双膦酸盐相关性颌骨坏死

doi:10.7518/hxkq.2017.01.004

摘要/Abstract

摘要：

双膦酸盐类（BPs）药物是一种强有力的骨吸收抑制剂,已广泛应用于临床治疗中。近年来,有关双膦酸盐相关性骨坏死（BRONJ）的报道日渐增多,该病临床上以骨面裸露、死骨形成、疼痛、口臭等为特征。由于目前发病机理不明确,临床上尚无完全有效的治疗方法,因此BRONJ的预防十分重要。本文就BRONJ的发病机制、危险因素、临床特征、治疗预后等方面的研究现状进行阐述,以期为临床提供帮助。

关键词: 双膦酸盐, 颌骨, 骨坏死

Abstract:

Bisphosphonates (BPs), as potent drugs inhibiting bone resorption, have been widely used for treatment of several diseases. In recent years, dentists and oral and maxillofacial surgeons reported continuously increasing cases of bis-phosphonate-related osteonecrosis of the jaws (BRONJ). This disease is clinically characterized by exposed bones, formation of sequestrum, pain, and halitosis. Provided that pathogenesis of BRONJ is unclear, effective treatments for this disease are currently unavailable. Thus, prevention plays an important role in the management of BRONJ. This review summarizes research progress on pathogenesis, risk factors, clinical characteristics, treatment, and prevention of this condition.

Key words: bisphosphonates, jaws, osteonecrosis

中图分类号:

R782.3⁺2

潘剑, 王杞章, 刘济远. 双膦酸盐相关性颌骨坏死[J]. 华西口腔医学杂志, 2017, 35(1): 29-36.

Jian Pan, Qizhang Wang, Jiyuan. Liu. Research progress on bisphosphonate-related osteonecrosis of the jaws[J]. West China Journal of Stomatology, 2017, 35(1): 29-36.

