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Current Understanding of the Pathophysiology of Osteonecrosis of the Jaw

  • Epidemiology and Pathophysiology (F Cosman and D Shoback, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Osteonecrosis of the jaw (ONJ) is a rare and severe necrotic bone disease reflecting a compromise in the body’s osseous healing mechanisms and unique to the craniofacial region. Antiresorptive and antiangiogenic medications have been suggested to be associated with the occurrence of ONJ; yet, the pathophysiology of this disease has not been fully elucidated. This article raises the current theories underlying the pathophysiology of ONJ.

Recent Findings

The proposed mechanisms highlight the unique localization of ONJ. The evidence-based mechanisms of ONJ pathogenesis include disturbed bone remodeling, inflammation or infection, altered immunity, soft tissue toxicity, and angiogenesis inhibition. The role of dental infections and the oral microbiome is central to ONJ, and systemic conditions such as rheumatoid arthritis and diabetes mellitus contribute through their impact on immune resiliency.

Summary

Current experimental studies on mechanisms of ONJ are summarized. The definitive pathophysiology is as yet unclear. Recent studies are beginning to clarify the relative importance of the proposed mechanisms. A better understanding of osteoimmunology and the relationship of angiogenesis to the development of ONJ is needed along with detailed studies of the impact of drug holidays on the clinical condition of ONJ.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O'Ryan F, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015;30(1):3–23.

    Article  PubMed  Google Scholar 

  2. Williams DW, Lee C, Kim T, Yagita H, Wu H, Park S, et al. Impaired bone resorption and woven bone formation are associated with development of osteonecrosis of the jaw-like lesions by bisphosphonate and anti-receptor activator of NF-kappaB ligand antibody in mice. Am J Pathol. 2014;184(11):3084–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pautke C, Kreutzer K, Weitz J, Knodler M, Munzel D, Wexel G, et al. Bisphosphonate related osteonecrosis of the jaw: a minipig large animal model. Bone. 2012;51(3):592–9.

    Article  CAS  PubMed  Google Scholar 

  4. Lopez-Jornet P, Camacho-Alonso F, Molina-Minano F, Gomez-Garcia F, Vicente-Ortega V. An experimental study of bisphosphonate-induced jaws osteonecrosis in Sprague-Dawley rats. J Oral Pathol Med. 2010;39(9):697–702.

    Article  CAS  PubMed  Google Scholar 

  5. Bi Y, Gao Y, Ehirchiou D, Cao C, Kikuiri T, Le A, et al. Bisphosphonates cause osteonecrosis of the jaw-like disease in mice. Am J Pathol. 2010;177(1):280–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Allen MR, Chu TM, Ruggiero SL. Absence of exposed bone following dental extraction in beagle dogs treated with 9 months of high-dose zoledronic acid combined with dexamethasone. J Oral Maxillofac Surg. 2013;71(6):1017–26.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lacey DL, Boyle WJ, Simonet WS, Kostenuik PJ, Dougall WC, Sullivan JK, et al. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov. 2012;11(5):401–19.

    Article  CAS  PubMed  Google Scholar 

  8. Rodan GA, Reszka AA. Bisphosphonate mechanism of action. Curr Mol Med. 2002;2(6):571–7.

    Article  CAS  PubMed  Google Scholar 

  9. Vermeer JA, Renders GA, Everts V. Osteonecrosis of the jaw-a bone site-specific effect of bisphosphonates. Curr Osteoporos Rep. 2016;14(5):219–25.

    Article  PubMed  Google Scholar 

  10. Sasaki MMT, Katafuchi M, Tokutomi K, Sato H. Higher contents of mineral and collagen but lower of hydroxylysine of collagen in mandibular bone compared with those of humeral and femoral bones in human. Journal of Hard Tissue Biology. 2010;19(3):175–80.

    Article  CAS  Google Scholar 

  11. Matsuura T, Tokutomi K, Sasaki M, Katafuchi M, Mizumachi E, Sato H. Distinct characteristics of mandibular bone collagen relative to long bone collagen: relevance to clinical dentistry. Biomed Res Int. 2014;2014:769414.

