, Volume 105, Issue 4, pp 484–493 | Cite as

Treatment of stage II medication-related osteonecrosis of the jaw with necrosectomy and autologous bone marrow mesenchymal stem cells

  • Pit Jacob Voss
  • Akihiko MatsumotoEmail author
  • Esteban Alvarado
  • Rainer Schmelzeisen
  • Fabian Duttenhöfer
  • Philipp Poxleitner
Original Article


Treatment strategies for medication-related osteonecrosis of the jaw (MRONJ) remain controversial. Although the AAOMS suggests a conservative approach, a surgical management with necrosectomy is often required when conservative management has failed. Moreover, recent studies have shown promising results using an early stage surgical treatment. Over the past decade, cell-based bone regeneration utilizing bone marrow mesenchymal stem cells (MSCs) received increased attention. MSCs are known to promote wound healing and induce new bone formation in compromised tissue. Accordingly, the aim of this study was to assess the role of MSCs in the management of MRONJ. This study included 6 patients referred to our department with the diagnosis of MRONJ. Upon informed consent, the patients underwent surgical resection of necrotic bone followed by MSCs grafting. The MSCs were separated from bone marrow cells aspirated from the iliac crest using a bone marrow aspirate concentrate system. The MSCs were grafted into the defect with autologous thrombin and the defect was covered with a collagen membrane. In all cases, bony edges were rounded and the wound was closed using a three-layered technique. In the follow-up from 12 to 54 months, all patients including those who had impaired conditions, sepsis, or pathological fracture, showed satisfactory healing with no signs of wound infection. This pilot study indicated that surgical management in combination with MSCs transplantation seems to be a promising treatment modality in the therapy of MRONJ.


Medication-related osteonecrosis of the jaw Bisphosphonate Mesenchymal stem cells Stem cell transplantation 




This study was supported by the Osteology Foundation Grant No. 08-026.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the local Ethics Committee of the University of Freiburg (Nr. 242/09).

Informed consent

All patients signed informed consent before involvement into the study.


