Osteonecrosis development by tooth extraction in zoledronate treated mice is inhibited by active vitamin D analogues, anti-inflammatory agents or antibiotics.

Invasive dental treatment such as tooth extraction following treatment with strong anti-bone resorptive agents, including bisphosphonates and denosumab, reportedly promotes osteonecrosis of the jaw (ONJ) at the extraction site, but strategies to prevent ONJ remain unclear. Here we show that in mice, administration of either active vitamin D analogues, antibiotics or anti-inflammatory agents can prevent ONJ development induced by tooth extraction during treatment with the bisphosphonate zoledronate. Specifically, tooth extraction during treatment with zoledronate induced osteonecrosis in mice, but administration of either 1,25(OH)2D3 or ED71, both active vitamin D analogues, significantly antagonized osteonecrosis development, even under continuous zoledronate treatment. 1,25(OH)2D3 or ED71 administration also significantly inhibited osteocyte apoptosis induced by tooth extraction and bisphosphonate treatment. Administration of either active vitamin D analogue significantly inhibited elevation of serum inflammatory cytokine levels in mice in response to injection of lipopolysaccharide, an infection mimetic. Furthermore, administration of either anti-inflammatory or antibiotic reagents significantly blocked ONJ development following tooth extraction and zoledronate treatment. These findings suggest that administration of active vitamin D, anti-inflammatory agents or antibiotics could prevent ONJ development induced by tooth extraction in patients treated with zoledronate.

Local delivery of hydrogel encapsulated vascular endothelial growth factor for the prevention of medication-related osteonecrosis of the jaw.

The anti-angiogenic effects of bisphosphonates have been hypothesized as one of the major etiologic factors in the development of medication-related osteonecrosis of the jaw (MRONJ), a severe debilitating condition with limited treatment options. This study evaluated the potential of a gelatine-hyaluronic acid hydrogel loaded with the angiogenic growth factor, vascular endothelial growth factor (VEGF), as a local delivery system to aid in maintaining vascularization in a bisphosphonate-treated (Zoledronic Acid) rodent maxillary extraction defect. Healing was assessed four weeks after implantation of the VEGF-hydrogel into extraction sockets. Gross examination and histological assessment showed that total osteonecrosis and inflammatory infiltrate was significantly reduced in the presence of VEGF. Also, total vascularity and specifically neovascularization, was significantly improved in animals that received VEGF hydrogel. Gene expression of vascular, inflammatory and bone specific markers within the defect area were also significantly altered in the presence of VEGF. Furthermore, plasma cytokine levels were assessed to determine the systemic effect of locally delivered VEGF and showed similar outcomes. In conclusion, the use of locally delivered VEGF within healing extraction sockets assists bone healing and prevents MRONJ via a pro-angiogenic and immunomodulatory mechanism.

Changes in serological bone turnover markers in bisphosphonate induced osteonecrosis of the jaws: A case control study.

BACKGROUND: There are a lot study confirmed the relationship of bone serum markers changes and skeletal irregularities. But there is no sufficient case control studies about the role of these markers on bisphosphonate induced osteonecrosis of jaws (BRONJ). AIMS: The aim of this study is to find out if there is any derangement of bone markers in bisphosphonate-treated patients with ONJ. METHODS: We obtained serum bone markers and other relevant endocrine assays on 20 patients with osteonecrosis of the jaw (ONJ) and 20 randomized healthy volunteers. All of the ONJ group treated with zoledronic acid and had been withdrawn from bisphosphonate for at least 6 months. Diagnostic criteria for ONJ were those formulated by the American Association of Oral and Maxillofacial Surgeons. Serum levels of several indices of bone remodeling were evaluated using commercial enzyme-linked immunosorbent assays. The biochemical assays were performed on N-Telopeptides of type I collagen (NTX), bone-specific alkaline phosphatase (ALP), calcitonin, osteocalcin, intact parathyroid hormone (PTH), T3, T4, TSH, and Vitamin D 25 hydroxy (Vit-D). RESULTS: In ONJ group, PTH level is statistically higher and TSH, Vit-D, osteocalcin and NTX levels statistically lower compared to control group. CONCLUSION: We conclude that these changes in PTH, Vit-D, TSH, osteocalcin and NTX levels maybe have a role in the pathophysiology of BRONJ. But the data need to be confirmed by future studies.