    PubMed  PubMed Central  Google Scholar 

  12. Matsuura T, Sasaki M, Katafuchi M, Tokutomi K, Mizumachi E, Makino M, et al. Characterization of the bone matrix and its contribution to tooth loss in human cadaveric mandibles. Acta Odontol Scand. 2014;72(8):753–61.

    Article  CAS  PubMed  Google Scholar 

  13. Cremers S, Papapoulos S. Pharmacology of bisphosphonates. Bone. 2011;49(1):42–9.

    Article  CAS  PubMed  Google Scholar 

  14. Wen D, Qing L, Harrison G, Golub E, Akintoye SO. Anatomic site variability in rat skeletal uptake and desorption of fluorescently labeled bisphosphonate. Oral Dis. 2011;17(4):427–32.

    Article  CAS  PubMed  Google Scholar 

  15. Babajko S, Meary F, Petit S, Fernandes I, Berdal A. Transcriptional regulation of MSX1 natural antisense transcript. Cells Tissues Organs. 2011;194(2–4):151–5.

    Article  CAS  PubMed  Google Scholar 

  16. Bendall AJ, Abate-Shen C. Roles for Msx and dlx homeoproteins in vertebrate development. Gene. 2000;247(1–2):17–31.

    Article  CAS  PubMed  Google Scholar 

  17. Berdal A, Molla M, Hotton D, Aioub M, Lezot F, Nefussi JR, et al. Differential impact of MSX1 and MSX2 homeogenes on mouse maxillofacial skeleton. Cells Tissues Organs. 2009;189(1–4):126–32.

    Article  CAS  PubMed  Google Scholar 

  18. Samee N, Geoffroy V, Marty C, Schiltz C, Vieux-Rochas M, Levi G, et al. Dlx5, a positive regulator of osteoblastogenesis, is essential for osteoblast-osteoclast coupling. Am J Pathol. 2008;173(3):773–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Babajko S, Petit S, Fernandes I, Meary F, LeBihan J, Pibouin L, et al. Msx1 expression regulation by its own antisense RNA: consequence on tooth development and bone regeneration. Cells Tissues Organs. 2009;189(1–4):115–21.

    Article  CAS  PubMed  Google Scholar 

  20. Reichert JC, Gohlke J, Friis TE, Quent VM, Hutmacher DW. Mesodermal and neural crest derived ovine tibial and mandibular osteoblasts display distinct molecular differences. Gene. 2013;525(1):99–106.

    Article  CAS  PubMed  Google Scholar 

  21. • Wehrhan F, Amann K, Mobius P, Weber M, Preidl R, Ries J, et al. BRONJ-related jaw bone is associated with increased Dlx-5 and suppressed osteopontin-implication in the site-specific alteration of angiogenesis and bone turnover by bisphosphonates. Clin Oral Investig. 2015;19(6):1289–98. This paper shows bisphosphonate affects BMP-2-Msx-1-Dlx-5 axis in human jaw bone samples which is the specific signal transduction pathway to govern osseous differentiation in neural crest cell-dervied bone structure, such as jaw bones. The findings of this study may help to explain the restriction of ONJ to craniofacial bones.

    Article  PubMed  Google Scholar 

  22. Wehrhan F, Hyckel P, Amann K, Ries J, Stockmann P, Schlegel K, et al. Msx-1 is suppressed in bisphosphonate-exposed jaw bone analysis of bone turnover-related cell signalling after bisphosphonate treatment. Oral Dis. 2011;17(4):433–42.

    Article  CAS  PubMed  Google Scholar 

  23. Asou Y, Rittling SR, Yoshitake H, Tsuji K, Shinomiya K, Nifuji A, et al. Osteopontin facilitates angiogenesis, accumulation of osteoclasts, and resorption in ectopic bone. Endocrinology. 2001;142(3):1325–32.

