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Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw

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An Erratum to this article was published on 26 October 2011

Abstract

In recent years, atypical femoral fractures and osteonecrosis of the jaw have emerged as potential complications of long-term bisphosphonate therapy; osteonecrosis of the jaw has also been reported in patients receiving high doses of denosumab. The pathophysiology of both conditions is poorly defined, and the underlying mechanisms are likely to differ. The initiation of atypical fractures in the lateral femoral shaft suggests that reduced tensile strength, possibly secondary to alterations in the material properties of bone resulting from low bone turnover, may be an important pathogenetic factor. Osteonecrosis of the jaw is characterised by infection, inflammation, bone resorption and bone necrosis, but the sequence in which these occur has not been established. However, the observation that bone resorption occurs in close proximity to microbial structures suggests that infection may be the most important trigger, often as a result of dental disease. Other possible pathogenetic factors include suppression of bone turnover, altered immune status and adverse effects of bisphosphonates on the oral mucosa.

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References

  1. Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster D, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Koval K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O’Keefe R, Papapoulos S, Sen HT, van der Meulen MC, Weinstein RS, Whyte M, American Society for Bone and Mineral Research (2010) J Bone Miner Res 25:2267–2294

    Article  PubMed  Google Scholar 

  2. Odvina CV, Zerwekh 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  CAS  Google Scholar 

  3. Nieves JW, Bilezikian JP, Lane JM, Einhorn TA, Wang Y, Steinbuch M, Cosman F (2010) Fragility fractures of the hip and femur: incidence and patient characteristics. Osteoporos Int 21:399–408

    Article  PubMed  CAS  Google Scholar 

  4. Giusti A, Hamdy NA, Papapoulos SE (2010) Atypical fractures of the femur and bisphosphonate therapy: a systematic review of case/case series studies. Bone 47:169–180

    Article  PubMed  CAS  Google Scholar 

  5. Abrahamsen B, Eiken P, Eastell R (2009) Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res 24:1095–1102

    Article  PubMed  CAS  Google Scholar 

  6. Abrahamsen B, Eiken P, Eastell R (2010) Cumulative alendronate dose and the long-term absolute risk of subtrochanteric and diaphyseal femur fractures: a register-based national cohort analysis. J Clin Endocrinol Metab 95:5258–5265

    Article  PubMed  CAS  Google Scholar 

  7. Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, Bucci-Rechtweg C, Cauley J, Leung PC, Boonen S, Santora A, de Papp A, Bauer DC (2010) Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med 362:1761–1771

    Article  PubMed  CAS  Google Scholar 

  8. Park-Wyllie LY, Mamdani MM, Juurlink DN, Hawker GA, Gunraj N, Austin PC, Whelan DB, Weiler PJ, Laupacis A (2011) Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA 305:783–789

    Article  PubMed  CAS  Google Scholar 

  9. Wang Z, Bhattacharyya T (2011) Trends in incidence of subtrochanteric fragility fractures and bisphosphonate use among the US elderly, 1996–2007. J Bone Miner Res 26:553–560

    Article  PubMed  CAS  Google Scholar 

  10. Lenart BA, Neviaser AS, Lyman S, Chang CC, Edobor-Osula F, Steele B, van der Meulen MC, Lorich DG, Lane JM (2009) Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int 20:1353–1362

    Article  PubMed  CAS  Google Scholar 

  11. Dell R, Greene D, Ott S, Silverman S, Eisemon E, Funahashi T, Adams A (2010) A retrospective analysis of all atypical femur fractures seen in a large California HMO from the years 2007 to 2009 ASBMR 2010 Annual Meeting, Toronto, Canada

  12. Isaacs JD, Shidiak L, Harris IA, Szomor ZL (2010) Femoral insufficiency fractures associated with prolonged bisphosphonate therapy. Clin Orthop Relat Res 468:3384–3392

    Article  PubMed  Google Scholar 

  13. Schilcher J, Michaelsson K, Aspenberg P (2011) Bisphosphonate use and atypical fractures of the femoral shaft. New Engl J Med 364:1728–1737

    Article  PubMed  CAS  Google Scholar 

  14. Rachkidi RE, Sari-Leret ML, Wolff S (2011) Atypical bilateral pedicle fracture in long-term bisphosphonate therapy. Spine (Phila Pa 1976). Mar 14. (in press)

