The influence of alendronate and tooth extraction on the incidence of osteonecrosis of the jaw among osteoporotic subjects.
Ontology highlight
ABSTRACT:
SUBMITTER: Chiu WY
PROVIDER: S-EPMC5918995 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Objectives: Osteonecrosis of the jaw (ONJ), a necrotic bone disease unique to the craniofacial region, is often observed among cancer patients treated with bisphosphonate (BP)-based chemotherapy and becomes a costly and debilitating source of pain and reduced quality of life. Elucidation of clinicopathological mechanism and biomarkers of ONJ that can indicate probable disease course would allow for better assessment of treatment strategies for individual patients. To address our overall goal of identifying novel diagnostic and prognostic strategies for ONJ, this study specifically aims to understand the alendronate (ALN) treatment-induced perturbation of bone proteome and microenvironmental pathophysiology of ONJ using targeted molecular analyses and computational approaches based on an in vitro cell culture system. This study also focuses on identifying proteome perturbation and potential molecular biomarkers during ONJ development. Methods: To understand the molecular mechanisms underlying ONJ, an unbiased and global proteomics approach combined with big data analysis using bioinformatics was applied. Biochemical and functional analyses were followed to tease out the mechanisms regulated by ALN treatment. Results: The current findings from our global proteomics study and biochemical analyses suggested that the RIPK3/Wnt/GSK3/β-catenin signaling pathway is significantly perturbed upon alendronate treatment, resulting in abnormal angiogenesis/inflammation/bone anabolism/remodeling/bone mineralization in the in vitro cell culture system. Conclusion: This investigation on potential key signaling mechanisms underlying ONJ will provide a rational basis for suppressing BP-induced ONJ and novel therapeutic strategies against ONJ.
2021-09-10 | PXD024585 | Pride
Project description:IntroductionSurgical interventions such as tooth extraction increase the chances of developing osteonecrosis of the jaw in patients receiving bisphosphonates (BPs) for the treatment of bone-related diseases. Tooth extraction is often performed to eliminate preexisting pathological inflammatory conditions that make the tooth unsalvageable; however, the role of such conditions on bisphosphonate-related osteonecrosis of the jaw (BRONJ) development after tooth extraction is not clearly defined. Here, we examined the effects of periapical periodontitis on tooth extraction-induced BRONJ development in mice.MethodsPeriapical periodontitis was induced by exposing the pulp of the maxillary first molar for 3 weeks in C57/BL6 mice that were intravenously administered with BPs. The same tooth was extracted, and after an 3 additional weeks, the mice were harvested for histologic, histomorphometric, and histochemical staining analyses.ResultsPulp exposure induced periapical radiolucency as shown by increased inflammatory cells, tartrate-resistant acid phosphatase-positive osteoclasts, and bone resorption. When BPs were administered, pulp exposure did not induce apical bone resorption despite the presence of inflammatory cells and tartrate-resistant acid phosphatase-positive osteoclasts. Although tooth extraction alone induced BRONJ lesions, pulp exposure further increased tooth extraction-induced BRONJ development as shown by the presence of more bone necrosis.ConclusionsOur study demonstrates that a preexisting pathological inflammatory condition such as periapical periodontitis is a predisposing factor that may exacerbate BRONJ development after tooth extraction. Our study further provides a clinical implication wherein periapical periodontitis should be controlled before performing tooth extraction in BP users in order to reduce the risk of developing BRONJ.
| S-EPMC5085836 | biostudies-literature
Project description:Osteoporosis is a major, growing healthcare issue. This is especially of concern in an ageing population like that of Singapore. Osteoporotic patients are at risk of fractures, which can result in increased morbidity and mortality. The use of antiresorptive therapy with bisphosphonates or denosumab has been proven to reduce fracture risk. However, the use of these medications has rarely been associated with the development of osteonecrosis of the jaw, a potentially debilitating condition affecting one or both jaws. Appropriate understanding of the patient's antiresorptive therapy regime, as well as early institution of preventive dental measures, can play an important role in preventing medication-related osteonecrosis of the jaw (MRONJ). Regular monitoring and prompt referral to specialist care is warranted for patients with established MRONJ.
| S-EPMC6119741 | biostudies-literature
Project description:Medication-related osteonecrosis of the jaw (MRONJ) is a rare but detrimental intraoral lesion that predominantly occurs in patients with long-term use of antiresorptive agents, such as bisphosphonate and denosumab, a human anti-receptor activator of NF-?B ligand (RANKL) monoclonal antibody (Ab). Surgical intervention, such as tooth extraction, is a known risk factor for MRONJ, which is often performed to eliminate preexiting pathologic inflammatory conditions, such as periodontal diseases. Nonetheless, it remains unknown whether pre-existing periodontal disease condition exacerbates, or removal of such condition ameliorates, MRONJ development after tooth extraction. In this study, we combined the ligature-induced periodontitis and the tooth extraction mouse models under the administration of zoledronic acid (ZOL) or anti-RANKL Ab, and provide experimental evidence that a pre-existing pathologic inflammatory condition exacerbates MRONJ development after tooth extraction in mice. Under ZOL administration, tooth extraction alone induced ONJ lesions; however, extraction of a ligature-placed tooth further exacerbated ONJ development. When the ligature was removed and the inflammatory condition was deescalated, ONJ development was ameliorated. Anti-RANKL Ab administration resulted in similar outcomes. Interestingly, unlike ZOL-administered mice, anti-RANKL Ab-administered mice exhibited complete absence of osteoclasts, suggesting that physical presence of osteoclasts is not directly involved in ONJ development. Collectively, our study demonstrated that periodontal disease is a functionally linked risk factor that predisposes ONJ development after tooth extraction in the presence of bisphosphonate and denosumab.