    Article  CAS  PubMed  Google Scholar 

  24. Hunter GK, Hauschka PV, Poole AR, Rosenberg LC, Goldberg HA. Nucleation and inhibition of hydroxyapatite formation by mineralized tissue proteins. Biochem J. 1996;317(Pt 1):59–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. •• Gong X, Yu W, Zhao H, Su J, Sheng Q. Skeletal site-specific effects of zoledronate on in vivo bone remodeling and in vitro BMSCs osteogenic activity. Sci Rep. 2017;7:36129. This study not only described histological differences in bone turnover between jaw bone and peripheral bone responding to zoledronate therapy but also exhibited their differences on cell proliferation, osteogenic differentiation and in vivo bone formation of BMSCs. It highlights the bisphosphonate-mediated ONJ tendency to occur in maxillofacial bones.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. • Su J, Feng M, Han W, Zhao H. The effects of bisphosphonate on the remodeling of different irregular bones in mice. J oral Pathol med. 2015;44(8):638-48. This study compared the effects of bisphosphonate on the remodeling of the jaw and ilium in mice after trauma. It found higher content of bisphosphonate and more significant bone necrotic lesions in the jaws after bisphosphonate treatment.

    Article  CAS  Google Scholar 

  27. • Lim SS, Lee B, Kim IS, Hwang SJ. Differential modulation of zoledronate and etidronate in osseous healing of an extracted socket and tibia defect. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;123(1):8–19. This paper demonstrated skeleton-specific bone healing during zoledronate use, in which zolendronate use potently suppressed bone remodeling and consequently impaired healing at the extraction site but allowed full regeneration of the tibial defect.

    Article  PubMed  Google Scholar 

  28. Yu YY, Lieu S, Hu D, Miclau T, Colnot C. Site specific effects of zoledronic acid during tibial and mandibular fracture repair. PLoS One. 2012;7(2):e31771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Araujo MG, Silva CO, Misawa M, Sukekava F. Alveolar socket healing: what can we learn? Periodontol 2000. 2015;68(1):122–34.

  30. Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006;38(5):617–27.

    Article  CAS  PubMed  Google Scholar 

  31. Russell RG. Bisphosphonates: the first 40 years. Bone. 2011;49(1):2–19.

    Article  CAS  PubMed  Google Scholar 

  32. • Nagaoka Y, Kajiya H, Ozeki S, Ikebe T, Okabe K. Mevalonates restore zoledronic acid-induced osteoclastogenesis inhibition. J Dent Res. 2015;94(4):594–601. This paper found exogenous mevalonic acid metabolites GGPP and GGOH could restore the inhibitory effects of zoledronate on osteoclastogenesis and bone remodeling, and hence render GGPP and GGOH as potential therapeutic agents for zoledronate-induced ONJ.

    Article  CAS  PubMed  Google Scholar 

  33. Ebetino FH, Hogan AM, Sun S, Tsoumpra MK, Duan X, Triffitt JT, et al. The relationship between the chemistry and biological activity of the bisphosphonates. Bone. 2011;49(1):20–33.

    Article  CAS  PubMed  Google Scholar 

  34. Tseng HC, Kanayama K, Kaur K, Park SH, Park S, Kozlowska A, et al. Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: role in osteoclast-mediated NK cell activation. Oncotarget. 2015;6(24):20002–25.

  35. Tsuboi K, Hasegawa T, Yamamoto T, Sasaki M, Hongo H, de Freitas PH, et al. Effects of drug discontinuation after short-term daily alendronate administration on osteoblasts and osteocytes in mice. Histochem Cell Biol. 2016;146(3):337–50.

    Article  CAS  PubMed  Google Scholar 

  36. Shah FA, Lee BEJ, Tedesco J, Larsson Wexell C, Persson C, Thomsen P, et al. Micrometer-sized magnesium whitlockite crystals in micropetrosis of bisphosphonate-exposed human alveolar bone. Nano Lett. 2017;17(10):6210–6.

