Journal of Oral and Maxillofacial Surgery
Volume 67, Issue 5, Supplement , Pages 61-70 , May 2009

The Pathogenesis of Bisphosphonate-Related Osteonecrosis of the Jaw: So Many Hypotheses, So Few Data

  • Matthew R. Allen, PhD

      Affiliations

    • Assistant Professor, Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN
    • Corresponding Author InformationAddress correspondence and reprint requests to Dr Allen: Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr, MS-5035, Indianapolis, IN 46202
  • ,
  • David B. Burr, PhD

      Affiliations

    • Professor and Chair, Departments of Anatomy and Cell Biology and Orthopaedic Surgery, Indiana University School of Medicine and Biomedical Engineering Program, Indiana University-Purdue University Indianapolis, Indianapolis, IN

References 

  1. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479
  2. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg. 2003;61:1115
  3. Mehrotra B, Fantasia J, Nissel-Horowitz S, et al. Osteonecrosis of the maxilla: An unusual complication of prolonged bisphosphonate therapy (A case report [abstract]). Proc Am Soc Clin Oncol. 2003;22:795
  4. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg. 2004;62:527
  5. Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg. 2003;61:1104
  6. Amler MH, Johnson PL, Salman I. Histological and histochemical investigation of human alveolar socket healing in undisturbed extraction wounds. J Am Dent Assoc. 1960;61:32
  7. Cardaropoli G, Araujo M, Lindhe J. Dynamics of bone tissue formation in tooth extraction sites (An experimental study in dogs). J Clin Periodontol. 2003;30:809
  8. Reid IR, Bolland MJ, Grey AB. Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity?. Bone. 2007;41:318
  9. Reid IR, Cundy T. Osteonecrosis of the jaw. Skeletal Radiol. 2009;38:107
  10. Mavrokokki T, Cheng A, Stein B, et al. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg. 2007;65:415
  11. Rubegni P, Fimiani M. Images in clinical medicine (Bisphosphonate-associated contact stomatitis). N Engl J Med. 2006;355:e25
  12. Reddy GT, Kumar TM, Veena KM. Formulation and evaluation of alendronate sodium gel for the treatment of bone resorptive lesions in periodontitis. Drug Deliv. 2005;12:217
  13. Lin JH. Bisphosphonates: A review of their pharmacokinetic properties. Bone. 1996;18:75
  14. Russell RG, Watts NB, Ebetino FH, et al. Mechanisms of action of bisphosphonates: Similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. 2008;19:733
  15. Russell RG, Xia Z, Dunford JE, et al. Bisphosphonates: An update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci. 2007;1117:209
  16. Rodan GA, Fleisch HA. Bisphosphonates: Mechanisms of action. J Clin Invest. 1996;97:2692
  17. Allen MR, Iwata K, Phipps R, et al. Alterations in canine vertebral bone turnover, microdamage accumulation, and biomechanical properties following 1-year treatment with clinical treatment doses of risedronate or alendronate. Bone. 2006;39:872
  18. Mashiba T, Turner CH, Hirano T, et al. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone. 2001;28:524
  19. Allen MR, Burr DB. Three years of alendronate treatment results in similar levels of vertebral microdamage as after one year of treatment. J Bone Miner Res. 2007;22:1759
  20. Allen MR, Burr DB. Mandible matrix necrosis in beagle dogs after 3 years of daily oral bisphosphonate treatment. J Oral Maxillofac Surg. 2008;66:987
  21. Boivin GY, Chavassieux PM, Santora AC, et al. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone. 2000;27:687
  22. McDonald MM, Dulai S, Godfrey C, et al. Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling. Bone. 2008;43:653
  23. Plotkin LI, Aguirre JI, Kousteni S, et al. Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal-regulated kinase activation. J Biol Chem. 2005;280:7317
  24. Idris AI, Rojas J, Greig IR, et al. Aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro. Calcif Tissue Int. 2008;82:191
  25. Follet H, Li J, Phipps RJ, et al. Risedronate and alendronate suppress osteocyte apoptosis following cyclic fatigue loading. Bone. 2007;40:1172
  26. Plotkin LI, Weinstein RS, Parfitt AM, et al. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest. 1999;104:1363
  27. Boyce RW, Paddock CL, Gleason JR, et al. The effects of risedronate on canine cancellous bone remodeling: Three-dimensional kinetic reconstruction of the remodeling site. J Bone Miner Res. 1995;10:211
