今日の臨床サポート

薬剤投与と顎骨壊死

著者: 松尾朗 東京医科大学 口腔外科学講座

監修: 近津大地 東京医科大学

著者校正/監修レビュー済:2017/12/25
患者向け説明資料

概要・推奨   

疾患のポイント:
  1. 骨吸収阻害薬や血管新生阻害薬に関連し顎骨壊死が出現することがある。
  1. 主な骨吸収阻害薬にはビスホスホネート(BP)、抗RANKLモノクローナル抗体(デノスマブ)、抗血管新生阻害薬には抗VEGF抗体がある。これらの薬剤を総称して骨修飾薬(Bone modifying Agents:BMA)と総称することもある。
  1. 薬剤投与に関連して出現した顎骨壊死(ONJ)の定義は、①骨吸収阻害薬や血管新生阻害薬の投与の既往、②8週間以上の骨露出、③放射線治療の既往がないこと、――である。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
松尾朗 : 特に申告事項無し[2021年]
監修:近津大地 : 特に申告事項無し[2021年]

まとめ

まとめ  
  1. ビスホスホネート(BP)や抗RANKLモノクローナル抗体(デノスマブ)は強力な骨吸収抑制作用を有する物質である[1]
  1. BPやデノスマブは、骨吸収を来す疾患の標準治療薬として広く用いられている[2]
  1. BPは原発性骨粗鬆症およびリウマチなどの自己免疫疾患や癌のホルモン療法に伴う2次性の骨粗鬆症に対し、経口投与が行われている[3]
  1. 固形癌の骨転移や多発性骨髄腫などへは、BPやデノスマブの経静脈投与がなされている[3]
  1. BP投与に関連して出現した顎骨壊死(BRONJ)の臨床報告が2003年以降急増し、世界的に問題となっている[4]
  1. デノスマブは、当初ONJが発症しない骨吸収抑制剤として期待されたが、やはり顎骨壊死(Denosumab-related osteonecrosis of jaw、DRONJ)が報告されている[5]
  1. 最近は、抗血管新生阻害薬である抗VEGF抗体による顎骨壊死も報告されるようになっている[4]
  1. アメリカ口腔顎顔面外科学会(AAOMS)のポジションぺーパーの最新版(2014)では、骨吸収骨吸収阻害薬や血管新生阻害薬による顎骨壊死を総称して薬剤関連顎骨壊死 (Medication-related osteonecrosis of jaw、MRONJ) と呼称するようになった[4]
  1. 顎骨壊死(ONJ)に対する国際タスクフォース委員会では、BP以外にデノスマブなどほかの骨吸収阻害剤も出現したため ARONJ(Anti bone resorptive agent-related osteonecrosis of jaw)と呼称しており[6]、日本のポジションペーパーでもそれに従い、ARONJの名称を用いている[7]
  1. ONJは抜歯などの口腔外科手術後に生じることが多い[4]
  1. 本疾患は非常に難治性である[4]
  1. ONJに対する各種提言では基本的に保存療法を勧めているが、明確な治療選択基準は確立されていない[4][6][7]
  1. 最近は手術療法の有効性の報告が多くなされるようになり、Stage 3がその適応といわれている。Stage 2での高い成功率を示したとの報告も多いが、明確な適応基準はない[8]
  1. 本疾患に対するエビデンスの高い前向き研究はきわめて少ない[9]

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文献 

著者: J R Berenson, L S Rosen, A Howell, L Porter, R E Coleman, W Morley, R Dreicer, S A Kuross, A Lipton, J J Seaman
雑誌名: Cancer. 2001 Apr 1;91(7):1191-200.
Abstract/Text BACKGROUND: This study evaluated the dose-response relation for zoledronic acid, a new generation high potency bisphosphonate, given as a 5-minute infusion in patients with malignant osteolytic disease.
METHODS: Two-hundred eighty patients with osteolytic lesions due to metastatic breast carcinoma or multiple myeloma were randomized to double-blind treatment with either 0.4, 2.0, or 4.0 mg of zoledronic acid or 90 mg pamidronate. The primary efficacy endpoint was the proportion of patients receiving radiation to bone. Other skeletal-related events, bone mineral density (BMD), bone markers, Eastern Cooperative Oncology Group performance status, pain and analgesic scores, and safety also were evaluated.
RESULTS: Zoledronic acid at doses of 2.0 and 4.0 mg and pamidronate at a dose of 90 mg each significantly reduced the need for radiation therapy to bone (P < 0.05) in contrast with 0.4 mg zoledronic acid, which did not. Skeletal-related events of any kind, pathologic fractures, and hypercalcemia also occurred less frequently in patients treated with 2.0 or 4.0 mg zoledronic acid or pamidronate than with 0.4 mg zoledronic acid. Increases in lumbar spine BMD (6.2-9.6%) and decreases in the bone resorption marker N-telopeptide (range, -37.1 to -60.8%) were observed for all treatment groups. Skeletal pain, fatigue, nausea, vomiting, and headache were the most commonly reported adverse events. Adverse events were similar in nature and frequency with zoledronic acid and pamidronate.
CONCLUSIONS: A 5-minute infusion of 2.0-4.0 mg zoledronic acid was at least as effective as a 2-hour 90-mg pamidronate infusion in treatment of osteolytic metastases. A 0.4-mg dose of zoledronic acid was significantly less effective. Both zoledronic acid and pamidronate were well tolerated.

Copyright 2001 American Cancer Society.
PMID 11283917  Cancer. 2001 Apr 1;91(7):1191-200.
著者: Salvatore L Ruggiero, Thomas B Dodson, John Fantasia, Reginald Goodday, Tara Aghaloo, Bhoomi Mehrotra, Felice O'Ryan, American Association of Oral and Maxillofacial Surgeons
雑誌名: J Oral Maxillofac Surg. 2014 Oct;72(10):1938-56. doi: 10.1016/j.joms.2014.04.031. Epub 2014 May 5.
Abstract/Text Strategies for management of patients with, or at risk for, medication-related osteonecrosis of the jaw (MRONJ) were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers in 2007 and 2009. The position papers were developed by a special committee appointed by the board and composed of clinicians with extensive experience in caring for these patients and basic science researchers. The knowledge base and experience in addressing MRONJ has expanded, necessitating modifications and refinements to the previous position paper. This special committee met in September 2013 to appraise the current literature and revise the guidelines as indicated to reflect current knowledge in this field. This update contains revisions to diagnosis, staging, and management strategies and highlights current research status. The AAOMS considers it vitally important that this information be disseminated to other relevant health care professionals and organizations.

