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Clinical Oral Investigations

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01-03-2018 | Review

Stage-specific therapeutic strategies of medication-related osteonecrosis of the jaws: a systematic review and meta-analysis of the drug suspension protocol

Authors: Luca Ramaglia, Agostino Guida, Vincenzo Iorio-Siciliano, Alessandro Cuozzo, Andrea Blasi, Anton Sculean

Published in: Clinical Oral Investigations | Issue 2/2018

Abstract

Objective

The most debated topic about medication-related osteonecrosis of the jaws (MRONJ) is its therapy, as there are no definitive guidelines. The aims of this systematic review were (a) to outline the best therapeutic approach according to the stage at diagnosis and (b) to perform a meta-analysis to assess whether the drug-holiday protocol may be or not an effective method in the management of MRONJ patients.

Materials and methods

The systematic review was performed following the PRISMA principles. Results were screened according to inclusion and exclusion criteria regarding staging before/after treatment, follow-up, and information provided by the authors. For statistical analysis, linear variables are reported as means and standard deviations, medians, and inter-quartile range (IQR); normality of data, according to the distribution of complete healing (primary outcome variable), was assessed with the Kolmogorov-Smirnov test. A p value < 0.05 was considered statistically significant for all tests.

Results

Thirteen studies were selected out of 1480. None of them was case-controlled or randomized. Conservative approach showed good results at early stages, but heterogeneous result at advanced stages (100% stage 0, stage I range 81–97%, stage II range 63.6–100%, stage III 73%). Surgical approach showed heterogeneous results at all stages (stage I range 0–100%, stage II range 52–100%, stage III range 50–100%). Statistical analysis showed a significantly higher prevalence of completely healed sites in patients who followed the drug-holiday protocol.

Conclusions

The results suggest that the current stage-specific approach for MRONJ therapy is based on a sound clinical rationale. Conservative treatment appears to yield better outcomes at early stages, while further investigations are needed to elucidate the best protocols for the management of advanced stages. The drug-holiday protocol statistically promotes complete healing after oral surgery procedures but the application should be dictated by the condition of each patient.

Clinical relevance

At present, early MRONJ stages should be primarily treated by means of a conservative approach while more advanced stages must be carefully evaluated. Individual decisions should be made for every single case even with respect to the drug-holiday protocol.

Green JR (2005) Zoledronic acid: pharmacologic profile of a potent bisphosphonate. J Organomet Chem 690(10):2439–2448. https://doi.org/10.1016/j.jorganchem.2004.09.069 CrossRef

Body JJ (2006) Bisphosphonates for malignancy-related bone disease: current status, future developments. Support Care Cancer 14(5):408–418. https://doi.org/10.1007/s00520-005-0913-5 CrossRefPubMed

Roger MJ, Gordon S, Benford HL (2000) Cellular and molecular mechanisms of action of bisphosphonates. Cancer 88(12 supplement):2961–2978CrossRef

Stresing V, Daubiné F, Benzaid I (2007) Bisphosphonates in cancer therapy. Cancer Lett 257:16–35CrossRefPubMed

Santini D, Vincenzi B, Avvisati G (2002) Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 8:1080–1084PubMed

Marx RE (2003) Letter to the editor. J Oral Maxillofac Surg 61:1115–1118CrossRefPubMed

Ruggiero SL, Mehrotra B, Rosenberg TJ (2004) Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 62:527–534CrossRefPubMed

Hellstein JW, Marek CL (2005) Bisphosphonate osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg 63:682–689CrossRefPubMed

Aghaloo TL, Felsenfeld AL, Tetradis S (2010) Osteonecrosis of the jaw in a patient on denosumab. J Oral Maxillofac Surg 68(5):959–963. https://doi.org/10.1016/j.joms.2009.10.010 CrossRefPubMedPubMedCentral

10.

Ruggiero SL, Dodson TB, Fantasia J (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):1938–1956. https://doi.org/10.1016/j.joms.2014.04.031 CrossRefPubMed

11.

Min You T, Lee KH, Lee SH (2015) Denosumab-related osteonecrosis of the jaw: a case report and management based on pharmacokinetics. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 120:548–553CrossRef

12.