    Article  CAS  PubMed  Google Scholar 

  37. Sinningen K, Tsourdi E, Rauner M, Rachner TD, Hamann C, Hofbauer LC. Skeletal and extraskeletal actions of denosumab. Endocrine. 2012;42(1):52–62.

    Article  CAS  PubMed  Google Scholar 

  38. • Kuroshima S, Al-Salihi Z, Yamashita J. Mouse anti-RANKL antibody delays oral wound healing and increases TRAP-positive mononuclear cells in bone marrow. Clin Oral Investig. 2016;20(4):727–36. This paper reported the application of the mouse anti-RANKL Ab significantly suppresses osteoclast development and delays wound healing in the palate, while it did not affect macrophages and fibroblasts.

  39. Nadella KR, Kodali RM, Guttikonda LK, Jonnalagadda A. Osteoradionecrosis of the jaws: clinico-therapeutic management: a literature review and update. J Maxillofac Oral Surg. 2015;14(4):891–901.

    Article  PubMed  PubMed Central  Google Scholar 

  40. • de Molon RS, Shimamoto H, Bezouglaia O, Pirih FQ, Dry SM, Kostenuik P, et al. OPG-Fc but not zoledronic acid discontinuation reverses osteonecrosis of the jaws (ONJ) in mice. J Bone Miner Res. 2015;30(9):1627–40. This study provides experimental evidence demonstrating that discontinuation of a RANKL inhibitor (OPG-Fc), but not a bisphosphonate (zoledronate), reverses features of osteonecrosis in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Soundia A, Hadaya D, Esfandi N, Gkouveris I, Christensen R, Dry SM, et al. Zoledronate impairs socket healing after extraction of teeth with experimental periodontitis. J Dent Res. 2018;97(3):312–20.

    Article  CAS  PubMed  Google Scholar 

  42. •• Soundia A, Hadaya D, Esfandi N, de Molon RS, Bezouglaia O, Dry SM, et al. Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease. Bone. 2016;90:133–41. This study investigated soft and hard tissue healing after extraction of teeth with or without periradicular infection in mice treated with zoledronate, or a RANKL inhibitor (OPG-Fc). For both antiresorptives, the normal mucosal healing and suppressed socket bone remodeling were found after extraction of a healthy tooth, while mucosal defect and ONJ were found when extracted teeth were periradicularlly infected. These findings support that dental disease is critical in the pathogenesis of ONJ.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Aghaloo TL, Cheong S, Bezouglaia O, Kostenuik P, Atti E, Dry SM, et al. RANKL inhibitors induce osteonecrosis of the jaw in mice with periapical disease. J Bone Miner Res. 2014;29(4):843–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li CL, Lu WW, Seneviratne CJ, Leung WK, Zwahlen RA, Zheng LW. Role of periodontal disease in bisphosphonate-related osteonecrosis of the jaws in ovariectomized rats. Clin Oral Implants Res. 2016;27(1):1–6.

    Article  PubMed  Google Scholar 

  45. Kumar SK, Gorur A, Schaudinn C, Shuler CF, Costerton JW, Sedghizadeh PP. The role of microbial biofilms in osteonecrosis of the jaw associated with bisphosphonate therapy. Curr Osteoporos Rep. 2010;8(1):40–8.

    Article  PubMed  Google Scholar 

  46. Pushalkar S, Li X, Kurago Z, Ramanathapuram LV, Matsumura S, Fleisher KE, et al. Oral microbiota and host innate immune response in bisphosphonate-related osteonecrosis of the jaw. Int J Oral Sci. 2014;6(4):219–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sedghizadeh PP, Kumar SK, Gorur A, Schaudinn C, Shuler CF, Costerton JW. Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg. 2008;66(4):767–75.

    Article  PubMed  Google Scholar 

  48. Almazrooa SA, Woo SB. Bisphosphonate and nonbisphosphonate-associated osteonecrosis of the jaw: a review. J Am Dent Assoc. 2009;140(7):864–75.

    Article  CAS  PubMed  Google Scholar 

  49. Kalyan S, Wang J, Quabius ES, Huck J, Wiltfang J, Baines JF, et al. Systemic immunity shapes the oral microbiome and susceptibility to bisphosphonate-associated osteonecrosis of the jaw. J Transl Med. 2015;13:212.

