Alendronate sodium induces G1 phase arrest and apoptosis in human umbilical vein endothelial cells by inhibiting ROS-mediated ERK1/2 signaling.

Bisphosphonates are potent bone resorption inhibitors, among which alendronate sodium (ALN) is commonly prescribed for most osteoporosis patients, but long-term application of ALN can cause bisphosphonate-related osteonecrosis of jaw (BRONJ), the pathogenesis of which remains unclear. Previous studies have suggested that bisphosphonates cause jaw ischemia by affecting the biological behavior of vascular endothelial cells, leading to BRONJ. However, the impacts of ALN on vascular endothelial cells and its mechanism remain unclear. The purpose of this work is to assess the influence of ALN on human umbilical vein endothelial cells (HUVECs) and clarify the molecular pathways involved. We found that high concentration of ALN induced G1 phase arrest in HUVECs, demonstrated by downregulation of Cyclin D1 and Cyclin D3. Moreover, high concentration of ALN treatment showed pro-apoptotic effect on HUVECs, demonstrated by increased levels of the cleaved caspase-3, the cleaved PARP and Bax, along with decreased levels of anti-apoptotic protein Bcl-2. Further experiments showed that ERK1/2 phosphorylation was decreased. Additionally, ALN provoked the build-up of reactive oxygen species (ROS) in HUVECs, leading to ERK1/2 pathway suppression. N-acetyl-L-cysteine (NAC), a ROS scavenger, efficiently promoted the ERK1/2 phosphorylation and mitigated the G1 phase arrest and apoptosis triggered by ALN in HUVECs. PD0325901, an inhibitor of ERK1/2 that diminishes the ERK1/2 phosphorylation enhanced the ALN-induced G1 phase arrest and apoptosis in HUVECs. These findings show that ALN induces G1 phase arrest and apoptosis through ROS-mediated ERK1/2 pathway inhibition in HUVECs, providing novel insights into the pathogenic process, prevention and treatment of BRONJ in individuals receiving extended use of ALN.

Bisphosphonates and Their Connection to Dental Procedures: Exploring Bisphosphonate-Related Osteonecrosis of the Jaws.

Bisphosphonates are widely used to treat osteoporosis and malignant tumors due to their effectiveness in increasing bone density and inhibiting bone resorption. However, their association with bisphosphonate-related osteonecrosis of the jaws (BRONJ) following invasive dental procedures poses a significant challenge. This review explores the functions, mechanisms, and side effects of bisphosphonates, emphasizing their impact on dental procedures. Dental patients receiving bisphosphonate treatment are at higher risk of BRONJ, necessitating dentists' awareness of these risks. Topical bisphosphonate applications enhance dental implant success, by promoting osseointegration and preventing osteoclast apoptosis, and is effective in periodontal treatment. Yet, systemic administration (intravenous or intraoral) significantly increases the risk of BRONJ following dental procedures, particularly in inflamed conditions. Prevention and management of BRONJ involve maintaining oral health, considering alternative treatments, and careful pre-operative and post-operative follow-ups. Future research could focus on finding bisphosphonate alternatives with fewer side effects or developing combinations that reduce BRONJ risk. This review underscores the need for further exploration of bisphosphonates and their implications in dental procedures.

Efficacy of hyaluronic acid, absorbable collagen sponge, and their combination in minimizing bisphosphonate-related osteonecrosis of the jaws (BRONJ) after dental extraction: a preliminary animal histomorphometric study.