  15. Wernecke G, Namdari S, DiCarlo EF, Schneider R, Lane J (2008) Case report of spontaneous, nonspinal fractures in a multiple myeloma patient on long-term pamidronate and zoledronic acid. HSS J 4:123–127

    Article  PubMed  Google Scholar 

  16. Puhaindran ME, Farooki A, Steensma MR, Hameed M, Healey JH, Boland PJ (2011) Atypical subtrochanteric femoral fractures in patients with skeletal malignant involvement treated with intravenous bisphosphonates. J Bone Joint Surg Am 93:1235–1242

    Article  PubMed  Google Scholar 

  17. Whyte MP (2009) Atypical femoral fractures, bisphosphonates, and adult hypophosphatasia. J Bone Miner Res 24:1132–1134

    Article  PubMed  Google Scholar 

  18. Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ (2000) Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone 27:687–694

    Article  PubMed  CAS  Google Scholar 

  19. Roschger P, Rinnerthaler S, Yates J, Rodan GA, Fratzl P, Klaushofer K (2001) Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women. Bone 29:185–191

    Article  PubMed  CAS  Google Scholar 

  20. Borah B, Dufresne TE, Ritman EL, Jorgensen SM, Liu S, Chmielewski PA, Phipps RJ, Zhou X, Sibonga JD, Turner RT (2006) Long-term risedronate treatment normalizes mineralization and continues to preserve trabecular architecture: sequential triple biopsy studies with microcomputed tomography. Bone 39:345–352

    Article  PubMed  CAS  Google Scholar 

  21. Roschger P, Lombardi A, Misof BM, Maier G, Fratzl-Zelman N, Fratzl P, Klaushofer K (2010) Mineralization density distribution of postmenopausal osteoporotic bone is restored to normal after long-term alendronate treatment: qBEI and sSAXS data from the fracture intervention trial long-term extension (FLEX). J Bone Miner Res 25:48–55

    Article  PubMed  CAS  Google Scholar 

  22. Donnelly E, Gladnick BP, Meredith DS, Lane JM, Boskey AL (2010) Bisphosphonate treatment reduces cortical tissue heterogeneity in postmenopausal women with fractures. Transactions Orthopaedic Research Society 56th Annual Meeting, New Orleans.

  23. Somford MP, Draijer FW, Thomassen BJ, Chavassieux PM, Boivin G, Papapoulos SE (2009) Bilateral fractures of the femur diaphysis in a patient with rheumatoid arthritis on long-term treatment with alendronate: clues to the mechanism of increased bone fragility. J Bone Miner Res 24:1736–1740

    Article  PubMed  Google Scholar 

  24. Allen MR, Gineyts E, Leeming DJ, Burr DB, Delmas PD (2008) Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra. Osteoporos Int 19(3):329–337

    Article  PubMed  CAS  Google Scholar 

  25. Tang SY, Allen MR, Phipps R, Burr DB, Vashishth D (2009) Changes in non-enzymatic glycation and its association with altered mechanical properties following 1-year treatment with risedronate or alendronate. Osteoporos Int 20:887–894

    Article  PubMed  CAS  Google Scholar 

  26. Tang SY, Zeenath U, Vashishth D (2007) Effects of non-enzymatic glycation on cancellous bone fragility. Bone 40(4):1144–1151

    Article  PubMed  CAS  Google Scholar 

  27. Viguet-Carrin S, Roux JP, Arlot ME, Merabet Z, Leeming DJ, Byrjalsen I, Delmas PD, Bouxsein ML (2006) Contribution of the advanced glycation end product pentosidine and of maturation of type I collagen to compressive biomechanical properties of human lumbar vertebrae. Bone 39:1073–1079

    Article  PubMed  CAS  Google Scholar 

  28. Allen MR, Iwata K, Phipps R, Burr DB (2006) Alterations in canine vertebral bone turnover, microdamage accumulation, and biomechanical properties following 1-year treatment with clinical treatment doses of risedronate or alendronate. Bone 39:872–879

    Article  PubMed  CAS  Google Scholar 

  29. Allen MR, Burr DB (2007) Three years of alendronate treatment results in similar levels of vertebral microdamage as after one year of treatment. J Bone Miner Res 22:1759–1765

    Article  PubMed  CAS  Google Scholar 

  30. Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB (2001) Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 28:524–531

