Top

Clinical Oral Investigations

Published in:

01-05-2019 | Original Article

Microbial diversity in infections of patients with medication-related osteonecrosis of the jaw

Authors: Matthias Zirk, Charlotte Wenzel, Johannes Buller, Joachim E. Zöller, Max Zinser, Franziska Peters

Published in: Clinical Oral Investigations | Issue 5/2019

Abstract

Objectives

A central role of infections in the treatment of MRONJ patients is widely accepted. An investigation of the MRONJ lesions’ biofilms as potential pathogens seems logical.

Materials and methods

We investigated the clinical data of our MRONJ patients who received surgery in advanced stage of the disease. Special attention was granted to the local colonizers harvested from osseous MRONJ specimens and submucosal putrid infections.

Results

Eleven out of 71 patients presented a spontaneous onset of the disease and for 60 out of 71 patients a trigger was detected. Breast cancer (29.6%) and prostate cancer (22.5%) were the most frequent underlying disease for prescription of an antiresorptive therapy, mostly zoledronate. Submucosal soft tissue biofilms significantly differed from biofilms harvested from the MRONJ lesions bottom, yet the most frequent bacteria were equally present in both groups: Streptococcus species (spp.), Prevotella spp., Actinomyces spp., Veillonella spp., and Parvimonas micra. The cephalosporins, cefuroxime and cefotaxime, and ß-lactam antibiotics with ß-lactamase inhibitor revealed the greatest susceptibility for the detected bacteria.

Conclusion

The bacteria from the submucosal areas and the bottom of the infected bone presented comparable susceptibility to the common antibiotics regimes. Streptococcus spp., Prevotella spp., and Veillonella spp. present a high abundance in MRONJ lesions beside Actinomyces spp. The MRONJ lesions bottom is in many cases not infected by Actinomyces spp.

Clinical relevance

The removal of the necrotic bone reduces the variety of bacteria found in MRONJ lesions, in particular at the bottom of the lesion.

Schubert M, Klatte I, Linek W, Muller B, Doring K, Eckelt U, Hemprich A, Berger U, Hendricks J (2012) The saxon bisphosphonate register - therapy and prevention of bisphosphonate-related osteonecrosis of the jaws. Oral Oncol 48(4):349–354CrossRefPubMed

Urade M, Tanaka N, Furusawa K, Shimada J, Shibata T, Kirita T, Yamamoto T, Ikebe T, Kitagawa Y, Fukuta J (2011) Nationwide survey for bisphosphonate-related osteonecrosis of the jaws in Japan. J Oral Maxillofac Surg: Off JAm Assoc Oral Maxillofac Surg 69(11):e364–e371CrossRef

Sternlicht H, Glezerman IG (2015) Hypercalcemia of malignancy and new treatment options. Ther Clin Risk Manag 11:1779–1788PubMedPubMedCentral

Eleutherakis-Papaiakovou E, Bamias A (2017) Antiresorptive treatment-associated ONJ. European journal of cancer care 26(6)

Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B (2009) American Association of Oral and Maxillofacial Surgeons Position Paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg 67(5, Supplement):2–12CrossRefPubMed

Heim N, Warwas FB, Wilms CT, Reich RH, Martini M (2017) Vitamin D (25-OHD) deficiency may increase the prevalence of medication-related osteonecrosis of the jaw. J Craniomaxillofac Surg: Off Publ Eur Assoc Craniomaxillofac Surg 45(12):2068–2074CrossRef

Zirk M, Kreppel M, Buller J, Pristup J, Peters F, Dreiseidler T, Zinser M, Zoller JE (2017) The impact of surgical intervention and antibiotics on MRONJ stage II and III - retrospective study. J Craniomaxillofac Surg: Off Publ Eur Assoc Craniomaxillofac Surg 45(8):1183–1189CrossRef

Hayashida S, Soutome S, Yanamoto S, Fujita S, Hasegawa T, Komori T, Kojima Y, Miyamoto H, Shibuya Y, Ueda N, Kirita T, Nakahara H, Shinohara M, Umeda M (2017) 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: Off J Am Soc Bone Miner Res 32(10):2022–2029CrossRef

Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O'Ryan F (2014) American Association of Oral and Maxillofacial Surgeons Position Paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg 72(10):1938–1956CrossRefPubMed

10.

Campisi G, Fedele S, Fusco V, Pizzo G, Di Fede O, Bedogni A (2014) Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents. Fut Oncol (London, England) 10(2):257–275CrossRef

11.

Ficarra G, Beninati F (2007) Bisphosphonate – related osteonecrosis of the jaws: the point of view of the oral pathologist. Clin CaseMiner Bone Metab 4(1):53–57

12.

