Bisphosphonate-related Osteonecrosis Of Jaw Research Articles

Mitigating jaw osteonecrosis: bioactive glass and pericardial membrane combination in a rat model

ObjectivesBisphosphonates (BFs) show clinical effectiveness in managing osteoporosis and bone metastases but pose risks of bisphosphonate-related jaw osteonecrosis (BRONJ). With no established gold standard for BRONJ treatment, our focus is on symptom severity reduction. We aimed to assess the preventive effects of bioactive glass and/or pericardial membrane in a preclinical BRONJ model, evaluating their potential to prevent osteonecrosis and bone loss post-tooth extractions in zoledronic acid (ZA)-treated animals.MethodsRats, receiving ZA or saline biweekly for four weeks, underwent 1st and 2nd lower left molar extractions. Pericardial membrane alone or with F18 bioglass was applied post-extractions. Microarchitecture analysis and bone loss assessment utilized computerized microtomography (CT) and positron emission tomography (PET) with 18F-FDG and 18F-NaF tracers. Histological analysis evaluated bone injury.ResultsExclusive alveolar bone loss occurred post-extraction in the continuous ZA group, inducing osteonecrosis, osteolysis, osteomyelitis, and abscess formation. Concurrent pericardial membrane with F18 bioglass application prevented these outcomes. Baseline PET/CT scans showed no discernible uptake differences, but post-extraction 18F-FDG tracer imaging revealed heightened glucose metabolism at the extraction site in the ZA-treated group with membrane, contrasting the control group.ConclusionThese findings suggest pericardial membrane with F18 bioglass effectively prevents BRONJ in the preclinical model.

Treatment of Bisphosphonate-related Osteonecrosis of Jaw (BRONJ) in Rabbit Model: A Proof-of-concept Animal Study Comparing Angiogenesis Factor Versus Autologous Bone Marrow-derived Osteoblasts (ABMDO)

Objective We created Bisphosphonate-related Osteonecrosis of Jaw (BRONJ) in rabbits and treated them with an angiogenesis factor or autologous bone marrow derived osteoblasts (ABMDO) to assess the efficacy of the treatment by Micro-computerized Tomography (M-CT) and histopathology. Materials and Methods Thirty female New Zealand rabbits were procured and were divided into three groups of 10 animals each. The number of animals to achieve statistical significance was based on the reported studies. Group I was control group (C), Group II was Osteoblast group (O), and Group III was angiogenesis group (P). In all Groups, BRONJ was produced. At 8 weeks of tooth extraction, BRONJ was confirmed histologically and radiologically in two rabbits from each group of animals. Group I received 0.5 of normal saline, Group II received a single dose of 5 million osteoblasts suspended in 0.5 ml, and Group III received 5 mg of angiogenesis factor thrice weekly for three weeks. The healing of BRONJ was assessed using M-CT and histopathology. Results In O and P groups, the extraction sockets healed and closed with normal-looking tissue, whereas in the C (control) group, suppuration with an area of necrosis was observed. Micro-CT analysis of socket revealed an exaggeration on non-mineralized soft tissue volume in the C group, whereas most of the bone promotion parameters were improved in the O and P groups with statistical difference (P<0.001) for the parameters bone volume, bone surface area, trabecular number and trabecular thickness. Histologically, the element of healing was represented by reactive bone formation and fibrosis, which were more prominent in groups O and P as compared to the control group. Conclusion Our study shows that ABMDO and angiogenesis factor have a robust potential to heal BRONJ. Clinical Relevance The study shows angiogenesis factor and osteoblasts heals BRONJ and warrant sincere human trials to tackle this unrelenting complication of bisphosphonates use.