Copyright © 2014 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.
PMID 25234529  J Oral Maxillofac Surg. 2014 Oct;72(10):1938-56. doi: 1・・・
著者: Athanassios Kyrgidis, Thrasivoulos-George Tzellos, Konstantinos Toulis, Amit Arora, Dimitrios Kouvelas, Stefanos Triaridis
雑誌名: Curr Clin Pharmacol. 2013 May;8(2):124-34.
Abstract/Text PURPOSE: Bone antiresorptive treatment is associated with osteonecrosis of the jaws. Interventions used to treat this complication are diverse, controversial, and largely empirical but certain risk factors could help in its avoidance. The aim of this evidence-based review is to elucidate any interventions that are effective in reducing the risk for development of ONJ in cancer patients receiving bone antiresorptive therapy and to quantify the effectiveness of such interventions.
MATERIALS & METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and other trial registries through January 2012. We selected randomized controlled trials (RCTs). Cohort studies were included only as long as there are no RCTs on the same modality.
RESULTS: Twelve studies were included in the systematic review while nine studies contributed to the various comparisons. Prescribing denosumab (DSB) instead of zoledronic acid (ZA) may not be expected to reduce risk ONJ (RR:0.71 [99% CI: 0.41-1.24], I2=0%). Prescribing clodronate (RR:10.15 [99% CI: 2.43-42.35], I2=0%) or pamidronate (RR:4.41 [99% CI: 1.90-10.24], I2=16%) instead of ZA may reduce risk for ONJ. Dental extractions remain the most potent risk factor for ONJ (RR:14.04, [99% CI: 10.36-19.03], I2=0%) and their avoidance can be considered an effective risk-reductive intervention. ONJ risk can be reduced by dental prophylactic measures (RR:0.45, [99% CI: 0.23-0.85], I2=7%).
CONCLUSIONS: DSB and ZA might cause ONJ more frequently compared with chlodornate or pamidronate. Prescription pamidronate and clodronate helps avoid the complication. Reducing the administered dose for denosumab and zoledronic acid might reduce risk for ONJ as well. More randomized clinical trials comparing reduced doses of these regimens against those currently approved are needed.

PMID 23092218  Curr Clin Pharmacol. 2013 May;8(2):124-34.
著者: Aliya A Khan, Archie Morrison, David A Hanley, Dieter Felsenberg, Laurie K McCauley, Felice O'Ryan, Ian R Reid, Salvatore L Ruggiero, Akira Taguchi, Sotirios Tetradis, Nelson B Watts, Maria Luisa Brandi, Edmund Peters, Teresa Guise, Richard Eastell, Angela M Cheung, Suzanne N Morin, Basel Masri, Cyrus Cooper, Sarah L Morgan, Barbara Obermayer-Pietsch, Bente L Langdahl, Rana Al Dabagh, K Shawn Davison, David L Kendler, George K Sándor, Robert G Josse, Mohit Bhandari, Mohamed El Rabbany, Dominique D Pierroz, Riad Sulimani, Deborah P Saunders, Jacques P Brown, Juliet Compston, International Task Force on Osteonecrosis of the Jaw
雑誌名: J Bone Miner Res. 2015 Jan;30(1):3-23. doi: 10.1002/jbmr.2405.
Abstract/Text This work provides a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence, pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offers recommendations for its management based on multidisciplinary international consensus. ONJ is associated with oncology-dose parenteral antiresorptive therapy of bisphosphonates (BP) and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1% to 15%), where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of ONJ is estimated at 0.001% to 0.01%, marginally higher than the incidence in the general population (<0.001%). New insights into the pathophysiology of ONJ include antiresorptive effects of BPs and Dmab, effects of BPs on gamma delta T-cells and on monocyte and macrophage function, as well as the role of local bacterial infection, inflammation, and necrosis. Advances in imaging include the use of cone beam computerized tomography assessing cortical and cancellous architecture with lower radiation exposure, magnetic resonance imaging, bone scanning, and positron emission tomography, although plain films often suffice. Other risk factors for ONJ include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, ill-fitting dentures, as well as other drugs, including antiangiogenic agents. Prevention strategies for ONJ include elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage. Management of ONJ is based on the stage of the disease, size of the lesions, and the presence of contributing drug therapy and comorbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Localized surgical debridement is indicated in advanced nonresponsive disease and has been successful. Early data have suggested enhanced osseous wound healing with teriparatide in those without contraindications for its use. Experimental therapy includes bone marrow stem cell intralesional transplantation, low-level laser therapy, local platelet-derived growth factor application, hyperbaric oxygen, and tissue grafting.

© 2014 American Society for Bone and Mineral Research.
PMID 25414052  J Bone Miner Res. 2015 Jan;30(1):3-23. doi: 10.1002/jbm・・・
著者: Eric R Carlson
雑誌名: J Oral Maxillofac Surg. 2014 Apr;72(4):655-7. doi: 10.1016/j.joms.2013.12.007. Epub 2013 Dec 15.
Abstract/Text
PMID 24480762  J Oral Maxillofac Surg. 2014 Apr;72(4):655-7. doi: 10.1・・・
著者: Matthew R Allen
雑誌名: Oral Maxillofac Surg Clin North Am. 2015 Nov;27(4):497-508. doi: 10.1016/j.coms.2015.06.002. Epub 2015 Aug 13.
Abstract/Text In the late 1990s and the early 2000s, bisphosphonates had become the clinical pillar of excellence for treating metabolic bone disease, and thus their connection with osteonecrosis of the jaw (ONJ) caused significant concern. Over the past decade, progress has been made in understanding what is now referred to as medication-related ONJ (MRONJ), because of its connections to agents other than bisphosphonates, although in many respects the progress has been slow. This review highlights the key basic science and translational (animal) studies in the area of MRONJ and suggests areas of focus as the field moves into the next decade.