    Article  PubMed  CAS  Google Scholar 

  31. Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB (2000) Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 15:613–620

    Article  PubMed  CAS  Google Scholar 

  32. Brennan O, Kennedy OD, Lee TC, Rackard SM, O’Brien FJ (2011) Effects of estrogen deficiency and bisphosphonate therapy on osteocyte viability and microdamage accumulation in an ovine model of osteoporosis. J Orthop Res 29:419–424

    Article  PubMed  Google Scholar 

  33. Stepan JJ, Burr DB, Pavo I, Sipos A, Michalska D, Li J, Fahrleitner-Pammer A, Petto H, Westmore M, Michalsky D, Sato M, Dobnig H (2007) Low bone mineral density is associated with bone microdamage accumulation in postmenopausal women with osteoporosis. Bone 41:378–385

    Article  PubMed  Google Scholar 

  34. Chapurlat RD, Arlot M, Burt-Pichat B, Chavassieux P, Roux JP, Portero-Muzy N, Delmas PD (2007) Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long term bisphosphonates: a bone biopsy study. J Bone Miner Res 22:1502–1509

    Article  PubMed  CAS  Google Scholar 

  35. Dobnig H, Stepan JJ, Burr DB, Li J, Michalská D, Sipos A, Petto H, Fahrleitner-Pammer A, Pavo I (2009) Teriparatide reduces bone microdamage accumulation in postmenopausal women previously treated with alendronate. J Bone Miner Res 24:1998–2006

    Article  PubMed  CAS  Google Scholar 

  36. Milgrom C, Finestone A, Novack V, Pereg D, Goldich Y, Kreiss Y, Zimlichman E, Kaufman S, Liebergall M, Burr D (2004) The effect of prophylactic treatment with risedronate on stress fracture incidence among infantry recruits. Bone 35:418–424

    Article  PubMed  CAS  Google Scholar 

  37. Kidd LJ, Cowling NR, Wu AC, Kelly WL, Forwood MR (2011) Bisphosphonate treatment delays stress fracture remodeling in the rat ulna. J Orthop Res May 19. doi:10.1002/jor.21464 [Epub ahead of print]

  38. Sloan AV, Martin JR, Li S, Li J (2010) Parathyroid hormone and bisphosphonate have opposite effects on stress fracture repair. Bone 47(2):235–240

    Article  PubMed  CAS  Google Scholar 

  39. Odvina CV, Levy S, Rao S, Zerwekh JE, Sudhaker Rao D (2010) Unusual mid-shaft fractures during long term bisphosphonate therapy. Clin Endocrinol (Oxf) 72:161–168

    Article  CAS  Google Scholar 

  40. Ing-Lorenzini K, Desmeules J, Plachta O (2009) Low-energy femoral fractures associated with the long-term use of bisphosphonates: a case series from a Swiss University Hospital. Drug Saf 32:775–785

    Article  PubMed  CAS  Google Scholar 

  41. Armamento-Villareal R, Napoli N, Diemer K, Watkins M, Civitelli R, Teitelbaum S, Novack D (2009) Bone turnover in bone biopsies of patients with low-energy cortical fractures receiving bisphosphonates: a case series. Calcif Tissue Int 85:37–44

    Article  PubMed  CAS  Google Scholar 

  42. Fournier P, Boissier S, Filleur S, Guglielmi J, Cabon F, Colombel M, Clézardin P (2002) Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 62:6538–6544

    PubMed  CAS  Google Scholar 

  43. Santini D, Vincenzi B, Dicuonzo G, Avvisati G, Massacesi C, Battistoni F, Gavasci M, Rocci L, Tirindelli MC, Altomare V, Tocchini M, Bonsignori M, Tonini G (2003) Zoledronic acid induces significant and long-lasting modification of circulating angiogenic factors in cancer patients. Clin Cancer Res 9:2893–2897

    PubMed  CAS  Google Scholar 

  44. Vincenzi B, Santini D, Dicuonzo G, Battistoni F, Gavasci M, La Cesa A, Grilli C, Virzì V, Gasparro S, Rocci L, Tonini G (2005) Zoledronic acid-related angiogenesis modifications and survival in advanced breast cancer patients. J Interferon Cytokine Res 25:144–151