Significance of medication discontinuation on bisphosphonate-related jaw osteonecrosis in a rat model

Bisphosphonate (BP) discontinuation has been advised as a measure to prevent the incidence of bisphosphonate-related osteonecrosis of the jaw (BRONJ), however, its efficacy remains controversial. This study aimed to analyze the efficacy of BP discontinuation in reducing BRONJ severity following tooth extraction in a rat model. Thirty-four male Sprague–Dawley rats were divided into two BRONJ model categories: oral administration (PO) of alendronate (1 mg/kg) for 3 and 8 weeks and intraperitoneal (IP) injection of pamidronate (3 mg/kg) and dexamethasone (1 mg/kg) for 20 days. The PO model was divided into five groups (a control group without BPs and four experimental groups with 1-week discontinuation). The IP model was divided into two groups consisting of group I (without discontinuation) and group II (1-week discontinuation). One molar from both sides of the mandible was extracted. After extraction, the PO models were sacrificed at 3 and 5 weeks, and the IP models were sacrificed either immediately or at 2, 4, 6, and 8 weeks. Micro-CT showed non-significant differences among PO groups but significant differences were observed between IP groups. Most bone remodeling parameters within group I of the IP model differed significantly (p-value < 0.05). Histologically, group I showed a significantly higher percentage of necrotic bone than group II (51.93 ± 12.75%, p < 0.05) and a higher number of detached osteoclasts in TRAP staining. With discontinuation of medication for at least 1 week in rats, the effects of BPs on alveolar bone are suppressed and bone turnover and osteoclast functions are restored.

Zoledronic acid promotes osteoclasts ferroptosis by inhibiting FBXO9-mediated p53 ubiquitination and degradation.

Bisphosphonates (BPs)-related osteonecrosis of jaw (BRONJ) is a severe complication of the long-term administration of BPs. The development of BRONJ is associated with the cell death of osteoclasts, but the underlying mechanism remains unclear. In the current study, the role of Zoledronic acid (ZA), a kind of bisphosphonates, in suppressing the growth of osteoclasts was investigated and its underlying mechanism was explored. The role of ZA in regulating osteoclasts function was evaluated in the RANKL-induced cell model. Cell viability was assessed by cell counting kit-8 (CCK-8) assay and fluorescein diacetate (FDA)-staining. We confirmed that ZA treatment suppressed cell viability of osteoclasts. Furthermore, ZA treatment led to osteoclasts death by facilitating osteoclasts ferroptosis, as evidenced by increased Fe2+, ROS, and malonyldialdehyde (MDA) level, and decreased glutathione peroxidase 4 (GPX4) and glutathione (GSH) level. Next, the gene expression profiles of alendronate- and risedronate-treated osteoclasts were obtained from Gene Expression Omnibus (GEO) dataset, and 18 differentially expressed genes were identified using venn diagram analysis. Among these 18 genes, the expression of F-box protein 9 (FBXO9) was inhibited by ZA treatment. Knockdown of FBXO9 resulted in osteoclasts ferroptosis. More important, FBXO9 overexpression repressed the effect of ZA on regulating osteoclasts ferroptosis. Mechanistically, FBXO9 interacted with p53 and decreased the protein stability of p53. Collectively, our study showed that ZA induced osteoclast cells ferroptosis by triggering FBXO9-mediated p53 ubiquitination and degradation.

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

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. 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. 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. 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.

The Potential Role of Angiogenic Osteoclast Inhibition in the Occurrence of Bisphosphonate-related Osteonecrosis of the Jaw

Bisphosphonate-related osteonecrosis of the jaw is a serious complication of systemic bisphosphonate administration, the mechanism of which remains unclear. Many hypotheses regarding pathophysiology are discussed, including the most commonly cited: suppression of bone remodeling and suppression of angiogenesis, but none of these would explain all the unique features of bisphosphonaterelated jaw osteonecrosis. Bisphosphonates are potent inhibitors of osteoclasts, and recent studies have shown that osteoclasts are important for bone angiogenesis. Therefore, we hypothesize that bisphosphonates inhibit osteoclastic stimulation of angiogenesis, thereby contributing to the occurrence of osteonecrosis of the jaws. This theory would partially explain the pathophysiology of bisphosphonate-related osteonecrosis of the jaw to the unfathomable.

