Kazan medical journalKazan medical journalКазанский медицинский журнал0368-48142587-9359Eco-Vector1886910.17816/KMJ2020-226ReviewsОбзорыReview ArticleBisphosphonate-related osteonecrosis of the jaw (BRONJ) in cancer patientsБисфосфонатный остеонекроз челюстей у онкологических пациентовEbzeevA KЭбзеевАзнаур Казимович
Russian Federation
ebzeev89@list.ruStavropol State Medical UniversityСтавропольский государственный медицинский университет1304202010122262312212201924012020Copyright ©; 2020, Ebzeev A.K.Copyright ©; 2020, Эбзеев А.К.2020Ebzeev A.K.Эбзеев А.К.http://creativecommons.org/licenses/by-nc-sa/4.0https://kazanmedjournal.ru/kazanmedj/article/view/18869

This literature review focuses on the latest advances in the study of osteonecrosis of the jaw in cancer patients taking bisphosphonates. Prescribing bisphosphonates for the treatment of metastatic bone disease is justifiable and unavoidable measure. The action of bisphosphonates leads to increase in bone tissue strength, but significantly suppressing normal bone remodelling, essential for repair, and becomes vulnerable to mechanical trauma and bacterial invasion. The unique anatomical and physiological features of the jaw bones determine their selective damage. The disease is characterized by progressive jaw necrosis, chronic inflammation of the surrounding tissues complicated by a pathological fracture and persistent oroantral fistula, which aggravates chronic pain and leads to a deterioration in the quality of life of patients. The occurrence of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a multifactorial process. Most often, it occurs in patients with long term treatment with zoledronic acid preparations against after tooth extraction. The fact of an increase in the incidence of osteonecrosis is undeniable for objective reasons, the main of which are an increase in cancer, an increase in the life expectancy of cancer patients and their need for bisphosphonate therapy. In the article, it was analyzed the latest scientific reports on the causes of the disease, risk factors and the pathogenesis of the disease. Data on the frequency of jaw osteonecrosis in different countries are presented. It was shown promising developments and summarizes information on existing methods for diagnosing jaw bisphosphonate osteonecrosis. Questions about the key approaches in the treatment of the disease, as well as about new experimental techniques, are examined. The main problems of the prevention of bisphosphonate-related osteonecrosis of the jaws are formulated.

Обзор литературы посвящён последним разработкам в изучении проблемы остеонекроза челюстей у онкологических пациентов, принимающих бисфосфонаты. Назначение бисфосфонатов при метастатическом поражении костей скелета — оправданная и необходимая мера. Действие бисфосфонатов приводит к тому, что костная ткань становится более прочной, однако значительно теряет способность к ремоделированию, а соответственно и к репарации, становится уязвимой к механической травме и бактериальной инвазии. Уникальные анатомические и физиологические особенности челюстных костей обусловливают их избирательное поражение. Заболевание характеризуется прогрессирующем некрозом челюстной кости, хроническим воспалением окружающих тканей, осложнениями в виде патологического перелома и стойкого ороантрального соустья, отягощает хронический болевой синдром, приводит к ухудшению качества жизни больных. Возникновение бисфосфонатного остеонекроза челюстей — мультифакторный процесс. Наиболее часто встречается при длительном приёме препаратов золедроновой кислоты на фоне предшествовавшего удаления зуба. Неоспорим факт увеличения роста частоты остеонекроза по объективным причинам, главные из которых — рост онкологической заболеваемости, увеличение продолжительности жизни онкологических больных и необходимости в их терапии бисфосфонатами. В статье проанализированы литературные сведения о причинах заболевания, факторах риска и патогенезе заболевания. Приведены данные о частоте остеонекроза челюстей в разных странах. Освещены перспективные разработки и обобщены сведения об уже существующих методах диагностики бисфосфонатного остеонекроза челюстей. Рассмотрены вопросы о ключевых подходах в лечении заболевания, а также о новых экспериментальных методиках. Сформулированы основные проблемы профилактики бисфосфонатного остеонекроза челюстей.