| S-EPMC6169128 | biostudies-literature
Project description:ObjectivesAntiresorptive medication has been reported to be associated with medication-related osteonecrosis of the jaw (MRONJ). This systematic review aims at investigating the incidence of and risk factors for MRONJ after tooth extractions in cancer patients treated with high-dose bisphosphonate and denosumab (BP and DS). MATERIAL AND METHODS: The protocol followed the PRISMA statement list and was registered in PROSPERO. Searches were performed for literature published up to April 2021 in the electronic databases PubMed, Embase, Web of Science, and CINAHL and then supplemented by manual research.ResultsThe search process resulted in 771 identified articles, of which seven studies fitted the population, intervention, comparison, and outcome framework. All were observational studies and four had control groups. A total of 550 patients treated with BP and DS were identified of whom 271 had received tooth extractions after medication onset. Due to significant heterogenicity in the collected data, only a qualitative analysis was performed. The MRONJ incidence after tooth extractions varied between 11% and 50% at the patient level. MRONJ occurred up to 3 years after the tooth extraction. Teeth affected by inflammation before the extraction and additional osteotomy during the surgical procedure were identified as risk factors.ConclusionsReliable methods of diagnosing MRONJ and adequate follow-up periods are important factors in obtaining the actual incidence of MRONJ after tooth extractions in patients treated with high-dose BP and DS.
| S-EPMC9932256 | biostudies-literature
Project description:Alendronate (ALN) is an antiresorptive agent widely used for the treatment of osteoporosis. Its suppressive effect on osteoclasts has been extensively studied. However, the effect of ALN on bone formation is not as clear as its effect on resorption. The objective was to determine the effect of short-term ALN on bone formation and tooth extraction wound healing. Molar tooth extractions were performed in mice. ALN, parathyroid hormone (PTH), or saline (vehicle control) was administered. PTH was used as the bone anabolic control. Mice were euthanized at 3, 5, 7, 10, and 21 d after extractions. Hard tissue healing was determined histomorphometrically. Neutrophils and lymphatic and blood vessels were quantified to evaluate soft tissue healing. Gene expression in the wounds was assessed at the RNA level. Furthermore, the vossicle bone transplant system was used to verify findings from extraction wound analysis. Alkaline phosphatase (ALP) was visualized in the vossicles to assess osteoblast activity. ALN exhibited no negative effect on bone formation. In intact tibiae, ALN increased bone mass significantly more than PTH did. Consistently, significantly elevated osteoblast numbers were noted. In the extraction sockets, bone fill in the ALN-treated mice was equivalent to the control. Genes associated with bone morphogenetic protein signaling, such as bmp2, nog, and dlx5, were activated in the extraction wounds of the ALN-treated animals. Bone formation in vossicles was significantly enhanced in the ALN versus PTH group. In agreement with this, ALN upregulated ALP activity considerably in vossicles. Neutrophil aggregation and suppressed lymphangiogenesis were evident in the soft tissue at 21 d after extraction, although gross healing of extraction wounds was uneventful. Bone formation was not impeded by short-term ALN treatment. Rather, short-term ALN treatment enhanced bone formation. ALN did not alter bone fill in extraction sockets.
| S-EPMC4547318 | biostudies-literature
Project description:Technetium-99 conjugated with methylene diphosphonate ((99)Tc-MDP) is a novel bisphosphonate derivative without radioactivity and has been successfully used to treat arthritis in China for years. Since bisphosphonate therapy has the potential to induce bisphosphonate-related osteonecrosis of the jaw (BRONJ), we examined whether (99)Tc-MDP represents a new class of bisphosphonate for antiresorptive therapy to ameliorate estrogen deficiency-induced bone resorption with less risk of causing BRONJ. We showed that (99)Tc-MDP-treated, ovariectomized (OVX) mice had significantly improved bone mineral density and trabecular bone volume in comparison to the untreated OVX group by inhibiting osteoclasts and enhancing osteogenic differentiation of bone marrow mesenchymal stem cells. To determine the potential of inducing BRONJ, (99)Tc-MDP/dexamethasone (Dex) or zoledronate/Dex was administered into C57BL/6J mice via the tail vein, followed by extraction of maxillary first molars. Interestingly, (99)Tc-MDP treatment showed less risk to induce osteonecrosis in the maxillary bones compared to zoledronate treatment group, partially because (99)Tc-MDP neither suppressed adaptive regulatory T cells nor activated the inflammatory T-helper-producing interleukin-17 cells. Taken together, our findings demonstrate that (99)Tc-MDP therapy may be a promising approach in the treatment of osteoporosis with less risk of causing BRONJ.
