Occurrence Of Bisphosphonate-related Osteonecrosis Of The Jaw Research Articles

Histopathological assessment of the preventive effect of leukocyte-platelet-rich fibrin on bisphosphonate-related osteonecrosis of the jaw following dental extraction: An animal study

BackgroundLeukocyte- and platelet-rich fibrin (L-PRF) could be considered a preventive measure in Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ). The present experiment aimed to assess the preventive effects of L-PRF on osteonecrosis of the jaw in rats. MethodsIn this interventional animal study with a split-mouth design, 28 rats were randomly allocated to saline (negative control), bisphosphonate (positive control), and Bis + L-PRF (case) groups. Bilateral extraction of maxillary molar teeth was performed followed by random application of L-PRF to one of the extraction sockets treated with Zoledronic acid for four weeks. Clinical occurrence of BRONJ and histopathologic evaluations were done, and data were subjected to the Kruskal-Wallis test, Mann-Whitney U test and exact Fisher test performed using SPSS 25. The significance level was set at 0.05. ResultsThe application of L-PRF resulted in a 41.67% reduction in osteonecrosis centers and the number of osteoclast cells. Also, Kruskal Wallis test results showed a significant difference among the three groups regarding the frequency distribution of inflammation severity. However, no significant difference was detected regarding the frequency distribution of the blood vessels (Kruskal Wallis test, P-value = 0.649). ConclusionIt could be inferred that possible preventive effects on the clinical occurrence of osteonecrosis could be expected from the application of L-PRF.

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

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

Tetrahedral framework nucleic acid carrying angiogenic peptide prevents bisphosphonate-related osteonecrosis of the jaw by promoting angiogenesis

The significant clinical feature of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is the exposure of the necrotic jaw. Other clinical manifestations include jaw pain, swelling, abscess, and skin fistula, which seriously affect the patients’ life, and there is no radical cure. Thus, new methods need to be found to prevent the occurrence of BRONJ. Here, a novel nanoparticle, tFNA-KLT, was successfully synthesized by us, in which the nanoparticle tetrahedral framework nucleic acid (tFNA) was used for carrying angiogenic peptide, KLT, and then further enhanced angiogenesis. TFNA-KLT possessed the same characteristics as tFNA, such as simple synthesis, stable structure, and good biocompatibility. Meanwhile, tFNA enhanced the stability of KLT and carried more KLT to interact with endothelial cells. First, it was confirmed that tFNA-KLT had the superior angiogenic ability to tFNA and KLT both in vitro and in vivo. Then we apply tFNA-KLT to the prevention of BRONJ. The results showed that tFNA-KLT can effectively prevent the occurrence of BRONJ by accelerating angiogenesis. In summary, the prepared novel nanoparticle, tFNA-KLT, was firstly synthesized by us. It was also firstly confirmed by us that tFNA-KLT significantly enhanced angiogenesis and can effectively prevent the occurrence of BRONJ by accelerating angiogenesis, thus providing a new avenue for the prevention of BRONJ and a new choice for therapeutic angiogenesis.

Machine Learning Approaches for Predicting Bisphosphonate-Related Osteonecrosis in Women with Osteoporosis Using VEGFA Gene Polymorphisms.

Objective: This nested case–control study aimed to investigate the effects of VEGFA polymorphisms on the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in women with osteoporosis. Methods: Eleven single nucleotide polymorphisms (SNPs) of the VEGFA were assessed in a total of 125 patients. Logistic regression was performed for multivariable analysis. Machine learning algorithms, namely, fivefold cross-validated multivariate logistic regression, elastic net, random forest, and support vector machine, were developed to predict risk factors for BRONJ occurrence. Area under the receiver-operating curve (AUROC) analysis was conducted to assess clinical performance. Results: The VEGFA rs881858 was significantly associated with BRONJ development. The odds of BRONJ development were 6.45 times (95% CI, 1.69–24.65) higher among carriers of the wild-type rs881858 allele compared with variant homozygote carriers after adjusting for covariates. Additionally, variant homozygote (GG) carriers of rs10434 had higher odds than those with wild-type allele (OR, 3.16). Age ≥ 65 years (OR, 16.05) and bisphosphonate exposure ≥ 36 months (OR, 3.67) were also significant risk factors for BRONJ occurrence. AUROC values were higher than 0.78 for all machine learning methods employed in this study. Conclusion: Our study showed that the BRONJ occurrence was associated with VEGFA polymorphisms in osteoporotic women.

