药物相关性颌骨坏死的发病机制及其防治

doi:10.7518/hxkq.2021.03.001

华西口腔医学杂志 ›› 2021, Vol. 39 ›› Issue (3): 245-254.doi: 10.7518/hxkq.2021.03.001

• 专家论坛 •

药物相关性颌骨坏死的发病机制及其防治

潘剑(), 刘济远

口腔疾病研究国家重点实验室国家口腔疾病临床医学研究中心四川大学华西口腔医院口腔颌面外科，成都 610041

收稿日期:2020-09-02 修回日期:2021-04-08 出版日期:2021-06-01 发布日期:2021-05-26
通讯作者: 潘剑 E-mail:jianpancn@163.com
作者简介:潘剑，教授，博士研究生导师，医学博士，四川大学华西口腔医院口腔外科主任。国际牙医师学院委员（FICD）、中华口腔医学会牙及牙槽外科专委会副主任委员，口腔颌面外科专委会委员，四川省卫生健康委员会学术和技术带头人，四川省口腔医学会牙及牙槽外科专委会主任委员，口腔颌面外科专委会副主任委员，口腔全科专委会及口腔装备委员会常委，四川省医学会口腔专委会委员，四川省抗癌协会头颈肿瘤专委会委员。担任《华西口腔医学杂志》和《国际口腔医学杂志》常务编委，《中国口腔颌面外科杂志》编委。主持国家自然基金和省部级基金12项，发表学术论文80余篇，参编专著16部。从事口腔颌面外科临床、科研、教学与管理工作20余年。
基金资助:
四川省科技计划项目(2020YFS0182);四川大学华西口腔医院临床研究项目(LCYJ2019-1)

Mechanism, prevention, and treatment for medication-related osteonecrosis of the jaws

Pan Jian(), Liu Jiyuan

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China

Received:2020-09-02 Revised:2021-04-08 Online:2021-06-01 Published:2021-05-26
Contact: Pan Jian E-mail:jianpancn@163.com
Supported by:
Science and Technology Program of Sichuan Province(2020YFS0182);Clinical Research Program of West China Hospital of Stomatology, Sichuan University(LCYJ2019-1)

摘要/Abstract

摘要：

药物相关性颌骨坏死（MRONJ）近年来发病率不断增高，目前认为其机制可能为骨重建抑制学说、血管生成抑制学说、口腔微生物感染学说、免疫抑制学说、细胞毒性、颌骨微裂纹形成及单核苷酸多态性等，但基于单机制进行防治效果均不理想。药物治疗前规范的口腔检查及相关疾病预处理，药物治疗期间定期口腔随访对MRONJ的预防具有重要意义。在MRONJ治疗过程中，准确判断其分期，根据指南进行标准化治疗的同时，也需考虑患者具体情况，进行个性化调整。本文将国内外最新相关研究及指南和四川大学华西口腔医院口腔颌面外科近年来对MRONJ诊治经验相结合，对其发病机制及防治策略展开阐述和讨论，供同行参考。

关键词: 药物相关性颌骨坏死, 机制, 预防, 诊断, 治疗

Abstract:

The morbidity rate of medication-related osteonecrosis of the jaws (MRONJ) increased rapidly in recent years. Thusfar, the mechanism of MRONJ has no consensus. The possible mechanisms may include bone remodeling inhibition theory, angiogenesis inhibition theory, oral microorganism infection theory, immunosuppression theory, cytotoxicity-targeted oral epithelial cells, microcrack formation of maxillary or mandibular bone, and single nucleotide polymorphism. However, the efficacy of prevention and treatment based on a single mechanism is not ideal. Routine oral examination before MRONJ-related drug treatment, treatment of related dental diseases, and regular oral follow-up during drug treatment are of great significance for the prevention of MRONJ. During the treatment of MRONJ, the stage of MRONJ must be determined accurately, treatment must be standardized in accordance with the guidelines, and personalized adjustments must be made considering the specific conditions of patients. This review aimed to combine the latest research and guidelines for MRONJ and the experiences on the treatment of MRONJ in the Maxillofacial Surgery Department of West China Hospital of Stomatology, Sichuan University, and discuss the strategies to improve the clinical process.