  50. Walsh MC, Choi Y. Biology of the RANKL-RANK-OPG system in immunity, bone, and beyond. Front Immunol. 2014;5:511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Nguyen NT, Hanieh H, Nakahama T, Kishimoto T. The roles of aryl hydrocarbon receptor in immune responses. Int Immunol. 2013;25(6):335–43.

    Article  CAS  PubMed  Google Scholar 

  52. Lescaille G, Coudert AE, Baaroun V, Javelot MJ, Cohen-Solal M, Berdal A, et al. Osteonecrosis of the jaw and nonmalignant disease: is there an association with rheumatoid arthritis? J Rheumatol. 2013;40(6):781–6.

    Article  PubMed  Google Scholar 

  53. Conte-Neto N, Bastos AS, Marcantonio RA, Junior EM. Epidemiological aspects of rheumatoid arthritis patients affected by oral bisphosphonate-related osteonecrosis of the jaws. Head Face Med. 2012;8:5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chiu WY, Yang WS, Chien JY, Lee JJ, Tsai KS. The influence of alendronate and tooth extraction on the incidence of osteonecrosis of the jaw among osteoporotic subjects. PLoS One. 2018;13(4):e0196419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. • de Molon RS, Hsu C, Bezouglaia O, Dry SM, Pirih FQ, Soundia A, et al. Rheumatoid arthritis exacerbates the severity of osteonecrosis of the jaws (ONJ) in mice. A randomized, prospective, controlled animal study. J Bone Miner Res. 2016;31(8):1596–607. This study investigated the interactions between rheumatoid arthritis and ONJ incidence and severity in a mouse model. It showed that the rheumatoid arthritis mice presented more severe ONJ lesions (more empty osteocytic lacunae and larger areas of osteonecrosis) in alveolar bones when mice were pretreated with zoledronate.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. • Zhang Q, Yu W, Lee S, Xu Q, Naji A, Le AD. Bisphosphonate induces osteonecrosis of the jaw in diabetic mice via NLRP3/Caspase-1-dependent IL-1beta mechanism. J Bone Miner Res. 2015;30(12):2300–12. This study investigated whether NLRP3 inflammasome activation contributes to ONJ development in diabetic mice. They found the diabetes-associated chronic inflammatory response may contribute to impaired socket wound healing and render oral wounds susceptible to the development of ONJ via NLRP3 activation in macrophages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Takaoka K, Yamamura M, Nishioka T, Abe T, Tamaoka J, Segawa E, et al. Establishment of an animal model of bisphosphonate-related osteonecrosis of the jaws in spontaneously diabetic torii rats. PLoS One. 2015;10(12):e0144355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Otton R, Mendonca JR, Curi R. Diabetes causes marked changes in lymphocyte metabolism. J Endocrinol. 2002;174(1):55–61.

    Article  CAS  PubMed  Google Scholar 

  59. Abe T, Sato T, Kokabu S, Hori N, Shimamura Y, Sato T, et al. Zoledronic acid increases the circulating soluble RANKL level in mice, with a further increase in lymphocyte-derived soluble RANKL in zoledronic acid- and glucocorticoid-treated mice stimulated with bacterial lipopolysaccharide. Cytokine. 2016;83:1–7.

    Article  CAS  PubMed  Google Scholar 

  60. Peer A, Khamaisi M. Diabetes as a risk factor for medication-related osteonecrosis of the jaw. J Dent Res. 2015;94(2):252–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ono T, Okamoto K, Nakashima T, Nitta T, Hori S, Iwakura Y, et al. IL-17-producing gamma delta T cells enhance bone regeneration. Nat Commun. 2016;7:10928.

  62. Kalyan S. It may seem inflammatory, but some T cells are innately healing to the bone. J Bone Miner Res. 2016;31(11):1997–2000.