Ozone therapy in the management of cancer-treatment toxicity [abstract]

PURPOSE: This presentation will be focused to show clinical and preclinical works using Ozone therapy in the management of side effects related to cancer treatments.&#x0D; &#x0D; MATERIAL AND METHODS: Published articles and our experience about the potential beneficial effects of Ozone therapy in different adverse events related with cancer treatments.&#x0D; &#x0D; RESULTS:&#x0D; 1. Clinical experiences have shown that Ozone therapy can decrease or avoid delay in the commencement of Radiotherapy and Chemotherapy in patients with delayed wound-healing after cancer surgery. These delays could lead to increased risk of tumor relapse.&#x0D; 2. Clinical studies have shown the success of Ozone therapy to treat different side effects of Radiotherapy, Chemotherapy and Surgery. In our institution Ozone therapy was used to treat: delayed healing after chemotherapy extravasation, radiation-induced dermatitis, fistula and fibrosis after cancer treatments, radiation-induced side effects such as: delayed-healing, vaginitis, cystitis, proctitis, brain injury. Other institutions have also described beneficial effects of Ozone therapy in the treatment of mucositis, wound infections or bisphosphonate-related jaw osteonecrosis in cancer patients&#x0D; 3. Finally, several preclinical studies have shown "protective" effect of Ozone preconditioning against selective toxicity induced by different chemotherapy drugs and radiation. These works suggest potential clinical application to prevent toxicity.&#x0D; &#x0D; DISCUSSION AND CONCLUSIONS: Several studies support the potential role of Ozone therapy as complementary treatment to avoid delay in the commencement of Radio-Chemotherapy and prevent or treat some side effects of cancer-treatments. However, as it happens with hyperbaric chambers and other more accepted therapies, well addressed clinical trials are required for a definitive demonstration. Meanwhile, our work with Ozone therapy looking for the improvement of quality of life and/or symptom management has to follow an appropriate information to cancer-patients.

Management of bisphosphonate related osteonecrosis of jaw (BRONJ) with topical drug delivary using custom made tray: A case report

Bisphosphonates (BPs) are effective inhibitors of osteoclast mediated bone resorption and thus frequently used in patients with multiple myeloma, osteoporosis, metabolic bone diseases and metastatic bone cancer. Inspite of its benefits, patients are at increased risk of developingBRONJ which adversely affects their quality of life. BPs induced inhibition of osteoclast function may cause defect in jaw bone physiologic remodeling which along with its antiangiogenic properties may predispose the patient to osteonecrosis of jaw. Here, we present a case in which patient with BRONJ who is terminally ill and only conservative management can be given responded favourably to topical medication using custom trays. Keywords: Bronj, Bisphosphonates, Zolendronate, Osteonecrosis, Custom made tray.

Use of Allogeneic Platelet Concentrates for the Surgical Treatment of Bisphosphonate -Related Osteo-Necrosis of Jaws (BRONJ): A Case

Use of Allogeneic Platelet Concentrates for the Surgical Treatment of Bisphosphonate -Related Osteo-Necrosis of Jaws (BRONJ): A Case

Early diagnosis of jaw osteomyelitis by easy digitalized panoramic analysis

BackgroundOsteomyelitis is an intraosseous inflammatory disease characterized by progressive inflammatory osteoclasia and ossification. The use of quantitative analysis to assist interpretation of osteomyelitis is increasingly being considered. The objective of this study was to perform early diagnosis of osteomyelitis on digital panoramic radiographs using basic functions provided by picture archiving and communication system (PACS), a program used to show radiographic images.MethodsThis study targeted a total of 95 patients whose symptoms were confirmed as osteomyelitis under clinical, radiologic, pathological diagnosis over 11 years from 2008 to 2017. Five categorized patients were osteoradionecrosis, bisphosphonate-related osteonecrosis of jaw (BRONJ, suppurative and sclerosing type), and bacterial osteomyelitis (suppurative and sclerosing type), and the control group was 117 randomly sampled. The photographic density in a certain area of the digital panoramic radiograph was determined and compared using the “measure area rectangle,” one of the basic PACS functions in INFINITT PACS® (INFINITT Healthcare, Seoul, South Korea). A conditional inference tree, one type of decision making tree, was generated with the program R for statistical analysis with SPSS®.ResultsIn the conditional inference tree generated from the obtained data, cases where the difference in average value exceeded 54.49 and the difference in minimum value was less than 54.49 and greater than 12.81 and the difference in minimum value exceeded 39 were considered suspicious of osteomyelitis. From these results, the disease could be correctly classified with a probability of 88.1%. There was no difference in photographic density value of BRONJ and bacterial osteomyelitis; therefore, it was not possible to classify BRONJ and bacterial osteomyelitis by quantitative analysis of panoramic radiographs based on existing research.ConclusionsThis study demonstrates that it is feasible to measure photographic density using a basic function in PACS and apply the data to assist in the diagnosis of osteomyelitis.