INTRODUCTION: There is no study on the effectiveness of hyaluronic acid (HA) placement either with or without absorbable collagen sponge (ACS) in reducing or preventing bisphosphonate-related osteonecrosis of the jaws (BRONJ). This preliminary animal study examined the efficacy of this clinically important treatment. METHODS: For simulating BRONJ, zoledronic acid was administered to 40 rats for 5 weeks. Two weeks later, a right first molar was extracted from each rat. The rats were randomized into four groups of socket treatments: control (empty extraction socket) or with sockets filled with ACS, HA, or HA+ACS (n=4×10). After 2 weeks, 5 rats in each group were sacrificed and subjected to histopathologic and histomorphometric evaluation. Eight weeks post-surgically, the rest of rats were euthanized and histologically examined. The Kruskal-Wallis test was used to compare the four treatments at each time point (α=0.05). RESULTS: Six rats were lost overall. In the second week, vascularization was higher in ACS group (P<0.05); osteoclast activity was not different between groups (P>0.05); empty lacunae were the most and fewest in control and HA+ACS groups, respectively (P<0.05); eosinophil infiltration was maximum in HA group (P<0.05); lymphocyte counts were maximum and minimum in the HA+ACS and ACS groups, respectively (P<0.05); the highest and lowest neutrophil counts were seen in ACS and control groups, respectively (P<0.05); and the extent of live bone did not differ between groups (P>0.05). In the eighth week, vascularization was not different in groups (P>0.05); the highest and lowest osteoclast activities were seen in the control and HA+ACS groups, respectively (P<0.05); empty lacunae were the most and fewest in control and HA+ACS, respectively (P<0.05); maximum and minimum numbers of eosinophils were in control and HA+ACS groups, respectively (P<0.05); HA and control groups exhibited the highest and lowest lymphocyte counts, respectively (P<0.05); the lowest and highest neutrophil counts were observed in HA+ACs and control groups, respectively (P<0.05); and the highest and lowest extents of the live bone were observed in HA+ACS and control groups, respectively (P<0.05). CONCLUSIONS: Within the limitations of this preliminary animal study, HA and especially HA+ACS seem a proper method for preventing or treating BRONJ.

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.

Bisphosphonate-related osteonecrosis of the jaws and dental surgery procedures in children and young people with osteogenesis imperfecta: A systematic review.

BACKGROUND: Bisphosphonates (BPs) contrast the bone fragility and improve bone density in some metastatic cancers and bone diseases, such as Osteogenesis Imperfecta (OI). BPs use has been associated with osteonecrosis of the jaws (BRONJs) in adults needing for invasive dental procedures. AIM: To conduct a systematic review on BRONJ occurrence after dental surgery in paediatric population under BPs therapy for OI, so as to identify the pre-surgical protocols adopted. DESIGN: According to PRISMA guidelines, Pubmed, Web of Science (WoS) and Cochrane were investigated on September 2018, and re-checked on July 2019. Inclusion criteria were English-language papers on children/young adults (until 24 years old) reporting dental/oral surgery procedures. RESULTS: Totally, 60 articles were found. After title/abstract reviews and duplicates exclusion, 22 eligible titles underwent full-text evaluation. Finally, 10 studies were included. CONCLUSIONS: The lack of BRONJ occurrence in paediatric population suffering OI and treated with BPs, was confirmed, but the reasons are still debated, being the BPs therapies and the surgical strategies various and not standardized. Longitudinal studies should evaluate what happens to those former children once adult, to evaluate the delayed BRONJs onset associated with the occurrence of comorbidities during the adulthood.

Antimicrobial photodynamic therapy improves the alveolar repair process and prevents the occurrence of osteonecrosis of the jaws after tooth extraction in senile rats treated with zoledronate.

This study evaluated the effects of antimicrobial photodynamic therapy (aPDT) in the alveolar repair of rats with major risk factors for bisphosphonate-related osteonecrosis of the jaws (BRONJ). Senile rats received 0.45 ml of vehicle (VEH and VEH/aPDT) or 0.45 ml of zoledronate (ZOL and ZOL/aPDT) every three days for seven weeks. After three weeks of treatment, the first lower left molar was extracted. VEH/aPDT and ZOL/aPDT were submitted to aPDT on the extraction site at 0, 2 and 4 days postoperatively. Euthanasia was performed 28 days postoperatively and the extraction site was evaluated by clinical, histological, histometric, histochemical and immunohistochemical analysis. ZOL showed tissue repair impairment; lower percentage of newly formed bone tissue (NFBT); higher percentage of non-vital bone tissue (NVBT); fewer mature collagen fibers and increased immunolabeling for tumor necrosis factor (TNFα), interleukin (IL)-1ß and IL-6. ZOL/aPDT showed clinical and histological characteristics of the extraction site, percentage of NFBT and percentage of mature collagen fiber similar to VEH. Percentage of NVBT and immunolabeling for inflammatory cytokines in ZOL/aPDT was lower than in ZOL. Immunolabeling for tartarato-resistant acid phosphatase (TRAP) was lower in ZOL and ZOL/aPDT. aPDT in the dental extraction site improves tissue repair process and prevents the occurrence of BRONJ-like lesions after tooth extraction.