osteonecrosisjawbisphosphonatesbisphosphonate-related osteonecrosis of the jawBRONJостеонекрозчелюстьбисфосфонатыManzyuk L.V., Bagrova S.G., Kopp M.V. et al. The use of osteomodifying agents for the prevention and treatment of bone tissue pathology in malignant neoplasms. Zlokachestvennye opukholi. Prakticheskie rekomenda­tsii RUSSCO. 2017; 7 (3 S2): 477–485. (In Russ.) DOI: 10.18027/2224-5057-2017-7-3s2-477-485.Манзюк Л.В., Багрова С.Г., Копп М.В. и др. Использование остеомодифицирующих агентов для профилактики и лечения патологии костной ткани при злокачественных новообразованиях. Злокачественные опухоли. Практические рекомендации. 2017; 7 (3 S2): 477–485. DOI: 10.18027/2224-5057-2017-7-3s2-477-485.Bolshakova S.A., Bychkov Y.M. Modern treatment of breast cancer bone metastases: from bisphosphonates to targeted therapy. Vestnik Rossiyskogo nauchnogo tsentra rentgenoradiologii Minzdrava Rossii. 2016; 16 (4): 1–28. (In Russ.)Большакова С.А., Бычков Ю.М. Современные подходы в лечении метастазов в кости рака молочной железы: от бисфосфонатов к таргетной терапии. Вестн. Рос. науч. центра рентгенорадиологии Минздрава России. 2016; 16 (4): 1–28.Leng S., Chen Y., Tsai W.Y. et al. Use of bisphosphonates in elderly patients with newly diagnosed multiple mye­loma. J. Natl. Compr. Canc. Netw. 2019; 17 (1): 22–28. DOI: 10.6004/jnccn.2018.7079.Ruggiero S.L., Dodson T.B., Fantasia J. et al. Ame­rican Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw — 2014 update. J. Oral Maxillofac. Surg. 2014; 72 (10): 1938–1956. DOI: 10.1016/j.joms.2014.04.031.McGowan K., Ivanovski S. Risk factors for medication-related osteonecrosis of the jaws: A systematic review. Oral Diseases. 2018; 24 (4): 527–536. DOI: 10.1111/odi.12708.Khan A.A., Morrison A., Kendler D.L. et al. Case-based review of Osteonecrosis of the Jaw (ONJ) and application of the International recommendations for ma­nagement from the International Task Force on ONJ. J. Clin. Densitom. 2017; 20 (1): 8–24. DOI: 10.1016/­j.jocd.­2016.09.005.Shibahara T., Morikawa T., Yago K. et al. National survey on bisphosphonate-related osteonecrosis of the jaws in Japan. J. Oral Maxillofac. Surg. 2018; 76 (10): 2105–2112. DOI: 10.1016/j.joms.2018.04.009.Cuevas-González M.V., Díaz-Aguirre С.M., Echevarría-Y-Pérez E., Cuevas-González J.C. Prevalence of osteonecrosis of the jaw and oral characteristics of oncologic patients treated with bisphosphonates at the General Hospital of Mexico. J. Korean Assoc. Oral Maxillofac. Surg. 2016; 42 (6): 365–369. DOI: 10.5125/jkaoms.2016.42.6.365.Hallmer F., Andersson G., Götrick B. et al. Prevalence, initiating factor, and treatment outcome of medication-related osteonecrosis of the jaw-a 4-year prospective study. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2018; 126 (6): 477–485. DOI: 10.1016/j.oooo.2018.08.015.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. Biomed. Res. Int. 2018, 16; 2018: 2684924. DOI: 10.1155/2018/2684924.Tardast A., Sjoman R., Loes S., Abtahi J. Bisphosphonate associated osteomyelitis of the jaw in patients with bony exposure: prevention, a new way of thinking. J. Appl. Oral Sci. 2015; 23 (3): 310–314. DOI: 10.1590/1678-775720140506.Dodson T.B. The frequency of medication-rela­ted osteonecrosis of the jaw and its associated risk factors. Oral Maxillofac Surg Clin North Am. 2015; 27 (4): 509–516. DOI: 10.1016/j.coms.2015.06.003.Panya S., Fliefel R., Probst F. et al. Role of microbiological culture and polymerase chain reaction (PCR) of actinomyces in medication-related osteonecrosis of the jaw (MRONJ). J. Craniomaxillofac. Surg. 2017; 45 (3): 357–363. DOI: 10.1016/j.jcms.2017.01.006.Vinogradova N.G., Lʹvov K.V., Kharitonova M.P. Prevalence and clinical features of drug-related osteonecroses of the jaws. Problemy stomatologii. 