Copyright © 2015 Elsevier Inc. All rights reserved.
PMID 26277349  Oral Maxillofac Surg Clin North Am. 2015 Nov;27(4):497-・・・
著者: Karim Fizazi, Michael Carducci, Matthew Smith, Ronaldo Damião, Janet Brown, Lawrence Karsh, Piotr Milecki, Neal Shore, Michael Rader, Huei Wang, Qi Jiang, Sylvia Tadros, Roger Dansey, Carsten Goessl
雑誌名: Lancet. 2011 Mar 5;377(9768):813-22. doi: 10.1016/S0140-6736(10)62344-6. Epub 2011 Feb 25.
Abstract/Text BACKGROUND: Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer.
METHODS: In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed.
FINDINGS: 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9-18·5) for patients on denosumab and 11·2 months (IQR 5·6-17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8-24·9) with denosumab compared with 17·1 months (15·0-19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71-0·95; p = 0·0002 for non-inferiority; p = 0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p = 0·09).
INTERPRETATION: Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer.
FUNDING: Amgen.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21353695  Lancet. 2011 Mar 5;377(9768):813-22. doi: 10.1016/S0140・・・
著者: Eriko Sumi, Toru Yamazaki, Shiro Tanaka, Keiichi Yamamoto, Takeo Nakayama, Kazuhisa Bessho, Masayuki Yokode
雑誌名: Pharmacoepidemiol Drug Saf. 2014 Apr;23(4):398-405. doi: 10.1002/pds.3562. Epub 2014 Jan 8.
Abstract/Text PURPOSE: The purpose of this study was to investigate the impact of risk communication about bisphosphonate (BP)-related osteonecrosis of the jaw (ONJ) on the number of reported cases to the Drug Adverse Reactions Reporting System and on the incidence proportion of ONJ in a hospital-based cohort study in Japan.
METHOD: We conducted a survey of the safety information on BP-related ONJ available from regulatory authorities, pharmaceutical manufacturers and academic associations. We also performed a trend analysis of a dataset from the Drug Adverse Reactions Reporting System and a sub-analysis, using previously constructed data from a retrospective cohort study.
RESULTS: Risk communication from pharmaceutical manufacturers and academic associations began within 1 year after revisions were made to the package inserts, in October 2006. Twenty times more cases of ONJ have been reported to regulatory authority since 2007, compared with the period before 2007. In our cohort, the incidence proportion of ONJ during and after 2009 was four times greater than before 2009. During this period, BPs were frequently prescribed, whereas there was no increase in the use of alternative agents, such as selective estrogen receptor modulators.
CONCLUSION: ONJ was increasingly diagnosed after risk communication efforts, but the impact of the communications was not clear. Safety notifications were diligently disseminated after the package insert was revised. However, there was no surveillance for ONJ before the revision.

© 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.
PMID 24399628  Pharmacoepidemiol Drug Saf. 2014 Apr;23(4):398-405. doi・・・
著者: Heike A Bischoff, Hannes B Stähelin, Walter Dick, Regula Akos, Margrith Knecht, Christian Salis, Matthias Nebiker, Robert Theiler, Michael Pfeifer, Bettina Begerow, Robert A Lew, Martin Conzelmann
雑誌名: J Bone Miner Res. 2003 Feb;18(2):343-51. doi: 10.1359/jbmr.2003.18.2.343.
Abstract/Text Specific receptors for vitamin D have been identified in human muscle tissue. Cross-sectional studies show that elderly persons with higher vitamin D serum levels have increased muscle strength and a lower number of falls. We hypothesized that vitamin D and calcium supplementation would improve musculoskeletal function and decrease falls. In a double-blind randomized controlled trial, we studied 122 elderly women (mean age, 85.3 years; range, 63-99 years) in long-stay geriatric care. Participants received 1200 mg calcium plus 800 IU cholecalciferol (Cal+D-group; n = 62) or 1200 mg calcium (Cal-group; n = 60) per day over a 12-week treatment period. The number of falls per person (0, 1, 2-5, 6-7, >7 falls) was compared between the treatment groups. In an intention to treat analysis, a Poisson regression model was used to compare falls after controlling for age, number of falls in a 6-week pretreatment period, and baseline 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum concentrations. Among fallers in the treatment period, crude excessive fall rate (treatment - pretreatment falls) was compared between treatment groups. Change in musculoskeletal function (summed score of knee flexor and extensor strength, grip strength, and the timed up&go test) was measured as a secondary outcome. Among subjects in the Cal+D-group, there were significant increases in median serum 25-hydroxyvitamin D (+71%) and 1,25-dihydroxyvitamin D (+8%). Before treatment, mean observed number of falls per person per week was 0.059 in the Cal+D-group and 0.056 in the Cal-group. In the 12-week treatment period, mean number of falls per person per week was 0.034 in the Cal+D-group and 0.076 in the Cal-group. After adjustment, Cal+D-treatment accounted for a 49% reduction of falls (95% CI, 14-71%; p < 0.01) based on the fall categories stated above. Among fallers of the treatment period, the crude average number of excessive falls was significantly higher in the Cal-group (p = 0.045). Musculoskeletal function improved significantly in the Cal+D-group (p = 0.0094). A single intervention with vitamin D plus calcium over a 3-month period reduced the risk of falling by 49% compared with calcium alone. Over this short-term intervention, recurrent fallers seem to benefit most by the treatment. The impact of vitamin D on falls might be explained by the observed improvement in musculoskeletal function.

PMID 12568412  J Bone Miner Res. 2003 Feb;18(2):343-51. doi: 10.1359/j・・・
著者: R M Neer, C D Arnaud, J R Zanchetta, R Prince, G A Gaich, J Y Reginster, A B Hodsman, E F Eriksen, S Ish-Shalom, H K Genant, O Wang, B H Mitlak
雑誌名: N Engl J Med. 2001 May 10;344(19):1434-41. doi: 10.1056/NEJM200105103441904.
Abstract/Text BACKGROUND: Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown.
METHODS: We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry.
RESULTS: New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache).
CONCLUSIONS: Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.