  28. Eriksen EF, Melsen F, Sod E, et al. Effects of long-term risedronate on bone quality and bone turnover in women with postmenopausal osteoporosis. Bone. 2002;31:620
  29. Iwata K, Li J, Follet H, et al. Bisphosphonates suppress periosteal osteoblast activity independent of resorption in rat femur and tibia. Bone. 2006;39:1053
  30. Allen MR, Follet H, Khurana M, et al. Anti-remodeling agents influence osteoblast activity differently in modeling- and remodeling-associated bone formation. Calcif Tissue Int. 2006;79:255
  31. Allen MR, Reinwald S, Burr DB. Alendronate reduces bone toughness of ribs without significantly increasing microdamage accumulation in dogs following 3 years of daily treatment. Calcif Tissue Int. 2008;82:354
  32. Mashiba T, Hirano T, Turner CH, et al. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res. 2000;15:613
  33. Reinwald S, Burr D. Review of nonprimate, large animal models for osteoporosis research. J Bone Miner Res. 2008;23:1353
  34. Garetto LP, Chen J, Parr JA, et al. Remodeling dynamics of bone supporting rigidly fixed titanium implants: A histomorphometric comparison in four species including humans. Implant Dent. 1995;4:235
  35. Han ZH, Palnitkar S, Rao DS, et al. Effects of ethnicity and age or menopause on the remodeling and turnover of iliac bone: Implications for mechanisms of bone loss. J Bone Miner Res. 1997;12:498
  36. Huja SS, Fernandez SA, Hill KJ, et al. Remodeling dynamics in the alveolar process in skeletally mature dogs. Anat Rec A Discov Mol Cell Evol Biol. 2006;288:1243
  37. Garetto LP, Tricker ND. Remodeling of bone surrounding the implant interface. In:  Garetto LP,  Turner CH,  Duncan RL, et al. editor. Bridging the Gap Between Dental & Orthopaedic Implants (3rd Annual Indiana Conference. Indianapolis, IN). 1998;
  38. Bamias A, Kastritis E, Bamia C, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: Incidence and risk factors. J Clin Oncol. 2005;23:8580
  39. Dimopoulos MA, Kastritis E, Anagnostopoulos A, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: Evidence of increased risk after treatment with zoledronic acid. Haematologica. 2006;91:968
  40. Corso A, Varettoni M, Zappasodi P, et al. A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma. Leukemia. 2007;21:1545
  41. Lewiecki EM, Miller PD, McClung MR, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res. 2007;22:1832
  42. Lipton A, Steger GG, Figueroa J, et al. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol. 2007;25:4431
  43. Helfrich MH. Osteoclast diseases and dental abnormalities. Arch Oral Biol. 2005;50:115
  44. Barry CP, Ryan CD, Stassen LF. Osteomyelitis of the maxilla secondary to osteopetrosis: A report of 2 cases in sisters. J Oral Maxillofac Surg. 2007;65:144
  45. Johnston CC, Lavy N, Lord T, et al. Osteopetrosis (A clinical, genetic, metabolic, and morphologic study of the dominantly inherited, benign form). Medicine (Baltimore). 1968;47:149
  46. Waguespack SG, Koller DL, White KE, et al. Chloride channel 7 (ClCN7) gene mutations and autosomal dominant osteopetrosis, type II. J Bone Miner Res. 2003;18:1513
  47. Ruggiero SL, Drew SJ. Osteonecrosis of the jaws and bisphosphonate therapy. J Dent Res. 2007;86:1013
  48. Bathi RJ, Masur VN. Pyknodysostosis—A report of two cases with a brief review of the literature. Int J Oral Maxillofac Surg. 2000;29:439
  49. Dimitrakopoulos I, Magopoulos C, Katopodi T. Mandibular osteomyelitis in a patient with pyknodysostosis: A case report of a 50-year misdiagnosis. J Oral Maxillofac Surg. 2007;65:580
  50. Harper RP, Fung E. Resolution of bisphosphonate-associated osteonecrosis of the mandible: Possible application for intermittent low-dose parathyroid hormone [rhPTH(1-34)]. J Oral Maxillofac Surg. 2007;65:573
  51. Lau AN, Ali SH, Adachi JD. Resolution of osteonecrosis of the jaw after teriparatide [recombinant human PTH (1-34)] therapy. Osteoporos Int. 2008;19(Suppl 1):S80
  52. Wang HL, Weber D, McCauley LK. Effect of long-term oral bisphosphonates on implant wound healing: Literature review and a case report. J Periodontol. 2007;78:584
  53. Malmgren B, Astrom E, Soderhall S. No osteonecrosis in jaws of young patients with osteogenesis imperfecta treated with bisphosphonates. J Oral Pathol Med. 2008;37:196