2017; 13 (4): 38–42. (In Russ.) DOI: 10.18481/2077-7566-2017-13-4-38-42.Виноградова Н.Г., Львов К.В., Харитонова М.П. Распространённость и клинические особенности медикаментозно ассоциированных остеонекрозов челюстей. Пробл. стоматол. 2017; 13 (4): 38–42. DOI: 10.18481/2077-7566-2017-13-4-38-42.Zhuravleva M.V., Zhuravlev L.V., Firsova I.V. Actual view on the problem of bisphosphonate related jaw osteonecrosis. Zdorovʹe i obrazovanie v XXI veke. 2018; 20 (5): 88–92. (In Russ.) DOI: 10.26787/nydha-2226-7425-2018-20-5-88-92.Журавлёва М.В., Журавлёв Л.В., Фирсова И.В. Современный взгляд на проблему бисфосфонатного остео­некроза челюстей (обзорная статья). Здоровье и образование в XXI веке. 2018; 20 (5): 88–92. DOI: 10.26787/nydha-2226-7425-2018-20-5-88-92.Gross C., Weber M., Creutzburg K. et al. Osteoclast profile of medication-related osteonecrosis of the jaw se­condary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis. J. Transl. Med. 2017; 15 (1): 128. DOI: 10.1186/s12967-017-1230-8.Wehrhan F., Gross C., Creutzburg K. et al. Osteoclastic expression of higher-level regulators NFATc1 and BCL6 in medication-related osteonecrosis of the jaw se­condary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis. J. Transl. Med. 2019; 17 (1): 69. DOI: 10.1186/s12967-019-1819-1.Yoneda T., Hagino H., Sugimoto T. et al. Antiresorptive agent-related osteonecrosis of the jaw: Position Paper 2017 of the Japanese Allied Committee on Osteonecrosis of the Jaw. J. Bone Miner. Metab. 2017; 35 (1): 6–19. DOI: 10.1007/s00774-016-0810-7.Kim S.M., Eo M.Y., Kim Y.S., Lee S.K. Histochemical observation of bony reversal lines in bisphosphonate-related osteonecrosis of the jaw. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2017; 123 (2): 220–228. DOI: 10.1016/­j.oooo.2016.09.225.Reva I.V., Reva G.V., Tolmachev V.E. et al. Mechanisms of osteonecrosis of the jaw in multiple myeloma. Sovremennye problemy nauki i obrazovaniya. 2015; 5: 167. (In Russ.)Рева И.В., Рева Г.В., Толмачёв В.Е. и др. Механизмы остеонекроза челюстей при миеломной болезни. Совр. пробл. науки и образования. 2015; 5: 167. DOI: 10.17513/spno.128-22105.Devlin H., Greenwall-Cohen J., Benton J. et al. Detecting the earliest radiological signs of bisphosphonate-­related osteonecrosis. Br. Dent. J. 2018; 224: 26–31. DOI: 10.1038/sj.bdj.2017.1001.Zhukova N.A. Staging of bisphosphonate-related osteonecrosis of the jaws inpatients with malignant tumors according multislice computed tomography. Meditsinskaya vizualizatsiya. 2016; (3): 17–27. (In Russ.)Жукова Н.А. Стадирование бисфосфонатного остеонекроза челюстей у больных злокачественными новообразованиями по данным мультисрезовой компьютерной томографии. Мед. визуализация. 2016; (3): 17–27.Goller-Bulut D., Ozcan G., Avci F. Changes in dimension of neurovascular canals in the mandible and ma­xilla: A radiographic finding in patients diagnosed with MRONJ. Med. Oral Patol. Oral Cir. Bucal. 2018; 23 (3): 282–289. DOI: 10.4317/medoral.22274.Kitagawa Y., Ohga N., Asaka T. et al. Imaging modalities for drug-related osteonecrosis of the jaw (3), Posi­tron emission tomography imaging for the diagnosis of medication-related osteonecrosis of the jaw. Jpn. Dent. Sci. Rev. 2019; 55 (1): 65–70. DOI: 10.1016/j.jdsr.2018.12.001.Valieva M.M., Nesterov O.V., Urakova E.V. et al. Early diagnosis of bisphosphonate-related osteonecroses of a jaw. Prakti­cheskaya meditsina. 2018; (7-2): 26–29. (In Russ.)