Detecting the effect of bisphosphonates during osteoporosis treatment on jawbones using multidetector computed tomography: The OSTEOSYR project.

AIM: The aim of the present cross-sectional study was to investigate the effects of bisphosphonates (BP), prescribed for osteoporosis, on jawbones using multidetector computed tomography (MDCT). METHODS: Fifty-three women who had dual-energy X-ray absorptiometry examination were scanned by MDCT. Both the cortical and the trabecular parts of the alveolar and the cortical bones were compared between BP users and non-BP users using a number of radiological measurements. Linear regression was used for the statistical analysis. RESULTS: The cortical part of the basal bone of the mandible revealed a significant increase in the BP group (.001 > P-value ≤ .026) after using BP for 5 years. No alternations were observed in the trabecular part of the basal bone or in the cortical or trabecular parts of the alveolar bone over the same duration. CONCLUSIONS: The use of BP as a treatment for osteoporosis for 5 years increased the thickness of the cortex of the basal bone of the mandible, as detected by MDCT. The other parts of the jawbones showed no influence by BP for such a purpose, as detected on MDCT images. Accordingly, models (equations) for predicting the alternations in the inferior cortex of the mandible induced by BP therapy during osteoporosis have been suggested.

Issues with the surgical treatment of antiresorptive agent-related osteonecrosis of the jaws.

Antiresorptive agent-related osteonecrosis of the jaw is a rare but significant complication in patients using antiresorptive agents such as bisphosphonates and denosumab. Although the disease is well recognized, and many studies have been performed on the management of this condition, the treatment of severe osteonecrosis is still a challenge. Most recent studies have shown an advantage of surgical treatment over conservative treatment for stage 2/3 patients, but there is no consensus on the appropriate surgical procedures for antiresorptive agent-related osteonecrosis of the jaw. Furthermore, patients with severe systemic conditions may not be appropriate for extensive surgical treatment, and the treatment protocol for such patients has not been established. In this review, issues regarding the current surgical treatment for antiresorptive agent-related osteonecrosis of the jaws are discussed, with an emphasis on the clinical aspects.

Effects of Zoledronic Acid in Experimental Periapical Lesions in Rats: An Imaging and Histological Analysis

Abstract The aim of this study was to assess the imaging and histological features of experimental periapical lesions, including the adjacent alveolar bone, in rats under zoledronic acid treatment. The study used 40 male Wistar rats distributed into 8 groups of 5 animals each: G1: induction of periapical lesion (PL) and weekly intraperitoneal administration (WIPA) of saline solution (0.9% NaCl) for 4 weeks; G2: PL induction and WIPA of zoledronic acid (0.15 mg/kg/week) for 4 weeks; G3: PL induction and WIPA of saline solution for 8 weeks; G4: PL induction and WIPA of zoledronic acid for 8 weeks; G5:WIPA of saline solution for 4 weeks and subsequent PL induction; G6: WIPA of zoledronic acid for 4 weeks and subsequent PL induction; G7: WIPA of saline solution for 8 weeks and subsequent PL induction; G8: WIPA of zoledronic acid for 8 weeks and subsequent PL induction. The administration of zoledronic acid or saline solution continued after PL induction until the euthanasia. Thus, cone beam computed tomography and histological analysis were performed. Statistical analyzes were performed by ANOVA and Kruskal-Wallis test. Groups treated with zoledronic acid showed significantly smaller size of PL than the groups treated with 0.9% NaCl (p<0.05). PLs were formed by chronic inflammation ranging from mild to moderate, with no difference between groups. In all specimens, no mandibular necrosis was observed. In conclusion, the presence of PLs apparently does not represent an important risk factor for the development of bisphosphonate-related osteonecrosis of the jaws.