    Article  PubMed  CAS  Google Scholar 

  45. Andersen TL, Sondergaard TE, Skorzynska KE, Dagnaes-Hansen F, Plesner TL, Hauge E, Plesner T, Delaisse J-M (2009) A physical mechanism for coupling bone resorption and formation in adult human bone. Am J Pathol 174:239–247

    Article  PubMed  CAS  Google Scholar 

  46. Girgis CM, Seibel MJ (2011) Guilt by association? Examining the role of bisphosphonate therapy in the development of atypical femoral fractures. Bone 48:963–965

    Article  PubMed  CAS  Google Scholar 

  47. Giusti A, Hamdy NAT, Dekkers OM, Ramautar SR, Dijkstra S, Papapoulos SE (2011) Atypical fractures and bisphosphonate therapy: a cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features. Bone 48:966–971

    Article  PubMed  CAS  Google Scholar 

  48. Unnanuntana A, Ashfaq K, Ton QV, Kleimeyer JP, Lane JM (2011) The effect of long-term alendronate treatment on cortical thickness of the proximal femur. Clin Orthop Relat Res. 2011 Jul 20. (in press)

  49. 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, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E, American Society for Bone and Mineral Research (2007) Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22:1479–1491

    Article  PubMed  Google Scholar 

  50. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B, Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons (2009) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw—2009 update. Aust Endod J 35:119–130

    Article  PubMed  Google Scholar 

  51. Khan AA, Sándor GK, Dore E, Morrison AD, Alsahli M, Amin F, Peters E, Hanley DA, Chaudry SR, Lentle B, Dempster DW, Glorieux FH, Neville AJ, Talwar RM, Clokie CM, Mardini MA, Paul T, Khosla S, Josse RG, Sutherland S, Lam DK, Carmichael RP, Blanas N, Kendler D, Petak S, Ste-Marie LG, Brown J, Evans AW, Rios L, Compston JE, Canadian Taskforce on Osteonecrosis of the Jaw (2009) Bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 36:478–490

    Article  PubMed  Google Scholar 

  52. Almazrooa SA, Woo SB (2009) Bisphosphonate and nonbisphosphonate-associated osteonecrosis of the jaw. A review. J Am Dent Assoc 140:864–875

    PubMed  CAS  Google Scholar 

  53. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV, Sleeboom H, Spencer A, Vadhan-Raj S, von Moos R, Willenbacher W, Woll PJ, Wang J, Jiang Q, Jun S, Dansey R, Yeh H (2011) Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29:1125–1132

    Article  PubMed  CAS  Google Scholar 

  54. Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813–822

    Article  PubMed  CAS  Google Scholar 

  55. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C, FREEDOM Trial (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756–765

    Article  PubMed  CAS  Google Scholar 

  56. Everts V, Korper W, Docherty AJ, Beertsen W (1999) Matrix metalloproteinase inhibitors block osteoclastic resorption of calvarial bone but not the resorption of long bone. Ann N Y Acad Sci 878:603–606

    Article  PubMed  CAS  Google Scholar 

  57. Hoff AO, Toth B, Hu M, Hortobagyi GN, Gagel RF (2011) Epidemiology and risk factors for osteonecrosis of the jaw in cancer patients. Ann N Y Acad Sci 1218:47–54

    Article  PubMed  CAS  Google Scholar 

  58. Narongroeknawin P, Danila MI, Humphreys LG Jr, Barasch A, Curtis JR (2010) Bisphosphonate-associated osteonecrosis of the jaw, with healing after teriparatide: a review of the literature and a case report. Spec Care Dentist 30:77–82

    Article  PubMed  Google Scholar 

  59. Lesclous P, Abi Najm S, Carrel JP, Baroukh B, Lombardi T, Willi JP, Rizzoli R, Saffar JL, Samson J (2009) Bisphosphonate-associated osteonecrosis of the jaw: a key role of inflammation? Bone 45:843–852

    Article  PubMed  CAS  Google Scholar 

  60. Catalano L, Del Vecchio S, Petruzziello F, Fonti R, Salvatore B, Martorelli C, Califano C, Caparrotti G, Segreto S, Pace L, Rotoli B (2007) Ann Hematol 86:415–423

    Article  PubMed  Google Scholar 

  61. Bedogni A, Blandamura S, Lokmic Z, Palumbo C, Ragazzo M, Ferrari F, Tregnaghi A, Pietrogrande F, Procopio O, Saia G, Ferretti M, Bedogni G, Chiarini L, Ferronato G, Ninfo V, Lo Russo L, Lo Muzio L, Nocini PF (2008) Oral Surg Oral Med Oral Pathol Oral Radiol Endod 105:358–364