Santos-Silva AR, Belizario Rosa GA, Castro GD (2013) Osteonecrosis of the mandible associated with bevacizumab therapy. Oral Surg Oral Med Oral Pathol Oral Radiol 115:E32–E36CrossRefPubMed

13.

Ramírez L, López RM, Casañas E (2015) New non-bisphosphonate drugs that produce osteonecrosis of the jaws. Oral Health Prev Dent 13:385–393PubMed

14.

Brunello A, Saia G, Bedogni A (2009) Worsening of osteonecrosis of the jaw during treatment with sunitinib in a patient with metastatic renal cell carcinoma. Bone 44(1):173–175. https://doi.org/10.1016/j.bone.2008.08.132 CrossRefPubMed

15.

Merigo E, Manfredi M, Meleti M (2005) Jaw bone necrosis without previous dental extractions associated with the use of bisphosphonates (pamidronate and zoledronate): a four-case report. J Oral Pathol Med 34(10):613–617. https://doi.org/10.1111/j.1600-0714.2005.00351.x CrossRefPubMed

16.

Migliorati CA, Siegel MA, Elting LS (2006) Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol 7(6):508–514. https://doi.org/10.1016/S1470-2045(06)70726-4 CrossRefPubMed

17.

McLeod NMH, Brennan PA, Ruggiero SL (2012) Bisphosphonate osteonecrosis of the jaw: a historical and contemporary review. Surgeon 10(1):36–42. https://doi.org/10.1016/j.surge.2011.09.002 CrossRefPubMed

18.

Otto S, Schreyer C, Hafner S (2012) Bisphosphonate-related osteonecrosis of the jaws—characteristics, risk factors, clinical features, localization and impact on oncological treatment. J Craniomaxillofac Surg 40:303–309CrossRefPubMed

19.

Lee CY, David T, Nishime M (2007) Use of platelet-rich plasma in the management of oral bisphosphonate-associated osteonecrosis of the jaw: a report of 2 cases. J Oral Implantol 33(6):371–382CrossRefPubMed

20.

Ruggiero SL, Dodson TB, Leon A (2009) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw—2009 update. J Oral Maxillofac Surg 67:2–12CrossRefPubMed

21.

Liberati A, Altman DG, Tetziaff J (2009) The PRISMA statement for reporting systematic and meta-analysis of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62(10):e1–e34. https://doi.org/10.1016/j.jclinepi.2009.06.006 CrossRefPubMed

22.

Petrucci MT, Gallucci C, Agrillo A (2007) Role of ozone therapy in the treatment of osteonecrosis of the jaws in multiple myeloma patients. Haematologica 92(9):1289–1290. https://doi.org/10.3324/haematol.11096 CrossRefPubMed

23.

Bocanegra-Pèrez S, Barrero MV, Hernández MS (2008) Bisphosphonate-associated osteonecrosis of the jaw. A proposal for conservative treatment. Med Oral Patol Oral Cir Bucal 13:E770–E773

24.

Agrillo A, Filiaci F, Ramieri V (2012) Bisphosphonate-related osteonecrosis of the jaw (BRONJ) 5 year experience in the treatment of 131 cases with ozone therapy. Eur Rev Med Pharmacol Sci 16:1741–1747PubMed

25.

Otto S, Baumann S, Ehrenfeld M (2013) Successful surgical management of osteonecrosis of the jaw due to RANK-ligand inhibitor treatment using fluorescence guided bone resection. J Craniomaxillofac Surg 41(7):694–698. https://doi.org/10.1016/j.jcms.2013.05.038 CrossRefPubMed

26.

Duarte LF, Reis HB, Tucci R (2014) Bisphosphonate-related osteonecrosis of the jaws: analysis of a case series at a dental school. Spec Care Dentist 34(2):77–83. https://doi.org/10.1111/scd.12023 CrossRef

27.

Campisi G, Fedele S, Fusco V (2014) Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents. Future Oncol 10(2):257–275. https://doi.org/10.2217/fon.13.211 CrossRefPubMed

28.

Altay MA, Tasar F, Tosun E (2014) Low-level laser therapy supported surgical treatment of bisphosphonate related osteonecrosis of jaws: a retrospective analysis of 11 cases. Photomed Laser Surg 32(8):468–475. https://doi.org/10.1089/pho.2014.3742 CrossRefPubMed

29.