Sensory denervation increases potential of bisphosphonates to induce osteonecrosis via disproportionate expression of calcitonin gene-related peptide and substance P.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side effect of systematic administration of bisphosphonates (BPs). Sensory innervation is crucial for bone healing. We established inferior alveolar nerve injury (IANI) and inferior alveolar nerve transection (IANT) models characterized by disorganized periosteum, increased osteoclasts, and unbalanced neuropeptide expression. Zoledronate injection disrupted neuropeptide expression in the IANI and IANT models by decreasing calcitonin gene-related peptide (CGRP) and increasing substance P (SP); associated with this, BRONJ prevalence was significantly higher in the IANT model, followed by the IANI model and the sham control. CGRP treatment significantly reduced BRONJ occurrence, whereas SP administration had the opposite effect. In vitro, RAW 264.7 cells were treated with BPs and then CGRP and/or SP to study changes in zoledronate toxicity; combined application of CGRP and SP decreased zoledronate toxicity, whereas CGRP or SP applied alone showed no effects. These results demonstrate that sensory denervation facilitates the occurrence of BRONJ and that CGRP used therapeutically may prevent BRONJ progression, provided that SP is also present. Further studies are necessary to determine the optimal ratio of CGRP to SP for promoting bone healing and to uncover the mechanism by which CGRP and SP cooperate.

Tetrahedral Framework Nucleic Acid Promotes the Treatment of Bisphosphonate-Related Osteonecrosis of the Jaws by Promoting Angiogenesis and M2 Polarization.

Bisphosphonates are often used to treat osteoporosis, malignant bone metastases, and hypercalcemia. However, it can cause serious adverse reactions, bisphosphonate-related osteonecrosis of the jaw (BRONJ), which seriously affects the quality of life of patients. At present, the treatment of BRONJ is still difficult to reach an agreement, and there is no effective treatment. Therefore, it is very important to find effective treatments. Many studies have shown that the occurrence of BRONJ may be due to unbalanced bone turnover, anti-angiogenesis, bacterial infection, direct tissue toxicity, and abnormal immune function. The previous research results show that tetrahedral framework nucleic acids (tFNAs), a new type of nanomaterial, can promote various biological activities of cells, such as cell proliferation, migration, anti-inflammation and anti-oxidation, and angiogenesis. Therefore, we intend to explore the potential of tFNAs in the treatment of BRONJ through this study. The results show that tFNAs can promote the treatment of BRONJ by promoting angiogenesis and promoting M2 polarization in macrophages and inhibiting M1 polarization both in vitro and in vivo. These results provide a theoretical basis for the application of tFNAs in the treatment of BRONJ and also provide new ideas and methods for the treatment of other diseases based on ischemia and immune disorders.

PDGF-BB exhibited therapeutic effects on rat model of bisphosphonate-related osteonecrosis of the jaw by enhancing angiogenesis and osteogenesis.