PMID 11346808  N Engl J Med. 2001 May 10;344(19):1434-41. doi: 10.1056・・・
著者: H Eidtmann, R de Boer, N Bundred, A Llombart-Cussac, N Davidson, P Neven, G von Minckwitz, J Miller, N Schenk, R Coleman
雑誌名: Ann Oncol. 2010 Nov;21(11):2188-94. doi: 10.1093/annonc/mdq217. Epub 2010 May 5.
Abstract/Text BACKGROUND: Aromatase inhibitors (AIs) are accepted as adjuvant therapy for postmenopausal women (PMW) with hormone-responsive early breast cancer (EBC) with superior efficacy to tamoxifen. However, increased bone loss is associated with AIs.
PATIENTS AND METHODS: PMW with EBC receiving letrozole (2.5 mg/day for 5 years) were randomly assigned to immediate zoledronic acid (ZOL; 4 mg every 6 months) or delayed ZOL (initiated only for fracture or high risk thereof).
RESULTS: Patients (N = 1065) had a median age of 58 years; 54% had received prior adjuvant chemotherapy. At 36 months, mean change in L2-L4 bone mineral density (BMD) was +4.39% for immediate versus -4.9% for delayed ZOL (P < 0.0001). Between-group differences were 5.27% at 12 months, 7.94% at 24 months, and 9.29% at 36 months (P < 0.0001 for all). At 36 months, the immediate-ZOL group had a significant 41% relative risk reduction for disease-free survival (DFS) events (P = 0.0314). Adverse events are consistent with the known safety profiles of the study drugs.
CONCLUSIONS: At 36 months, immediate ZOL was more effective in preserving BMD during letrozole therapy. Immediate versus delayed ZOL led to significantly improved DFS. Benefits are observed in the context of a favorable, well-established safety profile for letrozole and ZOL.

PMID 20444845  Ann Oncol. 2010 Nov;21(11):2188-94. doi: 10.1093/annonc・・・
著者: Akira Matsuo, Hayato Hamada, Hiroshi Kaise, Daichi Chikazu, Kimito Yamada, Norio Kohno
雑誌名: Acta Odontol Scand. 2014 Nov;72(8):656-63. doi: 10.3109/00016357.2014.887772. Epub 2014 Feb 12.
Abstract/Text OBJECTIVE: The clinical features of the early stages of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in patients with breast cancer remain unclear. A retrospective cohort study was conducted of patients with breast cancer who received intravenous bisphosphonate (BP) treatment in a single center in order to clarify the status of the early stages of BRONJ.
MATERIALS AND METHODS: A BRONJ oral monitoring program was established in 247 breast cancer patients given intravenous BP treatment at the institution. The differences in age, BP treatment period, number of remaining teeth, oral hygiene status, presence of regular oral monitoring and the existence of suspected BRONJ (stage 0) among eight BRONJ and 36 non-BRONJ subjects who completed oral examinations were then compared.
RESULTS: BRONJ was observed in 0.4% of subjects on the first visit to the oral surgery clinic and in 3.2% of subjects during the follow-up period. Logistic regression analysis revealed that the odds ratio for identifying patients with BRONJ during follow-up by the presence of stage 0 at first visit was 24.0 (95% confidence interval [CI] = 3.6-161.7). The area under the receiver operating characteristic curve for identifying subjects with BRONJ by the presence of stage 0 was 0.82 (95% CI = 0.63-1.00).
CONCLUSION: The results suggest that patients with stage 0 BRONJ on the first visit may progress to advanced BRONJ during the follow-up period. The oral monitoring program may contribute to the early detection of BRONJ.

PMID 24521290  Acta Odontol Scand. 2014 Nov;72(8):656-63. doi: 10.3109・・・
著者: Dolly Quispe, Runhua Shi, Gary Burton
雑誌名: Breast J. 2011 Sep-Oct;17(5):510-3. doi: 10.1111/j.1524-4741.2011.01119.x. Epub 2011 Jul 15.
Abstract/Text Bisphosphonate therapy is an important adjunct to the treatment of patients with bone metastasis. Osteonecrosis of the jaw (ONJ), a complication related to bisphosphonate therapy, is reported in up to 7% of patients with metastatic breast cancer. The objective of this study was to define the prevalence and to identify risk factors associated with development of ONJ in a predominantly low socio-economic population. Medical records of patients with a diagnosis of metastatic breast cancer with bone metastasis seen between 2002 and 2007 were reviewed. All patients received a minimum of four infusions of zolendronic acid. Data on demographics, insurance status, tobacco use, concurrent therapy, body mass index, and number of zolendronic acid infusions were analyzed. Of the 110 patient analyzed, 10 developed ONJ (9%) with the mean number of zolendronic acid infusions in patients with ONJ of 22.9 ± 17. ONJ was seen more frequently in Caucasian than in African Americans patients (15% versus 2%; p = 0.019). ONJ was associated with older age at diagnosis of metastatic breast cancer (p = 0.02), tobacco use (p = 0.049), but was not associated with SES or duration of therapy. After adjusting for SES, Caucasian patients were 9.1 times more likely to have ONJ when compared with African American patients. (95% CI 1.03-81.7). Our results suggest an increase prevalence of ONJ in Caucasian breast cancer patients. However, as our study population is small, additional studies to confirm this finding are needed.

© 2011 Wiley Periodicals, Inc.
PMID 21762241  Breast J. 2011 Sep-Oct;17(5):510-3. doi: 10.1111/j.1524・・・
著者: Hayato Hamada, Akira Matsuo, Toshiyuki Koizumi, Takafumi Satomi, Daichi Chikazu
雑誌名: J Craniomaxillofac Surg. 2014 Sep;42(6):924-9. doi: 10.1016/j.jcms.2014.01.012. Epub 2014 Jan 14.
Abstract/Text OBJECTIVES: The aim of this study was to establish a simple method for the early detection of bisphosphonate-related osteonecrosis of the jaw (BRONJ) using computed tomography (CT).
MATERIALS AND METHODS: CT images of the mandible were obtained from a total of 20 patients with BRONJ and 20 control subjects. BRONJ was classified into 2 groups, with bone exposure (Stage 1-3 BRONJ) or without (Stage 0 BRONJ). In each patient, 15 transaxial CT images were selected and 30 configured regions of interest (ROI) were identified. The ANOVA test was applied to test the relationship between the severity of systemic risk factors.
RESULTS: Regarding the local status of the mandible, significant differences were observed among the Stage 0 BRONJ, Stage 1-3 BRONJ, non-BRONJ and control groups in the cancellous bone CT radiodensity values, but there were no significant differences between the Stage 0 and Stage 1-3 BRONJ groups. In the cortical bone widths, significant differences were observed only between BRONJ and the controls.
CONCLUSIONS: Measuring cancellous bone CT radiodensity value has the potential to be a simple and quantitative method to detect the early stages of BRONJ.