    Article  CAS  PubMed  Google Scholar 

  63. Kalyan S, Quabius ES, Wiltfang J, Monig H, Kabelitz D. Can peripheral blood gammadelta T cells predict osteonecrosis of the jaw? An immunological perspective on the adverse drug effects of aminobisphosphonate therapy. J Bone Miner Res. 2013;28(4):728–35.

    Article  CAS  PubMed  Google Scholar 

  64. •• Movila A, Mawardi H, Nishimura K, Kiyama T, Egashira K, Kim JY, et al. Possible pathogenic engagement of soluble Semaphorin 4D produced by gamma deltaT cells in medication-related osteonecrosis of the jaw (MRONJ). Biochem Biophys Res Commun. 2016;480(1):42–7. This study found Sema4D produced by γδT cells plays a critical role in the pathogenesis of bisphosphonate-related ONJ. Mice with γδT cell deficiency were resistant to the induction of ONJ, while systemic administration of anti-Sema4D neutralizing mAb suppressed the onset of ONJ.

  65. Park S, Kanayama K, Kaur K, Tseng HC, Banankhah S, Quje DT, et al. Osteonecrosis of the jaw developed in mice: disease variants regulated by gammadelta T cells in oral mucosal barrier immunity. J Biol Chem. 2015;290(28):17349–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hagelauer N, Pabst AM, Ziebart T, Ulbrich H, Walter C. In vitro effects of bisphosphonates on chemotaxis, phagocytosis, and oxidative burst of neutrophil granulocytes. Clin Oral Investig. 2015;19(1):139–48.

    Article  PubMed  Google Scholar 

  67. Jin HM, Kee SJ, Cho YN, Kang JH, Kim MJ, Jung HJ, et al. Dysregulated osteoclastogenesis is related to natural killer T cell dysfunction in rheumatoid arthritis. Arthritis Rheumatol. 2015;67(10):2639–50.

    Article  Google Scholar 

  68. Moutsopoulos NM, Konkel JE. Tissue-specific immunity at the oral mucosal barrier. Trends Immunol. 2018;39(4):276–87.

    Article  CAS  PubMed  Google Scholar 

  69. • Kim S, Williams DW, Lee C, Kim T, Arai A, Shi S, et al. IL-36 induces bisphosphonate-related osteonecrosis of the jaw-like lesions in mice by inhibiting TGF-beta-mediated collagen expression. J Bone Miner Res. 2017;32(2):309–18. This study found that the pro-inflammatory cytokine IL-36α is responsible for the pathogenesis of bisphosphonate-related ONJ by inhibiting collagen expression. IL-36α may be used as a potential marker and a therapeutic target for the prevention and treatment of bisphosphonate-related ONJ.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. •• Ohlrich EJ, Coates DE, Cullinan MP, Milne TJ, Zafar S, Zhao Y, et al. The bisphosphonate zoledronic acid regulates key angiogenesis-related genes in primary human gingival fibroblasts. Arch Oral Biol. 2016;63:7–14. This study investigated the anti-angiogenic effects of bisphosphonates in the pathogenesis of bisphosphonate-related ONJ by examining the expression of angiogenesis-related genes in human gingival fibroblasts when treated with zoledronate in vitro. Zolendronate suppressed inflammation but increased gingival fibroblast angiogenesis gene expression (VEGF, BMP2), which is contrary to its antiangiogenic effect on vascular endothelial cells. This finding suggests a diversity of responses to bisphosphonate between different kinds of tissues in the oral cavity. This study also found zolendronate impaired the migration of gingival fibroblasts and slowed down wound healing.

    Article  CAS  PubMed  Google Scholar 

  71. Anitua E, Zalduendo M, Troya M, Orive G. PRGF exerts a cytoprotective role in zoledronic acid-treated oral cells. Clin Oral Investig. 2016;20(3):513–21.

    Article  PubMed  Google Scholar 

  72. Farah CS, Savage NW. Oral ulceration with bone sequestration. Aust Dent J. 2003;48(1):61–4.

    Article  CAS  PubMed  Google Scholar 

  73. Peters E, Lovas GL, Wysocki GP. Lingual mandibular sequestration and ulceration. Oral Surg Oral Med Oral Pathol. 1993;75(6):739–43.