Panya S, Fliefel R, Probst F, Troltzsch M, Ehrenfeld M, Schubert S, Otto S (2017) Role of microbiological culture and polymerase chain reaction (PCR) of actinomyces in medication-related osteonecrosis of the jaw (MRONJ). J Craniomaxillofac Surg: Off Publ Eur Assoc Craniomaxillofacial Surg 45(3):357–363CrossRef

13.

Katsarelis H, Shah NP, Dhariwal DK, Pazianas M (2015) Infection and medication-related osteonecrosis of the jaw. J Dent Res 94(4):534–539CrossRefPubMed

14.

Schipmann S, Metzler P, Rossle M, Zemann W, von Jackowski J, Obwegeser JA, Gratz KW, Jacobsen C: Osteopathology associated with bone resorption inhibitors - which role does Actinomyces play? A presentation of 51 cases with systematic review of the literature. J Oral Pathol Med: Off Publ Int Assoc Oral Pathol Am Acad Oral Pathol 2013, 42(8):587–593

15.

De Ceulaer J, Tacconelli E, Vandecasteele SJ (2014) Actinomyces osteomyelitis in bisphosphonate-related osteonecrosis of the jaw (BRONJ): the missing link? Eur J Clin Microbiol Infect Dis: Off Publ Eur Soc Clin Microbiol 33(11):1873–1880CrossRef

16.

Koerdt S, Dax S, Grimaldi H, Ristow O, Kuebler AC, Reuther T (2014) Histomorphologic characteristics of bisphosphonate-related osteonecrosis of the jaw. J Oral Pathol Med: Off Publ Int Assoc Oral Pathol Am Acad Oral Pathol 43(6):448–453CrossRef

17.

Sanchez BC, Chang C, Wu C, Tran B, Ton-That H (2017) Electron transport chain is biochemically linked to pilus assembly required for polymicrobial interactions and biofilm formation in the gram-positive actinobacterium Actinomyces oris. mBio, 8(3)

18.

Hall V (2008) Actinomyces--gathering evidence of human colonization and infection. Anaerobe 14(1):1–7CrossRefPubMed

19.

Kaplan I, Anavi K, Anavi Y, Calderon S, Schwartz-Arad D, Teicher S, Hirshberg A (2009) The clinical spectrum of Actinomyces-associated lesions of the oral mucosa and jawbones: correlations with histomorphometric analysis. Oral Surg, Oral Med, Oral pathol, Oral Radiol Endodontics 108(5):738–746CrossRef

20.

Panya S, Fliefel R, Probst F, Tröltzsch M, Ehrenfeld M, Schubert S, Otto S (2017) Role of microbiological culture and polymerase chain reaction (PCR) of actinomyces in medication-related osteonecrosis of the jaw (MRONJ). J Cranio-Maxillofac Surg 45(3):357–363CrossRef

21.

Sedghizadeh PP, Yooseph S, Fadrosh DW, Zeigler-Allen L, Thiagarajan M, Salek H, Farahnik F, Williamson SJ (2012) Metagenomic investigation of microbes and viruses in patients with jaw osteonecrosis associated with bisphosphonate therapy. Oral Surg Oral Med Oral Pathol Oral Radiol 114(6):764–770CrossRefPubMedPubMedCentral

22.

Kos M, Luczak K (2009) Bisphosphonates promote jaw osteonecrosis through facilitating bacterial colonisation. Bioscience Hypotheses 2(1):34–36CrossRef

23.

Pushalkar S, Li X, Kurago Z, Ramanathapuram LV, Matsumura S, Fleisher KE, Glickman R, Yan W, Li Y, Saxena D (2014) Oral microbiota and host innate immune response in bisphosphonate-related osteonecrosis of the jaw. Int J Oral Sci 6(4):219–226CrossRefPubMedPubMedCentral

24.

Hinson AM, Smith CW, Siegel ER, Stack BC, Jr.: Is bisphosphonate-related osteonecrosis of the jaw an infection? A histological and microbiological ten-year summary Int J Dent 2014, 2014:452737

25.

Wei X, Pushalkar S, Estilo C, Wong C, Farooki A, Fornier M, Bohle G, Huryn J, Li Y, Doty S, Saxena D (2012) Molecular profiling of oral microbiota in jawbone samples of bisphosphonate-related osteonecrosis of the jaw. Oral Dis 18(6):602–612CrossRefPubMed

26.

Ji X, Pushalkar S, Li Y, Glickman R, Fleisher K, Saxena D (2012) Antibiotic effects on bacterial profile in osteonecrosis of the jaw. Oral Dis 18(1):85–95CrossRefPubMed

27.

