国际口腔医学杂志 ›› 2017, Vol. 44 ›› Issue (2): 228-234.doi: 10.7518/gjkq.2017.02.023

• 综述 • 上一篇    下一篇

药物相关性颌骨坏死的研究进展

苏程,王泽坤,骆南羽,唐华   

  1. 口腔疾病研究国家重点实验室 华西口腔医院种植科(四川大学)成都 610041
  • 收稿日期:2016-03-10 出版日期:2017-03-01 发布日期:2017-03-01
  • 通讯作者: 唐华,副主任医师,博士,Email:8307873@qq.com
  • 作者简介:苏程,学士,Email:2927686124@qq.com
  • 基金资助:
    国际口腔种植学会基金(973_2014)

Research progress on medication-related osteonecrosis of the jaw

Su Cheng, Wang Zekun, Luo Nanyu, Tang Hua.   

  1. State Key Laboratory of Oral Diseases, Dept. of Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
  • Received:2016-03-10 Online:2017-03-01 Published:2017-03-01
  • Supported by:
    This study was supported by International Team of Implantology Research Foundation(973_2014).

摘要: 随着抗骨吸收和抗血管生成药物的不断使用,药物相关性颌骨坏死作为一种较严重的不良反应受到广泛关注。药物相关性颌骨坏死属于多因素影响的疾病,危险因素众多,在一般人群中的年发病率大致为每年1×10-5。目前存在多种假说解释有关机制。双膦酸盐和狄诺塞麦能抑制破骨细胞的分化及功能,促进破骨细胞凋亡,使骨吸收及骨重建减少。双膦酸盐的抗血管生成作用降低了颌骨区域血供,同时抑制了机体的免疫功能。口腔局部的菌群还会进一步加重组织损伤和减少血管生成。除此之外,双膦酸盐对口腔黏膜细胞的直接作用和颌骨的解剖结构都对骨坏死的发展有一定的作用。患者的治疗措施因患病情况存在差异,但均以减轻痛苦、控制软硬组织感染、延缓或停止骨坏死进程为主。本文就药物相关性颌骨坏死的危险因素、相关机制、分期以及预防治疗策略作一综述。

关键词: 双膦酸盐, 颌骨坏死, 病因学, 预防, 治疗

Abstract: Given the use of anti-resorptive and antiangiogenic drugs, medication-related osteonecrosis of the jaw (MRONJ) has gained wide attention as a severe side effect. MRONJ is a multifactorial disease with a number of risk factors. The population incidence of BRONJ is approximately 1×10-5 per year. Many hypotheses are proposed to explain the mechanism. Bisphosphonates and denosumab inhibit osteoclast differentiation and function and increase apoptosis, which lead to decreased bone resorption and remodeling. Bisphosphonates reduce the blood supply to the jaw area and has immuno-suppressive effects. Oral local flora can also aggravate the damage of tissues and reduce angiogenesis. The direct effect of bisphosphonates on oral mucosa cells and the anatomy of the jaw have a role on the development of osteonecrosis. According to sickness status, treatment Methods are different but are focused on reducing pain, treating soft and hard tissue infections, and delaying or stopping the process of osteonecrosis. This article reviewed the risk factors, relevant mechanisms, and prevention and treatment strategies.

Key words: bisphosphonates, osteonecrosis of the jaw, etiology, prevention, treatment

中图分类号: 

