODS: We prospectively enrolled 132 patients (20 men, 112 women) who were receiving oral bisphosphonates for the prevention or treatment of osteoporosis and required tooth extraction. All patients were managed using an identical protocol, which included preoperative antibiotic prophylaxis and did not necessarily require complete wound closure. The patients were classified into groups according to the duration of bisphosphonate administration: < 2 years (n = 51), 2-5 years (n = 41), 5-10 years (n = 28), and > 10 years (n = 12). The groups were compared regarding the time taken for the extraction socket to heal, and the occurrence of BRONJ. Follow-up duration was at least 3 months. RESULTS: A total of 274 teeth were removed. Long-term oral bisphosphonate therapy for > 5 years significantly delayed the healing of the extraction socket in comparison with administration for < 5 years; however, BRONJ did not develop in any group. There was no prolongation of wound healing due to systemic risk factors such as glucocorticoid administration and diabetes mellitus. There were no adverse skeletal events such as bone fracture. CONCLUSIONS: Patients who underwent tooth extraction with continued oral bisphosphonate therapy showed delayed healing of the extraction socket as the cumulative administration period prolonged, but BRONJ did not develop.

The effects of icariin on wound healing of extraction sites with administration of zoledronic and dexamethasone: A rat model study.

OBJECTIVE: This study was intended to investigate the effects of icariin on the healing of tooth extraction sites under the systemic administration of zoledronic and dexamethasone. METHOD: Thirty female rats underwent bilateral ovariectomy and were randomly assigned to 5 groups: SS group received a weekly injection of saline, while ZD, ZD + LICA, ZD + MICA, and ZD + HICA groups received zoledronic with dexamethasone for 8 weeks. One week later, mandibular first molars were extracted in all groups. Then, 30, 60, and 120 mg/kg icariin were intragastrically given to ZD + LICA, ZD + MICA, and ZD + HICA groups daily for 10 weeks, while saline was given to SS group and ZD group. Blood samples and mandibles were harvested for examinations after 10 weeks. RESULTS: Significantly smaller wound area was noted in SS and ZD + HICA groups, but the incidence of bisphosphonate-related osteonecrosis of the jaws (BRONJ) was not significantly different. Groups injected with zoledronic and dexamethasone had higher C-terminal cross-linked telopeptide of type 1 collagen (CTX-1), tartrate-resistant acid phosphatase 5b (TRACP 5b), and the number of osteoclast cells, with less vascular endothelial growth factor (VEGF) and osteocalcin (OCN). In contrast, CTX-1, TRACP 5b, and the number of osteoclast cells declined after using icariin and promoted VEGF and OCN were noted and the effects were in a dosage-dependent manner. CONCLUSION: Concurrent use of zoledronic and dexamethasone inhibits the expression of VEGF, OCN, and wound healing and increases the number of osteoclast cells, serum CTX-1, and TRACP-5b after discontinuation for 10 weeks. Icariin weakens those effects in a dose-dependent manner but does not influence the onset of BRONJ.

Efficacy of bovine lactoferrin in the post-surgical treatment of patients suffering from bisphosphonate-related osteonecrosis of the jaws: an open-label study.

Osteonecrosis of the jaws is an emerging pathological condition characterized by un-exposure or exposure of the necrotic bone, independently from the etiology. This term is usually referred to medication-related osteonecrosis of the jaws due to severe adverse reaction to certain medicines, as bisphosphonates, used for the treatment of cancer and osteoporosis. The management of patients with Bisphosphonate-Related Osteonecrosis of the Jaws (BRONJ) remains challenging because surgical and medical interventions may not eradicate this pathology. The goal of treatment of patients at risk of developing BRONJ or of those who have active disease is the preservation of quality of life by controlling pain, managing infection, and preventing the development of new areas of necrosis. The treatment of osteonecrosis consists in the surgical removal of necrotic bone followed by antibiotic therapy and application of sterile greasy gauze until the wound closure. The classical medical treatment has been compared with the innovative one consisting in the application of sterile greasy gauze soaked with bovine lactoferrin (bLf) after surgery. Here, for the first time, bLf efficacy on wound repair in subjects suffering from BRONJ with the progressive destruction of bone in the mandible or maxilla has been demonstrated. The positive results consist in a significant shorter time of wound closure (1 or 2 weeks) compared to that observed with classical surgical treatment (2-3 months). These promising results are an interesting tool for the innovative treatment of this pathology and for increasing the quality of life of these patients.

Bisphosphonate Modulation of the Gene Expression of Different Markers Involved in Osteoblast Physiology: Possible Implications in Bisphosphonate-Related Osteonecrosis of the Jaw.

The aim of the present study was to elucidate the role of osteoblasts in bisphosphonates-related osteonecrosis of the jaw (BRONJ). The specific objective was to evaluate the effect on osteoblasts of two nitrogen-containing BPs (zoledronate and alendronate) and one non-nitrogen-containing BP (clodronate) by analyzing modulations in their expression of genes essential for osteoblast physiology. Real-time polymerase chain reaction (RT-PCR) was used to study the effects of zoledronate, alendronate, and clodronate at doses of 10-5, 10-7, or 10-9 M on the expression of Runx-2, OSX, ALP, OSC, OPG, RANKL, Col-I, BMP-2, BMP-7, TGF-ß1, VEGF, TGF-ßR1, TGF-ßR2, and TGF-ßR3 by primary human osteoblasts (HOBs) and MG-63 osteosarcoma cells. Expression of these markers was found to be dose-dependent, with no substantive differences between these cell lines. In general, results demonstrated a significant increase in TFG-ß1, TGF-ßR1, TGF-ßR2, TGF-ßR3, and VEGF expressions and a significant reduction in RUNX-2, Col-1, OSX, OSC, BMP-2, BMP-7, ALP, and RANKL expressions, while OPG expression varied according to the dose and cell line. The results of this in vitro study of HOBS and MG-63 cell lines indicate that low BP doses can significantly affect the expression of genes essential for osteoblast growth and differentiation and of genes involved in regulating osteoblast-osteoclast interaction, possibly by increasing TGF-ß1 production. These findings suggest that osteoblasts may play an important role in BRONJ development, without ruling out other factors.