    Article  CAS  PubMed  Google Scholar 

  74. Scully C. Oral ulceration: a new and unusual complication. Br Dent J. 2002;192(3):139–40.

    Article  CAS  PubMed  Google Scholar 

  75. Zandi M, Dehghan A, Janbaz P, Malekzadeh H, Amini P. The starting point for bisphosphonate-related osteonecrosis of the jaw: alveolar bone or oral mucosa? A randomized, controlled experimental study. J Craniomaxillofac Surg. 2017;45(1):157–61.

    Article  PubMed  Google Scholar 

  76. Lang M, Zhou Z, Shi L, Niu J, Xu S, Lin W, et al. Influence of zoledronic acid on proliferation, migration, and apoptosis of vascular endothelial cells. Br J Oral Maxillofac Surg. 2016;54(8):889–93.

    Article  CAS  PubMed  Google Scholar 

  77. Basi DL, Lee SW, Helfman S, Mariash A, Lunos SA. Accumulation of VEGFR2 in zoledronic acid-treated endothelial cells. Mol Med Rep. 2010;3(3):399–403.

    Article  CAS  PubMed  Google Scholar 

  78. Blum A, Zarqh O, Peleg A, Sirchan R, Blum N, Salameh Y, et al. Vascular inflammation and endothelial dysfunction in fracture healing. Am J Orthop (Belle Mead NJ). 2012;41(2):87–91.

    Google Scholar 

  79. Sharma D, Hamlet SM, Petcu EB, Ivanovski S. The effect of bisphosphonates on the endothelial differentiation of mesenchymal stem cells. Sci Rep. 2016;6:20580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gao SY, Zheng GS, Wang L, Liang YJ, Zhang SE, Lao XM, et al. Zoledronate suppressed angiogenesis and osteogenesis by inhibiting osteoclasts formation and secretion of PDGF-BB. PLoS One. 2017;12(6):e0179248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Boquete-Castro A, Gomez-Moreno G, Calvo-Guirado JL, Aguilar-Salvatierra A, Delgado-Ruiz RA. Denosumab and osteonecrosis of the jaw. A systematic analysis of events reported in clinical trials. Clin Oral Implants Res. 2016;27(3):367–75.

    Article  PubMed  Google Scholar 

  82. Min JK, Kim YM, Kim YM, Kim EC, Gho YS, Kang IJ, et al. Vascular endothelial growth factor up-regulates expression of receptor activator of NF-kappa B (RANK) in endothelial cells. Concomitant increase of angiogenic responses to RANK ligand. J Biol Chem. 2003;278(41):39548–57.

  83. Misso G, Porru M, Stoppacciaro A, Castellano M, De Cicco F, Leonetti C, et al. Evaluation of the in vitro and in vivo antiangiogenic effects of denosumab and zoledronic acid. Cancer Biol Ther. 2012;13(14):1491–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhang X, Hamadeh IS, Song S, Katz J, Moreb JS, Langaee TY, et al. Osteonecrosis of the jaw in the United States Food and Drug Administration's adverse event reporting system (FAERS). J Bone Miner Res. 2016;31(2):336–40.

    Article  CAS  PubMed  Google Scholar 

  85. Garuti F, Camelli V, Spinardi L, Bucci L, Trevisani F. Osteonecrosis of the jaw during sorafenib therapy for hepatocellular carcinoma. Tumori. 2016;102(Suppl. 2).

    Article  Google Scholar 

  86. Bhandari S, Eris J. Drug points: premature osteonecrosis and sirolimus treatment in renal transplantation. BMJ. 2001;323(7314):665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Santos-Silva AR, Belizario Rosa GA, Castro Junior G, Dias RB, Prado Ribeiro AC, Brandao TB. Osteonecrosis of the mandible associated with bevacizumab therapy. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115(6):e32–6.