Resumo O objetivo deste estudo foi avaliar as características histológicas e de imagem de lesões periapicais experimentais, incluindo o osso alveolar adjacente, em ratos sob tratamento com ácido zoledrônico. O estudo utilizou 40 ratos Wistar, machos, distribuídos em 8 grupos de animais cada: G1: indução de lesão periapical (LP) e administração intraperitoneal semanal (AIS) de solução salina (NaCl 0.9%) por 4 semanas; G2: indução de LP e AIS de ácido zoledrônico (0,15 mg/kg/week) por 4 semanas; G3: indução de LP e AIS de solução salina por 8 semanas; G4: indução de LP e AIS de ácido zoledrônico por 8 semanas; G5- AIS de solução salina por 4 semanas e subsequente indução de LP; G6- AIS de ácido zoledrônico por 4 semanas e subsequente indução de LP; G7: AIS de solução salina por 8 semanas e subsequente indução de LP; G8: AIS de ácido zoledrônico por 8 semanas e subsequente indução de LP. A administração de ácido zoledrônico ou solução salina continuou após indução de LP até a eutanásia. Após isso, tomografia computadorizada de feixe cônico e análise histológica foram realizadas. Análises estatísticas foram realizadas por ANOVA e teste de Kruskal-Wallis. Os grupos tratados com ácido zoledrônico mostraram LPs significativamente menores que os grupos tratados com NaCl 0.9% (p <0.05). LPs eram formadas por inflamação crônica variando de leve a moderada, sem diferença entre os grupos. Em todos os espécimes, necrose mandibular não foi observada. Em conclusão, a presença de LPs aparentemente não representa um fator de risco importante para o desenvolvimento de osteonecrose relacionada ao uso de bisfosfonatos.

Diagnostic dilemma between medication-related osteonecrosis and oral squamous cell carcinoma in a mandibular lytic lesion.

Osteolytic lesions of the mandible are common, and there are two important differential diagnoses that must be considered: medication-related osteonecrosis of the jaws (MRONJ) and squamous cell carcinoma (SCC). In patients with a history of taking antiresorptive medication as well as risk factors for neoplasia it can be difficult to differentiate between the two. We describe two cases in both of which a mandibular osteolytic lesion was inadequately identified as either MRONJ or SCC because of confusing clinical and histopathological features. We also reviewed relevant publications to identify similar cases. Here we discuss our clinical dilemma when faced with two different conditions that present with similar clinical and histopathological features.

Search for a reliable model for bisphosphonate-related osteonecrosis of the jaw: establishment of a model in pigs and description of its histomorphometric characteristics.

The pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ) remains unknown, and the development of a reliable experimental model would help to improve our understanding of it. We used 12 domestic pigs of which 6 made up the experimental group and were treated with zoledronate 4mg intravenously weekly for 5 weeks, while the control group (n=6) were given no drugs. On day 60 the right second maxillary and mandibular third molars were extracted. Thirty days later 3 animals in each group were killed; the rest were killed 90 days later. Histopathological specimens from the extraction sites were analysed for bone density, collagen architecture, density of osteons, and the amount of non-mineralised bone. Bone density, amount of non-mineralised bone, and density of osteons differed significantly between the 2 groups (p<0.001 in each case), but the chromatic pattern dictated by the collagen architecture did not. Our results correspond to the observations that have been made in patients with BRONJ, which means that the histomorphometric conditions seen in patients can be reproduced in this experimental setting.

Surgical management of bisphosphonate-related osteonecrosis of the jaws: literature review.

PURPOSE: Surgical management of bisphosphonate-related osteonecrosis of the jaws (BRONJ) has been performed in an attempt to increase healing rates of the affected cases. This literature review aimed to identify clinical studies of surgical management of bisphosphonate-related osteonecrosis of the jaws (BRONJ) in order to assess their surgical treatment modalities, outcome and the follow-up. METHODS: A search in the PubMed (Medline) database using specific terms and/or phrases as "bisphosphonate-related osteonecrosis" or "jaw osteonecrosis", and "surgical treatment" or "surgical management" was conducted in order to identify clinical trials and cases of surgical treatment of BRONJ. The review search covered the time period from 2004 to 2014. All studies identified in the search were selected according to the inclusion criteria. Relevant information was recorded according to the following items: author, year, number of patients, BRONJ clinical stage, surgical treatment modality, clinical success, and follow-up. RESULTS: The initial database search yielded 345 titles. After filtering, 67 abstracts were selected culminating in 67 full text articles. A variety of surgical approach was found in this review: debridement, sequestrectomy bone resection, and bone reconstruction. Adjunctive therapies included hyperbaric oxygen, laser therapy, growth factors, and ozone. CONCLUSION: Although there are many indexed studies about BRONJ, well-documented reports concerning surgical therapeutically techniques are scarce, resulting from a lack of well-established protocols. Considerable differences were found regarding sample size, surgical treatment modalities and outcomes. Clinical studies with larger number of patients and longer follow-up are required to provide best information for each surgical treatment modality and its outcomes.