Prevalence and risk factors of medication-related osteonecrosis of the jaw in osteoporotic and breast cancer patients: a cross-sectional study.

PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) has been reported as a side effect of bisphosphonate (BP). The aim of this study was to identify the prevalence of MRONJ in women taking BP for osteoporosis and for metastatic breast cancer and correlate it with risk factors and biochemical markers of bone metabolism. METHODS: Patients taking oral or intravenous BP with osteoporosis (G1; n = 153; median 72.8 years) and with metastatic breast cancer (G2; n = 134; median 58.2 years) had their hospital charts reviewed, were submitted to dental inspection, and answered a health questionnaire. Fasting blood samples were randomly collected from both groups to measure osteocalcin, carboxy-terminal cross-linking telopeptide of type I collagen, intact parathyroid hormone and procollagen type 1 amino-terminal propeptide (P1NP), 25 hydroxyvitamin D (25OHD), creatinine, and total calcium. RESULTS: G1 was older (p = 0.001) and had more cases of diabetes (p = 0.043). P1NP was higher (p = 0.022) and 25OHD lower (p = 0.004) in G2 compared with G1. MRONJ was not found in the G1, whereas 4 cases (3%) were detected in G2. Positive risk factors for MRONJ were number of BP doses and number of visits to the dentist and dental extractions. The biochemical parameters, however, could not identify those who developed MRONJ. CONCLUSIONS: The prevalence of MRONJ was 3% in women with metastatic breast cancer receiving BP. No cases were identified in women receiving oral BP chronically for osteoporosis. P1NP was higher in women with metastatic breast cancer, even during treatment with antiresorptives, but could not differentiate those with MRONJ.

Antiresorptive Agents and Anti-Angiogenesis Drugs in the Development of Osteonecrosis of the Jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is a condition of exposed bone in the maxillofacial region, which occurs among subjects treated with antiresorptive agents or anti-angiogenesis drugs, despite the lack of a history of head or neck radiation treatment. Although there are still many points to be clarified about the mechanism of MRONJ, it is possible to hypothesize a common pathogenetic mechanism for two different classes of drugs: antiresorptive and anti-angiogenetic drugs. These drugs can inhibit angiogenesis by interfering with endothelial cell proliferation and survival, leading to loss of blood vessels and avascular necrosis. This hypothesis could be of immediate translational interest. Targeting the anti-angiogenetic effect of the antiresorptive agents could provide a new possibility for the prevention of treatment of MRONJ.

Biomarkers to predict the onset of biphosphonate-related osteonecrosis of the jaw: A systematic review.

BACKGROUND: The goal of this paper was to identify available biomarkers to predict the onset of biphosphonate-related osteonecrosis of the jaw (BRONJ). MATERIAL AND METHODS: Case-control studies comparing the different concentrations of a series of molecules detected in serum and urine as matrices of BRONJ affected patients vs. non-affected were included. PRISMA guidelines for systematic reviews were used for the present paper. Two reviewers independently screened electronic databases (Medline, Web of science, and The Cochrane Library) and performed hand searches. Risk of bias assessment of selected studies was performed by the Newcastle-Ottawa Scale. This study is registered as PROSPERO CRD42017078149. RESULTS: From a total of 601 identified studies, 7 (4 articles with high methodological quality and 3 with medium) articles were included. They investigate 2623 patients, of whom 91 (3.47%) developed BRONJ. A total of 7 biomarkers were identified and classified into 3 groups: bone turnover, angiogenesis and endocrine markers. Conflicting results were found in relation to most biomarkers. CONCLUSIONS: The present review suggests that no useful markers are currently available to evaluate BRONJ risk. Nevertheless, the present paper indicates that a paradigm shift from bone turnover biomarkers to angiogenesis and endocrine markers could shed light on this search.

Circulating microRNA Panel as a Novel Biomarker to Diagnose Bisphosphonate-Related Osteonecrosis of the Jaw.