参考文献 60

[1]	赵蕾, 吴亚菲. 双磷酸盐类药物用于牙周炎治疗的研究进展[J]. 牙体牙髓牙周病学杂志, 2006, 16(6):355-359.
	Zhao L, Wu YF.Review of the research of bisphosphonates in the management of periodontitis[J]. Chin J Conserv Dent, 2006, 16(6):355-359.
[2]	Abtahi J, Tengvall P, Aspenberg P.Bisphosphonate coating might improve fixation of dental implants in the maxilla: a pilot study[J]. Int J Oral Maxillofac Surg, 2010, 39(7):673-677.
[3]	Marx RE.Pamidronate(Aredia) and zoledronate(Zometa) induced avascular necrosis of the jaws: a growing epidemic[J]. J Oral Maxillofac Surg, 2003, 61(9):1115-1117.
[4]	Ruggiero SL, Dodson TB, Assael LA, et al.American Asso-ciation of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw—2009 update[J]. Aust Endod, 2009, 35(3):119-130.
[5]	Mcleod NM, Brennan PA, Ruggiero SL.Bisphosphonate osteonecrosis of the jaw: a historical and contemporary review[J]. Surgeon, 2012, 10(1):36-42.
[6]	Fliefel R, Tröltzsch M, Kühnisch J, et al.Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review[J]. Int J Oral Maxillofac Surg, 2015, 44(5):568-585.
[7]	Bonacina R, Mariani U, Villa F, et al.Preventive strategies and clinical implications for bisphosphonate-related osteo-necrosis of the jaw: a review of 282 patients[J]. J Can Dent Assoc, 2011, 77:b147.
[8]	Beninati F, Pruneti R, Ficarra G.Bisphosphonate-related osteonecrosis of the jaws (BRONJ)[J]. Med Oral Patol Oral Cir Bucal, 2013, 18(5):e752-e758.
[9]	Krimmel M, Ripperger J, Hairass M, et al.Does dental and oral health influence the development and course of bisphos-phonate-related osteonecrosis of the jaws (BRONJ)[J]. Oral Maxillofac Surg, 2014, 18(2):213-218.
[10]	Tardast A, Sjöman R, Løes S, et al.Bisphosphonate asso-ciated osteomyelitis of the jaw in patients with bony expo-sure: prevention, a new way of thinking[J]. J Applied Oral Sci, 2015, 23(3):310-314.
[11]	Hinson AM, Smith CW, Siegel ER, et al.Is bisphosphonate-related osteonecrosis of the jaw an infection? A histological and microbiological ten-year summary[J]. Int J Dent, 2014, 2014:452737.
[12]	Nisi M, La Ferla F, Karapetsa D, et al.Risk factors influen-cing BRONJ staging in patients receiving intravenous bis-phosphonates: a multivariate analysis[J]. Int J Oral Maxillo-fac Surg, 2015, 44(5):586-591.
[13]	Kim JH, Ko YJ, Kim JY, et al.Genetic investigation of bisphosphonate-related osteonecrosis of jaw (BRONJ) via whole exome sequencing and bioinformatics[J]. PLoS ONE, 2015, 10(2):e0118084.
[14]	Colucci S, Minielli V, Zambonin G, et al.Alendronate re-duces adhesion of human osteoclast-like cells to bone and bone protein-coated surfaces[J]. Calcif Tissue Int, 1998, 63(3):230-235.
[15]	Fleisch H.Bisphosphonates: mechanisms of action[J]. En-docr Rev, 1998, 97(1):1371-1381.
[16]	Hughes DE, Wright KR, Uy HL, et al.Bisphosphonates pro-mote apoptosis in murine osteoclasts in vitro and in vivo[J]. J Bone Miner Res, 2009, 10(10):1478-1487.
[17]	David P, Nguyen H, Barbier A, et al.The bisphosphonate tiludronate is a potent inhibitor of the osteoclast vacuolar H(+)-ATPase[J]. J Bone Miner Res, 1996, 11(10):1498-1507.
[18]	Viereck V, Emons G, Lauck V, et al.Bisphosphonates pami-dronate and zoledronic acid stimulate osteoprotegerin pro-duction by primary human osteoblasts[J]. Biochem Biophys Res Commun, 2002, 291(3):680-686.
[19]	Mackie PS, Fisher JL, Zhou H, et al.Bisphosphonates regu-late cell growth and gene expression in the UMR 106-01 clonal rat osteosarcoma cell line[J]. Br J Cancer, 2001, 84(7):951-958.
[20]	Rogers MJ, Gordon S, Benford HL, et al.Cellular and mole-cular mechanisms of action of bisphosphonates[J]. Cancer, 2000, 88(S12):2961-2978.
[21]	Niibe K, Ouchi T, Iwasaki R, et al.Osteonecrosis of the jaw in patients with dental prostheses being treated with bisphos-phonates or denosumab[J]. J Prosthodont Res, 2015, 59(1):3-5.