Ruggiero SL, Kohn N (2015) Disease stage and mode of therapy are important determinants of treatment outcomes for medication-related osteonecrosis of the jaw. J Oral Maxillofac Surg 73(12):S94–S100. https://doi.org/10.1016/j.joms.2015.09.024 CrossRefPubMed

30.

Yarom N, Yahalom R, Shoshani Y (2007) Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. Osteoporos Int 18(10):1363–1370. https://doi.org/10.1007/s00198-007-0384-2 CrossRefPubMed

31.

Rincón H, Rodríguez Z, Tambay C (2007) Osteonecrosis of the jaws and bisphosphonates. Report of fifteen cases. Therapeutic recommendations. Med Oral Patol Oral Cir Bucal 12:E267–E271

32.

Van den Wyngaert T, Claeys T, Huizing MT (2009) Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome. Ann Oncol 20:331–336CrossRefPubMed

33.

Ibrahim T, Barbanti F, Marrano GG (2008) Osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: a retrospective study. Oncologist 13(3):330–336. https://doi.org/10.1634/theoncologist.2007-0159 CrossRefPubMed

34.

Williamson RA (2010) Surgical management of bisphosphonate induced osteonecrosis of the jaws. Int J Oral Maxillofac Surg 39(3):251–255. https://doi.org/10.1016/j.ijom.2009.11.014 CrossRefPubMed

35.

Scoletta M, Arduino PG, Dalmasso P (2010) Treatment outcomes in patients with bisphosphonate-related osteonecrosis of the jaws: a prospective study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 110(1):46–53. https://doi.org/10.1016/j.tripleo.2010.02.020 CrossRefPubMed

36.

Vescovi P, Manfredi M, Merigo E (2010) Surgical approach with Er:YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT). Lasers Med Sci 25(1):101–113. https://doi.org/10.1007/s10103-009-0687-y CrossRefPubMed

37.

Moretti F, Pelliccioni GA, Montebugnoli L (2011) A prospective clinical trial for assessing the efficacy of a minimally invasive protocol in patients with bisphosphonate-associated osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 112(6):777–782. https://doi.org/10.1016/j.tripleo.2011.07.004 CrossRefPubMed

38.

Eckardt AM, Lemound J, Lindhorst D (2011) Surgical management of bisphosphonate-related osteonecrosis of the jaw in oncologic patients—a challenging problem. Anticancer Res 31(6):2313–2318PubMed

39.

Vescovi P, Merigo E, Meleti M (2014) Conservative surgical management of stage I bisphosphonate-related osteonecrosis of the jaw. Int J Dent 2014:107690CrossRefPubMedPubMedCentral

40.

Fukushima Y, Enoki Y, Nakaoka C (2015) Usability of surgical treatment in cases of bisphosphonate-related osteonecrosis of the jaw stage 2 with sequestrum. Ann Maxillofac Surg 5(1):67–70. https://doi.org/10.4103/2231-0746.161067 CrossRefPubMedPubMedCentral

41.

Bodem JP, Kargus S, Engel M (2015) Value of nonsurgical therapeutic management of stage I bisphosphonate-related osteonecrosis of the jaw. J Craniomaxillofac Surg 43(7):1139–1143. https://doi.org/10.1016/j.jcms.2015.05.019 CrossRefPubMed

42.

Wilde F, Heufelder M, Winter K (2011) The role of surgical therapy in the management of intravenous bisphosphonates-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 111(2):153–163. https://doi.org/10.1016/j.tripleo.2010.04.015 CrossRefPubMed

43.

Atalay B, Yalcin S, Emes Y (2011) Bisphosphonate-related osteonecrosis: laser-assisted surgical treatment or conventional surgery? Lasers Med Sci 26(6):815–823. https://doi.org/10.1007/s10103-011-0974-2 CrossRefPubMed

44.

Voss PJ, Oshero JJ, Müller A (2012) Surgical treatment of bisphosphonate-associated osteonecrosis of the jaw: technical report and follow up of 21 patients. J Craniomaxillofac Surg 40(8):719–725. https://doi.org/10.1016/j.jcms.2012.01.005 CrossRefPubMed

45.

Jabbour Z, El-Hakim M, Mesbah-Ardakani P (2012) The outcomes of conservative and surgical treatment of stage 2 bisphosphonate-related osteonecrosis of the jaws: a case series. Int J Oral Maxillofac Surg 41(11):1404–1409. https://doi.org/10.1016/j.ijom.2012.05.012 CrossRefPubMed

46.