There is no defined biomarker for BRONJ diagnosis with satisfactory performance in clinic. In this study, we established the BRONJ model and selected 7 microRNAs as candidate for BRONJ diagnosis from microRNA microarray reported by other research. Dysregulated microRNAs during BRONJ were detected and validated in two independent animal experiments using serum samples. In the first part, serum miR-21, miR-23a and miR-145 were significantly altered in between BRONJ and control group. And an Indice was constructed as -0.032+(0.154×miR-21)+(0.145×miR-23a)+(-0.700×miR-145) using logistic regression model to improve diagnostic performance. The performance of Indice to differentiate BRONJ subjects from control group was analyzed as AUC of 0.82 (95% CI, 0.72-0.92) or 0.85 (95% CI, 0.73-0.97) in the first or second part. Moreover, the predictive performance of Indice to discriminate BRONJ-1w and BRONJ-4w from control group was displayed as AUC of 0.65 (95% CI, 0.47-0.84) or 0.75 (95% CI, 0.60-0.91), which was better than individual circulating microRNAs. In addition, the expressions of candidate microRNAs were validated in human samples. Consequently, we investigated a combined Indice constructed with circulating microRNAs for BRONJ diagnosis and prediction.

Altered microRNA expression profile in the peripheral lymphoid compartment of multiple myeloma patients with bisphosphonate-induced osteonecrosis of the jaw.

Bisphosphonates are formidable inhibitors of osteoclast-mediated bone resorption employed for therapy of multiple myeloma (MM) subjects with osteolytic lesions. Osteonecrosis of the jaw (ONJ) is an uncommon drug-induced adverse event of these agents. MicroRNAs (miRNAs) are a group of small, noncoding RNAs nucleotides, which are essential post-transcriptional controllers of gene expression. They have a central role in the normal bone development. The goal of our study was to investigate 18 miRNAs, whose targets were previously validated and described in MM subjects without ONJ, in peripheral lymphocytes of MM subjects with bisphosphonate-induced ONJ. Utilizing reverse transcription quantitative polymerase chain reaction, we evaluated miRNAs in five healthy subjects and in five MM patients with ONJ. Our experimental data revealed that a diverse miRNA signature for ONJ subjects emerged with respect to control subjects. Using the filter for in silico analysis, among the 18 miRNAs, we recognized 14 dysregulated miRNAs. All these miRNAs were significantly over-expressed in patients vs controls (MIR-16-1, MIR-21, MIR-23A, MIR-28, MIR-101-1, MIR-124-1, MIR-129, MIR-139, MIR-145, MIR-149, MIR-202, MIR-221, MIR-424, MIR-520). Among them, six were strongly upregulated (fourfold upregulated and more). These miRNAs target numerous pathways and genes implicated in calcium ion binding, bone resorption, mineralization of bone matrix, and differentiation and maintenance of bone tissue. A modified microRNA expression profile after zoledronate therapy could participate to the onset of ONJ. Targeting these miRNAs could provide a new opportunity for the prevention or treatment of ONJ.

Cross-Sectional Study of four Serological Bone Turnover Markers for the Risk Assessment of Medication-Related Osteonecrosis of the Jaw.

BACKGROUND: Despite the benefits related to the use of bisphosphonates and denosumab, medication-related osteonecrosis of the jaw (MRONJ) is a serious complication. The purpose of this study was to investigate the utility of 4 biochemical markers including serum c-terminal telopeptide cross-link of type I collagen (s-CTX), serum osteocalcin (s-OC), serum parathormon (s-PTH), and serum bone-specific alkaline phosphatase (s-BAP) as useful clinical tools to help assess the risk for MRONJ prior to invasive oral surgery. MATERIALS AND METHODS: Twenty patients diagnosed with MRONJ and 20 controls who have been on antiresorptive therapies with no occurrence of MRONJ were included in this 2-arm cross-sectional study. The s-CTX, s-OC, s-PTH, and s-BAP values were measured. Mann-Whitney U test compared the s-CTX, s-OC, s-PTH, and s-BAP values of the MRONJ group and the controls (P < 0.05). RESULTS: Lower values were observed in the MRONJ group compared with the control group for s-CTX (130.00 pg/mL versus 230.0 pg/mL; P = 0.12) and for s-OC (10.6 ng/mL versus 14.80 ng/mL; P = 0.051) both without significance and for s-BAP (0.23 µkat/L versus 0.31 µkat/L; P = 0.002) with significance. By contrast, the median s-PTH value of the MRONJ group was higher (30.65 ng/L versus 25.50 ng/L; P = 0.89), but without significance. CONCLUSIONS: The evaluation of the 4 biochemical markers showed that only the value of s-BAP was significantly decreased in the MRONJ patients compared with the controls. Presently, because of the lack of evidence, a routine check prior to oral surgery for the risk assessment of MRONJ cannot be recommended.