Boff RC, Salum FG, Figueiredo MA, Cherubini K Important aspects regarding the role of microorganisms in bisphosphonate-related osteonecrosis of the jaws. Arch Oral Biol 59(8):790–799

28.

Beth-Tasdogan NH, Mayer B, Hussein H, Zolk O (2017) Interventions for managing medication-related osteonecrosis of the jaw. Cochrane Database Syst Rev 10:CD012432PubMed

29.

Comas-Calonge A, Figueiredo R, Gay-Escoda C (2017) Surgical treatment vs. conservative treatment in intravenous bisphosphonate-related osteonecrosis of the jaws. Systematic review. J Clin Exp Dent 9(2):e302–e307PubMedPubMedCentral

30.

Silva LF, Curra C, Munerato MS, Deantoni CC, Matsumoto MA, Cardoso CL, Curi MM (2016) Surgical management of bisphosphonate-related osteonecrosis of the jaws: literature review. Oral Maxillofac Surg 20(1):9–17CrossRefPubMed

31.

Khan AA, Morrison A, Kendler DL, Rizzoli R, Hanley DA, Felsenberg D, McCauley LK, O'Ryan F, Reid IR, Ruggiero SL et al (2017) 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 Densitometry: Off J Int Soc Clin Densitometry 20(1):8–24CrossRef

32.

Klingelhoffer C, Zeman F, Meier J, Reichert TE, Ettl T (2016) Evaluation of surgical outcome and influencing risk factors in patients with medication-related osteonecrosis of the jaws. J Craniomaxillofac Surg: Off Publ Eur Assoc Craniomaxillofac Surg 44(10):1694–1699CrossRef

33.

Graziani F, Vescovi P, Campisi G, Favia G, Gabriele M, Gaeta GM, Gennai S, Goia F, Miccoli M, Peluso F, Scoletta M, Solazzo L, Colella G (2012) Resective surgical approach shows a high performance in the management of advanced cases of bisphosphonate-related osteonecrosis of the jaws: a retrospective survey of 347 cases. J Oral Maxillofac Surg: Off J Am Assoc Oral Maxillofac Surg 70(11):2501–2507CrossRef

34.

Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, Diel IJ, Takahashi S, Shore N, Henry DH et al: Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 2012, 23(5):1341–1347

35.

Kim KM, Rhee Y, Kwon Y-D, Kwon T-G, Lee JK, Kim D-Y (2015) Medication related osteonecrosis of the jaw: 2015 position statement of the Korean Society for Bone and Mineral Research and the Korean Association of Oral and Maxillofacial Surgeons. J Bone Metab 22(4):151–165CrossRefPubMedPubMedCentral

36.

Gaudin E, Seidel L, Bacevic M, Rompen E, Lambert F (2015) Occurrence and risk indicators of medication-related osteonecrosis of the jaw after dental extraction: a systematic review and meta-analysis. J Clin Periodontol 42(10):922–932CrossRefPubMed

37.

Lombard T, Neirinckx V, Rogister B, Gilon Y, Wislet S (2016) Medication-related osteonecrosis of the jaw: new insights into molecular mechanisms and cellular therapeutic approaches. Stem Cells Int 2016:8768162CrossRefPubMedPubMedCentral

38.

Hoefert S, Schmitz I, Tannapfel A, Eufinger H (2010) Importance of microcracks in etiology of bisphosphonate-related osteonecrosis of the jaw: a possible pathogenetic model of symptomatic and non-symptomatic osteonecrosis of the jaw based on scanning electron microscopy findings. Clin Oral Investig 14(3):271–284CrossRefPubMed

39.

Russmueller G, Seemann R, Weiss K, Stadler V, Speiss M, Perisanidis C, Fuereder T, Willinger B, Sulzbacher I, Steininger C (2016) the association of medication-related osteonecrosis of the jaw with Actinomyces spp infection Scientific reports , 6:31604

40.

Lopes RN, Rabelo GD, Rocha AC, Carvalho PA, Alves FA (2015) Surgical therapy for bisphosphonate-related osteonecrosis of the jaw: six-year experience of a single institution. J Oral Maxillofac Surg: Off J Am Assoc Oral Maxillofac Surg 73(7):1288–1295CrossRef

41.

Bennhoff DF (1984) Actinomycosis: diagnostic and therapeutic considerations and a review of 32 cases. Laryngoscope 94(9):1198–1217CrossRefPubMed

42.

Wong VK, Turmezei TD, Weston VC (2011) Actinomycosis. BMJ 343:d6099CrossRefPubMed

43.