CT imaging features of antiresorptive agent-related osteonecrosis of the jaw/medication-related osteonecrosis of the jaw.

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ)/medication-related osteonecrosis of the jaw (MRONJ) include both bisphosphonate-related osteonecrosis of jaw (BRONJ) and denosumab-related osteonecrosis of jaw (DRONJ). The purpose of this study is to study radiological characteristics of ARONJ/MRONJ. These imaging features may serve as one useful aid for assessing ARONJ/MRONJ. CT scans of 74 Japanese patients, who were clinically diagnosed by inclusion criteria of ARONJ/MRONJ, obtained between April 1, 2011 and September 30, 2016, were evaluated. We investigated the CT imaging features of ARONJ/MRONJ, and clarified radiological differentiation between BRONJ and DRONJ, BRONJ due to oral bisphosphonate administration and due to intravenous bisphosphonate administration, BRONJ with respective kinds of medication, BRONJ with long-term administration and short-term administration, BRONJ with each clinical staging respectively. Fisher's exact test, χ2 test, Student's t-test and analysis of variance were performed in the statistical analyses. Unilateral maxillary sinusitis was detected in all patients with upper ARONJ/MRONJ (100%). DRONJ showed large sequestrum more frequently than BRONJ (3/4, 75 vs 3/35, 8.6%, p < 0.05). DRONJ showed periosteal reaction more frequently than BRONJ (4/10, 40 vs 7/65, 10.1%, p < 0.05). Patients of BRONJ resulting from intravenous bisphosphonate administration showed larger and more frequent buccolingual cortical bone perforations than BRONJ resulting from oral bisphosphonate administration (7/8, 87.5 vs 11/30, 36.7%, p < 0.05). There was no significant correlation between CT findings and respective kinds of medication, long/short-term administration, clinical stages of BRONJ. ARONJ/MRONJ has characteristic CT image findings which could be useful for its assessment.

Diş Hekimlerinin Bifosfonatlar ve Bifosfonat İlişkili Çene Nekrozu Hakkında Bilgi, Düşünce ve Davranışlarının Değerlendirilmesi

Diş Hekimlerinin Bifosfonatlar ve Bifosfonat İlişkili Çene Nekrozu Hakkında Bilgi, Düşünce ve Davranışlarının Değerlendirilmesi

Observational study of the bisphosphonate-related osteonecrosis of jaws.

IntroductionThe bisphosphonate-related osteonecrosis of the jaw was first referred to in 2003. Bisphosphonates action is focused on the osteoclasts. The drastic inhibition of the osteoclastic function is harmful for the jaws which are the only bones of the human skeleton in relative contact with the external environment. The adverse effects of the bisphosphonate-related therapy include the pathology for which they are prescribed, the atypical fractures in pathological bone.MethodThe aim of this research was to analyze the risk factors and the treatment methods in case of osteonecrosis of the jaws. To achieve these goals, the author analyzed the observation sheets of the patients admitted to the Oral and Maxillofacial Surgery Clinic during the period 2010–2015. The inclusion criteria were as follows: treatment with bisphosphonates, current or previous; the lesions of the mucous gingiva of the maxillaries followed by exposed necrotic bone, older than 8 weeks, with no tendency of healing; specific radiological image showing extended osteolysis with diffuse outline or radiopacity surrounded by radio-transparence, representing the necrotic bone sequestered; no metastasis in the necrotic maxillary bone; patient with no medical background of cervical-facial radiations. The patients who met these criteria were admitted in the study after signing the informed consent. Afterwards, the information found in the notes of the observational sheet (anamnesis, general examination and the imagistic investigation, treatment, postoperative recovery, prescription, postoperative recommendations) were gathered and submitted for statistic analysisResultsOf the 20 patients in total, 13 were women and 7 men, of ages ranging from 43 to 83. The most numerous cases were registered in the seventh age decade. All patients included in the study had lesions of the gingival maxillary mucosal areas with exposure of the subjacent necrotic bone. 60% of them were under intravenous treatment with zoledronic acid (Zometa®). A single patient was under oral treatment with bisphosphonates. 19 of these 20 patients developed osteonecrosis following a dental extraction while one case was due to the instability of the mandibular mobile prosthesis. 61% of the patients included in the study developed a necrotic process in the mandibular bone, 80% of the localizations were in the posterior area. As first intention, the choice of treatment was represented by local lavages with antiseptic solutions, general antibiotics and sequestrectomy. Of these patients, a third had relapsed and needed radical surgery treatment.ConclusionsPrevention of the bisphosphonate-related osteonecrosis of the jaw represents the best method of treatment. The development of bone sequesters damages the volume of the maxillary bone as such, reducing the chances for prosthetic functional rehabilitation of the dento-maxillary system. An increase in the quality of life by oral restoration of these patients may represent a challenge.