  1. 1.
    Aghaloo TL, Felsenfeld AL, Tetradis S. Osteonecrosis of the jaw in a patient on denosumab. J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg. 2010;68(5):959–63.CrossRefGoogle Scholar
  2. 2.
    Taylor KH, Middlefell LS, Mizen KD. Osteonecrosis of the jaws induced by anti-RANK ligand therapy. Br J Oral Maxillofac Surg. 2010;48(3):221–3.CrossRefPubMedGoogle Scholar
  3. 3.
    Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’Ryan F. American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg. 2014;72(10):1938–56.CrossRefGoogle Scholar
  4. 4.
    Anastasilakis AD, Toulis KA, Polyzos SA, Anastasilakis CD, Makras P. Long-term treatment of osteoporosis: safety and efficacy appraisal of denosumab. Ther Clin Risk Manag. 2012;8:295–306.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Rustemeyer J, Bremerich A. Bisphosphonate-associated osteonecrosis of the jaw: what do we currently know? A survey of knowledge given in the recent literature. Clin Oral Invest. 2010;14(1):59–64.CrossRefGoogle Scholar
  6. 6.
    Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, Nooka A, Sayegh G, Guarneri V, Desrouleaux K. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Min Res Off J Am Soc Bone Min Res. 2008;23(6):826–36.CrossRefGoogle Scholar
  7. 7.
    Agrillo A, Petrucci MT, Tedaldi M, Mustazza MC, Marino SM, Gallucci C, Iannetti G. New therapeutic protocol in the treatment of avascular necrosis of the jaws. J Craniofac Surg. 2006;17(6):1080–3.CrossRefPubMedGoogle Scholar
  8. 8.
    Stockmann P, Vairaktaris E, Wehrhan F, Seiss M, Schwarz S, Spriewald B, Neukam FW, Nkenke E. Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up. Support Care Cancer Off J Multinatl Assoc Support Care Cancer. 2010;18(4):449–60.Google Scholar
  9. 9.
    Voss PJ, Joshi Oshero J, Kovalova-Muller A, Veigel Merino EA, Sauerbier S, Al-Jamali J, Lemound J, Metzger MC, Schmelzeisen R. Surgical treatment of bisphosphonate-associated osteonecrosis of the jaw: technical report and follow up of 21 patients. J Cranio Maxillo Facial Surg Off Publ Eur Assoc Cranio Maxillo Facial Surg. 2012;40(8):719–25.CrossRefGoogle Scholar
  10. 10.
    Williamson RA. Surgical management of bisphosphonate induced osteonecrosis of the jaws. Int J Oral Maxillofac Surg. 2010;39(3):251–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Curi MM, Cossolin GS, Koga DH, Zardetto C, Christianini S, Feher O, Cardoso CL, dos Santos MO. Bisphosphonate-related osteonecrosis of the jaws–an initial case series report of treatment combining partial bone resection and autologous platelet-rich plasma. J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg. 2011;69(9):2465–72.CrossRefGoogle Scholar
  12. 12.
    Atalay B, Yalcin S, Emes Y, Aktas I, Aybar B, Issever H, Mandel NM, Cetin O, Oncu B. Bisphosphonate-related osteonecrosis: laser-assisted surgical treatment or conventional surgery? Lasers Med Sci. 2011;26(6):815–23.CrossRefPubMedGoogle Scholar
  13. 13.
    Dong Y, Li Y, Huang C, Gao K, Weng X. Systemic application of teriparatide for steroid induced osteonecrosis in a rat model. BMC Musculoskel Disord. 2015;16:163.CrossRefGoogle Scholar
  14. 14.
    Kakehashi H, Ando T, Minamizato T, Nakatani Y, Kawasaki T, Ikeda H, Kuroshima S, Kawakami A, Asahina I. Administration of teriparatide improves the symptoms of advanced bisphosphonate-related osteonecrosis of the jaw: preliminary findings. Int J Oral Maxillofac Surg. 2015;44(12):1558–64.CrossRefPubMedGoogle Scholar
  15. 15.
    Cicciu M, Herford AS, Juodzbalys G, Stoffella E. Recombinant human bone morphogenetic protein type 2 application for a possible treatment of bisphosphonates-related osteonecrosis of the jaw. J Craniofac Surg. 2012;23(3):784–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Salamon A, Toldy E. Use of mesenchymal stem cells from adult bone marrow for injured tissue repair. Orv Hetil. 2009;150(27):1259–65.CrossRefPubMedGoogle Scholar
  17. 17.
    Iohara K, Nakashima M, Ito M, Ishikawa M, Nakasima A, Akamine A. Dentin regeneration by dental pulp stem cell therapy with recombinant human bone morphogenetic protein 2. J Dent Res. 2004;83(8):590–5.CrossRefPubMedGoogle Scholar
  18. 18.
    Sun Y, Feng Y, Zhang C. The effect of bone marrow mononuclear cells on vascularization and bone regeneration in steroid-induced osteonecrosis of the femoral head. Joint Bone Spine Revue du Rhumatisme. 2009;76(6):685–90.CrossRefGoogle Scholar
  19. 19.
    Ueda M, Yamada Y, Ozawa R, Okazaki Y. Clinical case reports of injectable tissue-engineered bone for alveolar augmentation with simultaneous implant placement. Int J Periodontics Restor Dent. 2005;25(2):129–37.Google Scholar