[22]	Stopeck AT, Lipton A, Body JJ, et al.Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study[J]. J Clin Oncol, 2010, 28(35):5132-5139.
[23]	Weinstein RS, Roberson PK, Manolagas SC.Giant osteo-clast formation and long-term oral bisphosphonate therapy[J]. N Engl J Med, 2009, 360(1):53-62.
[24]	Grey A, Reid IR.Differences between the bisphosphonates for the prevention and treatment of osteoporosis[J]. Ther Clin Risk Manag, 2006, 2(1):77-86.
[25]	Petcu EB, Ivanovski S, Wright RG, et al.Bisphosphonate-related osteonecrosis of jaw (BRONJ): an anti-angiogenic side-effect[J]. Diagn Pathol, 2012, 7(1):78.
[26]	Tang X, Zhang Q, Shi S, et al.Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha/VEGF signaling pathways in human breast can-cer cells[J]. Int J Cancer, 2010, 126(1):90-103.
[27]	Ferretti G, Fabi A, Carlini P, et al.Zoledronic-acid-induced circulating level modifications of angiogenic factors, metal-loproteinases and proinflammatory cytokines in metastatic breast cancer patients[J]. Oncology, 2005, 69(1):35-43.
[28]	Giraudo E, Inoue M, Hanahan D.An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis[J]. J Clin Invest, 2004, 114(5):623-633.
[29]	Wood J, Bonjean K, Ruetz S, et al.Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid[J]. J Pharmacol Exp Ther, 2002, 302(3):1055-1061.
[30]	Tsurushima H, Kokuryo S, Sakaguchi O, et al.Bacterial promotion of bisphosphonate-induced osteonecrosis in Wis-tar rats[J]. Int J Oral Maxillofac Surg, 2013, 42(11):1481-1487.
[31]	Wei X, Pushalkar S, Estilo C, et al.Molecular profiling of oral microbiota in jawbone samples of bisphosphonate-related osteonecrosis of the jaw[J]. Oral Dis, 2012, 18(6):602-612.
[32]	Rasmusson L, Abtahi J.Bisphosphonate associated osteo-necrosis of the jaw: an update on pathophysiology, risk fac-tors, and treatment[J]. Int J Dent, 2014, 2014:471035.
[33]	Pigrau-Serrallach C, Cabral-Galeano E, Almirante-Gragera B, et al.Long-term follow-up of jaw osteomyelitis associated with bisphosphonate use in a tertiary-care center[J]. Enferm Infecc Microbiol Clin, 2014, 32(1):18-22.
[34]	Anavi-Lev K, Anavi Y, Chaushu G, et al.Bisphosphonate related osteonecrosis of the jaws: clinico-pathological in-vestigation and histomorphometric analysis[J]. Oral Surg Oral Med Oral Pathol Oral Radiol, 2013, 115(5):660-666.
[35]	De Ceulaer J, Tacconelli E, Vandecasteele SJ.Actinomyces osteomyelitis in bisphosphonate-related osteonecrosis of the jaw (BRONJ): the missing link[J]. Eur J Clin Microbiol Infect Dis, 2014, 33(11):1873-1880.
[36]	Bagan JV, Jimenez Y, Murillo J, et al.Jaw osteonecrosis associated with bisphosphonates: multiple exposed areas and its relationship to teeth extractions. Study of 20 cases[J]. Oral Oncol, 2006, 42(3):327-329.
[37]	Pichardo SE, Van Merkesteyn JP.Bisphosphonate related osteonecrosis of the jaws: spontaneous or dental origin[J]. Oral Surg Oral Med Oral Pathol Oral Radiol, 2013, 116(3): 287-292.
[38]	Kalyan S, Wang J, Quabius ES, et al.Systemic immunity shapes the oral microbiome and susceptibility to bisphos-phonate-associated osteonecrosis of the jaw[J]. J Transl Med, 2015, 13(1):1-13.
[39]	Wolf AM, Rumpold H, Tilg H, et al.The effect of zole-dronic acid on the function and differentiation of myeloid cells[J]. Haematologica, 2006, 91(9):1165-1171.
[40]	Reid IR, Bolland MJ, Grey AB.Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity[J]. Bone, 2007, 41(3):318-320.
[41]	Reid IR.Osteonecrosis of the jaw: who gets it, and why[J]. Bone, 2009, 44(1):4-10.
[42]	Ikeda T, Kuraguchi J, Kogashiwa Y, et al.Successful treat-ment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) patients with sitafloxacin: new strategies for the treatment of BRONJ[J]. Bone, 2015, 73:217-222.
