Dataset Information

Medication-Related Osteonecrosis of the Jaw (MRONJ): Are Antiresorptive Drugs the Main Culprits or Only Accomplices? The Triggering Role of Vitamin D Deficiency.

ABSTRACT: Osteonecrosis of the jaw (ONJ) is a severe clinical condition characterized mostly but not exclusively by an area of exposed bone in the mandible and/or maxilla that typically does not heal over a period of 6-8 weeks. The diagnosis is first of all clinical, but an imaging feedback such as Magnetic Resonance is essential to confirm clinical suspicions. In the last few decades, medication-related osteonecrosis of the jaw (MRONJ) has been widely discussed. From the first case reported in 2003, many case series and reviews have appeared in the scientific literature. Almost all papers concerning this topic conclude that bisphosphonates (BPs) can induce this severe clinical condition, particularly in cancer patients. Nevertheless, the exact mechanism by which amino-BPs would be responsible for ONJ is still debatable. Recent findings suggest a possible alternative explanation for BPs role in this pattern. In the present work we discuss how a condition of osteomalacia and low vitamin D levels might be determinant factors.

SUBMITTER: Dalle Carbonare L

PROVIDER: S-EPMC7915474 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Medication-Related Osteonecrosis of the Jaw (MRONJ): Are Antiresorptive Drugs the Main Culprits or Only Accomplices? The Triggering Role of Vitamin D Deficiency.

Dalle Carbonare Luca L Mottes Monica M Valenti Maria Teresa MT

Nutrients 20210208 2

Osteonecrosis of the jaw (ONJ) is a severe clinical condition characterized mostly but not exclusively by an area of exposed bone in the mandible and/or maxilla that typically does not heal over a period of 6-8 weeks. The diagnosis is first of all clinical, but an imaging feedback such as Magnetic Resonance is essential to confirm clinical suspicions. In the last few decades, medication-related osteonecrosis of the jaw (MRONJ) has been widely discussed. From the first case reported in 2003, many ...[more]

PMID: 33567797

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Project description:Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse event affecting patients with cancer and patients with osteoporosis who have been treated with powerful antiresorptives (pARs) or angiogenesis inhibitors (AgIs). pARs, including nitrogen-containing bisphosphonates (N-BPs; e.g., zoledronic acid, alendronate) and anti-RANKL antibodies (e.g., denosumab), are used to manage bone metastases in patients with cancer or to prevent fragility fractures in patients with osteoporosis. Though significant advances have been made in understanding MRONJ, its pathophysiology is still not fully elucidated. Multiple species have been used in preclinical MRONJ research, including the rat, mouse, rice rat, rabbit, dog, sheep, and pig. Animal research has contributed immensely to advancing the MRONJ field, particularly, but not limited to, in developing models and investigating risk factors that were first observed in humans. MRONJ models have been developed using clinically relevant doses of systemic risk factors, like N-BPs, anti-RANKL antibodies, or AgIs. Specific local oral risk factors first noted in humans, including tooth extraction and inflammatory dental disease (e.g., periodontitis, periapical infection, etc.), were then added. Research in rodents, particularly the rat, and, to some extent, the mouse, across multiple laboratories, has contributed to establishing multiple relevant and complementary preclinical models. Models in larger species produced accurate clinical and histopathologic outcomes suggesting a potential role for confirming specific crucial findings from rodent research. We view the current state of animal models for MRONJ as good. The rodent models are now reliable enough to produce large numbers of MRONJ cases that could be applied in experiments testing treatment modalities. The course of MRONJ, including stage 0 MRONJ, is characterized well enough that basic studies of the molecular or enzyme-level findings in different MRONJ stages are possible. This review provides a current overview of the existing models of MRONJ, their more significant features and findings, and important instances of their application in preclinical research.

Project description:Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of antiresorptive or antiangiogenic medications, used in the treatment of bone malignancy or osteoporosis. Bone necrosis, mainly represented by osteocytic death, is always present in MRONJ sites; however, the role of osteocyte death in MRONJ pathogenesis is unknown. High mobility group box 1 (HMGB1) is a non-histone nucleoprotein that in its acetylated form accumulates in the cytoplasm, whereas non-acetylated HMGB1 localizes in the nucleus. SIRT1 deacetylase regulates cellular localization of HMGB1. Interestingly, HMGB1 is released during cell necrosis and promotes inflammation through signaling cascades, including activation of the RAGE receptor. Here, we utilized a well-established mouse MRONJ model that utilizes ligature-induced experimental periodontitis (EP) and treatment with either vehicle or zolendronic acid (ZA). Initially, we evaluated HMGB1-SIRT1 expression in osteocytes at 1, 2, and 4 weeks of treatment. Significantly increased cytoplasmic and perilacunar HMGB1 expression was observed at EP sites of ZA versus vehicle (Veh) animals at all time points. SIRT1 colocalized with cytoplasmic HMGB1 and presented a statistically significant increased expression at the EP sites of ZA animals for all time points. RAGE expression was significantly higher in the submucosal tissues EP sites of ZA animals compared with those in vehicle group. To explore the significance of increased cytoplasmic and extracellular HMGB1 and increased RAGE expression in MRONJ pathogenesis, we used pharmacologic inhibitors of these molecules. Combined HMGB1/RAGE inhibition resulted in lower MRONJ incidence with statistically significant decrease in osteonecrotic areas and bone exposure versus non-inhibitor treated ZA animals. Together, our data point to the role of HMGB1 as a central alarmin, overexpressed at early phase of MRONJ pathogenesis during osteocytic death. Moreover, HMGB1-RAGE pathway may represent a new promising therapeutic target in patients at high risk of MRONJ. © 2022 American Society for Bone and Mineral Research (ASBMR).

Dataset Information

Medication-Related Osteonecrosis of the Jaw (MRONJ): Are Antiresorptive Drugs the Main Culprits or Only Accomplices? The Triggering Role of Vitamin D Deficiency.

Publications

Medication-Related Osteonecrosis of the Jaw (MRONJ): Are Antiresorptive Drugs the Main Culprits or Only Accomplices? The Triggering Role of Vitamin D Deficiency.

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