    Article  PubMed  Google Scholar 

  62. Raje N, Woo SB, Hande K, Yap JT, Richardson PG, Vallet S, Treister N, Hideshima T, Sheehy N, Chhetri S, Connell B, Xie W, Tai YT, Szot-Barnes A, Tian M, Schlossman RL, Weller E, Munshi NC, Van Den Abbeele AD, Anderson KC (2008) Clinical, radiographic, and biochemical characterization of multiple myeloma patients with osteonecrosis of the jaw. Clin Cancer Res 14:2387–2395

    Article  PubMed  CAS  Google Scholar 

  63. O’Ryan FS, Khoury S, Liao W, Han MM, Hui RL, Baer D, Martin D, Liberty D, Lo JC (2009) Intravenous bisphosphonate-related osteonecrosis of the jaw: bone scintigraphy as an early indicator. J Oral Maxillofac Surg 67:1363–1372

    Article  PubMed  Google Scholar 

  64. Bénichou OD, Laredo JD, de Vernejoul MC (2000) Type II autosomal dominant osteopetrosis (Albers-Schönberg disease): clinical and radiological manifestations in 42 patients. Bone 26:87–93

    Article  PubMed  Google Scholar 

  65. Allen MR (2009) Bisphosphonates and osteonecrosis of the jaw: moving from the bedside to the bench. Cells Tissues Organs 189:289–294

    Article  PubMed  CAS  Google Scholar 

  66. Allen MR (2007) Animal models of osteonecrosis of the jaw. J Musculoskelet Neuronal Interact 7:358–360

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  68. Allen MR (2011) The effects of bisphosphonates on jaw bone remodeling, tissue properties, and extraction healing. Odontol 99:8–17

    Article  CAS  Google Scholar 

  69. Hansen T, Kunkel M, Weber A, James Kirkpatrick C (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 

  70. Guarneri V, Miles D, Robert N, Diéras V, Glaspy J, Smith I, Thomssen C, Biganzoli L, Taran T, Conte P (2010) Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat 122:181–188

    Article  PubMed  CAS  Google Scholar 

  71. Brunello A, Saia G, Bedogni A, Scaglione D, Basso U (2009) Worsening of osteonecrosis of the jaw during treatment with sunitinib in a patient with metastatic renal cell carcinoma. Bone 44:173–175

    Article  PubMed  CAS  Google Scholar 

  72. Kunzmann V, Bauer E, Wilhelm M (1999) Gamma/delta T-cell stimulation by pamidronate. N Engl J Med 340:737–738

    Article  PubMed  CAS  Google Scholar 

  73. Kunzmann V, Bauer E, Feurle J, Weiβinger F, Tony HP, Wilhelm M (2000) Stimulation of γδ T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood 96:384–392

    PubMed  CAS  Google Scholar 

  74. Das H, Wang L, Kamath A, Bukowski JF (2001) Vgamma2Vdelta2 T-cell receptor-mediated recognition of aminobisphosphonates. Blood 98:1616–1618

    Article  PubMed  CAS  Google Scholar 

  75. Nair SP, Meghji S, Wilson M, Reddi K, White P, Henderson B (1996) Bacterially induced bone destruction: mechanisms and misconceptions. Infect Immun 64:2371–2380

    PubMed  CAS  Google Scholar 

  76. Meghji S, Crean SJ, Hill PA, Sheikh M, Nair SP, Heron K, Henderson B, Mawer EB, Harris M (1998) Surface-associated protein from Staphylococcus aureus stimulates osteoclastogenesis: possible role in S. aureus-induced bone pathology. Br J Rheumatol 37:1095–1101

    Article  PubMed  CAS  Google Scholar 

  77. Sedghizadeh PP, Kumar SK, Gorur A, Schaudinn C, Shuler CF, Costerton JW (2009) Microbial biofilms in osteomyelitis of the jaw and osteonecrosis of the jaw secondary to bisphosphonate therapy. J Am Dent Assoc 140:1259–1265

    PubMed  Google Scholar 

  78. Hikita H, Miyazawa K, Tabuchi M, Kimura M, Goto S (2009) Bisphosphonate administration prior to tooth extraction delays initial healing of the extraction socket in rats. J Bone Miner Metab 27:663–672