Copyright © 2014 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
PMID 24503386  J Craniomaxillofac Surg. 2014 Sep;42(6):924-9. doi: 10.・・・
著者: Robert E Marx, Joseph E Cillo, Juan J Ulloa
雑誌名: J Oral Maxillofac Surg. 2007 Dec;65(12):2397-410. doi: 10.1016/j.joms.2007.08.003.
Abstract/Text PURPOSE: To assess the risk and time course of oral bisphosphonate-induced osteonecrosis of the jaws.
MATERIALS AND METHODS: Detailed data from 30 consecutive cases were compared with 116 cases due to intravenous aminobisphosphonates.
RESULTS: Results in part noted a higher incidence related to alendronate (Fosamax; Merck, Whitehouse Station, NJ), a 94.7% predilection for the posterior mandible, and a 50% occurrence spontaneously, with the remaining 50% resulting from an oral surgical procedure, mostly tooth removals. Just over 53% of patients were taking their oral bisphosphonate for osteopenia, 33.3% for documented osteoporosis, and 13.4% for steroid-induced osteoporosis related to 4 or more years of prednisone therapy for an autoimmune condition. There was a direct exponential relationship between the size of the exposed bone and the duration of oral bisphosphonate use. There was also a direct correlation between reports of pain and clinical evidence of infection. The morning fasting serum C-terminal telopeptide (CTX) test results were observed to correlate to the duration of oral bisphosphonate use and could indicate a recovery of bone remodeling with increased values if the oral bisphosphonate was discontinued. A stratification of relative risk was seen as CTX values less than 100 pg/mL representing high risk, CTX values between 100 pg/mL and 150 pg/mL representing moderate risk, and CTX values above 150 pg/mL representing minimal risk. The CTX values were noted to increase between 25.9 pg/mL to 26.4 pg/mL for each month of a drug holiday indicating a recovery of bone remodeling and a guideline as to when oral surgical procedures can be accomplished with the least risk. In addition, drug holidays associated with CTX values rising above the 150 pg/mL threshold were observed to correlate to either spontaneous bone healing or a complete healing response after an office-based debridement procedure.
CONCLUSIONS: Oral bisphosphonate-induced osteonecrosis is a rare but real entity that is less frequent, less severe, more predictable, and more responsive to treatment than intravenous bisphosphonate-induced osteonecrosis. The morning fasting serum C-terminal telopeptide bone suppression marker is a useful tool for the clinician to assess risks and guide treatment decisions.

PMID 18022461  J Oral Maxillofac Surg. 2007 Dec;65(12):2397-410. doi: ・・・
著者: C I Ripamonti, M Maniezzo, T Campa, E Fagnoni, C Brunelli, G Saibene, C Bareggi, L Ascani, E Cislaghi
雑誌名: Ann Oncol. 2009 Jan;20(1):137-45. doi: 10.1093/annonc/mdn526. Epub 2008 Jul 22.
Abstract/Text BACKGROUND: Screening of the oral cavity and dental care was suggested as mandatory preventive measures of osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BPs). We investigated the occurrence of ONJ before and after implementation of dental preventive measures when starting BP therapy.
PATIENTS AND METHODS: Since April 2005, 154 consecutive patients treated with BPs (POST-Group) have undergone a baseline mouth assessment (dental visit +/- orthopantomography of the jaws) to detect potential dental conditions and dental care if required. A retrospective review was also conducted of all consecutive cancer patients with bone metastases (PRE-Group) and treated for the first time with BPs from January 1999 to April 2005 in our clinic without receiving any preventive measure. Incidence proportion and incidence rate (IR) were used to estimate the incidence of ONJ.
RESULTS: Among the study population (966 patients; male/female=179/787), 73% had breast cancer. 25% of patients were given zoledronic acid (ZOL), 62% pamidronate (PAM), 8% PAM followed by ZOL and 5% clodronate. ONJ was observed in 28 patients (2.9%); we observed a reduction in the incidence of ONJ from 3.2% to 1.3%, when comparing-pre and post-implementation of preventive measures programme. Considering the patients exposed to ZOL, the performance of a dental examination and the application of preventive measures led to a sustained reduction in ONJ IR (7.8% in the PRE-Group versus 1.7% in the POST-Group; P=0.016), with an IR ratio of 0.30 (95% confidence interval 0.03-1.26).
CONCLUSIONS: ONJ is a manageable and preventable condition. Our data confirm that the application of preventive measures can significantly reduce the incidence of ONJ in cancer patients receiving BPs therapy. Dental exams combined to the identification of patients at risk in cooperation with the Dental Team can improve outcomes and increase the number of ONJ-free patients.

PMID 18647964  Ann Oncol. 2009 Jan;20(1):137-45. doi: 10.1093/annonc/m・・・
著者: M A Dimopoulos, E Kastritis, C Bamia, I Melakopoulos, D Gika, M Roussou, M Migkou, E Eleftherakis-Papaiakovou, D Christoulas, E Terpos, A Bamias
雑誌名: Ann Oncol. 2009 Jan;20(1):117-20. doi: 10.1093/annonc/mdn554. Epub 2008 Aug 9.
Abstract/Text BACKGROUND: Osteonecrosis of the jaw (ONJ) is a well-described complication of bisphosphonates use in patients with multiple myeloma (MM). We investigated whether the occurrence of ONJ decreased after the implementation of preventive measures in 128 patients with MM who received zoledronic acid.
PATIENTS AND METHODS: Patients with MM who received zoledronic acid were included in this analysis. Patients with a previous use of other bisphosphonates were excluded; patients were stratified into group A (n=38) and group B (n=90) if treatment was started before or after the implementation of preventive measures.
RESULTS: One hundred and twenty-eight patients were included in this analysis. Sixteen patients (12.5%) developed ONJ--group A: 8 (26.3%), group B: 2 (6.7%) (P=0.002). The incidence rate (IR) was 0.671/100 person-months for group A and 0.230/100 person-months for group B [IR ratio 2.92, P=0.029, 95% confidence interval 1.06-8.03]. No patient in group B developed stage III ONJ.
CONCLUSION: In conclusion, the risk of developing ONJ after treatment of zoledronic acid is reduced (but not deleted) by the implementation of preventive measures.