The mechanism and effective treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) are still uncertain. Our previous study revealed that zoledronate (ZOL) preferentially inhibited osteoclasts formation and platelet-derived growth factor-BB (PDGF-BB) secretion, causing suppression of angiogenesis and osteogenesis in vitro. The present study aimed to elucidate whether PDGF-BB had therapeutic effects on rat model of BRONJ by enhancing angiogenesis and angiogenesis. Firstly, rat model of BRONJ was established by ZOL and dexamethasone administration, followed by teeth extraction. The occurrence of BRONJ was confirmed and detected dead bone formation by maxillae examination, micro-CT scan and HE staining (10/10). Compared to control rats (0/10), both angiogenesis and mature bone formation were suppressed in BRONJ-like rats, evidenced by enzyme-linked immunosorbent assay (ELISA) for VEGF (P < 0.01), immunohistochemistry of CD31 (P < 0.05) and OCN (P < 0.01). Moreover, in the early stage of bone healing, the number of preosteoclasts (P < 0.001) and PDGF-BB secretion (P < 0.05) were significantly decreased in bisphosphonates-treated rats, along with the declined numbers of microvessels (P < 0.05) and osteoblasts (P < 0.05). In vitro study, CCK8 assay, alizarin red S staining and western blot assay showed that mandible-derived bone marrow mesenchymal stem cells (BMMSCs) in BRONJ-like rats presented suppressed functions of proliferation, osteogenesis and angiogenesis. Interestingly, recombinant PDGF-BB was able to rescue the impaired functions of BMMSCs derived from BRONJ-like rats at more than 10 ng/ml. Then fibrin sealant with or without recombinant PDGF-BB were tamped into the socket after debridement in BRONJ rats. After 8 weeks, fibrin sealant containing PDGF-BB showed significant therapeutic effects on BRONJ-like rats (bone healing: 8/10 vs 3/10, P < 0.05) with enhancing microvessels and mature bone formation. Our study suggested that the inhibition of angiogenesis and osteogenesis, the potential mechanisms of BRONJ, might partly result from suppression of PDGF-BB secretion in the early stage of bone healing. PDGF-BB local treatment after debridement might avail the healing of BRONJ by increasing angiogenesis and osteogenesis.

Adipose-derived stem cells prevent the onset of bisphosphonate-related osteonecrosis of the jaw through transforming growth factor \u03b2-1-mediated gingival wound healing

BackgroundDue to its complex pathogenesis and low clinical cure rate, bisphosphonate-related osteonecrosis of the jaw (BRONJ) poses a substantial challenge for oral and maxillofacial surgeons. Therefore, the treatment of BRONJ should focus on prevention. In clinical studies, primary wound closure can significantly reduce the incidence of BRONJ. Whether local stem cell transplantation can promote primary gingival healing in patients with a medication history and prevent BRONJ has not been reported.MethodsIn this study, animals were divided into a healthy group (non-drug treatment), a BP group, a hydroxyapatite (HA) group, and an adipose-derived stem cell (ADSC) group. All groups except the healthy group were treated with BPs and immunosuppressive drugs once per week for 8 weeks, simulating clinical use for the treatment of cancer patients with bone metastasis, to induce BRONJ-like animals. After the sixth drug treatment, the bilateral premolars were extracted in all groups. In contrast to the healthy and BP groups, the extraction sockets in the HA and ADSC groups were filled with HA or HA + ADSCs simultaneously post extraction to observe the preventive effect of ADSCs on the occurrence of BRONJ. At 2 and 8 weeks post extraction, animals from all groups were sacrificed.ResultsAt 8 weeks post transplantation, ADSCs prevented the occurrence of BRONJ, mainly through accelerating healing of the gingival epithelium at 2 weeks post extraction. We also found that ADSCs could upregulate the expression of transforming growth factor β1 (TGF-β1) and fibronectin in tissue from animals with a medication history by accelerating gingival healing of the extraction socket. A rescue assay further demonstrated that TGF-β1 and fibronectin expression decreased in TGF-β1-deficient ADSC-treated animals, which partially abolished the preventive effect of ADSCs on the onset of BRONJ.ConclusionADSCs prevent the onset of BRONJ, mainly by upregulating the expression of TGF-β1 and fibronectin to promote primary gingival healing, ultimately leading to bone regeneration in the tooth extraction socket. Our new findings provide a novel stem cell treatment for the prevention of BRONJ.

Prophylaxis of osteonecrosis in the case of patients treated with bisphosphonates: A review paper.

Bisphosphonates are a group of medicines used in the treatment of oncological osteoporosis, Paget disease and osteogenesis imperfecta. They significantly interfere with the regeneration processes of bone tissue and have a tendency to accumulate in the areas of increased bone remodeling, i.e., the maxilla and the mandible. One of their most serious and problematic side effects is the induction of bisphosphonaterelated osteonecrosis of the jaw (BRONJ), characterized by an exposed, necrotic bone in the maxillofacial area, which lasts longer than 8 weeks, in the case of a patient who is using or was using bisphosphonates and who did not undergo radiotherapy in this anatomical area. Dentistry manipulations are one of the factors which may increase the risk of BRONJ occurrence. The existing recommendations for preventing osteonecrosis are ambiguous. Some authors recommend that the bisphosphonate therapy be discontinued prior to dental procedures, while others say that there is no evidence for the effectiveness of interrupting the therapy. There is also no unequivocal attitude toward antibiotic prophylaxis. According to this research, each case should be considered individually, primarily having regard to the good of a patient.