Bisphosphonates in multiple myeloma: an updated network meta-analysis.

Bisphosphonates are specific inhibitors of osteoclastic activity and are used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010 and 2012. To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus non-aminobisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression-free survival (PFS), and decreases skeletal-related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw (ONJ) and hypocalcemia. We searched MEDLINE, Embase (September 2011 to July 2017) and the CENTRAL (2017, Issue 7) to identify all randomized controlled trial (RCT) in MM up to July 2017 using a combination of text and MeSH terms. Any randomized controlled trial (RCT) comparing bisphosphonates versus placebo/no treatment/bisphosphonates and observational studies or case reports examining bisphosphonate-related ONJ in patients with MM were eligible for inclusion. Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) using a random-effects model. We used meta-regression to explore statistical heterogeneity. Network meta-analysis using Bayesian approach was conducted. In this update, we included four new studies (601 participants), resulting in a total of 24 included studies.Twenty RCTs compared bisphosphonates with either placebo or no treatment and four RCTs involved another bisphosphonate as a comparator. The 24 included RCTs enrolled 7293 participants. Pooled results showed that there was moderate-quality evidence of a reduction in mortality with on OS from 41% to 31%, but the confidence interval is consistent with a larger reduction and small increase in mortality compared with placebo or no treatment (HR 0.90, 95% CI 0.76 to 1.07; 14 studies; 2706 participants). There was substantial heterogeneity among the included RCTs (I2 = 65%) for OS. To explain this heterogeneity we performed a meta-regression assessing the relationship between bisphosphonate potency and improvement in OS, which found an OS benefit with zoledronate but limited evidence of an effect on PFS. This provided a further rationale for performing a network meta-analyses of the various types of bisphosphonates that were not compared head-to-head in RCTs. Results from network meta-analyses showed evidence of a benefit for OS with zoledronate compared with etidronate (HR 0.56, 95% CI 0.29 to 0.87) and placebo (HR 0.67, 95% CI 0.46 to 0.91). However, there was no evidence for a difference between zoledronate and other bisphosphonates.The effect of bisphosphonates on disease progression (PFS) is uncertain. Based on the HR of 0.75 (95% CI 0.57 to 1.00; seven studies; 908 participants), 47% participants would experience disease progression without treatment compared with between 30% and 47% with bisphosphonates (low-quality evidence). There is probably a similar risk of non-vertebral fractures between treatment groups (RR 1.03, 95% CI 0.68 to 1.56; six studies; 1389 participants; moderate-quality evidence). Pooled analysis demonstrated evidence for a difference favoring bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; seven studies; 1116 participants; moderate-quality evidence) and skeletal-related events (SREs) (RR 0.74, 95% CI 0.63 to 0.88; 10 studies; 2141 participants; moderate-quality evidence). The evidence for less pain with bisphosphonates was of very low quality (RR 0.75, 95% CI 0.60 to 0.95; eight studies; 1281 participants).Bisphosphonates may increase ONJ compared with placebo but the confidence interval is very wide (RR 4.61, 95% CI 0.99 to 21.35; P = 0.05; six studies; 1284 participants; low-quality evidence). The results from the network meta-analysis did not show any evidence for a difference in the incidence of ONJ (eight RCTs, 3746 participants) between bisphosphonates. Data from nine observational studies (1400 participants) reported an incidence of 5% to 51% with combination of pamidronate and zoledronate, 3% to 11% with zoledronate alone, and 0% to 18% with pamidronate alone.The pooled results showed no evidence for a difference in increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.59; seven studies; 1829 participants; low-quality evidence).The pooled results showed no evidence for a difference in increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74; three studies; 1090 participants; low-quality evidence). The results from network meta-analysis did not show any evidence for differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used. Use of bisphosphonates in participants with MM reduces pathological vertebral fractures, SREs and pain. Bisphosphonates were associated with an increased risk of developing ONJ. For every 1000 participants treated with bisphosphonates, about one patient will suffer from the ONJ. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or non-aminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate was found to be better than placebo and first-generation bisposphonate (etidronate) in pooled direct and indirect analyses for improving OS and other outcomes such as vertebral fractures. Direct head-to-head trials of the second-generation bisphosphonates are needed to settle the issue if zoledronate is truly the most efficacious bisphosphonate currently used in practice.