[43]	宋爱梅, 杨丕山, 吕春旭, 等. 以多发弥漫性牙周脓肿为表现的二膦酸盐相关颌骨坏死一例[J]. 中华口腔医学杂志, 2015, 50(3):164-166.
	Song AM, Yang PS, Lü CX, et al.Bisphosphonate related osteonecrosis of the jaw (BRONJ) -one case report patients with multiple diffuse periodontal abscess[J]. Chin J Stomatol, 2015, 50(3):164-166.
[44]	Mishima S, Takahashi K, Tomioka T, et al.Numb chin syn-drome as initial manifestation of bisphosphonate-related osteomyelitis of the jaw and methotrexate-associated lym-phoproliferative disorders: a rare case[J]. Br J Oral Maxil-lofac Surg, 2016, 54(1):114-115.
[45]	Khosla S, Burr D, Cauley J, et al.Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the Ame-rican Society for Bone and Mineral Research[J]. J Bone Miner Res, 2007, 22(10):1479-1491.
[46]	Chiandussi S, Biasotto M, Dore F, et al.Clinical and diag-nostic imaging of bisphosphonate-associated osteonecrosis of the jaws[J]. Dentomaxillofac Radiol, 2006, 35(4):236-243.
[47]	Phal PM, Myall RW, Assael LA, et al.Imaging findings of bisphosphonate-associated osteonecrosis of the jaws[J]. AJNR Am J Neuroradiol, 2007, 28(6):1139-1145.
[48]	Hansen T, Kunkel M, Weber A, et al.Osteonecrosis of the jaws in patients treated with bisphosphonates-histomorpho-logic analysis in comparison with infected osteoradionecrosis[J]. J Oral Pathol Med, 2006, 35(3):155-160.
[49]	Hansen T, Kunkel M, Springer E, et al.Actinomycosis of the jaws-histopathological study of 45 patients shows sig-nificant involvement in bisphosphonate-associated osteone-crosis and infected osteoradionecrosis[J]. Virchows Arch, 2007, 451(6):1009-1017.
[50]	Marx RE, Tursun R.Suppurative osteomyelitis, bisphospho-nate induced osteonecrosis, osteoradionecrosis: a blinded histopathologic comparison and its implications for the me-chanism of each disease[J]. Int J Oral Maxillofac Surg, 2012, 41(3):283-289.
[51]	Alons K, Kuijpers SC, de Jong E, et al. Treating low- and medium-potency bisphosphonate-related osteonecrosis of the jaws with a protocol for the treatment of chronic suppu-rative osteomyelitis: report of 7 cases[J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2009, 107(2):e1-e7.
[52]	Vescovi P, Merigo E, Meleti M, et al.Bisphosphonate-asso-ciated osteonecrosis (BON) of the jaws: a possible treatment[J]. J Oral Maxillofac Surg, 2006, 64(9):1460-1462.
[53]	Ruggiero SL, Dodson TB, Fantasia J, et al.American Asso-ciation of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw-2014 update[J]. J Oral Maxillofac Surg, 2014, 72(10):1938-1956.
[54]	Van den Wyngaert T, Claeys T, Huizing MT, et al. Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of out-come[J]. Ann Oncol, 2009, 20(2):331-336.
[55]	Holzinger D, Seemann R, Klug C, et al.Long-term success of surgery in bisphosphonate-related osteonecrosis of the jaws (BRONJs)[J]. Oral Oncol, 2013, 49(1):66-70.
[56]	Freiberger JJ.Utility of hyperbaric oxygen in treatment of bisphosphonate-related osteonecrosis of the jaws[J]. J Oral Maxillofac Surg, 2009, 67(5 Suppl):96-106.
[57]	Boykin JV Jr, Baylis C.Hyperbaric oxygen therapy mediates increased nitric oxide production associated with wound healing: a preliminary study[J]. Adv Skin Wound Care, 2007, 20(7):382-388.
[58]	Scoletta M, Arduino PG, Reggio L, et al.Effect of low-level laser irradiation on bisphosphonate-induced osteonecrosis of the jaws: preliminary results of a prospective study[J]. Photomed Laser Surg, 2010, 28(2):179-184.
[59]	Ruggiero SL, Fantasia J, Carlson E.Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diag-nosis, staging and management[J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2006, 102(4):433-441.
[60]	Abtahi J, Agholme F, Aspenberg P.Prevention of osteone-crosis of the jaw by mucoperiosteal coverage in a rat model[J]. Int J Oral Maxillofac Surg, 2013, 42(5):632-636.