Bisphosphonate-related osteonecrosis of the jaw: from the sine qua non condition of bone exposure to a non-exposed BRONJ entity.

The present work aimed to review the literature focusing on the diagnostic criteria for bisphosphonate-related osteonecrosis of the jaw (BRONJ) and its implications regarding the management of the disease. Since the report of the first cases, BRONJ concepts, diagnostic criteria and guidelines have been changed. The presence of bone exposure in the oral cavity was at first a sine qua non condition for diagnosis. However, it seems that the great concern now is the possibility of occurrence of BRONJ without this feature. Some authors warn that the bone exposure criterion leads to late diagnosis and poor response to treatment. Meanwhile, some radiographic features, such as bone sclerosis, have been postulated as early signs of the disease. Criticisms have also been raised about the clinical staging system of BRONJ. While there is no consensus on the subject, common sense recommends treating symptomatic patients taking bisphosphonate as having BRONJ despite the absence of bone exposure; and asymptomatic patients must be kept under dental follow-up, since all of them are at risk for BRONJ.

Legal liability in bisphosphonate-related osteonecrosis of the jaw.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an adverse reaction that may occur in patients administered with bisphosphonates (BP). This condition can cause high morbidity and hinder quality of life. Its treatment is complex and often unsatisfactory, and prevention strategies may have limited effectiveness, if any. Thus, managing patients treated with BP may result in exposure of the practitioner to legal liability or malpractice claims: legal actions pursuant to BRONJ are reported to be underway on three continents. Nonetheless, the attribution of liability, if any, is a complex process requiring, on the basis of current knowledge, a robust and pragmatic approach to the facts, which must be identified from the point of view of the time, place and individuals involved. This means a comprehensive consideration of the sequence of actions from bisphosphonates prescription to BRONJ occurrence (as well as immediately after, and any action potentially related to its causation or worsening) is required in order to determine if a breach in informing, diagnosing, managing or referring the patient took place, as well as determining if the patient was compliant in attending to prescriptions and follow-up programmes.

Accurate Approach in the Treatment of Oral Bisphosphonate–Related Jaw Osteonecrosis

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is not completely understood and difficult to treat. Even though the occurrence of BRONJ is mainly related to the therapy with intravenous bisphosphonates (BPs), this article reports a case of long-term oral BP use and BRONJ occurrence. In addition, a literature review provides some additional information about BPs, BRONJ, and also a guideline for the prevention and treatment of BRONJ stages. A 79-year-old patient presented intense and persistent pain, purulent secretion, and exposed bone at the right side of the lower jaw. Thus, she was submitted to anamnesis, radiologic and tomographic examinations, and bacterial culture and sensitivity tests. These procedures were followed by surgical debridement of the bone and surrounding tissues/cyst and antibiotic prescription and histopathologic analysis of the fragments. Together, the examinations performed showed the occurrence of stage 2 BRONJ. Moreover, the antibiotic prescription, discontinuation of oral BP, and surgical procedures ensure that the patient had no more symptoms. Therefore, considering the presented case, we believe that an accurate approach is promising to diagnose and treat stage 2 BRONJ and other associated pathologic findings.