Short-Term Teriparatide and Recombinant Human Bone Morphogenetic Protein-2 for Regenerative Approach to Medication-Related Osteonecrosis of the Jaw: A Preliminary Study.

Our objective was to examine whether adjunct teriparatide administration and local application of recombinant human bone morphogenetic protein-2 (rhBMP-2) is beneficial for the regeneration of jaw bone in patients with medication-related osteonecrosis of the jaw (MRONJ). This study enrolled 17 patients diagnosed with MRONJ. All patients received sequestrectomy under general or local anesthesia with suspension of bisphosphonate. The bone regeneration ratio was compared on cone beam computed tomography (CBCT) scans, acquired immediately post-operation and after 6 months. The patients were divided into groups, based on their treatment regimens: teriparatide combined with rhBMP-2 (parathyroid hormone [PTH]+BMP), rhBMP-2 (BMP), and the control. Biochemical markers were also evaluated at the baseline (T0), 1 month (T1), and 3 months (T2) after surgery. Significant increase was observed in the values of the biochemical markers, serum osteocalcin, and serum C-terminal telopeptide cross-link of type I collagen, within 3 months of surgery in the PTH+BMP group, whereas the mean value in the BMP group did not show a significant change. In all groups, the MRONJ lesions were healed and new bone formation was detected in the CBCT images. The regeneration ratio was significantly greater in the group PTH+BMP than in the BMP and control groups. Significantly greater amount of bone formation was observed in the group PTH+BMP than in the BMP and control groups. Local application of rhBMP-2 alone also had a beneficial effect on bone regeneration but was not more significant than control. Based on these findings, administration of short-term teriparatide with rhBMP-2 in MRONJ patients may maximize the regeneration of bone after surgery. © 2017 American Society for Bone and Mineral Research.

Serum levels of RANKL and OPG, and the RANKL/OPG ratio in bisphosphonate-related osteonecrosis of the jaw: Are they useful biomarkers for the advanced stages of osteonecrosis?

BACKGROUND: We determined whether serum levels of Receptor Activator for Nuclear Factor κ B Ligand (RANKL), Osteoprotegerin (OPG), and the RANKL/OPG ratio could be useful biomarkers for the severity of oral lesions in bisphosphonate-related osteonecrosis of the jaw (BRONJ). MATERIAL AND METHODS: A case-control study in which Group 1 consisted of 41 patients with BRONJ due to intravenous bisphosphonates, and Group 2 consisted of 44 healthy control cases. The plasma levels of RANKL and OPG were analyzed by an ELISA assay. The OPG/RANKL ratio was also calculated. We determined if the mean serum values differed among the different stages of BRONJ. RESULTS: Serum levels of RANKL were lower in Group 1 than in Group 2 (p =0.01), and serum levels of OPG were higher in patients with BRONJ than in the controls (p =0.006). The ratio of RANKL/OPG was greater in the controls than in Group 1 (p >0.01). There were no significant differences in the serum levels of RANKL and OPG among the different stages of osteonecrosis (p >0.05). CONCLUSIONS: Serum levels of RANKL and OPG, and the RANKL/OPG ratio were not valuable biomarkers for determining the severity of oral lesions in patients with BRONJ.

Interrelationship of clinical, radiographic and haematological features in patients under bisphosphonate therapy.