What is the impact of bisphosphonate therapy upon dental implant survival? A systematic review and meta-analysis.

OBJECTIVE: A systematic review and meta-analysis are carried out to assess the scientific evidence that bisphosphonate therapy can decrease the success rate of dental implants. MATERIAL AND METHODS: The PubMed (Medline) database was used to search for articles published up until February 22, 2014. The meta-analysis was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). The Newcastle-Ottawa scale (NOS) was used to assess study quality. RESULTS: The combinations of search terms resulted in a list of 256 titles. Fourteen finally met the inclusion criteria and were thus selected for inclusion in the systematic review. Eight studies (six retrospective and two prospective) were included in the meta-analysis, with a total of 1288 patients (386 cases and 902 controls) and 4562 dental implants (1090 dental implants in cases and 3472 in controls). The summary odds ratio (OR = 1.43, P = 0.156) indicates that there is not enough evidence that bisphosphonates have a negative impact upon implant survival. According to the number need to harm (NNH), over 500 dental implants are required in patients receiving bisphosphonate treatment to produce a single implant failure. CONCLUSION: Our results show that dental implant placement in patients receiving bisphosphonates does not reduce the dental implant success rate. On the other hand, such patients are not without complications, and risk evaluation therefore must be established on an individualized basis, as one of the most serious though infrequent complications of bisphosphonate therapy is bisphosphonate-related osteonecrosis of the jaws. Given the few studies included in our meta-analysis, further prospective studies involving larger sample sizes and longer durations of follow-up are required to confirm the results obtained.

Role of periodontal disease in bisphosphonate-related osteonecrosis of the jaws in ovariectomized rats.

OBJECTIVE: This study aimed to investigate the role of progressive periodontal disease in inducing bisphosphonate-related osteonecrosis of the jaws (BRONJ) using an ovariectomized (OVX) rat model mimicking human intracortical remodeling process. MATERIALS AND METHODS: Thirty 12-week-old Spraque-Dawly (SD) female rats were randomly assigned into two groups. All rats underwent bilateral ovariectomy. Six weeks after surgery, zoledronic acid (ZA) or vehicle control was administered intraperitoneally for 12 weeks. On the same day of injection, a cotton ligature was placed subgingivally around the first left lower molar to induce periodontitis. All animals were sacrificed 12 weeks after injection. The entire mandibles were harvested for micro-computed tomography (micro-CT) and histological examinations. RESULTS: Micro-CT examination showed that ligature placement caused significant alveolar bone loss both in ZA (0.63 ± 0.13 vs. 0.38 ± 0.06 mm, P < 0.001) and in control (0.88 ± 0.19 vs. 0.40 ± 0.06 mm, P < 0.001) groups. Whereas in the ZA group, bone loss was attenuated compared with the control group (P < 0.01); the bone mineral density in the ZA group (1.00 ± 0.02 g/cm(3)) was significantly higher than that in vehicle control group (0.96 ± 0.03 g/cm(3), P < 0.001). Histological examination found necrotic bone tissue with extensive, empty lacunae in two of 15 rats in ZA group, but in none of the control group. CONCLUSION: Bisphosphonates inhibit alveolar bone resorption in progressive periodontal disease, which might benefit the management of periodontitis, but increase the risk of developing BRONJ.

Effects of alendronate on the peri-implant bone in rats.

OBJECTIVES: The purpose of this study was to determine the effects of alendronate on the peri-implant bone in rat maxillae with the aid of micro-computed tomographic, histologic, and biochemical analyses. MATERIALS AND METHODS: Thirty-six male Sprague-Dawley rats were used. After extraction of the maxillary first molars, each rat was given periodic subcutaneous injections of either alendronate (alendronate group) or saline (control group). Customized implants were placed bilaterally 4 weeks after these injections. The rats were sacrificed at either 4, 8, or 12 weeks after implantation (4-, 8-, and 12-week groups, respectively; n = 6 rats per group). Microcomputed tomographic and histologic analyses were conducted for all rats. Biochemical analyses were performed at four time points for the 12-week groups. RESULTS: There were no significant differences between the groups on microcomputed tomographic and histologic analyses. All of the measured biochemical parameters tended to decrease over time, with significant differences among some time points within each group. The serum osteocalcin level was significantly lower in the 12-week alendronate group than in the control group (P < 0.05). CONCLUSIONS: Three approaches were utilized in evaluating the effects of alendronate. It appears serum osteocalcin levels may serve as an adjuvant marker for this purpose, although further studies are required to confirm this.

