Inter J Stomatol ›› 2017, Vol. 44 ›› Issue (2): 228-234.doi: 10.7518/gjkq.2017.02.023

• Reviews • Previous Articles     Next Articles

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).

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

CLC Number: 

  • R782.1

TrendMD: 
[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] Wang Nannan,He Hong,Hua Fang. Research progress on the risk factors of orthodontically induced enamel demineralization [J]. Int J Stomatol, 2024, 51(1): 91-98.
[2] Han Chong,He Dongning,Yu Feiyan,Wu Dongchao. Research progress on the mechanism and treatment of pain after oral implants [J]. Int J Stomatol, 2024, 51(1): 99-106.
[3] Sun Xu,Deng Zhennan,Wen Cai,Zhao Ying. Implant surface micromorphological changes after Er: YAG laser irradiation observed under scanning electron microscope [J]. Int J Stomatol, 2023, 50(6): 669-673.
[4] Huang Yuanhong,Peng Xian,Zhou Xuedong.. Progress in research into the effect of Rhizoma Drynariae on the treatment of bone-related diseases in the oral cavity [J]. Int J Stomatol, 2023, 50(6): 679-685.
[5] Yang Jing,Liu Denggao.. Research progress on endoscopy-assisted laser lithotripsy in the treatment of sialolithiasis [J]. Int J Stomatol, 2023, 50(6): 704-710.
[6] Liu Yang,Yin Deqiang. Introducing a novel digital articulation workflow with high precision [J]. Int J Stomatol, 2023, 50(5): 499-505.
[7] Ji Xiao,Zhang Lan,Huang Dingming.. Diagnosis and treatment of odontogenic and non-odontogenic maxillary sinusitis [J]. Int J Stomatol, 2023, 50(5): 566-572.
[8] Zhao Yuanxi,Su Qin.. Application and development of supplementary techniques in removing the remaining filling materials of root canal retreatment [J]. Int J Stomatol, 2023, 50(5): 581-586.
[9] Gong Meiling,Cheng Xingqun,Wu Hongkun.. Research progress on the correlation between Parkinson’s disease and periodontitis [J]. Int J Stomatol, 2023, 50(5): 587-593.
[10] Liu Ting,Wu Xiuping.. Research progress on oral-craniomaxillofacial features and treatment of Down syndrome [J]. Int J Stomatol, 2023, 50(5): 618-622.
[11] Chen Yifei,Zhang Binjing,Feng Shuqi,Xu Rui,Yang Shuxian,Li Yuqing. Effects of flavonoids on oral microorganisms and its mechanism [J]. Int J Stomatol, 2023, 50(2): 210-216.
[12] Qin Yichun,Tan Xuelian,Huang Dingming.. Clinical research progress on glandular odontogenic cyst [J]. Int J Stomatol, 2023, 50(1): 100-107.
[13] Li Ting,Yang Xuecai,Wang Junwei.. Children with Williams-Beuren syndrome associated with cranial and maxillofacial deformity [J]. Int J Stomatol, 2023, 50(1): 108-113.
[14] Chen Xiaoli,Zhang Fan,Liu Chengcheng. Application progress on photobiomodulation in the prevention and treatment of oral complications after radiothe-rapy [J]. Int J Stomatol, 2022, 49(6): 707-716.
[15] Wang Qiqiu,Zhi Qinghui.. Research progress on treatments of enamel white spot lesions [J]. Int J Stomatol, 2022, 49(6): 717-723.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
[1] . [J]. Foreign Med Sci: Stomatol, 1999, 26(06): .
[2] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[3] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[4] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[5] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[6] . [J]. Foreign Med Sci: Stomatol, 1999, 26(04): .
[7] . [J]. Foreign Med Sci: Stomatol, 2005, 32(06): 458 -460 .
[8] . [J]. Foreign Med Sci: Stomatol, 2005, 32(06): 452 -454 .
[9] . [J]. Inter J Stomatol, 2008, 35(S1): .
[10] . [J]. Inter J Stomatol, 2008, 35(S1): .