OBJECTIVES: To analyze the clinical, radiographic and haematological aspects of patients under bisphosphonate therapy. METHODS: A retrospective study was conducted where the records of patients taking bisphosphonates were analyzed considering the occurrence of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Evaluation included panoramic and periapical radiographies, haematological examinations and clinical features. Radiographies were analyzed determining the presence or absence of bone sclerosis, osteolysis, persisting alveolar socket, narrowing of the mandibular canal, widening of the periodontal ligament space, periradicular radiolucency, sequestrum and thickening of the lamina dura. Laboratory tests consisted of complete blood count, fasting serum glucose, erythrocyte sedimentation rate (ESR) and serum levels of calcium, phosphorus, alkaline phosphatase, parathormone (PTH) and C-terminal telopeptide of collagen I (CTX). RESULTS: Alkaline phosphatase and ESR were significantly higher in the BRONJ group, whereas fasting serum glucose, CTX, PTH, calcium and phosphorus did not significantly differ. BRONJ showed association with smoking, tooth extraction, anaemia and leukocytosis. On radiographic analysis, persisting alveolar socket, osteolysis, bone sclerosis and narrowing of the mandibular canal were significantly more prevalent in the BRONJ group. Thickening of the lamina dura, periapical radiolucencies, widening of the periodontal ligament space and sequestrum did not significantly differ between the groups. CONCLUSIONS: BRONJ is a multifactorial disease with high morbidity, which requires experimental studies to clarify the role of the reported risk factors and clinical radiographic signs to improve its diagnosis.

Efficacy of the C-terminal telopeptide test in predicting the development of bisphosphonate-related osteonecrosis of the jaw: a systematic review.

This systematic review evaluated the efficacy of the morning fasting serum C-terminal telopeptide (CTX) test in predicting the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). A comprehensive search of studies published up to March 2016, and listed in the PubMed/MEDLINE, Web of Science, and Cochrane Library databases, was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This review has been registered in the PROSPERO international prospective register of systematic reviews (CRD42016036717). The search identified 542 publications; eight studies were finally deemed eligible for inclusion according to the study criteria. These studies included a total 1442 patients (mean age 66.7 years). The most prescribed drug was alendronate, with osteoporosis being the most frequent indication for the prescription of bisphosphonates. Tooth extraction was the most common trigger for BRONJ. Of all patients evaluated after bisphosphonate treatment, only 24 (1.7%) developed BRONJ. All eight of the selected studies found that CTX levels were not predictive of the development of BRONJ. In conclusion, this systematic review indicates that the CTX test has no predictive value in determining the risk of osteonecrosis in patients taking bisphosphonates.

Assessing the utility of serum C-telopeptide cross-link of type 1 collagen as a predictor of bisphosphonate-related osteonecrosis of the jaw: A systematic review and meta-analysis.

BACKGROUND: The authors of this systematic review and meta-analysis assessed the utility of serum C-telopeptide cross-link of type 1 collagen (sCTX), a biomarker of bone resorption, as a predictor of the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). TYPES OF STUDIES REVIEWED: The authors searched for studies involving adult participants, written in English, and published through January 20, 2016, using the following electronic databases: the Cochrane Library, MEDLINE via PubMed, and Web of Science. They also searched Google Scholar and the reference lists of all eligible trials and reviews. They identified 16 articles that met their inclusion criteria (9 controlled studies and 7 case series). They applied the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for systematic reviews and meta-analyses. They independently extracted data in duplicate, including the characteristics of study participants, risk factors, control groups, and outcomes. They assessed risk of bias, and they resolved any disagreements between review authors through discussion. RESULTS: A meta-analysis with 9 controlled studies revealed no significant difference in mean sCTX values between patients with BRONJ and control participants (difference in means, -31.417; 95% confidence interval [CI], -91.560 to 28.726; P = .306). A second meta-analysis with 4 studies showed no significant difference in risk of having an sCTX value below 150 picograms per milliliter for patients with BRONJ compared with control participants (risk ratio, 1.892; 95% CI, 0.636-5.626; P = .251). CONCLUSIONS AND PRACTICAL IMPLICATIONS: A systematic review of the literature with meta-analysis does not support the use of sCTX levels as a predictor of the development of BRONJ. Further prospective large sample studies are needed to understand the role of sCTX as a predictor for BRONJ.

Serum Markers of Bone Turnover and Angiogenesis in Patients With Bisphosphonate-Related Osteonecrosis of the Jaw After Discontinuation of Long-Term Intravenous Bisphosphonate Therapy.