  • R782.1
[1] Brown JE, Coleman RE. The present and future role of bisphosphonates in the management of patients with breast cancer[J]. Breast Cancer Res, 2002, 4(1): 24-29.
[2] Marx RE. Pamidronate(Aredia) and zoledronate(Zo-meta) induced avascular necrosis of the jaws: a gro-wing epidemic[J]. J Oral Maxillofac Surg, 2003, 61 (9):1115-1117.
[3] Colella G, Campisi G, Fusco V. American Asso-ciation of Oral and Maxillofacial Surgeons position paper: bisphosphonate-related osteonecrosis of the jaws-2009 update: the need to refine the BRONJ definition[J]. J Oral Maxillofac Surg, 2009, 67(12): 2698-2699.
[4] Pelaz A, Junquera L, Gallego L, et al. Epidemiology, pharmacology and clinical characterization of bis-phosphonate-related osteonecrosis of the jaw. A re-trospective study of 70 cases[J]. Acta Otorrinolarin-gol Esp, 2015, 66(3):139-147.
[5] Rogers SN, Palmer NO, Lowe D, et al. United Kingdom nationwide study of avascular necrosis of the jaws including bisphosphonate-related necrosis[J]. Br J Oral Maxillofac Surg, 2015, 53(2):176-182.
[6] American Dental Association Council on Scientific Affairs. Dental management of patients receiving oral bisphosphonate therapy: expert panel recommenda-tions[J]. J Am Dent Assoc, 2006, 137(8):1144-1150.
[7] Günaldi M, Afsar CU, Duman BB, et al. Effect of the cumulative dose of zoledronic acid on the pathoge-nesis of osteonecrosis of the jaws[J]. Oncol Lett, 2015, 10(1):439-442.
[8] Kos M. Incidence and risk predictors for osteone-crosis of the jaw in cancer patients treated with in-travenous bisphosphonates[J]. Arch Med Sci, 2015, 11(2):319-324.
[9] Nisi M, La Ferla F, Karapetsa D, et al. Risk factors influencing BRONJ staging in patients receiving intravenous bisphosphonates: a multivariate analysis [J]. Int J Oral Maxillofac Surg, 2015, 44(5):586-591.
[10] Hutcheson A, Cheng A, Kunchar R, et al. A C-terminal crosslinking telopeptide test-based protocol for pa-tients on oral bisphosphonates requiring extraction: a prospective single-center controlled study[J]. J Oral Maxillofac Surg, 2014, 72(8):1456-1462.
[11] Ristow O, Gerngroß C, Schwaiger M, et al. Is bone turnover of jawbone and its possible over suppression by bisphosphonates of etiologic importance in patho-genesis of bisphosphonate-related osteonecrosis[J]. J Oral Maxillofac Surg, 2014, 72(5):903-910.
[12] Thumbigere-Math V, Michalowicz BS, Hodges JS, et al. Periodontal disease as a risk factor for bisphos-phonate-related osteonecrosis of the jaw[J]. J Perio-dontol, 2014, 85(2):226-233.
[13] Vaszilko M, Kovacs E, Restar L, et al. Potential significance of antiestrogen therapy in the develop-ment of bisphosphonate related osteonecrosis of the jaw[J]. J Craniomaxillofac Surg, 2014, 42(8):1932- 1936.
[14] Huang YF, Chang CT, Muo CH, et al. Impact of bisphosphonate-related osteonecrosis of the jaw on osteoporotic patients after dental extraction: a popula-tion-based cohort study[J]. PLoS One, 2015, 10(4):e0120756.