    Article  PubMed  CAS  Google Scholar 

  79. Landesberg R, Woo V, Cremers S, Cozin M, Marolt D, Vunjak-Novakovic G, Kousteni S, Raghavan S (2011) Potential pathophysiological mechanisms in osteonecrosis of the jaw. Ann N Y Acad Sci 1218:62–79

    Article  PubMed  CAS  Google Scholar 

  80. Ravosa MJ, Ning J, Liu Y, Stack MS (2011) Bisphosphonate effects on the behaviour of oral epithelial cells and oral fibroblasts. Arch Oral Biol 56:491–498

    Article  PubMed  CAS  Google Scholar 

  81. Pabst AM, Ziebart T, Koch FP, Taylor KY, Al-Nawas B, Walter C (2011) The influence of bisphosphonates on viability, migration, and apoptosis of human oral keratinocytes-in vitro study. Clin Oral Investig 2011 Jan 12 (in press)

  82. Yamashita J, Koi K, Yang DY, McCauley LK (2011) Effect of zoledronate on oral wound healing in rats. Clin Cancer Res 17:1405–1414

    Article  PubMed  CAS  Google Scholar 

  83. Allam E, Allen M, Chu TM, Ghoneima A, Jack Windsor L (2011) In vivo effects of zoledronic acid on oral mucosal epithelial cells. Oral Dis 17:291–297

    Article  PubMed  CAS  Google Scholar 

  84. Pazianas M (2010) Osteonecrosis of the jaw and the role of macrophages. JNCI 103:232–240

    PubMed  Google Scholar 

  85. Rogers MJ, Chilton KM, Coxon FP, Lawry J, Smith MO, Suri S, Russell RG (1996) Bisphosphonates induce apoptosis in mouse macrophage-like cells in vitro by a nitric oxide-independent mechanism. J Bone Miner Res 11:1482–1491

    Article  PubMed  CAS  Google Scholar 

  86. Hewison M (2010) Vitamin D and the immune system: new perspectives on an old theme. Endocrinol Metab Clin North Am 39:365–379

    Article  PubMed  CAS  Google Scholar 

  87. Seshasayee D, Wang H, Lee WP, Gribling P, Ross J, Van Bruggen N, Carano R, Grewal IS (2004) A novel in vivo role for osteoprotegerin ligand in activation of monocyte effector function and inflammatory response. J Biol Chem 279:30202–30209

    Article  PubMed  CAS  Google Scholar 

  88. Ferrari-Lacraz S, Ferrari S (2011) Do RANKL inhibitors (denosumab) affect inflammation and immunity? Osteoporos Int 22:435–446

    Article  PubMed  CAS  Google Scholar 

  89. English BC, Baum CE, Adelberg DE, Sissung TM, Kluetz PG, Dahut WL, Price DK, Figg WD (2010) A SNP in CYP2C8 is not associated with the development of bisphosphonate-related osteonecrosis of the jaw in men with castrate-resistant prostate cancer. Ther Clin Risk Manag 6:579–583

    PubMed  CAS  Google Scholar 

  90. Sarasquete ME, García-Sanz R, Marín L, Alcoceba M, Chillón MC, Balanzategui A, Santamaria C, Rosiñol L, de la Rubia J, Hernandez MT, Garcia-Navarro I, Lahuerta JJ, González M, San Miguel JF (2008) Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis. Blood 112(7):2709–2712

    Article  PubMed  CAS  Google Scholar 

  91. Marini F, Tonelli P, Cavalli L, Cavalli T, Masi L, Falchetti A, Brandi ML (2011) Pharmacogenetics of bisphosphonate-associated osteonecrosis of the jaw. Front Biosci (Elite Ed) 3:364–370

    Article  Google Scholar 

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Conflicts of interest

Prof. Compston has served on advisory boards for MSD, Novartis, Sanofi Aventis, GlaxoSmithKline and Amgen and has received speaking fees from MSD, Amgen and Warner Chilcott.

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    J. Compston

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00198-011-1827-3

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Compston, J. Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw. Osteoporos Int 22, 2951–2961 (2011). https://doi.org/10.1007/s00198-011-1804-x

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  • DOI: https://doi.org/10.1007/s00198-011-1804-x

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