Валиева М.М., Нестеров О.В., Уракова Е.В. и др. Ранняя диагностика бисфосфонатных остеонекрозов челюстей. Практич. мед. 2018; (7-2): 26–29.Sletov A.A., Mikhalʹchenko D.V., Zhidovinov A.V. et al. Diagnostics and forecasting of surgical treatment of patients with osteonecrosis and aseptic osteomyelitis of the maximum bone. Krymskiy terapevticheskiy zhurnal. 2018; (1): 73–77. (In Russ.)Слетов А.А., Михальченко Д.В., Жидовинов А.В. и др. Диагностика и прогнозирование хирургического лечения пациентов с остеонекрозами и асептическими остеомиелитами челюстных костей. Крымский терапевтич. ж. 2018; (1): 73–77.Manea H.C., Urechescu H.C., Balica N.C. Bisphosphonates-induced osteonecrosis of the jaw — epidemiolo­gical, clinical and histopathological aspects. Rom. J. Morphol. Embryol. 2018; 59 (3): 825–831. PMID: 30534822.Hallmer F., Bjornland T., Andersson G. et al. Bacterial diversity in medication-related osteonecrosis of the jaw. Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radiol. 2017; 123 (4): 436–444. DOI: 10.1016/j.oooo.2016.11.011.Poxleitner P., Engelhardt M., Schmelzeisen R., Voss P. The prevention of medication-related osteonecrosis of the jaw. Dtsch. Arztebl. Int. 2017; 114 (5): 63–69. DOI: 10.3238/arztebl.2017.0063.Spevak E.M., Khristoforando D.Yu., Davydov A.B. Assessment of bone meta­bolism in patients with bisphosphonate osteonecrosis of the jaws. Rossiyskiy stomatologicheskiy zhurnal. 2017; 21 (4): 197–199. (In Russ.) DOI: 10.18821/1728-2802-2017-21-4-197-199.Спевак Е.М., Христофорандо Д.Ю., Давыдов А.Б. Оценка состояния костного метаболизма у пациентов с бисфосфонатным остеонекрозом челюстей. Рос. стом. ж. 2017; 21 (4): 197–199. DOI: 10.18821/1728-2802-2017-21-4-197-199.Shin W.J., Kim C.H. Prognostic factors for outcome of surgical treatment in medication-related osteonecrosis of the jaw. J. Korean Assoc. Oral Maxillofac. Surg. 2018; 44 (4): 174–181. DOI: 10.5125/jkaoms.2018.44.4.174.Zirk M., Kreppel M., Buller J. et al. The impact of surgical intervention and antibiotics on MRONJ stage II and III — Retrospective study. J. Craniomaxillofac. Surg. 2017; 45 (8): 1183–1189. DOI: 10.1016/j.jcms.2017.05.027.Bermúdez-Bejarano E.B., Serrera-Figallo M.A., Gutiérrez-Corrales A. et al. Prophylaxis and antibiotic the­rapy in management protocols of patients treated with oral and intravenous bisphosphonates. J. Clin. Exp. Dent. 2017; 9 (1): 141–149. DOI: 10.4317/jced.53372.Lopes R.N., Rabelo G.D., Rocha A.C. et al. Surgical therapy for bisphosphonate-related osteonecrosis of the jaw: six-year experience of a single institution. J. Oral Maxillofac. Surg. 2015; 73: 1288–1295. DOI: 10.1016/j.joms.2015.01.008.Caldroney S., Ghazali N., Dyalram D., Lubek J.E. Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw. Int. J. Oral Maxillofac. Surg. 2017; 46 (7): 871–876. DOI: 10.1016/j.ijom.2017.01.023.García-de Marcos J.A., Rey-Biel J. Submental perforator flap for soft-tissue reconstruction in bisphosphonate-related osteonecrosis of the jaws. Craniomaxillofac. Trauma Reconstr. 2017; 10 (4): 299–305. DOI: 10.1055/s-0036-1593472.Otto S., Ristow O., Pache C. et al. Fluorescence-guided surgery for the treatment of medication-­related osteonecrosis of the jaw: A prospective cohort study. J. Craniomaxillofac. Surg. 2016; 44 (8): 1073–1080. DOI: 10.1016/j.jcms.2016.05.018.Poli P.P., Souza F.A., Maiorana C. Adjunctive use of antimicrobial photodynamic therapy in the treatment of medication-related osteonecrosis of the jaws: A case report. Photodiagnosis Photodyn. Ther. 2018; 23: 99–101. DOI: 10.1016/j.pdpdt.2018.06.004.Procacci P., Albanese M., Trevisiol L. et al. Medication-related osteonecrosis of the posterior maxilla: surgical treatment using a combined transnasal endoscopic and intraoral approach, our experience with seven consecutive patients. Clin. Otolaryngol. 