Key words: medication-related osteonecrosis of the jaws, mechanism, prevention, diagnosis, treatment

中图分类号:

R 782.3⁺2

潘剑, 刘济远. 药物相关性颌骨坏死的发病机制及其防治[J]. 华西口腔医学杂志, 2021, 39(3): 245-254.

Pan Jian, Liu Jiyuan. Mechanism, prevention, and treatment for medication-related osteonecrosis of the jaws[J]. West China Journal of Stomatology, 2021, 39(3): 245-254.

图/表 6

图 1

表 1

表 2

图 2

图 3

图 4

参考文献 49

1	Russell RG. Bisphosphonates: the first 40 years[J]. Bone, 2011, 49(1): 2-19.
2	Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws[J]. J Oral Maxillofac Surg, 2007, 65(3): 369-376.
3	Ruggiero SL, Dodson TB, Fantasia J, et al. American Association 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.
4	Wang Q, Liu J, Qi S, et al. Clinical analysis of medication related osteonecrosis of the jaws: a growing severe complication in China[J]. J Dent Sci, 2018, 13(3): 190-197.
5	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.
	Pan J, Wang QZ, Liu JY. Research progress on bisphosphonate-related osteonecrosis of the jaws[J]. West China J Stomatol, 2017, 35(1): 29-36.
6	Rogers MJ, Gordon S, Benford HL, et al. Cellular and molecular mechanisms of action of bisphosphonates[J]. Cancer, 2000, 88(12): 2961-2978.
7	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.
8	Fleisch H. Bisphosphonates: mechanisms of action[J]. Endocr Rev, 1998, 19(1): 80-100.
9	Weinstein RS, Roberson PK, Manolagas SC. Giant osteoclast formation and long-term oral bisphosphonate the-rapy[J]. N Engl J Med, 2009, 360(1): 53-62.
10	Córdova LA, Guilbaud F, Amiaud J, et al. Severe compromise of preosteoblasts in a surgical mouse model of bisphosphonate-associated osteonecrosis of the jaw[J]. J Craniomaxillofac Surg, 2016, 44(9): 1387-1394.
11	Hattner R, Epker BN, Frost HM. Suggested sequential mode of control of changes in cell behaviour in adult bone remodelling[J]. Nature, 1965, 206(983): 489-490.
12	Shimizu E, Tamasi J, Partridge NC. Alendronate affects osteoblast functions by crosstalk through EphrinB1-EphB[J]. J Dent Res, 2012, 91(3): 268-274.
13	Ziebart T, Koch F, Klein MO, et al. Geranylgeraniol-a new potential therapeutic approach to bisphosphonate associated osteonecrosis of the jaw[J]. Oral Oncol, 2011, 47(3): 195-201.
14	Pabst AM, Krüger M, Ziebart T, et al. Isoprenoid geranylgeraniol: the influence on cell characteristics of endothelial progenitor cells after bisphosphonate therapy in vitro[J]. Clin Oral Investig, 2015, 19(7): 1625-1633.
15	Pabst AM, Krüger M, Blatt S, et al. Angiogenesis in the development of medication-related osteonecrosis of the jaws: an overview[J]. Dent J (Basel), 2016, 5(1): 2.
16	Pabst AM, Krüger M, Sagheb K, et al. The influence of geranylgeraniol on microvessel sprouting after bisphosphonate substitution in an in vitro 3D-angiogenesis assay[J]. Clin Oral Investig, 2017, 21(3): 771-778.
17	Lang M, Zhou Z, Shi L, et al. Influence of zoledronic acid on proliferation, migration, and apoptosis of vascular endothelial cells[J]. Br J Oral Maxillofac Surg, 2016, 54(8): 889-893.