  54. Schwartz S, Joseph C, Iera D, et al. Bisphosphonates, osteonecrosis, osteogenesis imperfecta and dental extractions: A case series. J Can Dent Assoc. 2008;74:537
  55. Kingsmill VJ. Post-extraction remodeling of the adult mandible. Crit Rev Oral Biol Med. 1999;10:384
  56. Li C, Mori S, Li J, et al. Long-term effect of incadronate disodium (YM-175) on fracture healing of femoral shaft in growing rats. J Bone Miner Res. 2001;16:429
  57. Li J, Mori S, Kaji Y, et al. Concentration of bisphosphonate (incadronate) in callus area and its effects on fracture healing in rats. J Bone Miner Res. 2000;15:2042
  58. Peter CP, Cook WO, Nunamaker DM, et al. Effect of alendronate on fracture healing and bone remodeling in dogs. J Orthop Res. 1996;14:74
  59. Altundal H, Guvener O. The effect of alendronate on resorption of the alveolar bone following tooth extraction. Int J Oral Maxillofac Surg. 2004;33:286
  60. Olson HM, Hagen A. Inhibition of post-extraction alveolar ridge resorption in rats by dichloromethane diphosphonate. J Periodontal Res. 1982;17:669
  61. Bonewald LF. Osteocytes as dynamic multifunctional cells. Ann N Y Acad Sci. 2007;1116:281
  62. Turner CH, Robling AG, Duncan RL, et al. Do bone cells behave like a neuronal network?. Calcif Tissue Int. 2002;70:435
  63. Weinstein RS, Jilka RL, Parfitt AM, et al. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids (Potential mechanisms of their deleterious effects on bone). J Clin Invest. 1998;102:274
  64. Enlow DH. Functions of the Haversian system. Am J Anat. 1962;110:269
  65. Frost HM. In vivo osteocyte death. J Bone Joint Surg Am. 1960;42:138
  66. Burr DB, Hooser M. Alterations to the en bloc basic fuchsin staining protocol for the demonstration of microdamage produced in vivo. Bone. 1995;17:431
  67. Frost HM. Micropetrosis. J Bone Joint Surg Am. 1960;42:144
  68. Hansen T, Kunkel M, Weber A, et al. Osteonecrosis of the jaws in patients treated with bisphosphonates—Histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med. 2006;35:155
  69. Allen MR. Bisphosphonates and osteonecrosis of the jaw: moving from the bedside to the bench. Cells Tissues Organs. 2009;189:289
  70. Masarachia P, Weinreb M, Balena R, et al. Comparison of the distribution of 3H-alendronate and 3H-etidronate in rat and mouse bones. Bone. 1996;19:281
  71. Lin JH, Duggan DE, Chen IW, et al. Physiological disposition of alendronate, a potent anti-osteolytic bisphosphonate, in laboratory animals. Drug Metab Dispos. 1991;19:926
  72. Roelofs AJ, Coxon FP, Ebetino FH, et al. Use of a fluorescent analogue of risedronate to study localization and cellular uptake of bisphosphonates in vivo. Bone. 2008;42:S85
  73. Plotkin LI, Manolagas SC, Bellido T. Transduction of cell survival signals by connexin-43 hemichannels. J Biol Chem. 2002;277:8648
  74. Plotkin LI, Manolagas SC, Bellido T. Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblasts/osteocytes with novel analogs. Bone. 2006;39:443
  75. Plotkin LI, Lezcano V, Thostenson J, et al. Connexin 43 is required for the anti-apoptotic effect of bisphosphonates on osteocytes and osteoblasts in vivo. J Bone Miner Res. 2008;23:1712
  76. Nancollas GH, Tang R, Phipps RJ, et al. Novel insights into actions of bisphosphonates on bone: Differences in interactions with hydroxyapatite. Bone. 2006;38:617
  77. Leu CT, Luegmayr E, Freedman LP, et al. Relative binding affinities of bisphosphonates for human bone and relationship to antiresorptive efficacy. Bone. 2006;38:628
  78. Kim HK. Introduction to osteonecrosis of the femoral head (OFH) and osteonecrosis of the jaw (ONJ). J Musculoskelet Neuronal Interact. 2007;7:350
  79. Store G, Boysen M. Mandibular osteoradionecrosis: Clinical behaviour and diagnostic aspects. Clin Otolaryngol Allied Sci. 2000;25:378
  80. Store G, Grandstrom G. Osteoradionecrosis of the mandible: A microradiographic study of cortical bone. Scand J Plast Reconstr Hand Surg. 1999;33:307
  81. Guise TA. Antitumor effects of bisphosphonates: Promising preclinical evidence. Cancer Treat Rev. 2008;34(Suppl 1):S19
  82. Lipton A. Emerging role of bisphosphonates in the clinic—Antitumor activity and prevention of metastasis to bone. Cancer Treat Rev. 2008;34(Suppl 1):S25
  83. Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther. 2002;302:1055