[15] Smidt-Hansen T, Folkmar TB, Fode K, et al. Com-bination of zoledronic acid and targeted therapy is active but may induce osteonecrosis of the jaw in patients with metastatic renal cell carcinoma[J]. J Oral Maxillofac Surg, 2013, 71(9):1532-1540.
[16] Ogata K, Katagiri W, Osugi M, et al. Evaluation of the therapeutic effects of conditioned media from mesenchymal stem cells in a rat bisphosphonate-related osteonecrosis of the jaw-like model[J]. Bone, 2015, 74:95-105.
[17] Hokugo A, Christensen R, Chung EM, et al. Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats[J]. J Bone Miner Res, 2010, 25(6):1337-1349.
[18] Salino S, Bodard AG, Gourmet R. Bisphosphonate-related osteonecrosis of the jaw: clinical series(45 patients)[J]. Oral Oncol Suppl, 2009, 3(1):137-138.
[19] Melea PI, Melakopoulos I, Kastritis E, et al. Con-servative treatment of bisphosphonate-related os-teonecrosis of the jaw in multiple myeloma patients [J]. Int J Dent, 2014, 2014:427273.
[20] Katz J, Gong Y, Salmasinia D, et al. Genetic poly-morphisms and other risk factors associated with bisphosphonate induced osteonecrosis of the jaw[J]. Int J Oral Maxillofac Surg, 2011, 40(6):605-611.
[21] Aghaloo TL, Cheong S, Bezouglaia O, et al. RANKL inhibitors induce osteonecrosis of the jaw in mice with periapical disease[J]. J Bone Miner Res, 2014, 29(4):843-854.
[22] van Beek ER, Cohen LH, Leroy IM, et al. Differen-tiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates[J]. Bone, 2003, 33(5):805-811.
[23] Rogers MJ, Crockett JC, Coxon FP, et al. Bio-chemical and molecular mechanisms of action of bisphosphonates[J]. Bone, 2011, 49(1):34-41.
[24] Cheong S, Sun S, Kang B, et al. Bisphosphonate uptake in areas of tooth extraction or periapical disease[J]. J Oral Maxillofac Surg, 2014, 72(12): 2461-2468.
[25] Pichardo SE, Kuypers SC, van Merkesteyn JP. Deno-sumab osteonecrosis of the mandible: a new entity? A case report[J]. J Craniomaxillofac Surg, 2013, 41(4):e65-e69.
[26] Malan J, Ettinger K, Naumann E, et al. The relationship of denosumab pharmacology and osteonecrosis of the jaws[J]. Oral Surg Oral Med Oral Pathol Oral Radiol, 2012, 114(6):671-676.
[27] Pabst AM, Ziebart T, Ackermann M, et al. Bisphos-phonates’ antiangiogenic potency in the development of bisphosphonate-associated osteonecrosis of the jaws: influence on microvessel sprouting in an in vivo 3D Matrigel assay[J]. Clin Oral Invest, 2014, 18(3): 1015-1022.
[28] Misso G, Porru M, Stoppacciaro A, et al. Evaluation of the in vitro and in vivo antiangiogenic effects of denosumab and zoledronic acid[J]. Cancer Biol Ther, 2012(14):1491-1500.
[29] Daniele S, Bruno V, Giordano D, et al. Zoledronic acid induces significant and long-lasting modifica-tions of circulating angiogenic factors in cancer pa-tients[J]. Clin Cancer Res, 2003(8):2893-2897.