18	Wang Q, Liu J, Guo T, et al. Epidermal growth factor reverses the inhibitory effects of the bisphosphonate, zoledronic acid, on human oral keratinocytes and human vascular endothelial cells in vitro via the epidermal growth factor receptor (EGFR)/Akt/phosphoinositide 3-kinase (PI3K) signaling pathway[J]. Med Sci Monit, 2019, 25: 700-710.
19	Zirk M, Wenzel C, Buller J, et al. Microbial diversity in infections of patients with medication-related osteonecrosis of the jaw[J]. Clin Oral Investig, 2019, 23(5): 2143-2151.
20	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.
21	Russmueller G, Seemann R, Weiss K, et al. The association of medication-related osteonecrosis of the jaw with Actinomyces spp. infection[J]. Sci Rep, 2016, 6: 31604.
22	Silveira FM, Etges A, Correa MB, et al. Microscopic evaluation of the effect of oral microbiota on the development of bisphosphonate-related osteonecrosis of the jaws in rats[J]. J Oral Maxillofac Res, 2016, 7(4): e3.
23	Wolf AM, Rumpold H, Tilg H, et al. The effect of zoledronic acid on the function and differentiation of myeloid cells[J]. Haematologica, 2006, 91(9): 1165-1171.
24	Zhang Q, Atsuta I, Liu S, et al. Il-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bis-phosphonate-related osteonecrosis of the jaws[J]. Clin Cancer Res, 2013, 19(12): 3176-3188.
25	Movila A, Mawardi H, Nishimura K, et al. Possible pa-thogenic engagement of soluble Semaphorin 4D produ-ced by γδT cells in medication-related osteonecrosis of the jaw (MRONJ)[J]. Biochem Biophys Res Commun, 2016, 480(1): 42-47.
26	Tseng HC, Kanayama K, Kaur K, et al. Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: role in osteoclast-mediated NK cell activation[J]. Oncotarget, 2015, 6(24): 20002-20025.
27	Grassi F, Manferdini C, Cattini L, et al. T cell suppression by osteoclasts in vitro[J]. J Cell Physiol, 2011, 226(4): 982-990.
28	Jung J, Park JS, Righesso L, et al. Effects of an oral bis-phosphonate and three intravenous bisphosphonates on several cell types in vitro[J]. Clin Oral Investig, 2018, 22(7): 2527-2534.
29	Hoefert S, Schmitz I, Tannapfel A, et al. Importance of microcracks in etiology of bisphosphonate-related osteonecrosis of the jaw: a possible pathogenetic model of sym-ptomatic and non-symptomatic osteonecrosis of the jaw based on scanning electron microscopy findings[J]. Clin Oral Investig, 2010, 14(3): 271-284.
30	Guo Z, Cui W, Que L, et al. Pharmacogenetics of medication-related osteonecrosis of the jaw: a systematic review and meta-analysis[J]. Int J Oral Maxillofac Surg, 2020, 49(3): 298-309.
31	Sarasquete ME, García-Sanz R, Marín L, et al. Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis[J]. Blood, 2008, 112(7): 2709-2712.
32	Arduino PG, Menegatti E, Scoletta M, et al. Vascular endothelial growth factor genetic polymorphisms and haplotypes in female patients with bisphosphonate-related osteonecrosis of the jaws[J]. J Oral Pathol Med, 2011, 40(6): 510-515.
33	Di Martino MT, Arbitrio M, Guzzi PH, et al. A peroxisome proliferator-activated receptor gamma (PPARG) polymorphism is associated with zoledronic acid-related osteonecrosis of the jaw in multiple myeloma patients: analysis by DMET microarray profiling[J]. Br J Haematol, 2011, 154(4): 529-533.