Oral Bisphosphonate–Associated Osteonecrosis of the Jaw After Implant Surgery: A Case Report and Literature Review

This report documents a case of bisphosphonate-related osteonecrosis of the jaw (BRONJ) after dental implant placement in an osteoporotic patient treated with alendronate for 6 years. A 63-year-old patient underwent rehabilitation of the posterior mandible with 2 dental implants in 2006 while taking alendronate to treat osteoporosis. The surgical procedure was uneventful. Both implants integrated well, and in November 2006 the patient wore a fixed partial prosthesis. Alendronate was never discontinued. In June 2008 a painful cheek swelling of the left mandible developed, associated with gingival bleeding. Since then, the patient underwent several courses of antibiotics, without relief of symptoms. In June 2009 the patient was referred to our department. An area of infected and exposed necrotic bone in the left mandible enclosed 1 dental implant. A panoramic radiograph and computed tomography scan showed an increased bone marrow density with peri-implant bone sequestration. The technetium Tc 99m scintigraphy-labeled granulocytes were positive for active bone infection. Bone exposure persisted for 8 weeks, and diagnosis of oral nitrogen-containing bisphosphonate (N-BP)-related osteonecrosis was made. On the basis of a review of the literature, this is the 10th case of BRONJ after implant placement in patients taking oral N-BPs. Despite the low risk of BRONJ occurrence after implant surgery in oral N-BP users, the fate of dental implants in these patients remains uncertain. Therefore patients at risk must be given a full explanation of the potential risks of implant failure and BRONJ development. Because the potential role of infection is still debated, great attention should be paid to the long-term oral hygiene of implant-prosthetic restorations.

A pilot case–control study on the alveolar bone density measurement in risk assessment for bisphosphonate-related osteonecrosis of the jaw

SummaryAlveolar bone mineral density (BMD) measured by radiography standardized by aluminum step wedge pasted on the film and digitized by a computer system was significantly higher around osteonecrosis lesions than in control cases in a pilot case–control study. High alveolar bone density appears useful as a local risk factor for bisphosphonate-related osteonecrosis of the jaw (BRONJ).IntroductionIn an attempt to find a reliable test method predicting the occurrence of BRONJ in addition to various risk factors suggested, an increase of alveolar bone density near the necrotic lesions was found by computerized radiogrammetry using dental films pasted with an aluminum step wedge (Bone RightⓇ, Dentalgraphic⋅Com Company, Himeji) in six cases of BRONJ.MethodsThe bone mineral density surrounding the osteonecrosis lesions showed distinctly higher density in BRONJ cases compared with age-matched controls. In one subject on bisphosphonate treatment in whom two extractions were simultaneously carried out, BRONJ occurred only at the location with extremely high alveolar bone density, but not at the other site with normal density.ConclusionThis method may be useful in detecting a rise of alveolar BMD frequently occurring near the necrotic lesion in subjects with impending risk for BRONJ.

What impact do systemically administrated bisphosphonates have on oral implant therapy? A systematic review

The aim of this systematic review is to evaluate, analysing the dental literature, whether: * Patients on intravenous (IV) or oral bisphosphonates (BPs) can receive oral implant therapy and what could be the risk of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ)? * Osseointegrated implants could be affected by BP therapy. A Medline search was conducted and all publications fulfilling the inclusion and exclusion criteria from 1966 until December 2008 were included in the review. Moreover, the Cochrane Data Base of Systematic Reviews, and the Cochrane Central Register of Controlled Trials and EMBASE (from 1980 to December 2008) were searched for English-language articles published between 1966 and 2008. Literature search was completed by a hand research accessing the references cited in all identified publications. The literature search rendered only one prospective and three retrospective studies. The prospective controlled non-randomized clinical study followed patients with and without BP medication up to 36 months after implant therapy. The patients in the experimental group had been on oral BPs before implant therapy for periods ranging between 1 and 4 years. None of the patients developed BRONJ and implant outcome was not affected by the BP medication. The three selected retrospective studies (two case-controls and one case series) yielded very similar results. All have followed patients on oral BPs after implant therapy, with follow-up ranging between 2 and 4 years. BRONJ was never reported and implant survival rates ranged between 95% and 100%. The literature search on BRONJ including guidelines and recommendations found 59 papers, from which six were retrieved. Among the guidelines, there is a consensus on contraindicating implants in cancer patients under IV-BPs and not contraindicating dental implants in patients under oral-BPs for osteoporosis. From the analysis of the one prospective and the three retrospective series (217 patients), the placement of an implant may be considered a safe procedure in patients taking oral BPs for <5 years with regard to the occurrence of BRONJ since in these studies no BRONJ has been reported. Moreover, the intake of oral-BPs did not influence short-term (1-4 years) implant survival rates.