[30] Borke JL, McAllister B, Harris T, et al. Correlation of changes in the mandible and retina/choroid vas-culature of a rat model of BRONJ[J]. J Cranioma-xillofac Surg, 2015, 43(7):1144-1150.
[31] Santos-Silva AR, Belizário Rosa GA, Castro Júnior GD, et al. Osteonecrosis of the mandible associated with bevacizumab therapy[J]. Oral Surg Oral Med Oral Pathol Oral Radiol, 2013, 115(6):e32-e36.
[32] Koch FP, Walter C, Hansen T, et al. Osteonecrosis of the jaw related to sunitinib[J]. Oral Maxillofac Surg, 2011, 15(1):63-66.
[33] Otto S, Tröltzsch M, Jambrovic V, et al. Tooth ex-traction in patients receiving oral or intravenous bis-phosphonate administration: a trigger for BRONJ development[J]. J Craniomaxillofac Surg, 2015, 43 (6):847-854.
[34] Sakaguchi O, Kokuryo S, Tsurushima H, et al. Lipo-polysaccharide aggravates bisphosphonate-induced osteonecrosis in rats[J]. Int J Oral Maxillofac Surg, 2015(4):528-534.
[35] López-Jornet P, Camacho-Alonso F, Martínez-Ca-novas A, et al. Perioperative antibiotic regimen in rats treated with pamidronate plus dexamethasone and subjected to dental extraction: a study of the changes in the jaws[J]. J Oral Maxillofac Surg, 2011, 69(10): 2488-2493.
[36] Otto S, Pautke C, Opelz C, et al. Osteonecrosis of the jaw: effect of bisphosphonate type, local concentra-tion, and acidic milieu on the pathomechanism[J]. J Oral Maxillofac Surg, 2010, 68(11):2837-2845.
[37] Aguirre JI, Akhter MP, Kimmel DB, et al. Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats(Oryzomys palustris) with periodontitis[J]. J Bone Miner Res, 2012, 27(10): 2130-2143.
[38] Hoefert S, Schmitz I, Weichert F, et al. Macrophages and bisphosphonate-related osteonecrosis of the jaw (BRONJ): evidence of local immunosuppression of macrophages in contrast to other infectious jaw diseases[J]. Clin Oral Invest, 2014, 19(2):497-508.
[39] Pushalkar S, Li X, Kurago Z, et al. Oral microbiota and host innate immune response in bisphosphonate-related osteonecrosis of the jaw[J]. Int J Oral Sci, 2014, 6(4):219-226.
[40] Scheper MA, Badros A, Chaisuparat R, et al. Effect of zoledronic acid on oral fibroblasts and epithelial cells: a potential mechanism of bisphosphonate-as-sociated osteonecrosis[J]. Br J Haematol, 2009, 144 (5):667-676.
[41] Ohnuki H, Izumi K, Terada M, et al. Zoledronic acid induces S-phase arrest via a DNA damage response in normal human oral keratinocytes[J]. Arch Oral Biol, 2012, 57(7):906-917.
[42] Kim RH, Lee RS, Williams D, et al. Bisphosphonates induce senescence in normal human oral keratino-cytes[J]. J Dent Res, 2011, 90(6):810-816.
[43] Çankaya M, Cizmeci Şenel F, Kadioglu Duman M, et al. The effects of chronic zoledronate usage on the jaw and long bones evaluated using RANKL and osteoprotegerin levels in an animal model[J]. Int J Oral Maxillofac Surg, 2013, 42(9):1134-1139.
[44] Bauss F, Pfister T, Papapoulos S. Ibandronate uptake in the jaw is similar to long bones and vertebrae in the rat[J]. J Bone Miner Metab, 2008, 26(4):406-408.