Wound healing protein profiles in the postoperative exudate of bisphosphonate-related osteonecrosis of mandible.

Recurrent bacterial infections in cases of bisphosphonate-related osteonecrosis of jaw (BRONJ) frequently occur. Therefore, BRONJ are usually treated by radical saucerization followed by intensive antibiotic medications without bisphosphonatetherapy. The postoperative exudate (POE) from BRONJ lesions may directly indicate the inflammatory status of osteomyelitis in patients, but so far, the POE has rarely been examined for its expression of various cytokines and wound healing proteins. A total of 27 cases of BRONJ, which involved the mandible, were selected and their individual POE collected 6h, 1day, and 2days after surgical intervention was analyzed by immunoprecipitation highperformance liquid chromatography (IP-HPLC). The different protein expressions in the BRONJ POE were compared with findings from ten cases of chronic mandibular osteomyelitis (CMO) exudate as the control group. For the protein expressions for inflammation, osteogenesis, and angiogenesis, in the 6h POE sample, the BRONJ exudate exhibited more expression of IL-10, IL-28, OPG, and osteocalcin, but less expression of TNFα and LL-37 than the control. In the 1day POE sample, the BRONJ exudate showed more expression of TNFα, IL-6, 8, 12, 28, α1-antitrypsin, VEGF-A, and VEGF-C, but less expression of CD68, lysozyme, bFGF, RANKL, bFGF, and ALP than the control. In the 2day POE sample, the BRONJ exudate consistently showed more expression of LL-37, β-defensin-1, and VEGF-A than the control. The present BRONJ POE revealed the rapid progress of bony wound healing through increased molecular signaling for inflammation, angiogenesis, and osteogenesis compared to the control. Therefore, it was suggested that the POE obtained from the postoperative bony lesions should be collected and analyzed by the IP-HPLC method to predict the prognosis of seriously complicated inflammatory bony diseases such as BRONJ.

Bisphosphonate related osteonecrosis of the maxilla: A case report

Introduction. Bisphosphonates are a group of medications which have an important role in the treatment of some bone diseases. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a side effect of intravenous bisphosphonate therapy. The mechanism of action by which they may cause osteonecrosis is questionable. BRONJ is defined by the American Association of Oral and Maxillofacial Surgeons (AAOMS) and classified into four stages (0-3). Treatment of BRONJ depends on the stage of disease and includes conservative treatment (stage 0 and 1) and surgical treatment (surgical debridement in stage 2 and sequestrectomy in stage 3). Case report. We presented a patient who had breast cancer, with stage 3 of bisphosphonate-related osteonecrosis of the upper jaw after zoledronic acid therapy for diffuse metastasis of the vertebrae. Before the treatment with zoledronic acid the patient was treated by a dentist. The osteonecrosis of the upper jaw started a year and a half after the start of zoledronic acid therapy and after tooth 24 extraction. She was treated by an oral surgeon at the beginning according to the protocol of AAOMS. The patient was sent to a maxillofacial surgeon due to the disease progression, and after computed tomography (CT) examination resection of the upper jaw was done. Conclusion. BRONJ is a condition with the specific clinical presentation, and it can be very serious for the patient, therefore it is necessary to emphasize the importance of screening. The doctors in different specialties (oncologist, dentist, oral surgeon and maxillofacial surgeon) must cooperate and control the patients under treatment with bisphosphonates before the therapy starts, as well as during and after it, in order to prevent, recognize on time and treat properly this complication.