2018; 43 (2): 685–691. DOI: 10.1111/coa.12999.Laimer J., Steinmassl O., Hechenberger M. et al. Intraoral vacuum-assisted closure therapy — A pilot study in medication-related osteonecrosis of the jaw. J. Oral Ma­xillofac. Surg. 2017; 75 (10): 2154–2161. DOI: 10.1016/j.joms.2017.02.033.Blus C., Giannelli G., Szmukler-Moncler S., Orru G. Treatment of medication-related osteonecrosis of the jaws (MRONJ) with ultrasonic piezoelectric bone surgery. A case series of 20 treated sites. Oral Maxillofac. Surg. 2017; 21 (1): 41–48. DOI: 10.1007/s10006-016-0597-7.Voss P.J., Matsumoto A., Alvarado E. et al. Treatment of stage II medication-related osteonecrosis of the jaw with necrosectomy and autologous bone marrow mesenchymal stem cells. Odontology. 2017; 105 (4): 484–493. DOI: 10.1007/s10266-017-0295-4.Del Fabbro M., Gallesio G., Mozzati M. Autologous platelet concentrates for bisphosphonate-related osteonecrosis of the jaw treatment and prevention. A systematic review of the literature. Eur. J. Cancer. 2015; 51 (1): 62–74. DOI: 10.1016/j.ejca.2014.10.015.Momesso G.A., de Souza Batista F.R., de Sousa C.A. et al. Successful use of lower-level laser therapy in the treatment of medication-related osteonecrosis of the jaw. J. Lasers Med. Sci. 2017; 8 (4): 201–203. DOI: 10.15171/jlms.2017.37.Makeeva I.M., Volkov A.G., Dikopova N.Zh. et al. Treatment of bisphosphonate necrosis of the jaws with ozone obtained by ultraviolet irradiation. Head and neck. 2017; (3): 73–75. (In Russ.)Макеева И.М., Волков А.Г., Дикопова Н.Ж. и др. Лечение бисфосфонатных некрозов челюстей озоном, полученным с помощью ультрафиолетового излучения. Голова и шея. 2017; (3): 73–75.Owosho A.A., Estilo C.L., Huryn J.M. et al. Pento­xifylline and tocopherol in the management of cancer patients with medication-related osteonecrosis of the jaw: an observational retrospective study of initial case series. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2016; 122 (4): 455–459. DOI: 10.1016/j.oooo.2016.06.019.Petrosyan A.L., Kutukova S.I., Chefu S.G. et al. Sulodexide as a choice of prevention of bisphosphonate osteonecrosis. Smolenskiy meditsinskiy alʹmanakh. 2018; (4): 118–120. (In Russ.)Петросян А.Л., Кутукова С.И., Чефу С.Г. и др. Сулодексид как выбор профилактики бисфосфонатного остеонекроза. Смоленский мед. альманах. 2018; (4): 118–120.Kakehashi H., Ando T., Minamizato T. et al. Administration of teriparatide improves the symptoms of advanced bisphosphonate-related osteonecrosis of the jaw: preliminary findings. Int. J. Oral Maxillofac. Surg. 2015; 44 (12): 1558–1564. DOI: 10.1016/j.ijom.2015.07.018.Bedogni A., Bettini G., Bedogni G. et al. Is vitamin D deficiency a risk factor for osteonecrosis of the jaw in patients with cancer? A matched case-control study. J. Craniomaxillofac. Surg. 2019; 47 (8): 1203–1208. DOI: 10.1016/j.jcms.2019.03.007.Hayashida S., Soutome S., Yanamoto S. et al. Eva­luation of the treatment strategies for medication-related osteonecrosis of the jaws (MRONJ) and the factors affec­ting treatment outcome: a multicenter retrospective study with propensity score matching analysis. J. Bone Miner. Res. 2017; 32: 2022–2029. DOI: 10.1002/jbmr.3191.McDonnell F., Steel C. The importance of dental screening prior to commencing anti-resorptive therapy for treatment of cancer: A case report and discussion. Prim. Dent. J. 2018; 7 (3): 42–45. PMID: 30428967.