[45] Ristow O, Otto S, Troeltzsch M, et al. Treatment per-spectives for medication-related osteonecrosis of the jaw(MRONJ)[J]. J Craniomaxillofac Surg, 2015, 43 (2):290-293.
[46] Freiberger JJ, Padilla-Burgos R, McGraw T, et al. What is the role of hyperbaric oxygen in the manage-ment of bisphosphonate-related osteonecrosis of the jaw: a randomized controlled trial of hyperbaric oxy-gen as an adjunct to surgery and antibiotics[J]. J Oral Maxillofac Surg, 2012, 70(7):1573-1583.
[47] Kim KM, Park W, Oh SY, et al. Distinctive role of 6-month teriparatide treatment on intractable bispho-sphonate-related osteonecrosis of the jaw[J]. Osteopo-ros Int, 2014, 25(5):1625-1632.
[48] Ikeda T, Kuraguchi J, Kogashiwa Y, et al. Successful treatment of bisphosphonate-related osteonecrosis of the jaw(BRONJ) patients with sitafloxacin: new stra-tegies for the treatment of BRONJ[J]. Bone, 2015, 73:217-222.
[49] Marcuzzi A, Tommasini A, Crovella S, et al. Natural isoprenoids inhibit LPS-induced-production of cyto-kines and nitric oxide in aminobisphosphonate-treated monocytes[J]. Int Immunopharmacol, 2010, 10(6): 639-642.
[50] Ziebart T, Koch F, Klein MO, et al. Geranylgeraniol— a new potential therapeutic approach to bisphos-phonate associated osteonecrosis of the jaw[J]. Oral Oncol, 2011, 47(3):195-201.
[51] Barba-Recreo P, Del Castillo Pardo de Vera JL, Georgiev-Hristov T, et al. Adipose-derived stem cells and platelet-rich plasma for preventive treatment of bisphosphonate-related osteonecrosis of the jaw in a murine model[J]. J Craniomaxillofac Surg, 2015, 43 (7):1161-1168.
[52] Eduardo A, Mar Z, María T, et al. PRGF exerts a cyto-protective role in zoledronic acid-treated oral cells[J]. Clin Oral Invest, 2016(3):513-521.
[53] Torres S, Chen C, Leroux B, et al. Fractal dimension evaluation of cone beam computed tomography in patients with bisphosphonate-associated osteonecrosis [J]. Dentomaxillofac Rad, 2011, 40(8):501-505.
[54] Chiandussi S, Biasotto M, Dore F, et al. Clinical and diagnostic imaging of bisphosphonate-associated osteonecrosis of the jaws[J]. Dentomaxillofac Radiol, 2006, 35(4):236-243.
[55] Hamada H, Matsuo A, Koizumi T, et al. A simple evaluation method for early detection of bispho-sphonate-related osteonecrosis of the mandible using computed tomography[J]. J Craniomaxillofac Surg, 2014, 42(6):924-929.
[56] Agaçayak KS, Yuksel H, Atilgan S, et al. Experimen-tal investigation of relationship between trauma and bisphosphonate-related osteonecrosis[J]. Niger J Clin Pract, 2014, 17(5):559-564.
[57] Sparabombe S, Vitali L, Nori A, et al. Risk assess-ment of BRONJ in oncologic patients treated with bisphosphonates: follow-up to 18 months[J]. Int J Dent, 2014, 2014:475859.
[58] Heufelder MJ, Hendricks J, Remmerbach T, et al. Principles of oral surgery for prevention of bispho-sphonate-related osteonecrosis of the jaw[J]. Oral Surg Oral Med Oral Pathol Oral Radiol, 2014, 117(6):e429-e435.