PMID 18689864  Ann Oncol. 2009 Jan;20(1):117-20. doi: 10.1093/annonc/m・・・
著者: Akira Matsuo, Hayato Hamada, Hidetoshi Takahashi, Ayako Okamoto, Hiroshi Kaise, Daichi Chikazu
雑誌名: Odontology. 2016 Sep;104(3):363-71. doi: 10.1007/s10266-015-0207-4. Epub 2015 May 9.
Abstract/Text It remains unclear whether dental implants are a risk factor for the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We retrospectively evaluated the status of dental implants in patients given intravenous bisphosphonates (BPs) in a breast cancer cohort to elucidate the risk for BRONJ at the implant site. We established a BRONJ oral monitoring program for 247 breast cancer patients given intravenous BP in our institution. The 3-year cumulative incidence rate was determined. The systemic and local risk factors of 44 patients who completed comprehensive oral examinations were evaluated by logistic regression analysis. The 3-year cumulative incidence rate of the 247 patients was 0.074 % (8/247, 95 % CI 0.0081-0.014). In the 44 orally examined patients, 6 (13.6 %: 6/44) had dental implants. Of these 6 patients, 1 developed BRONJ at the implant site. There were no significant differences in the age, total BP treatment period, number of residual teeth, time of regular oral monitoring, oral hygiene level, or dental implant insertion. Although a case of ONJ was identified, dental implants which were inserted before intravenous BP administration were not a risk factor for the development of ONJ in breast cancer patients.

PMID 25956267  Odontology. 2016 Sep;104(3):363-71. doi: 10.1007/s10266・・・
著者: Ada Cheung, Ego Seeman
雑誌名: N Engl J Med. 2010 Dec 16;363(25):2473-4. doi: 10.1056/NEJMc1002684. Epub 2010 Oct 16.
Abstract/Text
PMID 20950167  N Engl J Med. 2010 Dec 16;363(25):2473-4. doi: 10.1056/・・・
著者: Jun Iwamoto, Kaori Yago, Yoshihiro Sato, Hideo Matsumoto
雑誌名: Clin Drug Investig. 2012 Aug 1;32(8):547-53. doi: 10.2165/11634430-000000000-00000.
Abstract/Text We report on the case of a severely osteoporotic elderly Japanese woman with bisphosphonate-associated osteonecrosis of the jaw (ONJ), who was treated successfully with teriparatide. A 79-year-old woman with severe osteoporosis and bisphosphonate-associated ONJ was treated with teriparatide after debridement of the necrotic tissue in the jaw bone. Computed tomography (CT) images revealed the bone defect in the mandible after debridement of the necrotic tissue associated with ONJ. According to the attending dentist, the ONJ healed after 2 months of therapy. After 3 months of treatment, a robust increase in the serum level of the bone formation marker, serum intact procollagen type 1 N-terminal propeptide, was noted and a repeat CT revealed improvement of the bone defect of the mandible. These results suggest the beneficial effects of teriparatide therapy in the severely osteoporotic elderly woman with ONJ.

PMID 22734599  Clin Drug Investig. 2012 Aug 1;32(8):547-53. doi: 10.21・・・
著者: Alberto Bedogni, Giorgia Saia, Giordana Bettini, Anita Tronchet, Andrea Totola, Giorgio Bedogni, Giuseppe Ferronato, Pier Francesco Nocini, Stella Blandamura
雑誌名: Oral Oncol. 2011 May;47(5):420-4. doi: 10.1016/j.oraloncology.2011.02.024. Epub 2011 Mar 24.
Abstract/Text Surgical treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is controversial. Current recommendations contraindicate aggressive surgery because its results are unpredictable and may trigger disease progression. In this prospective study, we assessed the effectiveness of surgical resection of the jaws in cancer patients with BRONJ. Between June 2004 and July 2009, 30 cancer patients with refractory BRONJ underwent surgical resection of the jaws at our Units. They were followed-up weekly for the first month, at 3-month intervals up to 1 year, and at 6-month intervals up to 2 years. Panoramic radiographs and CT-scan were obtained at 3, 6, 12, 18 and 24 months. Primary outcomes were the 24-month recurrence rate of BRONJ and the 24-month mortality rate. Secondary outcomes were post-operative complications, duration of hospital stay after surgery, time to return to oral diet, and degree of oral pain. The 30 patients had a median age of 66 years and were mostly females (80%). Twenty-eight underwent a single resection and two had both jaws resected, for a total of 32 resected jaws. The cumulative recurrence rate of BRONJ in resected jaws 3.1% and 9.4% at 3 and 6 months, respectively. All the jaws with recurrent BRONJ had osteomyelitis at the margins of bone resection. The cumulative incidence of death was 3%, 12% and 16% at 12, 18 and 24 months. Surgical resection of BRONJ was highly effective, with few post-operative complications and were not associated with long-term mortality.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21439892  Oral Oncol. 2011 May;47(5):420-4. doi: 10.1016/j.oralon・・・
著者: Eric R Carlson, John D Basile
雑誌名: J Oral Maxillofac Surg. 2009 May;67(5 Suppl):85-95. doi: 10.1016/j.joms.2009.01.006.
Abstract/Text PURPOSE: Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a poorly understood pathologic entity from the standpoints of its nomenclature, frequency, pathogenesis, and best method of treatment. In particular, numerous recommendations have been made for treatment involving nonsurgical therapy. It is the purpose of this article to specifically examine the success of resection of the necrotic bone in the mandible and maxilla in these patients.
PATIENTS AND METHODS: We identified 103 sites of BRONJ in 82 patients. Of these sites of osteonecrosis, 32 were in the maxilla and 71 were in the mandible. Of the patients, 30 were taking an oral bisphosphonate medication whereas 52 were taking a parenteral bisphosphonate medication. Resection was performed in 95 sites of osteonecrosis in 74 patients, whereas 8 sites diagnosed in 8 patients were not resected. A total of 27 sites of BRONJ were resected in patients treated with oral bisphosphonates, and 68 sites of BRONJ were resected in patients treated with parenteral bisphosphonates.
RESULTS: Of the 95 resected sites, 87 (91.6%) healed in an acceptable fashion with resolution of disease. Of 27 resected sites in patients taking an oral bisphosphonate medication, 26 (96.3%) healed satisfactorily, with refractory disease developing in 1 site. Of 68 resected sites in patients taking a parenteral bisphosphonate medication, 61 (89.7%) healed satisfactorily, with refractory disease developing in 7 sites. All 29 patients (100%) undergoing resection of the maxilla related to either an oral or parenteral bisphosphonate healed acceptably. The 8 patients who had the development of refractory disease did so with a range of 7 to 250 days postoperatively (mean, 73 days). Of the 8 sites of refractory disease, 6 developed after a marginal resection of the mandible for BRONJ. Three sites of new primary disease developed in 2 patients postoperatively. Both patients were taking a parenteral bisphosphonate medication. Histologic examination of the resected specimens identified malignant disease in 4 specimens in 3 patients.
CONCLUSION: Resection of BRONJ permits acceptable healing in patients taking an oral bisphosphonate medication. In addition, resection of BRONJ of the maxilla in patients taking an oral or parenteral bisphosphonate medication follows a predictable course with regard to healing. Resection of BRONJ of the mandible in patients taking a parenteral bisphosphonate medication follows a variable postoperative course, although a high degree of success is realized. Surgeons should consider resection of necrotic bone of the maxilla and mandible that develops in patients taking bisphosphonate medications. In addition, refractory disease can be successfully managed with a more aggressive resection, specifically, a segmental resection of the mandible after a marginal resection of the mandible where refractory disease developed.