Important aspects concerning alendronate-related osteonecrosis of the jaws: a literature review.

OBJECTIVE: To conduct a literature review on sodium alendronate, focusing on osteonecrosis of the jaws, a serious potential side effect. BACKGROUND: Sodium alendronate is a bisphosphonate that is widely used for the treatment of osteopenia, osteoporosis and Paget's disease. Like other bisphosphonates, it inhibits bone resorption by inactivating osteoclasts. Alendronate has evident benefits in the treatment of these diseases, but it is associated with jaw osteonecrosis, although less frequently compared with intravenous bisphosphonates. Therefore, some preventive measures should be taken to avoid this side effect. MATERIAL AND METHODS: We reviewed the literature regarding the pharmacological aspects, mechanism of action, indications of use and side effects of sodium alendronate, as well as the management of patients under this therapy. CONCLUSION: The benefits of sodium alendronate are scientifically proven, but a serious adverse effect is osteonecrosis. Therefore, it is crucial to prepare the oral cavity before bisphosphonate therapy, providing a careful dental evaluation and all needed dental treatment.

O efeito do ácido zoledrônico na microestrutura óssea analisado pela micro-CT em mandíbulas de ratos wistar / Zoledronic acid effect on the bone microarchitecture of the jaw of rats by Micro-CT

Os bisfosfonatos são medicamentos amplamente e efetivamente utilizados para o tratamento de doenças osteolíticas. Entretanto, na cavidade oral, é de particular relevância, pois possuem como efeito adverso a osteonecrose dos maxilares induzida pelo uso de bisfosfonatos. Sua etiopatogenia ainda não é bem estabelecida, os métodos de detecção são insatisfatórios e as terapias recomendadas são por vezes, medidas paliativas e ineficazes. Pouco ainda é sabido sobre o efeito do Ácido Zoledrônico na microestrutura óssea, portanto, propusemo-nos a realizar um estudo em modelo animal que analisasse o trabeculado ósseo da mandíbula através da Micro-CT. Foram utilizados 24 ratos machos (Rattus novergicus, albinus, Wistar), com 12 semanas de vida, divididos em 2 grupos: grupo controle (cloreto de sódio 0,9%) e grupo ácido zoledrônico (ácido zoledrônico 0,6mg/kg). As substâncias foram administradas via intraperitoneal a cada 28 dias em um total de 5 doses. Após 150 dias do início do experimento, foi realizada a eutanásia dos animais e então as amostras foram preparadas e escaneadas (Skyscan 1174) para análise da microestrutura óssea através da Micro- CT. O teste t-student demonstrou diferença estatisticamente significativa (p<0,05) em todos os fatores: volume ósseo, densidade óssea, fator de padrão trabecular, índice de modelo estrutural, espessura trabecular, separação trabecular, porosidade total exceção de número de trabéculas e volume tecidual, demonstrando que há alterações significativas na estrutura trabecular pelo uso de bisfosfonatos. O grupo medicado com ácido zoledrônico comparado ao grupo controle demonstrou trabéculas mais espessas, menos separadas e com menores ligações...

Bisphosphonates are widely and effectively drugs used for the treatment of osteolytic disorders. However, in the oral cavity, this situation is of particular relevance as it can lead to bisphosphonate related osteonecrosis of the jaws. Its etiopathogenesis is still not established, detection methods are unsatisfactory and recommended therapies are sometimes palliative and often ineffective. Little is known about the effect of zoledronic acid on the quality of trabecular bone, therefore, we proposed to conduct a study in an animal model to examine the trabecular bone of the jaw through the Micro-CT. 24 male rats were used (Rattus norvegicus, Albinus, Wistar), with 12 weeks old, divided into 2 groups: control group (sodium chloride 0.9%) and group with zoledronic acid (zoledronic acid 0.6 mg / kg). The substances were administered intraperitoneally every 28 days for a total of 5 doses. After 150 days from the beginning of the experiment, the animals were sacrificed and then the samples were prepared and scanned (Skyscan 1174) for analysis of the bone microstructure through Micro-CT. The "t-student" test demonstrated statistically significant differences (p<0.05) in all factors: bone volume, osseous density, trabecular pattern, structure model index, trabecular thickness, trabecular separation, total porosity except trabecular number and tissue volume, demonstrating that there are significant changes in the trabecular structure of the bisphosphonates. Zoledronic Acid compared to control group shows thicker, less separate and lower connected trabeculae...