  84. Fournier P, Boissier S, Filleur S, et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res. 2002;62:6538
  85. Schenk R, Merz WA, Muhlbauer R, et al. Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl 2 MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats. Calcif Tissue Res. 1973;11:196
  86. Hellstein JW, Marek CL. Bisphosphonate osteochemonecrosis (bis-phossy jaw): Is this phossy jaw of the 21st century?. J Oral Maxillofac Surg. 2005;63:682
  87. Hansen T, Kunkel M, Springer E, et al. Actinomycosis of the jaws—Histopathological study of 45 patients shows significant involvement in bisphosphonate-associated osteonecrosis and infected osteoradionecrosis. Virchows Arch. 2007;451:1009
  88. Estilo CL, Fornier M, Farooki A, et al. Osteonecrosis of the jaw related to bevacizumab. J Clin Oncol. 2008;26:4037
  89. Parfitt AM. The mechanism of coupling: A role for the vasculature. Bone. 2000;26:319
  90. Somerman MJ, McCauley LK. Bisphosphonates: Sacrificing the jaw to save the skeleton?. Bonekey Osteovision. 2006;3:12
  91. Adeyemo WL, Ladeinde AL, Ogunlewe MO. Clinical evaluation of post-extraction site wound healing. J Contemp Dent Pract. 2006;7:40
  92. Amler MH. Disturbed healing of extraction wounds. J Oral Implantol. 1999;25:179
  93. Trombelli L, Farina R, Marzola A, et al. Modeling and remodeling of human extraction sockets. J Clin Periodontol. 2008;35:630
  94. Deckers MM, Van Beek ER, Van Der Pluijm G, et al. Dissociation of angiogenesis and osteoclastogenesis during endochondral bone formation in neonatal mice. J Bone Miner Res. 2002;17:998
  95. Tothill P, MacPherson JN. The distribution of blood flow to the whole skeleton in dogs, rabbits and rats measured with microspheres. Clin Phys Physiol Meas. 1986;7:117
  96. Rowell LB. Human Cardiovascular Control. New York, NY: Oxford University Press; 1993;
  97. Colleran PN, Wilkerson MK, Bloomfield SA, et al. Alterations in skeletal perfusion with simulated microgravity: A possible mechanism for bone remodeling. J Appl Physiol. 2000;89:1046
  98. Bloomfield SA, Hogan HA, Delp MD. Decreases in bone blood flow and bone material properties in aging Fischer-344 rats. Clin Orthop Relat Res. 2002;248
  99. Delp MD, Colleran PN, Wilkerson MK, et al. Structural and functional remodeling of skeletal muscle microvasculature is induced by simulated microgravity. Am J Physiol Heart Circ Physiol. 2000;278:H1866
  100. Lurie AG, Matteson SR. 99MTc-diphosphonate bone imaging and uptake in healing rat extraction sockets. J Nucl Med. 1976;17:688
  101. McDougall IR. Skeletal scintigraphy. West J Med. 1979;130:503
  102. Sedghizadeh PP, Kumar SK, Gorur A, et al. Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg. 2008;66:767
  103. Yeung MK. Molecular and genetic analyses of Actinomyces spp. Crit Rev Oral Biol Med. 1999;10:120
  104. Nair SP, Meghji S, Wilson M, et al. Bacterially induced bone destruction: Mechanisms and misconceptions. Infect Immun. 1996;64:2371
  105. Pap T, Claus A, Ohtsu S, et al. Osteoclast-independent bone resorption by fibroblast-like cells. Arthritis Res Ther. 2003;5:R163
  106. Mundy GR, Elefteriou F. Boning up on ephrin signaling. Cell. 2006;126:441
  107. Zhao C, Irie N, Takada Y, et al. Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab. 2006;4:111
  108. Khamaisi M, Regev E, Yarom N, et al. Possible association between diabetes and bisphosphonate-related jaw osteonecrosis. J Clin Endocrinol Metab. 2007;92:1172
  109. Wessel JH, Dodson TB, Zavras AI. Zoledronate, smoking, and obesity are strong risk factors for osteonecrosis of the jaw: A case-control study. J Oral Maxillofac Surg. 2008;66:625
  110. AAOMS. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 2007;65:369

 Dr Allen has research contracts with The Alliance for Better Bone Health (Mason, OH), and Amgen (Thousand Oaks, CA). He also serves as a consultant for Procter and Gamble and Merck and Co. Dr Burr has research grants from The Alliance for Better Bone Health, Eli Lilly, and Amgen. He is a consultant and is on the speakers bureau for Eli Lilly and The Alliance for Better Bone Health. Dr Burr also has Material Transfer Agreements with Merck, Eli Lilly, and NephroGenex Inc.

PII: S0278-2391(09)00112-8

doi: 10.1016/j.joms.2009.01.007

Journal of Oral and Maxillofacial Surgery
Volume 67, Issue 5, Supplement , Pages 61-70 , May 2009