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      Therapeutics and Clinical Risk Management (submit here)

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      Evaluation of medication-related osteonecrosis of the jaw using the Japanese Adverse Drug Event Report database


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          Bisphosphonates (BPs) and denosumab are widely used to treat osteoporosis and complications associated with bone metastases. However, medication-related osteonecrosis of the jaw (MRONJ) is a serious problem.


          The objective of this study was to evaluate the frequency, outcome, and characteristics of patients with drug-induced MRONJ.


          Retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database from the Pharmaceuticals and Medical Devices Agency. Adverse event reports submitted to JADER between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) was calculated.


          Among the BPs that cause MRONJ, zoledronate was the most common; therefore, we compared the characteristics of cases of MRONJ induced by zoledronate with those induced by denosumab. Among the 3,875 (68.1% women) cases of MRONJ, zoledronate-related MRONJ accounted for 1,283 (56.0% women) and denosumab-related MRONJ accounted for 322 (55.3% women). MRONJ was more frequent after 70 years of age regardless of the use of either zoledronate or denosumab; onset occurred after 1 year from the denosumab treatment, but it is unknown when onset occurred after zoledronate treatment. The outcomes for MRONJ were poor, with 406 reports on zoledronate (31.6%) and 152 reports on denosumab (47.2%) demonstrating nonrecovery. Zoledronate (ROR: 319.3, 95% CI: 296.0–344.4) had the highest ROR among BP agents. Denosumab had a high ROR (ROR: 155.2, 95% CI: 136.5–176.3). Zoledronate and denosumab were used in similar patient backgrounds, and their use resulted in a similar frequency of MRONJ.


          The findings of this comprehensive evaluation of MRONJ using the JADER database will be helpful for prescribing medications to elderly patients.

          Most cited references15

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          Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research.

          ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force. The increasing recognition that use of bisphosphonates may be associated with osteonecrosis of the jaw (ONJ) led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address a number of key questions related to this disorder. A multidisciplinary expert group reviewed all pertinent published data on bisphosphonate-associated ONJ. Food and Drug Administration drug adverse event reports were also reviewed. A case definition was developed so that subsequent studies could report on the same condition. The task force defined ONJ as the presence of exposed bone in the maxillofacial region that did not heal within 8 wk after identification by a health care provider. Based on review of both published and unpublished data, the risk of ONJ associated with oral bisphosphonate therapy for osteoporosis seems to be low, estimated between 1 in 10,000 and <1 in 100,000 patient-treatment years. However, the task force recognized that information on incidence of ONJ is rapidly evolving and that the true incidence may be higher. The risk of ONJ in patients with cancer treated with high doses of intravenous bisphosphonates is clearly higher, in the range of 1-10 per 100 patients (depending on duration of therapy). In the future, improved diagnostic imaging modalities, such as optical coherence tomography or MRI combined with contrast agents and the manipulation of image planes, may identify patients at preclinical or early stages of the disease. Management is largely supportive. A research agenda aimed at filling the considerable gaps in knowledge regarding this disorder was also outlined.
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            American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws.

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              Biochemical and molecular mechanisms of action of bisphosphonates.

              This review describes the key discoveries over the last 15 years that have led to a clearer understanding of the molecular mechanisms by which bisphosphonate drugs inhibit bone resorption. Once released from bone mineral surfaces during bone resorption, these agents accumulate intracellularly in osteoclasts. Simple bisphosphonates such as clodronate are incorporated into non-hydrolysable analogues of adenosine triphosphate, which induce osteoclast apoptosis. The considerably more potent nitrogen-containing bisphosphonates are not metabolised but potently inhibit farnesyl pyrophosphate (FPP) synthase, a key enzyme of the mevalonate pathway. This prevents the synthesis of isoprenoid lipids necessary for the post-translational prenylation of small GTPases, thereby disrupting the subcellular localisation and normal function of these essential signalling proteins. Inhibition of FPP synthase also results in the accumulation of the upstream metabolite isopentenyl diphosphate, which is incorporated into the toxic nucleotide metabolite ApppI. Together, these properties explain the ability of bisphosphonate drugs to inhibit bone resorption by disrupting osteoclast function and survival. These discoveries are also giving insights into some of the adverse effects of bisphosphonates, such as the acute phase reaction that is triggered by inhibition of FPP synthase in peripheral blood monocytes. Copyright © 2010 Elsevier Inc. All rights reserved.

                Author and article information

                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                24 December 2018
                : 15
                : 59-64
                Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka 569-1094, Japan, hosohata@ 123456gly.oups.ac.jp
                Author notes
                Correspondence: Keiko Hosohata, Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan, Tel +81 72 690 1271, Fax +81 72 690 1023, Email hosohata@ 123456gly.oups.ac.jp
                © 2019 Inada et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                medication-related osteonecrosis of the jaw,pharmacovigilance,spontaneous reporting system,reporting odds ratio,japanese adverse drug event report database


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