[59] Dayisoylu EH, Üngör C, Tosun E, et al. Does an alkaline environment prevent the development of bisphosphonate-related osteonecrosis of the jaw? An experimental study in rats[J]. Oral Surg Oral Med Oral Pathol Oral Radiol, 2014, 117(3):329-334.
[60] Goodday RH. Preventive strategies for patients at risk of medication-related osteonecrosis of the jaw[J]. Oral Maxillofac Surg Clin North Am, 2015, 27(4): 527-536.
[61] Hellstein JW, Adler RA, Edwards B, et al. Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: execu-tive summary of recommendations from the American Dental Association Council on Scientific Affairs[J]. J Am Dent Assoc, 2011, 142(11):1243-1251.
[62] Borges C, Spivakovsky S. Adjusted protocol for dental extractions in oncology patients taking anti-resorptive drugs may reduce occurrence of medica-tion-related osteonecrosis of the jaw[J]. Evid Based Dent, 2016, 17(1):14-15.
[63] Madrid C, Bouferrache K, Abarca M, et al. Bisphos-phonate-related osteonecrosis of the jaws: how to manage cancer patients[J]. Oral Oncol, 2010, 46(6): 468-470.
[1] 刘世一, 陈中, 张素欣. 程序性死亡受体/配体免疫治疗策略在人乳头瘤病毒阳性头颈部鳞状细胞癌中的研究进展[J]. 国际口腔医学杂志, 2024, 51(1): 21-27.
[2] 和子慕, 李风兰. 数字化口腔定位支架在头颈部肿瘤放射治疗中的应用现状[J]. 国际口腔医学杂志, 2024, 51(1): 28-35.
[3] 傅豫, 何薇, 黄兰. 铁死亡在口腔疾病中的研究进展[J]. 国际口腔医学杂志, 2024, 51(1): 36-44.
[4] 韩冲,何东宁,余飞燕,吴东潮. 口腔种植术后疼痛机制及治疗的研究进展[J]. 国际口腔医学杂志, 2024, 51(1): 99-106.
[5] 胡佳,王秀清,卢国英,黄晓晶. 再生性牙髓治疗在成人根尖发育不全恒牙应用的研究进展[J]. 国际口腔医学杂志, 2023, 50(6): 686-695.
[6] 陆磊,王鑫,康泽标,谢富强. 计算机辅助导航手术在复杂颌面部骨折中的应用新进展[J]. 国际口腔医学杂志, 2023, 50(6): 696-703.
[7] 杨冬叶,朱萍,吴淑仪. 舌位的影响因素及临床意义[J]. 国际口腔医学杂志, 2023, 50(6): 723-728.
[8] 戢晓,张岚,黄定明. 牙源性与非牙源性上颌窦炎鉴别诊断及其治疗方案的研究进展[J]. 国际口腔医学杂志, 2023, 50(5): 566-572.
[9] 赵苑汐,苏勤. 根管再治疗中根管充填物去除辅助技术的应用与发展[J]. 国际口腔医学杂志, 2023, 50(5): 581-586.
[10] 宋文鹏,龚蓓文,李聃,曾剑玉,仇玲玲. 机械疗法在正畸治疗中应用的研究进展[J]. 国际口腔医学杂志, 2023, 50(5): 603-612.
[11] 刘婷,武秀萍. 唐氏综合征的口腔-颅颌面表征及治疗进展[J]. 国际口腔医学杂志, 2023, 50(5): 618-622.
[12] 吴思佳,舒畅,王洋,王媛,邓淑丽,王慧明. 根管内感染控制对年轻恒牙牙髓再生治疗的影响及研究进展[J]. 国际口腔医学杂志, 2023, 50(4): 388-394.
[13] 高宇天,苏勤. 酸性氧化电位水在根管治疗中的研究与应用[J]. 国际口腔医学杂志, 2023, 50(4): 401-406.
[14] 范琳,孙江. 微针在口腔医学中的应用[J]. 国际口腔医学杂志, 2023, 50(4): 472-478.
[15] 陈卓,石冰,李精韬. 唇腭裂患者外鼻生长特征的研究进展[J]. 国际口腔医学杂志, 2023, 50(3): 279-286.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
[1] 张新春. 桩冠修复与无髓牙的保护[J]. 国际口腔医学杂志, 1999, 26(06): .
[2] 王昆润. 长期单侧鼻呼吸对头颅发育有不利影响[J]. 国际口腔医学杂志, 1999, 26(05): .
[3] 彭国光. 颈淋巴清扫术中颈交感神经干的解剖变异[J]. 国际口腔医学杂志, 1999, 26(05): .
[4] 杨凯. 淋巴化疗的药物运载系统及其应用现状[J]. 国际口腔医学杂志, 1999, 26(05): .
[5] 康非吾. 种植义齿下部结构生物力学研究进展[J]. 国际口腔医学杂志, 1999, 26(05): .
[6] 柴枫. 可摘局部义齿用Co-Cr合金的激光焊接[J]. 国际口腔医学杂志, 1999, 26(04): .
[7] 孟姝,吴亚菲,杨禾. 伴放线放线杆菌产生的细胞致死膨胀毒素及其与牙周病的关系[J]. 国际口腔医学杂志, 2005, 32(06): 458 -460 .
[8] 费晓露,丁一,徐屹. 牙周可疑致病菌对口腔黏膜上皮的粘附和侵入[J]. 国际口腔医学杂志, 2005, 32(06): 452 -454 .
[9] 赵兴福,黄晓晶. 变形链球菌蛋白组学研究进展[J]. 国际口腔医学杂志, 2008, 35(S1): .
[10] 庞莉苹,姚江武. 抛光和上釉对陶瓷表面粗糙度、挠曲强度及磨损性能的影响[J]. 国际口腔医学杂志, 2008, 35(S1): .