Denosumab and osteonecrosis of the jaws - the pharmacology, pathogenesis and a report of two cases.

Denosumab (Amgen, Thousand Oaks, California, USA) is a new bone antiresorptive agent used in patients with osteoporosis or metastatic cancer to the bones. As with the bisphosphonates that are used as antiresorptive medications, denosumab has been associated with osteonecrosis of the jaws (ONJ). Over the past two years there has been an increase in the literature describing ONJ in patients receiving agents such as denosumab. Due to promising study results that demonstrate the effectiveness of denosumab in avoiding skeletal complications related to osteoporosis and metastatic bone disease, more patients will receive denosumab in the future. It is reported that this has the potential to become a comparable challenge to bisphosphonate related osteonecrosis of the jaws (BRONJ) for clinicians. This article describes the management of two patients that developed ONJ while receiving denosumab, reviews the incidence of ONJ associated with denosumab, and contrasts the pharmacokinetics of denosumab and the bisphosphonates. The importance of avoiding interventional dental treatment until denosumab has been withdrawn for six months cannot be overstated.

Bisphosphonate Related Osteonecrosis of the Jaw: An Update.

OBJECTIVES: The aim of this paper is to summarize different diagnostic criteria as well as probable aetiopathogenesis of bisphosphonates related osteonecrosis of the jaw. MATERIALS AND METHODS: The electronic search of peer-reviewed journals were performed in MEDLINE (PubMed) database in order to find the relevant articles on bisphosphonates related osteonecrosis of the jaw (BP-related ONJ). The search was restricted to English language articles, published from January 2002 to May 2013. On the basis of these articles, probable aetiopathogenesis and different diagnostic criteria of BP-related ONJ were summarized. RESULTS: BP-related ONJ is related to the development of avascular necrosis or dead jaw bones. In recent literature many given hypotheses show the aetiopathogenesis and diagnosis of BP-related ONJ which are interlinked and have multifactorial nature. Their diagnosis revolves around four main diagnostic criteria that differentiate it from other conditions which can delay bone healing. CONCLUSIONS: Factors like potency of bisphosphonates, biology of jaw bone, antiangiogenic property of bisphosphonates and soft tissue toxicity in combination with present infection, other drugs, pre-existing pathologies, compromised immune response and dentoalveolar trauma may lead to development of BP-related ONJ.

Effects of bisphosphonate treatment on DNA methylation in osteonecrosis of the jaw.

Bisphosphonates are used in the treatment of hypocalcaemia, mainly in cancer and osteoporosis. Some patients experience adverse events, such as BP-related osteonecrosis of the jaw (BRONJ). DNA methylation plays a key role in gene regulation in many tissues, but its involvement in bone homeostasis is not well characterized, and no information is available regarding altered methylation in BRONJ. Using the Illumina Infinium HumanMethylation27 BeadChip assay, we performed an epigenome-wide association study in peripheral blood samples from 68 patients treated with nitrogenous BP, including 35 with BRONJ. Analysis of the estimated cumulative BP exposure distribution indicated that the exposure of the case group to BP was slightly higher than that of the control group; more severely affected cases (i.e., with BRONJ in both mandible and maxilla) were significantly more exposed to BP than were those with BRONJ only in the mandible or maxilla (one-sided Wilcoxon rank sum test, p=0.002). Logistic regression analysis confirmed the positive association between cumulative bisphosphonates exposure and risk of BRONJ (OR 1.015 per mg of cumulative exposure, 95% CI 1.004-1.032, p=0.036). Although no statistically significant differences were observed between case and control groups, methylation levels of probes mapping on three genes, ERCC8, LEPREL1 and SDC2, were strongly associated with cumulative BP exposure levels (p<1.31E-007). Enrichment analysis, combining differentially methylated genes with genes involved in the mevalonate pathway, showed that BP treatment can affect the methylation pattern of genes involved in extracellular matrix organization and inflammatory responses, leading to more frequent adverse effects such as BRONJ. Differences in DNA methylation induced by BP treatment could be involved in the pathogenesis of the bone lesion.