Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

The aim of this study was to evaluate a possible role of microcracks in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (ONJ) and to discuss an etiological model. Bone samples from 35 patients with ONJ were analyzed. Control samples were taken from five patients with osteomyelitis (OM), ten patients with osteoradionecrosis, seven patients with osteoporosis and bisphosphonate medication without signs of ONJ, and six osteoporotic elderly patients. Samples were examined using scanning electron microscopy. In 54% of the bone samples of patients with ONJ, microcracks were seen. Inflammatory and connective tissue reactions within the microcracks were evident in 82% of the cases, indicating that these cracks were not artificial. In contrast, only 29% of samples from patients with oral bisphosphonate medication without ONJ, no sample from patients with OM, none of the osteoradionecrosis group, and only 17% from patients with osteoporosis showed microcracks. Statistically significant differences could be found between the ONJ group and the group after irradiation and the group with OM, respectively. The evidence of microcracks could be a first step in the pathogenesis of bisphosphonate-related ONJ. The accumulation of these microcracks leads to a situation that could be named “non-symptomatic ONJ”. Disruptions of the mucosal integrity may then allow bacterial invasion, leading to jawbone infection with exposed bone, fistulas, and pain. This state could be called “symptomatic ONJ”. Furthermore, an assumed local immunosuppression as indicated by various studies could explain the severe courses of therapy-resistant ONJ as regularly observed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Abu-Id MH, Acil Y, Gottschalk J, Kreusch T (2006) Bisphosphonatassoziierte Osteonekrose des Kiefers. Mund Kiefer Gesichtschir 10:73–81

    Article  PubMed  Google Scholar 

  2. Allen MR, Burr DB (2008) Mandible matrix necrosis in beagle dogs after 3 years of daily oral bisphosphonate treatment. J Oral Maxillofac Surg 66:987–994

    Article  PubMed  Google Scholar 

  3. Altundal H, Guevener OE (2004) The effect of alendronate on resorption of the alveolar bone following tooth extraction. Int J Oral Maxillofac Surg 33:286–293

    Article  PubMed  Google Scholar 

  4. Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, Fenton R, Gahres N, Sausville E, Ord R, Meiller T (2006) Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 24:945–952

    Article  PubMed  Google Scholar 

  5. Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Papadimitriou C, Terpos E, Dimopoulos A (2005) Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23:8580–8587

    Article  PubMed  Google Scholar 

  6. Bouvier M, Hylander WL (1981) Effect of bone strain on cortical bone structure in macaques (Macaca mulatta). J Morph 167:1–12

    Article  PubMed  Google Scholar 

  7. Bras J, de Jonge HKT, van Merkensteyn JPR (1990) Osteoradionecrosis of the mandible: pathogenesis. Am J Otolaryngol 11:244–250

    Article  PubMed  Google Scholar 

  8. Bukowski JF, Dascher CC, Das H (2005) Alternative bisphosphonate targets and mechanisms of action. Biochem Biophys Res Commun 328:746–750

    Article  PubMed  Google Scholar 

  9. Burr DB, Hooser M (1995) Alterations to the en bloc basic fuchsin staining protocol for the demonstration of microdamage produced in vivo. Bone 17:431–433

    Article  PubMed  Google Scholar 

  10. Burr DB, Stafford T (1990) Validity of the bulk staining technique to separate artificial from in vivo bone microdamage. Clin Orthop Relat Res 260:305–308

    PubMed  Google Scholar 

  11. Burr DB, Martin RB, Schaffler MB, Radin EL (1985) Bone remodeling in response to in vivo fatigue microdamage. J Biomech 18:189–200

    Article  PubMed  Google Scholar 

  12. Conti L, Casetti R, Cardone M, Varano B, Martino A, Belardelli F, Poccia F, Gessani S (2005) Reciprocal activating interaction between dendritic cells and pamidronate-stimulated gammadelta T cells: role of CD86 and inflammatory cytokines. J Immunol 174:252–260

    PubMed  Google Scholar 

  13. Day JS, Ding M, Bednarz P, van der Linden JC, Mashiba T, Hirano T, Johnston CC, Burr DB, Hvid I, Sumner DR, Weinans H (2004) Bisphosphonate treatment affects trabecular bone apparent modulus through micro-architecture rather than matrix properties. J Orthop Res 22:465–471

    Article  PubMed  Google Scholar 

  14. Dechow PC, Hylander WL (2000) Elastic properties and masticatory bone stress in the macaque mandible. Am J Phys Anthropol 112:553–574

    Article  PubMed  Google Scholar 

  15. Dicuonzo G, Vincenzi B, Santini D, Avvisati L, Rocci L, Battistoni F, Gavasci M, Borzomati D, Coppola R, Tonini G (2003) Fever after zoledronic acid administration is due to increase in TNF-alpha and IL-6. J Interferon Cytokine Res 23:649–654

    Article  PubMed  Google Scholar 

  16. Dieli F, Gebbia N, Poccia F, Gaccamo N, Montesano C, Fulfaro F, Arcara C, Valerio MR, Meraviglia S, Di Sano C, Sireci G, Salerno A (2003) Induction of gammadelta T-lymphocyte effector functions by bisphosphonate zoledronic acid in cancer patients in vivo. Blood 102:2310–2311