34	Choi H, Lee JH, Kim HJ, et al. Genetic association between VEGF polymorphisms and BRONJ in the Korean population[J]. Oral Dis, 2015, 21(7): 866-871.
35	Beth-Tasdogan NH, Mayer B, Hussein H, et al. Interventions for managing medication-related osteonecrosis of the jaw[J]. Cochrane Database Syst Rev, 2017, 10(10): CD012432.
36	Scottish Dental Clinical Effectiveness Programme. Oral health management of patients at risk of medication-related osteonecrosis of the jaw[J]. Br Dent J, 2017, 222(12): 930.
37	Drudge-Coates L, Van den Wyngaert T, Schiødt M, et al. Preventing, identifying, and managing medication-related osteonecrosis of the jaw: a practical guide for nurses and other allied healthcare professionals[J]. Support Care Cancer, 2020, 28(9): 4019-4029.
38	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.
39	王杞章, 刘济远, 潘剑. 药物性颌骨坏死的研究进展[J]. 华西口腔医学杂志, 2018, 36(5): 568-572.
	Wang QZ, Liu JY, Pan J. Progress on medication-related osteonecrosis of the jaw[J]. West China J Stomatol, 2018, 36(5): 568-572.
40	Dodson TB. CTX and its role in managing patients exposed to oral bisphosphonates [J]. J Oral Maxillofac Surg, 2010, 68(2): 487-489.
41	Marx RE, Cillo JE Jr, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment[J]. J Oral Maxillofac Surg, 2007, 65(12): 2397-2410.
42	Di Fede O, Panzarella V, Mauceri R, et al. The dental management of patients at risk of medication-related osteonecrosis of the jaw: new paradigm of primary prevention[J]. Biomed Res Int, 2018, 2018: 2684924.
43	Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus[J]. J Bone Miner Res, 2015, 30(1): 3-23.
44	Bermúdez-Bejarano EB, Serrera-Figallo MÁ, Gutiérrez-Corrales A, et al. Prophylaxis and antibiotic therapy in management protocols of patients treated with oral and intravenous bisphosphonates[J]. J Clin Exp Dent, 2017, 9(1): e141-e149.
45	Yoneda T, Hagino H, Sugimoto T, et al. Bisphosphonate-related osteonecrosis of the jaw: position paper from the Allied Task Force Committee of Japanese Society for Bone and Mineral Research, Japan Osteoporosis Society, Japanese Society of Periodontology, Japanese Society for Oral and Maxillofacial Radiology, and Japanese Society of Oral and Maxillofacial Surgeons[J]. J Bone Miner Metab, 2010, 28(4): 365-383.
46	Lerman MA, Xie W, Treister NS, et al. Conservative management of bisphosphonate-related osteonecrosis of the jaws: staging and treatment outcomes[J]. Oral Oncol, 2013, 49(9): 977-983.
47	Beth-Tasdogan NH, Mayer B, Hussein H, et al. Interventions for managing medication-related osteonecrosis of the jaw[J]. Cochrane Database Syst Rev, 2017, 10(10): CD012432.
48	Peleg M, Lopez EA. The treatment of osteoradionecrosis of the mandible: the case for hyperbaric oxygen and bone graft reconstruction[J]. J Oral Maxillofac Surg, 2006, 64(6): 956-960.
49	Bocci V. Ozone as Janus: this controversial gas can be either toxic or medically useful[J]. Mediators Inflamm, 2004, 13(1): 3-11.