PMID 19371819  J Oral Maxillofac Surg. 2009 May;67(5 Suppl):85-95. doi・・・
著者: Giorgia Saia, Stella Blandamura, Giordana Bettini, Anita Tronchet, Andrea Totola, Giorgio Bedogni, Giuseppe Ferronato, Pier Francesco Nocini, Alberto Bedogni
雑誌名: J Oral Maxillofac Surg. 2010 Apr;68(4):797-804. doi: 10.1016/j.joms.2009.10.026.
Abstract/Text PURPOSE: To evaluate the occurrence of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in patients exposed to nitrogen-containing bisphosphonates (NBPs) requiring surgical tooth extraction.
PATIENTS AND METHODS: Sixty high-risk patients exposed to NBPs underwent surgical tooth extraction with bone biopsy and were treated with a 7-day cycle of oral antibiotics and discontinuation of NBPs for 1 month. BRONJ was defined as the occurrence of any BRONJ stage (0-3) at 3, 6, or 12 months of follow-up. Inferential analysis was performed on a per-bone (maxilla and/or mandible) basis (n = 72). The time to BRONJ was calculated, and age, gender, cancer diagnosis, and baseline osteomyelitis were evaluated as potential predictors. Exact logistic regression was used to model the time-to-outcome relationship, and hazard rates were calculated from logistic probabilities.
RESULTS: BRONJ was detected at 3 months' follow-up in 4 bones and at 6 months in 1 further bone. In the whole cohort of bones, the hazard rate of BRONJ was 5.6% at 3 months and 1.5% at 6 months. Baseline osteomyelitis was a strong risk factor for BRONJ development (odds ratio, 156.96; exact 95% confidence interval, 18.99 to infinity; exact P < .0001).
CONCLUSION: In this 12-month follow-up study, BRONJ was a rare outcome in high-risk NBP users who underwent surgical tooth extraction. Moreover, baseline osteomyelitis was a very strong risk factor for BRONJ development.

2010 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.
PMID 20307765  J Oral Maxillofac Surg. 2010 Apr;68(4):797-804. doi: 10・・・
著者: P F Nocini, G Saia, G Bettini, M Ragazzo, S Blandamura, L Chiarini, A Bedogni
雑誌名: Eur J Surg Oncol. 2009 Apr;35(4):373-9. doi: 10.1016/j.ejso.2008.05.002. Epub 2008 Jun 17.
Abstract/Text AIMS: To point out the feasibility of microsurgical reconstruction of the mandible in patients with bisphosphonate-related osteonecrosis (BRONJ).
METHODS: Seven patients with extensive mandibular osteonecrosis underwent subtotal mandibulectomy and immediate reconstruction with a free fibula flap. They were six women and one man aged 49-72 years. The mean size of the bone and oral mucosa defects were 18.5 and 22.5 cm(2) respectively.
RESULTS: The mean time of surgical intervention was 12 h. All flaps survived and the postoperative course was uneventful. Oral feeding was resumed 14 days after surgery in all cases. The donor legs healed without complications. The pathology report confirmed the diagnosis of BRONJ in all patients. Normal bone was detected at the resection margins in six out of seven patients. Patients were followed-up at intervals of 3 months. After a median follow-up time of 23 months, no clinical and radiographic evidence of recurrent BRONJ were detected in six patients. One patient with osteomyelitis at the resection margins had signs of recurrent BRONJ 6 months after surgery. The overall curative rate of the population was 86%.
CONCLUSIONS: Despite the limited number of patients studied so far, our data show that mandible reconstruction with the fibula flap is feasible and does not influence the natural course of the primary disease in BRONJ-resected patients.