    Article  PubMed  Google Scholar 

  17. Enzendam J, Kosterman K, Spijkerboer H, Bleumink R, Hassing I, van Rooijen N, Vos JG, Pieters R (2005) Macrophages are involved in hexachlorobenzene-induced adverse effects. Toxicol Appl Pharmacol 209:19–27

    Article  Google Scholar 

  18. Frost HM (1960) Presence of microscopic cracks in vivo in bone. Henry Ford Hosp Med Bull 8:25–35

    Google Scholar 

  19. Hansen T, Kunkel M, Kirkpatrick CJ, Weber A (2006) Actimomyces in infected osteoradionecrosis—underestimated? Human Pathol 37:61–67

    Article  Google Scholar 

  20. Hansen T, Kunkel M, Weber A, Kirkpatrick CJ (2006) Osteonecrosis of the jaws in patients treated with bisphosphonates—histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med 35:155–160

    Article  PubMed  Google Scholar 

  21. Hansen T, Wagner W, Kirkpatrick CJ, Kunkel M (2006) Infected osteoradionecrosis of the mandible: follow-up study suggests deterioration in outcome for patients with actinomyces-positive bone biopsies. Int J Oral Maxillofac Surg 35:1001–1004

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  23. Hess LM, Jeter NJ, Benham-Hutchins M, Alberts DS (2008) Factors associated with osteonecrosis of the jaw among bisphosphonate users. Am J Med 121:475–483

    Article  PubMed  Google Scholar 

  24. Hewitt RE, Lissina A, Green AE, Slay ES, Price DA, Sewell AK (2005) The bisphosphonate acute phase response: rapid and copious production of proinflammatory cytokines by peripheral blood gd T cells in response to aminobishosphonates is inhibited by statins. Clin Exp Immunol 139:101–111

    Article  PubMed  Google Scholar 

  25. Hoefert S, Eufinger H (2006) Nekrosen der Kieferknochen unter Bisphosphonattherapie. Orthopäde 35:204–209

    Article  PubMed  Google Scholar 

  26. Hoefert S, Wierich W, Eufinger H, Krempien B (2006) BP-associated avascular necrosis (AN) of the jaws: histological findings. Bone 38(Suppl):76

    Article  Google Scholar 

  27. Hu JH, Ding M, Soballe K, Bechtold JE, Danielsen CC, Days JS, Hvid I (2002) Effects of short-term alendronate treatment on the three-dimensional microstructural, physical, and mechanical properties of dog trabecular bone. Bone 31:591–597

    Article  PubMed  Google Scholar 

  28. Huja SS, Hasan MS, Pidaparti R, Turner CH, Garetto LP, Burr DB (1999) Development of a fluorescent light technique for evaluating microdamage in bone subjected to fatigue loading. J Biomech 32:1243–1249

    Article  PubMed  Google Scholar 

  29. Huk OL, Zukor DJ, Antoniou J, Petit A (2003) Effect of pamidronate on the stimulation of macrophage TNF-alpha release by ultra-high-molecular-weight polyethylene particles: a role for apoptosis. J Orthop Res 21:81–87

    Article  PubMed  Google Scholar 

  30. Jereczek-Fossa BA, Orechia R (2002) Radiotherapy-induced mandibular bone complications. Cancer Treat Rev 28:65–74

    Article  PubMed  Google Scholar 

  31. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Lillian Shum L, Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E (2007) Bisphosphonate-associated osteonecrosis of the jaw: report of the task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22:1479–1491

    Article  PubMed  Google Scholar 

  32. Landesberg R, Cozin M, Cremers S, Woo V, Kousteni S, Sinha S, Garrett-Sinha LA, Raghavan S (2008) Inhibition of oral mucosal cell wound healing by bisphosphonates. J Oral Maxillofac Surg 66:839–847

    Article  PubMed  Google Scholar 

  33. Lee TC, Mohsin S, Taylor D, Parkesh R, Gunnlaugsson T, O’Brien FJ, Giehl M, Gowin W (2003) Detecting microdamage in bone. J Anat 203:161–172

    Article  PubMed  Google Scholar 

  34. Leemans JC, Juffermans NP, Florquin S, van Rooijen N, Vervoordeldank MJ, Verbon A, Deventer SJH, van der Poll T (2001) Depletion of alveolar macrophages exerts protective effects in pulmonary tuberculosis in mice. J Immunol 166:4604–4611

    PubMed  Google Scholar 

  35. Li J, Mashiba T, Burr DB (2001) Bisphosphonate treatment suppresses not only stochastic remodeling but also the targeted repair of microdamage. Cacif Tissue Int 69:281–286