Ferlito S, Puzzo S, Palermo F (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):425–429. https://doi.org/10.1016/j.bjoms.2011.08.004 CrossRefPubMed

47.

Bocanegra-Pèrez S, Vicente-Barrero M, Knezevic M (2012) Use of platelet-rich plasma in the treatment of bisphosphonate related osteonecrosis of the jaw. Int J Oral Maxillofac Surg 41(11):1410–1415. https://doi.org/10.1016/j.ijom.2012.04.020 CrossRefPubMed

48.

Mozzati M, Gallesio G, Pol R (2013) A report on a 7-year follow up of the surgical management with PRGF-ENDORET® of oncologic patients affected by intravenous bisphosphonate related osteonecrosis of the jaw. Surgery S12:011

49.

Kim JW, Kim SJ, Kim M (2014) Leucocyte-rich and platelet-rich fibrin for the treatment of bisphosphonate-related osteonecrosis of the jaw: a prospective feasibility study. Br J Oral Maxillofac Surg 52(9):854–859. https://doi.org/10.1016/j.bjoms.2014.07.256 CrossRefPubMed

50.

Longo F, Guida A, Aversa C (2014) Platelet rich plasma in the treatment of bisphosphonate-related osteonecrosis of the jaw: personal experience and review of the literature. Int J Dent Article ID 298945. https://doi.org/10.1155/2014/298945

51.

Rugani P, Acham S, Kirnbauer B (2015) Stage-related treatment concept of medication-related osteonecrosis of the jaw—a case series. Clin Oral Investig 19(6):1329–1338. https://doi.org/10.1007/s00784-014-1384-1 CrossRefPubMed

52.

Reich W, Bilkenroth U, Schubert J (2015) Surgical treatment of bisphosphonate-associated osteonecrosis: prognostic score and long-term results. J Craniomaxillofac Surg 43(9):1809–1822. https://doi.org/10.1016/j.jcms.2015.07.035 CrossRefPubMed

53.

Lopes RN, Rabelo GD, Rocha AC (2015) Surgical therapy for bisphosphonate-related osteonecrosis of the jaw: six year experience of a single institution. J Oral Maxillofac Surg 73(7):1288–1295. https://doi.org/10.1016/j.joms.2015.01.008 CrossRefPubMed

54.

Bodem JP, Schaal C, Kargus S (2016) Surgical management of bisphosphonate-related osteonecrosis of the jaw stages II and III. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 121(4):367–372. https://doi.org/10.1016/j.oooo.2015.10.033 CrossRef

55.

Nisi M, La Ferla F, Karapetsa D (2016) Conservative surgical management of patients with bisphosphonate-related osteonecrosis of the jaw: a series of 120 patients. Br J Oral Maxillofac Surg 54(8):930–935. https://doi.org/10.1016/j.bjoms.2016.06.015 CrossRefPubMed

56.

Marx RE (2014) A decade of bisphosphonate bone complications: what it has taught us about bone physiology. Int J Oral Maxillofac Implants 29(2):e247–e258. https://doi.org/10.11607/jomi.te61 CrossRefPubMed

Title: Stage-specific therapeutic strategies of medication-related osteonecrosis of the jaws: a systematic review and meta-analysis of the drug suspension protocol
Authors: Luca Ramaglia
Agostino Guida
Vincenzo Iorio-Siciliano
Alessandro Cuozzo
Andrea Blasi
Anton Sculean
Publication date: 01-03-2018
Publisher: Springer Berlin Heidelberg
Published in: Clinical Oral Investigations / Issue 2/2018
Print ISSN: 1432-6981
Electronic ISSN: 1436-3771
DOI: https://doi.org/10.1007/s00784-017-2325-6

At a glance: The STEP trials

Springer Medicine

Stage-specific therapeutic strategies of medication-related osteonecrosis of the jaws: a systematic review and meta-analysis of the drug suspension protocol

Abstract

Objective

Materials and methods

Results

Conclusions

Clinical relevance

At a glance: The STEP trials

Springer Medicine

Abstract

Objective

Materials and methods

Results

Conclusions

Clinical relevance

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