PURPOSE: To analyze serum markers of bone turnover, angiogenesis, endocrine function, and inflammation in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) who discontinued long-term intravenous bisphosphonate (BP) therapy. PATIENTS AND METHODS: Serum samples were obtained from 25 BRONJ patients who had discontinued long-term intravenous BP therapy for an average of 11.4 ± 8.7 months and 48 non-BRONJ controls who continued receiving intravenous BP therapy. Samples were analyzed for total alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, C-telopeptide, vascular endothelial growth factor, triiodothyronine, thyroxine, thyroid-stimulating hormone, 25-hydroxyvitamin D, and C-reactive protein. RESULTS: The mean number of BP infusions was significantly higher in BRONJ patients compared with controls (38.4 ± 26.3 infusions vs 18.8 ± 7.2 infusions, P < .0001); however, the duration of BP therapy was not significantly different between the groups (P = .23). Overall, there were no significant differences in any of the markers between BRONJ patients and controls (all P values ≥ .16). In a subgroup analysis that matched BRONJ patients and controls according to mean age and number of BP infusions (10 BRONJ patients and 48 controls), log10 vascular endothelial growth factor (2.9 ± 0.4 pg/mL vs 2.4 ± 0.4 pg/mL, P < .001) and C-reactive protein (34 ± 26 mg/L vs 13 ± 8 mg/L, P < .01) levels were significantly higher in BRONJ patients compared with controls. Within BRONJ patients, none of the serum markers were correlated with duration of BP discontinuation. CONCLUSIONS: Levels of bone turnover and endocrine markers in BRONJ patients who discontinue long-term intravenous BP therapy are similar to those in non-BRONJ controls receiving intravenous BP therapy. However, levels of angiogenesis and inflammation markers are higher in BRONJ patients who discontinue long-term intravenous BP therapy. The prolonged skeletal half-life of BPs may suppress bone turnover markers in BRONJ patients for several years after discontinuation of intravenous BP therapy, suggesting an extended effect on bone homeostasis.

Experimental investigation of relationship between trauma and bisphosphonate-related osteonecrosis.

BACKGROUND: Bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) disease is rare, but there are serious side-effects of BP therapy in patients. In some patients, surgery is needed and could not be cured. A standard test is not available showing the risk of jaw osteonecrosis in routine use. The measurement of serum C-terminal telopeptide (CTX) levels has been used in diseases of BRONJ resorption and antiresorptive therapy. AIM: This paper is aimed at investigating the relationship between traumatic procedures and presence of BP-related osteonecrosis. MATERIALS AND METHODS: Thirty male Wistar albino rats with weighing 200 ± 20 g were used for the experimental procedures. Rats were randomly divided into three groups each containing 10 rats as follows: Group 1 (traumatic extraction group), Group 2 (atraumatic extraction group), and Group 3 (control group). All groups, zoledronic acid (ZA) (0.3 mg/kg/week) [1] was diluted with physiological saline and given subcutaneously for 2 months. After the 2 months, Group 1 was subjected to traumatic extraction of right first lower molars, and Group 2 was subjected to atraumatic extractions of the right first lower molars. Group 3 was subjected to no extractions as a control group. Animals were euthanized 32 days after tooth extractions, and the ZA administration protocol was maintained until the animals' death. After sacrifice, blood samples were collected for C-terminal cross-linking telopeptide of type I collagen (CTX-1) levels, clinical and radiological findings were recorded. RESULTS: The bone resorption marker CTX-1 showed a significant difference among the groups. CTX-1 was measured significantly higher in blood samples of Group 2 (4.15 ± 0.34; P = 0.001) than Group 1 (3.77 ± 0.34; P = 0.0001). No, statistically significant changes were found between Groups 1 and 2 as for clinical and radiological assessment. CONCLUSION: This study provides preliminary observations for the development of an animal model of BRONJ. Although clinical and radiological findings were not relevant, serum CTX values are reliable biochemical markers for predicting BRONJ and also atraumatic surgical procedures are important to prevent BRONJ.

Distinctive role of 6-month teriparatide treatment on intractable bisphosphonate-related osteonecrosis of the jaw.