| S-EPMC3850783 | biostudies-literature
Project description:Methods for preventing medication-related osteonecrosis of the jaw (MRONJ) in cancer patients who have received high-dose bisphosphonate (BP) or denosumab (Dmab) have not yet been established. Tooth extraction after starting medication has been believed to be a major risk factor for MRONJ, and therefore this procedure tends to be avoided. This study investigated the risk factors for MRONJ, with a special reference to the correlation between tooth extraction and development of MRONJ. One hundred and thirty-five cancer patients who were administrated high-dose BP or Dmab were enrolled in the study. Demographic factors, general condition, treatment factors, and dental findings were examined retrospectively using medical records and panoramic X-ray findings. The cumulative occurrence rate of MRONJ was calculated using the Kaplan-Meier method, and the correlation between these variables and development of MRONJ was analyzed by univariate and multivariate Cox regression analysis. MRONJ developed in 18 of 135 patients. The 1-, 2-, and 3-year cumulative occurrence rates were 8.6%, 21.5%, and 29.2%, respectively. The duration of medication before first visit to the dental unit and the presence of a tooth with clinical symptoms were significantly correlated with the development of MRONJ. The rate of MRONJ occurrence in patients who had teeth with clinical symptoms, but who did not undergo tooth extraction, became higher 2 years later than that in patients who underwent extraction of teeth with symptoms, although not significant. Early dental examination and effective preventative care to avoid infection/inflammation are important for preventing MRONJ.
| S-EPMC6062135 | biostudies-literature
Project description:Purpose of reviewOsteonecrosis of the jaw (ONJ) is an uncommon condition noted to occur in patients with cancer who are receiving intravenous bisphosphonates. The cause of ONJ remains unknown. The leading hypotheses addressing the mechanism of ONJ are reviewed here.Recent findingsThe present clinical data suggest that ONJ may occur in approximately 5% of patients with metastatic bone disease. The ability to predict an individual's risk of developing ONJ remains elusive. It is likely that an altered bone microenvironment and/or host defense mechanisms effected by medications used to treat patients with metastatic bone disease contributes to the development of ONJ. Medications that significantly reduce osteoclastic activity are associated with ONJ. Preclinical models of ONJ are being developed but to establish such an intricate systemic condition in animals is challenging.SummaryThe ONJ field has progressed via knowledge gained by case reports, population-based studies, and emerging animal models. Still, there are myths that need to be resolved and important clues that need to be investigated. Understanding the pathophysiology of this condition will be critical to improve patient care. Communications between oncologists, dentists, basic scientists, and patients are central to effective treatment and research for this condition.
| S-EPMC2962852 | biostudies-literature
Project description:Background/purposeThe incidence of medication-related osteonecrosis of the jaw is increasing worldwide, mostly due to the use of antiresorptive agents (ARAs) such as bisphosphonate (BP) and denosumab (Dmab). However, the proportion of BP-related osteonecrosis of the jaw (BRONJ) and Dmab-related osteonecrosis of the jaw (DRONJ) among all ARA-related osteonecrosis of the jaw (ARONJ) cases is not clear; this hinders appropriate treatment, recurrence-prevention planning, and avoidance of unnecessary Dmab withdrawal. Moreover, the causative drug administered at each disease stage remains unknown. Therefore, we conducted a retrospective study of patients with ARONJ who visited oral and maxillofacial surgery departments at hospitals in Hyogo Prefecture, Japan, over 3 years to classify and compare patient characteristics with those having BRONJ and DRONJ. We sought to identify the proportion of DRONJ in ARONJ.Materials and methodsAfter excluding stage 0 patients, 1021 patients were included (471 high-dose; 560 low-dose). ARA treatment for bone metastases of malignant tumors and multiple myeloma was considered high dose, while that for cancer treatment-induced bone loss and osteoporosis was low dose.ResultsLow doses of BP and Dmab accounted for >50% patients; the results differed from those in other countries. DRONJ accounted for 58% and 35% of high-dose and low-dose cases, respectively. Stage 3 ARONJ cases comprised 92 (19.5%) low-dose BRONJ, 39 (20.1%) high-dose BRONJ, 24 (30%) low-dose DRONJ, and 68 (24.5%) high-dose DRONJ. Eighty-nine patients who received switch therapy were divided into BRONJ or DRONJ, but there was no difference in the ratio of each stage compared to the non-switch therapy.ConclusionTo the best of our knowledge, this is the first study to clarify the proportion of BRONJ and DRONJ cases, causative drug, and its doses by disease stages. DRONJ accounted for approximately 30% of the ARONJ, approximately 60% of which was due to high doses.
| S-EPMC10316444 | biostudies-literature