    Article  PubMed  Google Scholar 

  88. Koch FP, Walter C, Hansen T, Jager E, Wagner W. Osteonecrosis of the jaw related to sunitinib. Oral Maxillofac Surg. 2011;15(1):63–6.

    Article  PubMed  Google Scholar 

  89. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg. 2014;72(10):1938–56.

    Article  PubMed  Google Scholar 

  90. Van den Wyngaert T, Huizing MT, Vermorken JB. Bisphosphonates and osteonecrosis of the jaw: cause and effect or a post hoc fallacy? Ann Oncol. 2006;17(8):1197–204.

    Article  PubMed  Google Scholar 

  91. Fantasia JE. The role of antiangiogenic therapy in the development of osteonecrosis of the jaw. Oral Maxillofac Surg Clin North Am. 2015;27(4):547–53.

    Article  PubMed  Google Scholar 

  92. Cackowski FC, Anderson JL, Patrene KD, Choksi RJ, Shapiro SD, Windle JJ, et al. Osteoclasts are important for bone angiogenesis. Blood. 2010;115(1):140–9.

    Article  CAS  PubMed  Google Scholar 

  93. • Thumbigere-Math V, Michalowicz BS, Hughes PJ, Basi DL, Tsai ML, Swenson KK, et al. Serum markers of bone turnover and angiogenesis in patients with bisphosphonate-related osteonecrosis of the jaw after discontinuation of long-term intravenous bisphosphonate therapy. J Oral Maxillofac Surg. 2016;74(4):738–46. This study examined the effect of drug holiday on serum markers of ONJ patients. It found that ONJ patients after drug holiday showed higher levels of angiogenesis and inflammation markers but similar bone turnover and endocrine markers to those in non-ONJ controls receiving intravenous bisphosphonate therapy. With the limitation of the cross-sectional nature of this study, it suggests a drug holiday may not improve the suppressed bone turnover in ONJ but may improve angiogenesis to benefit the healing of ONJ. However, a further prospective randomized control study should be designed to verify this result.

  94. Malan J, Ettinger K, Naumann E, Beirne OR. The relationship of denosumab pharmacology and osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114(6):671–6.

    Article  PubMed  Google Scholar 

  95. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337–42.

    Article  CAS  PubMed  Google Scholar 

  96. Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, 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):1341–7.

    Article  CAS  PubMed  Google Scholar 

  97. Higuchi T, Soga Y, Muro M, Kajizono M, Kitamura Y, Sendo T, et al. Replacing zoledronic acid with denosumab is a risk factor for developing osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125(6):547–51.

    Article  PubMed  Google Scholar 

  98. Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled freedom trial and its extension. J Bone Miner Res. 2018;33(2):190–8.

    Article  CAS  PubMed  Google Scholar 

  99. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61(9):1115–7.

    Article  PubMed  Google Scholar 

  100. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004;62(5):527–34.

    Article  PubMed  Google Scholar 

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Acknowledgements

NIH DK053904, CA093900, and DE022327 provided partial support for this work. Appreciation goes to Srishti Gupta for assistance with illustration.

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Authors and Affiliations

  1. Department of Periodontology, University of Florida College of Dentistry, Gainesville, FL, 32610, USA

    J. Chang & A. E. Hakam

  2. Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, 1011 North University Ave, Ann Arbor, MI, 48109, USA

    L. K. McCauley

  3. Department of Pathology, Medical School, University of Michigan, Ann Arbor, MI, USA

    L. K. McCauley

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  1. J. Chang
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  2. A. E. Hakam
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  3. L. K. McCauley
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Correspondence to L. K. McCauley.

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Laurie McCauley reports having investments in AMGEN, outside the submitted work. Abeer Hakam and Jia Chang declares no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Epidemiology and Pathophysiology

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Chang, J., Hakam, A.E. & McCauley, L.K. Current Understanding of the Pathophysiology of Osteonecrosis of the Jaw. Curr Osteoporos Rep 16, 584–595 (2018). https://doi.org/10.1007/s11914-018-0474-4

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