UNLABELLED: The administration of teriparatide (TPTD) in conjunction with periodontal care could provide faster and more favorable clinical outcomes in previously refractory bisphosphonate-related osteonecrosis of the jaws (BRONJ) cases compared to conventional dental care, combination of surgery and antimicrobial treatment. We also found that underlying vitamin D levels might influence the response to TPTD treatment. INTRODUCTION: Treatment of BRONJ is quite challenging and there are no standard treatment modalities. In this retrospective, longitudinal study, we examined whether additional TPTD administration could be beneficial for the resolution of BRONJ lesions compared to conservative management, such as antimicrobial treatment with or without surgery, and also studied the factors influencing the response to TPTD. METHODS: Twenty-four cases of intractable BRONJ were included: 15 subjects were assigned to the TPTD group and the other 9 subjects, who refused TPTD administration, were assigned to the non-TPTD group. All subjects in both groups continued calcium and vitamin D supplementation and the TPTD group additionally received a daily subcutaneous injection of 20 µg TPTD for 6 months. RESULTS: While 60.0% of the non-TPTD group showed one stage of improvement in BRONJ, 40.0% of the group did not show any improvement in disease status. In the TPTD group, 62.5% of the treated subjects showed one stage of improvement and the other 37.5% demonstrated a marked improvement, including two stages of improvement or complete healing, and there was not a single case that did not improve. The clinical improvement of BRONJ was statistically better in the TPTD group after the 6-month treatment (p < 0.05). Moreover, patients with higher baseline serum 25(OH)D levels showed better clinical therapeutic outcomes with TPTD. CONCLUSIONS: We observed the beneficial effects of TPTD on BRONJ, and subjects with optimal serum vitamin D concentrations seemed to reap the maximum therapeutic effects of TPTD. A prospective, randomized, controlled trial should be needed to further evaluate the therapeutic efficacy of TPTD in the resolution of BRONJ.

Oxidative stress in bisphosphonate-related osteonecrosis of the jaws.

OBJECTIVES: To analyze whether oxidative stress (OS) changes are present in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) versus controls. MATERIALS AND METHODS: Oxidative stress was analyzed in serum and unstimulated saliva of three groups: Group 1 consisted of 24 patients who had been treated with intravenous bisphosphonates (ivBPs) and developed BRONJ, group 2 consisted of 20 patients who had received ivBPs and did not develop BRONJ, and group 3 comprised 17 control subjects. Reduced glutathione (GSH), malondialdehyde (MDA), oxidized glutathione (GSSG), and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxo-dG) levels, as well as the GSSG/GSH ratio, were measured. RESULTS: Mean serum and saliva levels of MDA, GSSG, and 8-oxo-dG and the GSSG/GSH ratio were significantly higher in patients with BRONJ than in controls. We found no significant difference in OS according to BRONJ stage, sex, or location in the jaws. Logistic regression analysis revealed that the GSSG/GSH ratio was a significant factor predicting the development of BRONJ (P = 0.01). CONCLUSIONS: Oxidative stress was detected in patients with BRONJ, and the GSSG/GSH ratio was the most significant OS variable found; it was a significant factor predicting the development of BRONJ.

Interleukin-6 concentration changes in plasma and saliva in bisphosphonate-related osteonecrosis of the jaws.

AIM: To determine the plasma and saliva levels of IL-6 in patients with bisphosphonate-related osteonecrosis of the jaws (BRONJ) and to investigate whether there is a correlation between more advanced stages of BRONJ and levels of IL-6. MATERIAL AND METHODS: We studied three groups: group 1 consisted of 30 patients with BRONJ due to intravenous bisphosphonates (ivBP), group 2 consisted of 25 patients treated with ivBP but without BRONJ, and group 3 consisted of 15 healthy controls. In each case, we assayed plasma and saliva IL-6 samples using an ELISA test. RESULTS: Significantly, higher IL-6 values were found in both saliva and plasma in group 1 vs groups 2 and 3 (P < 0.01). Group 1 showed no differences in plasma or saliva IL-6 according to patient gender (P > 0.05), type of tumor, BRONJ location, etiology of BRONJ, or disease stage (P > 0.05). We found higher plasma and saliva IL-6 values in the more advances stages of BRONJ, although the differences were not statistically significant. CONCLUSIONS: Plasma and saliva IL-6 values were higher in our patients with BRONJ than in controls and therefore might be a useful tool for monitoring the severity of BRONJ.