    Article  Google Scholar 

  36. Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1118

    Article  PubMed  Google Scholar 

  37. Marx RE, Sawatari Y, Fortin M, Broumand V (2005) Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63:1567–1575

    Article  PubMed  Google Scholar 

  38. Mendenhall WM (2004) Mandibular osteoradionecrosis. J Clin Oncol 22:4867–4868

    Article  PubMed  Google Scholar 

  39. Migliorati CA (2003) Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 21:253–254

    Article  Google Scholar 

  40. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Sook-Bin MS (2005) Managing the care of patients with bisphosphonate-associated osteonecrosis. An American academy of oral medicine position paper. JADA 136:1658–1668

    PubMed  Google Scholar 

  41. Moreau MF, Guillet C, Massin P, Chavalier S, Gascan H, Basle MF, Chapparad D (2007) Comparative effects of five bisphosphonates on apoptosis of macrophage cells in vitro. Biochem Pharmacol 73:718–723

    Article  PubMed  Google Scholar 

  42. O’Brien FJ, Brennan O, Kennedy OD, Lee C (2005) Microcracks in cortical bone: how do they affect bone biology? Curr Osteoporos Rep 3:39–45

    Article  PubMed  Google Scholar 

  43. Odvina CV, Zerwkh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY (2005) Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 90:1294–1301

    Article  PubMed  Google Scholar 

  44. Ott SM (2005) Editoral: long-term safety of bisphosphonates. J Clin Endocrinol Metab 90:1897–1899

    Article  PubMed  Google Scholar 

  45. Papapoulos SE (2001) Catabolic and anabolic signals in bone: therapeutic implications. Curr Opin Clin Nutr Metab Care 4:191–196

    Article  PubMed  Google Scholar 

  46. Peleg M, Lopez EAL (2006) The treatment of osteoradionecrosis of the mandible: the case for hyperbaric oxygen and bone graft reconstruction. J Oral Maxillofac Surg 64:956–960

    Article  PubMed  Google Scholar 

  47. Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T (1999) Prevention of osteocyte and osteoblast apoptosis by bisphophonates and calcitonin. J Clin Invest 104:1363–1374

    Article  PubMed  Google Scholar 

  48. Reid IR, Bolland MJ, Grey AB (2007) Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone 47:318–320

    Article  Google Scholar 

  49. Rizzoli R, Burlet N, Cahall D, Delmas PD, Eriksen EF, Felsenberg D, Grbic J, Jontell M, Landesberg R, Laslop A, Wollenhaupt M, Papapoulos S, Sezer O, Sprafka M, Reginster JY (2008) Osteonecrosis of the jaw and bisphosphonate treatment for osteoporosis. Bone 42:841–847

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  51. Ruggiero SL, Fantasia J, Carlson E (2006) Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102:433–441

    Article  PubMed  Google Scholar 

  52. Sarin J, DeRossi SS, Akintoye SO (2008) Updates on bisphosphonates and potential pathobiology of bisphosphonate-induced jaw osteonecrosis. Oral Dis 14:277–285

    Article  PubMed  Google Scholar 

  53. Schaffler MB, Pitchford K, Choi K, Riddle M (1994) Examination of compact bone microdamage using back-scattered electron microscopy. Bone 15:483–488

    Article  PubMed  Google Scholar 

  54. Sedghizadeh PP, Kumar SKS, Gorur A, Schaudinn C, Shuler CF, Costerton JW (2008) Identification of microbiofilms in osteonecrosis of the jaws secondary to bisphosphonte therapy. J Oral Maxillofac Surg 66:767–775

    Article  PubMed  Google Scholar 

  55. Takagi K, Takagi M, Kanangat S, Warrington KJ, Shigemitsu H, Postlethwaite AE (2005) Modulation of TNF-alpha gene expression by IFN-gamma and pamidronate in murine macrophages: regulation by STAT1-dependent pathways. J Immunol 174:1801–1810

    PubMed  Google Scholar 

  56. van Poznak C (2006) The phenomenon of osteonecrosis of the jaw in patients with metastatic breast cancer. Cancer Invest 24:110–112

    Article  PubMed  Google Scholar 

  57. Wannfors K, Hammarström L (1985) Infectious foci in chronic osteomyelitis of the jaws. Int J Oral Surg 14:493–503

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Burkhard Krempien (MD, PhD), professor emeritus of the Institute of Pathology, University of Heidelberg, Heidelberg, Germany, who first mentioned the importance of the microcracks seen in jaws under BP medication after his histological examinations of some specimen of our patients and also Walter Wierich (MD, PhD), Institute of Pathology, Recklinghausen, Germany, for his technical support and some important hints.

Conflicts of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, Regional Plastic Surgery, Knappschaftskrankenhaus, Academic Teaching Hospital of the Ruhr-Universität Bochum, Dorstener Str. 151, 45657, Recklinghausen, Germany

    Sebastian Hoefert & Harald Eufinger

  2. Department of Pathology, BG-Hospital Bergmannsheil, Ruhr-Universität Bochum, Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany

    Inge Schmitz & Andrea Tannapfel

Authors
  1. Sebastian Hoefert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Inge Schmitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Tannapfel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Harald Eufinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sebastian Hoefert.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hoefert, S., Schmitz, I., Tannapfel, A. et al. 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 Invest 14, 271–284 (2010). https://doi.org/10.1007/s00784-009-0300-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-009-0300-6

Keywords

Search

Navigation