PMID 18562154  Eur J Surg Oncol. 2009 Apr;35(4):373-9. doi: 10.1016/j.・・・
著者: Marco Mozzati, Giorgia Gallesio, Valentina Arata, Renato Pol, Matteo Scoletta
雑誌名: Oral Oncol. 2012 May;48(5):469-74. doi: 10.1016/j.oraloncology.2011.12.004. Epub 2012 Jan 20.
Abstract/Text Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an important complication in cancer patients taking intravenous BPs (BPs). In most cases, BRONJ is associated with an oral surgery procedure involving jaw bone. Currently, BRONJ management remains controversial, and there is no definitive standard of care for this disease. In fact, several articles in the recent literature discuss treatments that range from topical to surgical treatment, without definitive conclusion about treatment. A clinical study was conducted on 32 patients treated with i.v BPs for oncologic pathologies affected by BRONJ. The patients were treated by resection of the necrotic bone with primary closure of the mucosa over the bony defect using plasma rich in growth factors (PRGF). Orthopanoramic and computed tomography were performed before and after surgery. No intraoperative complications were observed, and all 32 cases were treated successfully. Our data on the use of PRGF demonstrate positive results for this surgical treatment. PRGF may enhance vascularization and regeneration of osseous and epithelial tissues.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 22265335  Oral Oncol. 2012 May;48(5):469-74. doi: 10.1016/j.oralo・・・
著者: Roland Baron, Serge Ferrari, R Graham G Russell
雑誌名: Bone. 2011 Apr 1;48(4):677-92. doi: 10.1016/j.bone.2010.11.020. Epub 2010 Dec 9.
Abstract/Text To treat systemic bone loss as in osteoporosis and/or focal osteolysis as in rheumatoid arthritis or periodontal disease, most approaches target the osteoclasts, the cells that resorb bone. Bisphosphonates are currently the most widely used antiresorptive therapies. They act by binding the mineral component of bone and interfere with the action of osteoclasts. The nitrogen-containing bisphosphonates, such as alendronate, act as inhibitors of farnesyl-pyrophosphate synthase, which leads to inhibition of the prenylation of many intracellular signaling proteins. The discovery of RANKL and the essential role of RANK signaling in osteoclast differentiation, activity and survival have led to the development of denosumab, a fully human monoclonal antibody. Denosumab acts by binding to and inhibiting RANKL, leading to the loss of osteoclasts from bone surfaces. In phase 3 clinical studies, denosumab was shown to significantly reduce vertebral, nonvertebral and hip fractures compared with placebo and increase areal BMD compared with alendronate. In this review, we suggest that the key pharmacological differences between denosumab and the bisphosphonates reside in the distribution of the drugs within bone and their effects on precursors and mature osteoclasts. This may explain differences in the degree and rapidity of reduction of bone resorption, their potential differential effects on trabecular and cortical bone, and the reversibility of their actions.

Copyright © 2010 Elsevier Inc. All rights reserved.
PMID 21145999  Bone. 2011 Apr 1;48(4):677-92. doi: 10.1016/j.bone.2010・・・
著者: Tetsuya Ikeda, Jun Kuraguchi, Yasunao Kogashiwa, Hidenori Yokoi, Takafumi Satomi, Naoyuki Kohno
雑誌名: Bone. 2015 Apr;73:217-22. doi: 10.1016/j.bone.2014.12.021. Epub 2014 Dec 27.
Abstract/Text BRONJ has become a well-known, occasionally severe side effect of bisphosphonate therapy, as well as a clinical problem. Although treatment recommendations exist, no standard therapy has yet been established for BRONJ. Also, these recommendations identify several limitations that prevent clinicians from confidently diagnosing BRONJ. The aim of the present study was to establish a treatment approach in which all patients with exposed, infected bone or intraoral/extraoral fistulas were treated with sitafloxacin (STFX). We examined 20 BRONJ patients, fourteen with cancer and six with osteoporosis. We used the current updated definition of BRONJ (12), except that we included patients who had shown symptoms for a minimum of only one month, rather than two months. Thus half of our patients had infection with no exposed, necrotic bone in the oral cavity. We purposely excluded all patients exhibiting no signs of infection (current Stages 0 and 1). In addition, each potentially causative organism was isolated from pus collected from an intraoral or extraoral fistula in ten patients on their first visit to our department. 90% of the patients had received a course of treatment with common antibiotics. STFX was administered to all patients. We then re-evaluated the lesion every other week, to determine whether epithelialization was present. We recommended surgical treatment for cases without epithelialization within 4 weeks after the onset of administration of STFX even if bone was not exposed at the lesion. 19 of our 20 cases of Stages 2-3 BRONJ responded to 2-10 weeks of STFX treatment by entering either a remission or healed phase. While surgery was done on thirteen cases, seven others reached such phases without surgery. Every patient had at least one bacterial species that showed resistance to common antibiotics. All species in all patients were susceptible to STFX. Our results indicate that STFX, with or without minor surgery, gives a high probability of controlling infection in BRONJ patients with persistent infection after use of common antibiotics, leading to remission and/or complete healing in 95% of patients.

Copyright © 2014. Published by Elsevier Inc.
PMID 25549869  Bone. 2015 Apr;73:217-22. doi: 10.1016/j.bone.2014.12.0・・・
著者: Gurpreet K Chadha, Azadeh Ahmadieh, Satish Kumar, Parish P Sedghizadeh
雑誌名: J Oral Implantol. 2013 Aug;39(4):510-20. doi: 10.1563/AAID-JOI-D-11-00234.
Abstract/Text Bisphosphonate (BP) drugs are a commonly prescribed group of medications used in the treatment of metabolic and oncologic bone disorders. The aim of this study was to conduct a systematic review in order to evaluate whether patients on BP therapy are appropriate candidates for dental implants as compared to patients not taking BP drugs with respect to successful implant osseointegration and the risk of developing bisphosphonate-related osteonecrosis of the jaw. Based on the current literature, a history of oral or intravenous BP use is not an absolute contraindication for dental implant placement, and dental implants can osseointegrate successfully in this patient population. Importantly, the studies currently available on this topic are of moderate to weak strength of evidence with inherent bias and limitations, and hence results must be interpreted in this context. Well-controlled studies with higher strength of evidence and larger population sizes are required to address this topic more accurately in the future.

PMID 23964780  J Oral Implantol. 2013 Aug;39(4):510-20. doi: 10.1563/A・・・

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