Bisphosphonate related osteonecrosis of jaw: A case report

Bisphonates are used widely to treat osteoporosis, hyperglycemia of malignancy, bone metastasis of solid tumors. However a relationship has been reported between the use of bisphosphonates and osteonecrosis of jaw. Clinical presentation of bisphosphonates related osteonecrosis of jaw (BRONJ) includes gingival ulceration with exposed necrotic bone in the oral cavity involving either maxilla or mandible that has persisted for 6-8 weeks. And in severe cases it may cause spontaneous pain, tooth mobility, pathological fracture. Though treatment recommendation's exists, no definitive standard of care has been established for BRONJ and surgery was previously reported as capable of exacerbating bone exposure. The present study shows a case report of patient of BRONJ treated as conservatively as possible. Patient was managed with observation, oral antibacterial rinse, analgesics for pain control. After follow up of 18 months, healing of the lesion was achieved and patient became symptom free.

Prevention of bisphosphonate-related mandibular fractures.

SUMMARYMandibular fracture is usually the clinical end of bisphosphonate-related osteonecrosis of the jaw. This is a painful complication and patients cannot feed as usual, with a worsening of their quality of life. The goal of treatment in bisphosphonate related osteonecrosis of jaw (BRONJ) patients is to slow progression of bone necrosis. We present a novel technique for treatment of severe mandibular BRONJ in stage 3 patients that present with a high risk to develop fracture, since they have a residual unaffected mandibular bone height less than 6 mm. We treated 10 patients in this clinical situation with an extra-oral application of a reconstructive plate superficial to the platysma, to keep the plate separated from the infected site to avoid contamination and consequent need of removal, followed by an intraoral approach for active curettage of mandibular necrosis. The preservation of blood supply to the mandible and avoidance of direct contact of the infected site with the reconstructive plate are some advantages of this technique. This plate allows enhancement of mandibular strength, allowing proper treatment of the BRONJ site on the oral side without fear of causing a mandibular fracture when the residual mandible is thin. This technical solution guarantees these patients an extended disease-free period since it is effective in preventing mandibular fractures in patients with low mandibular residual height left after the BRONJ onset.

Are there any differences in mandibular morphology of patients with bisphosphonate-related osteonecrosis of jaws?: a case-control study.

The aim of this study was to compare the morphological differences in the mandible between patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) and healthy individuals and to detect the correlation between these parameters on panoramic radiography and CBCT. The CBCT and panoramic images of patients with BRONJ (n = 32) and control groups (n = 32) were included in the study. All the comparisons were analyzed between the osteonecrosed and healthy sides of patients with BRONJ and control group. The panoramic radiographs were used to measure the values of the condyle angle, gonial angle, antegonial angle, antegonial depth, condylar height and ramal height. The mandibular cortical index (MCI) and bone quality index (BQI) were also examined on cross-sectional scans of CBCT images. There were significant differences in the MCI (p = 0.014) and BQI (p = 0.021) between the left and right side of the BRONJ group and also between the osteonecrosed side of the BRONJ and control group (p < 0.0001). No significant difference was found in other comparisons. The outcomes of the present study indicate that bisphosphonates influenced some internal morphological changes in the mandible. These changes may be a reason of BRONJ. But, these changes are not reflective of the measured values obtained using panoramic radiographs on the external morphology of the mandible.

Simultaneous Application of Bone Morphogenetic Protein-2 and Platelet-Rich Fibrin for the Treatment of Bisphosphonate-Related Osteonecrosis of Jaw.

Simultaneous Application of Bone Morphogenetic Protein-2 and Platelet-Rich Fibrin for the Treatment of Bisphosphonate-Related Osteonecrosis of Jaw.