Thukral R, Shrivastav K, Mathur V, Barodiya A, Shrivastav S (2017) Actinomyces: a deceptive infection of oral cavity. J Korean Assoc Oral Maxillofac Surg 43(4):282–285CrossRefPubMedPubMedCentral

44.

Hallmer F, Bjornland T, Andersson G, Becktor JP, Kristoffersen AK, Enersen M (2017) Bacterial diversity in medication-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol 123(4):436–444CrossRefPubMed

45.

Bowler PG, Duerden BI, Armstrong DG (2001) Wound microbiology and associated approaches to wound management. Clin Microbiol Rev 14(2):244–269CrossRefPubMedPubMedCentral

46.

Bae S, Sun S, Aghaloo T, Oh JE, McKenna CE, Kang MK, Shin KH, Tetradis S, Park NH, Kim RH (2014) Development of oral osteomucosal tissue constructs in vitro and localization of fluorescently-labeled bisphosphonates to hard and soft tissue. Int J Mol Med 34(2):559–563CrossRefPubMedPubMedCentral

47.

Ziebart T, Halling F, Heymann P, Neff A, Blatt S, Jung J, Pabst A, Righesso L, Walter C (2016) Impact of soft tissue pathophysiology in the development and maintenance of bisphosphonate-related osteonecrosis of the jaw (BRONJ), vol 4

48.

Bocanegra-Pérez MS, Vicente-Barrero M, Sosa-Henríquez M, Rodríguez-Bocanegra E, Limiñana-Cañal JM, López-Márquez A, Pérez-Plasencia D, Ramos-Macías A (2012) Bone metabolism and clinical study of 44 patients with bisphosphonate-related osteonecrosis of the jaws. Med Oral, Patol Oral Cir Bucal 17(6):e948–e955CrossRef

49.

Stefanopoulos PK, Kolokotronis AE (2004) The clinical significance of anaerobic bacteria in acute orofacial odontogenic infections. Oral Surg, Oral Med, Oral Pathol, Oral Radiol, Endodontol 98(4):398–408CrossRef

50.

Duerden BI (1994) Virulence factors in anaerobes. Clin Infect Dis: Off Publ Infect Dis Soc Am 18(Suppl 4):S253–S259CrossRef

51.

Bermudez-Bejarano EB, Serrera-Figallo MA, Gutierrez-Corrales A, Romero-Ruiz MM, Castillo-de-Oyague R, Gutierrez-Perez JL, Torres-Lagares D (2017) Prophylaxis and antibiotic therapy in management protocols of patients treated with oral and intravenous bisphosphonates. J Clin Exp Dent 9(1):e141–e149PubMedPubMedCentral

52.

Ferlito S, Puzzo S, Palermo F, Verzì P (2012) Treatment of bisphosphonate-related osteonecrosis of the jaws: presentation of a protocol and an observational longitudinal study of an Italian series of cases. Br J Oral Maxillofac Surg 50(5):425–429CrossRefPubMed

53.

Brook I (2008) Actinomycosis: diagnosis and management. South Med J 101(10):1019–1023CrossRefPubMed

54.

Smith AJ, Hall V, Thakker B, Gemmell CG (2005) Antimicrobial susceptibility testing of Actinomyces species with 12 antimicrobial agents. J Antimicrob Chemother 56(2):407–409CrossRefPubMed

Title: Microbial diversity in infections of patients with medication-related osteonecrosis of the jaw
Authors: Matthias Zirk
Charlotte Wenzel
Johannes Buller
Joachim E. Zöller
Max Zinser
Franziska Peters
Publication date: 01-05-2019
Publisher: Springer Berlin Heidelberg
Published in: Clinical Oral Investigations / Issue 5/2019
Print ISSN: 1432-6981
Electronic ISSN: 1436-3771
DOI: https://doi.org/10.1007/s00784-018-2655-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Microbial diversity in infections of patients with medication-related osteonecrosis of the jaw

Abstract

Objectives

Materials and methods

Results

Conclusion

Clinical relevance

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objectives

Materials and methods

Results

Conclusion

Clinical relevance

Please log in to get access to this content

Other articles of this Issue 5/2019

Diagnostic accuracy of panoramic radiography in the detection of calcified carotid artery atheroma: a meta-analysis

Influence of different thickeners in at-home tooth bleaching: a randomized clinical trial study

Characteristics, treatment and outcome of bleeding after tooth extraction in patients on DOAC and phenprocoumon compared to non-anticoagulated patients—a retrospective study of emergency department consultations

Distances of root apices to adjacent anatomical structures in the anterior maxilla: an analysis using cone beam computed tomography

Prevalence of degenerative joint disease of the temporomandibular joint: a systematic review

Effect of sucralfate against hydrochloric acid-induced dental erosion