  20. 20.
    Handschel J, Meyer U. Infection, vascularization, remodelling-are stem cells the answers for bone diseases of the jaws? Head Face Med. 2011;7:5.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Warren SM, Fong KD, Chen CM, Loboa EG, Cowan CM, Lorenz HP, Longaker MT. Tools and techniques for craniofacial tissue engineering. Tissue Eng. 2003;9(2):187–200.CrossRefPubMedGoogle Scholar
  22. 22.
    Sauerbier S, Stubbe K, Maglione M, Haberstroh J, Kuschnierz J, Oshima T, Xavier SP, Brunnberg L, Schmelzeisen R, Gutwald R. Mesenchymal stem cells and bovine bone mineral in sinus lift procedures—an experimental study in sheep. Tissue Eng C Methods. 2010;16(5):1033–9.CrossRefGoogle Scholar
  23. 23.
    Freiberger JJ, Padilla-Burgos R, Chhoeu AH, Kraft KH, Boneta O, Moon RE, Piantadosi CA. Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series. J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg. 2007;65(7):1321–7.CrossRefGoogle Scholar
  24. 24.
    Muschler GF, Boehm C, Easley K. Aspiration to obtain osteoblast progenitor cells from human bone marrow: the influence of aspiration volume. J Bone Joint Surg Am Vol. 1997;79(11):1699–709.CrossRefGoogle Scholar
  25. 25.
    Gutwald R, Haberstroh J, Kuschnierz J, Kister C, Lysek DA, Maglione M, Xavier SP, Oshima T, Schmelzeisen R, Sauerbier S. Mesenchymal stem cells and inorganic bovine bone mineral in sinus augmentation: comparison with augmentation by autologous bone in adult sheep. Br J Oral Maxillofac Surg. 2010;48(4):285–90.CrossRefPubMedGoogle Scholar
  26. 26.
    Schmelzeisen R, Gutwald R, Oshima T, Nagursky H, Vogeler M, Sauerbier S. Making bone II: maxillary sinus augmentation with mononuclear cells—case report with a new clinical method. Br J Oral Maxillofac Surg. 2011;49(6):480–2.CrossRefPubMedGoogle Scholar
  27. 27.
    Duttenhoefer F, Hieber SF, Stricker A, Schmelzeisen R, Gutwald R, Sauerbier S. Follow-up of implant survival comparing ficoll and bone marrow aspirate concentrate methods for hard tissue regeneration with mesenchymal stem cells in humans. BioRes Open Access. 2014;3(2):75–6.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Sauerbier S, Stricker A, Kuschnierz J, Buhler F, Oshima T, Xavier SP, Schmelzeisen R, Gutwald R. In vivo comparison of hard tissue regeneration with human mesenchymal stem cells processed with either the FICOLL method or the BMAC method. Tissue Eng C Methods. 2010;16(2):215–23.CrossRefGoogle Scholar
  29. 29.
    Elda S, Czerninski R, Avgil M, Or R. Hematopoietic stem cells local transplantation for the treatment of osteonecrosis of the jaws. Support Care Cancer. 2005;13:455.Google Scholar
  30. 30.
    Cella L, Oppici A, Arbasi M, Moretto M, Piepoli M, Vallisa D, Zangrandi A, Di Nunzio C, Cavanna L. Autologous bone marrow stem cell intralesional transplantation repairing bisphosphonate related osteonecrosis of the jaw. Head Face Med. 2011;7:16.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Fournier P, Boissier S, Filleur S, Guglielmi J, Cabon F, Colombel M, Clezardin P. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res. 2002;62(22):6538–44.PubMedGoogle Scholar
  32. 32.
    Gonzalvez-Garcia M, Rodriguez-Lozano FJ, Villanueva V, Segarra-Fenoll D, Rodriguez-Gonzalez MA, Onate-Sanchez R, Blanquer M, Meseguer-Olmo L, Moraleda JM. Mesenchymal stem cells and bisphosphonate-related osteonecrosis of the jaw: the future? Oral Dis. 2012;18(8):823–4.CrossRefPubMedGoogle Scholar
  33. 33.
    Gruber R, Mayer C, Schulz W, Graninger W, Peterlik M, Watzek G, Luyten FP, Erlacher L. Stimulatory effects of cartilage-derived morphogenetic proteins 1 and 2 on osteogenic differentiation of bone marrow stromal cells. Cytokine. 2000;12(11):1630–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Reddi AH. Cartilage morphogenetic proteins: role in joint development, homoeostasis, and regeneration. Ann Rheum Dis. 2003;62(Suppl 2):ii73–8.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Tsumaki N, Tanaka K, Arikawa-Hirasawa E, Nakase T, Kimura T, Thomas JT, Ochi T, Luyten FP, Yamada Y. Role of CDMP-1 in skeletal morphogenesis: promotion of mesenchymal cell recruitment and chondrocyte differentiation. J Cell Biol. 1999;144(1):161–73.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kos M, Brusco D, Kuebler J, Engelke W. Clinical comparison of patients with osteonecrosis of the jaws, with and without a history of bisphosphonates administration. Int J Oral Maxillofac Surg. 2010;39(11):1097–102.CrossRefPubMedGoogle Scholar
  37. 37.