检查方式	使用建议
根尖片	可初步辅助判断，典型特征包括硬膜增厚、牙槽骨骨小梁密度增加、牙周膜间隙增宽等，但是使用较少
全景片	相对根尖片，可纳入判断的结构更多，表现为骨小梁密度增加、拔牙窝不完全愈合、骨片形成、下颌神经管或上颌窦底骨皮质增厚等，可以作为影像学检查选择之一
螺旋CT及CBCT	典型病变包括弥漫性骨硬化、骨溶解区形成、骨皮质糜烂、骨膜增生、瘘管形成及拔牙牙槽窝不完全愈合。一般来说，该影像学显示区域大于临床暴露区域。在观察骨质改变上，螺旋CT及CBCT效果相当，但CBCT的辐射相对小得多
MRI	在观察骨质改变上，与CT相当，在评估骨坏死早期骨髓变化以及围绕骨坏死区域的软组织变化方面占优势，在临床症状出现之前可出现骨髓信号强度的降低
闪烁扫描和PET	有早期核素浓集，死骨形成后会有核素摄取下降的特点，对于检测早期疾病具有高灵敏度

临床分期	临床特点	治疗建议
危险期	无任何主观症状，无骨坏死表现	无需治疗，口腔卫生宣教
0	无骨坏死或骨暴露，有非特异性临床症状，可能发生进一步病变	全身系统治疗，包括止痛药和抗生素的使用
Ⅰ	有骨暴露或骨坏死，无临床症状，无感染征兆	抗菌含漱液，临床定期随访，向患者交代病情
Ⅱ	骨暴露或骨坏死，伴局灶感染	抗菌含漱液含漱，全身抗生素治疗，控制疼痛，游离死骨表浅清创，减少软组织刺激
Ⅲ	骨暴露或骨坏死，伴疼痛感染，同时具有以下一个或多个表现：病理性骨折，口外瘘道，病灶超出牙槽骨范围的颌骨	抗生素类含漱液，全身抗生素治疗，控制疼痛，选择性局部清创或手术切除

[1]	李审绥, 吴沉洲, 李龙江. 光动力疗法治疗口腔疾病的研究进展[J]. 华西口腔医学杂志, 2021, 39(2): 215-220.
[2]	刘伟, 李春洁, 李龙江. 口腔癌颌骨侵犯的分子机制研究进展[J]. 华西口腔医学杂志, 2021, 39(2): 221-226.
[3]	藕小平, 郦芳挺, 吴渺夷. 下颌骨分泌性癌1例[J]. 华西口腔医学杂志, 2021, 39(2): 227-229.
[4]	仇学梅, 江潞. 唇炎诊断性新分类及其临床诊断路径[J]. 华西口腔医学杂志, 2021, 39(2): 238-244.
[5]	刘超峰, 许艳华, 刘彦. 应用Andrews六要素对矫治结束病例的疗效评价研究[J]. 华西口腔医学杂志, 2021, 39(1): 48-52.
[6]	黄威, 李颖辉, 郭凯利, 周永川, 李向军. 唇腭裂术后瘢痕及上颌扩弓联合前牵引治疗对上颌骨发育综合影响的有限元分析[J]. 华西口腔医学杂志, 2020, 38(6): 642-646.
[7]	赖静, 白远亮, 柏银, 梅杰, 张芷玮, 唐雯静, 黄姣. 牙周基础治疗对慢性肾病伴牙周炎患者炎症因子影响的Meta分析[J]. 华西口腔医学杂志, 2020, 38(6): 672-680.
[8]	钟宁莹, 王丽萍. 锶成骨机制的研究进展[J]. 华西口腔医学杂志, 2020, 38(6): 697-703.
[9]	程国平, 叶畅畅, 唐兢, 孟姝, 吴亚菲, 丁一. 不同特点妊娠期牙龈瘤的治疗体会[J]. 华西口腔医学杂志, 2020, 38(6): 718-725.
[10]	宋应亮, 张思佳. 对种植体周围炎的认识与预防[J]. 华西口腔医学杂志, 2020, 38(5): 479-483.
[11]	钟来平. 口腔鳞状细胞癌临床诊治的规范化和个体化：机遇与挑战[J]. 华西口腔医学杂志, 2020, 38(5): 484-488.
[12]	郭伟. 晚期头颈恶性肿瘤程序性细胞死亡蛋白1免疫治疗的临床研究述评[J]. 华西口腔医学杂志, 2020, 38(5): 489-494.
[13]	张婷, 陈度, 苗雷英, 谢思静, 汤旭娜. 激光熔融数字化导板技术辅助钙化根管的治疗[J]. 华西口腔医学杂志, 2020, 38(5): 525-531.
[14]	任立志, 孙睿. 左侧下颌骨婴幼儿肌纤维瘤病1例[J]. 华西口腔医学杂志, 2020, 38(5): 594-597.
[15]	雷可昕, 白贺天, 杨淞月, 李敬, 陈谦明. 环状RNA与口腔鳞状细胞癌研究进展[J]. 华西口腔医学杂志, 2020, 38(4): 425-430.

药物相关性颌骨坏死的发病机制及其防治

Mechanism, prevention, and treatment for medication-related osteonecrosis of the jaws

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 6

参考文献 49

相关文章 15

编辑推荐

Metrics

本文评价