    Mast G, Otto S, Mucke T, Schreyer C, Bissinger O, Kolk A, Wolff KD, Ehrenfeld M, Sturzenbaum SR, Pautke C. Incidence of maxillary sinusitis and oro-antral fistulae in bisphosphonate-related osteonecrosis of the jaw. J Cranio Maxillo Facial Surg Off Publ Eur Assoc Cranio Maxillo Facial Surg. 2012;40(7):568–71.CrossRefGoogle Scholar
  38. 38.
    Pautke C, Bauer F, Tischer T, Kreutzer K, Weitz J, Kesting M, Holzle F, Kolk A, Sturzenbaum SR, Wolff KD. Fluorescence-guided bone resection in bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg. 2009;67(3):471–6.CrossRefGoogle Scholar
  39. 39.
    Fleisher KE, Doty S, Kottal S, Phelan J, Norman RG, Glickman RS. Tetracycline-guided debridement and cone beam computed tomography for the treatment of bisphosphonate-related osteonecrosis of the jaw: a technical note. J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg. 2008;66(12):2646–53.CrossRefGoogle Scholar
  40. 40.
    Wilde F, Heufelder M, Winter K, Hendricks J, Frerich B, Schramm A, Hemprich A. 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. 2011;111(2):153–63.CrossRefPubMedGoogle Scholar
  41. 41.
    Lemound J, Eckardt A, Kokemuller H, von See C, Voss PJ, Tavassol F, Rucker M, Rana M, Gellrich NC. Bisphosphonate-associated osteonecrosis of the mandible: reliable soft tissue reconstruction using a local myofascial flap. Clin Oral Invest. 2012;16(4):1143–52.CrossRefGoogle Scholar
  42. 42.
    Khan AA, Sandor GK, Dore E, Morrison AD, Alsahli M, Amin F, Peters E, Hanley DA, Chaudry SR, Dempster DW. Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw. J Rheum. 2008;35(7):1391–7.PubMedGoogle Scholar
  43. 43.
    Yoneda T, Hagino H, Sugimoto T, Ohta H, Takahashi S, Soen S, Taguchi A, Toyosawa S, Nagata T, Urade M. 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 Bone Min Metab. 2010;28(4):365–83.CrossRefGoogle Scholar
  44. 44.
    Marx RE. Reconstruction of defects caused by bisphosphonate-induced osteonecrosis of the jaws. J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg. 2009;67(5 Suppl):107–19.CrossRefGoogle Scholar
  45. 45.
    Bartl R. Practical guidelines for the management of osteoporosis–evidence-based and cost-effective. Dtsch Med Wochenschr. 2007;132(18):995–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Otto S, Troltzsch M, Jambrovic V, Panya S, Probst F, Ristow O, Ehrenfeld M, Pautke C. Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: a trigger for BRONJ development? J Cranio Maxillo Facial Surg Off Publ Eur Assoc Cranio Maxillo Facial Surg. 2015;43(6):847–54.CrossRefGoogle Scholar
  47. 47.
    Wilde F, Hendricks J, Riese C, Pausch NC, Schramm A, Heufelder M. Bone regeneration without bone grafting after resection of a segment of the mandible to treat bisphosphonate-related osteonecrosis of the jaw. J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg. 2011;69(10):2657–62.CrossRefGoogle Scholar
  48. 48.
    Hellstein JW, Marek CL. Bisphosphonate osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg Off J Am Assoc Oral Maxillofac Surg. 2005;63(5):682–9.CrossRefGoogle Scholar
  49. 49.
    Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int J Establ Result Coop Eur Found Osteoporos Natl Osteoporos Found USA. 2008;19(6):733–59.CrossRefGoogle Scholar
  50. 50.
    Allegra A, Oteri G, Nastro E, Alonci A, Bellomo G, Del Fabro V, Quartarone E, Alati C, De Ponte FS, Cicciu D. Patients with bisphosphonates-associated osteonecrosis of the jaw have reduced circulating endothelial cells. Hematol Oncol. 2007;25(4):164–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Kikuiri T, Kim I, Yamaza T, Akiyama K, Zhang Q, Li Y, Chen C, Chen W, Wang S, Le AD. Cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw-like disease in mice. J Bone Min Res Off J Am Soc Bone Min Res. 2010;25(7):1668–79.CrossRefGoogle Scholar
  52. 52.
    Li Y, Xu J, Mao L, Liu Y, Gao R, Zheng Z, Chen W, Le A, Shi S, Wang S. Allogeneic mesenchymal stem cell therapy for bisphosphonate-related jaw osteonecrosis in Swine. Stem Cells Dev. 2013;22(14):2047–56.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Society of The Nippon Dental University 2017

Authors and Affiliations

  • Pit Jacob Voss
    • 1
  • Akihiko Matsumoto
    • 2
    Email author
  • Esteban Alvarado
    • 3
  • Rainer Schmelzeisen
    • 1
  • Fabian Duttenhöfer
    • 1
  • Philipp Poxleitner
    • 1
  1. 1.Department of Oral and Maxillofacial SurgeryUniversity Medical Center FreiburgFreiburg im BreisgauGermany
  2. 2.Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental ScienceKyushu UniversityFukuokaJapan
  3. 3.Section of Orthodontics and Maxillofacial SurgeryLatinamerican University of Science and TechnologyBarrio TournónCosta Rica

Personalised recommendations