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Fracture Healing: Back to Basics and Latest Advances

  • Ippokratis Pountos
  • Peter V. Giannoudis
Chapter
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Abstract

Our understanding in the mechanisms promoting bone repair and involvement of molecular mediators and cellular elements in fracture healing are ever expanding. What was initially perceived as a simple process, nowadays is known to be very complex and multifaceted. The aim of this chapter is to present the fundamental principles of fracture healing, factors that can influence it adversely, and key approaches to stimulate a successful fracture healing response.

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Notes

Conflict of Interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this chapter.

References

  1. 1.
    Lane WAL. The operative treatment of fractures. 2nd ed. London: The Medical Publishing Co. Ltd; 1914.Google Scholar
  2. 2.
    Danis R. Théorie et pratique de 1’ostéosynthèse. Paris: Masson; 1949.Google Scholar
  3. 3.
    Kolar P, Gaber T, Perka C, Duda GN, Buttgereit F. Human early fracture hematoma is characterized by inflammation and hypoxia. Clin Orthop Relat Res. 2011;469(11):3118–26.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Burke D, Dishowitz M, Sweetwyne M, Miedel E, Hankenson KD, Kelly DJ. The role of oxygen as a regulator of stem cell fate during fracture repair in TSP2-null mice. J Orthop Res. 2013;31(10):1585–96.CrossRefPubMedGoogle Scholar
  5. 5.
    Wray JB. The biochemical characteristics of the fracture hematoma in man. Surg Gynecol Obstet. 1970;130(5):847–52.PubMedGoogle Scholar
  6. 6.
    Mountziaris PM, Mikos AG. Modulation of the inflammatory response for enhanced bone tissue regeneration. Tissue Eng Part B Rev. 2008;14(2):179–86.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Xing Z, Lu C, Hu D, Miclau T 3rd, Marcucio RS. Rejuvenation of the inflammatory system stimulates fracture repair in aged mice. J Orthop Res. 2010;28(8):1000–6.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Friedman AD. Cell cycle and developmental control of hematopoiesis by Runx1. J Cell Physiol. 2009;219(3):520–4.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Karnes JM, Daffner SD, Watkins CM. Multiple roles of tumor necrosis factor-alpha in fracture healing. Bone. 2015;78:87–93.CrossRefPubMedGoogle Scholar
  10. 10.
    Mountziaris PM, Spicer PP, Kasper FK, Mikos AG. Harnessing and modulating inflammation in strategies for bone regeneration. Tissue Eng Part B Rev. 2011;17(6):393–402.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Nam D, Mau E, Wang Y, Wright D, Silkstone D, Whetstone H, Whyne C, Alman B. T-lymphocytes enable osteoblast maturation via IL-17F during the early phase of fracture repair. PLoS One. 2012;7(6):e40044.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Relat Res. 1998;(355 Suppl):S7–21.Google Scholar
  13. 13.
    Bianco P, Cancedda FD, Riminucci M, Cancedda R. Bone formation via cartilage models: the “borderline” chondrocyte. Matrix Biol. 1998;17(3):185–92.CrossRefPubMedGoogle Scholar
  14. 14.
    Daftari TK, Whitesides TE Jr, Heller JG, Goodrich AC, McCarey BE, Hutton WC. Nicotine on the revascularization of bone graft. An experimental study in rabbits. Spine (Phila Pa 1976). 1994;19(8):904–11.CrossRefGoogle Scholar
  15. 15.
    Rubenstein I, Yong T, Rennard SI, Mayhan WG. Cigarette smoke extract attenuates endothelium-dependent arteriolar dilatation in vivo. Am J Phys. 1991;261(6 Pt 2):H1913–8.Google Scholar
  16. 16.
    Brighton CT, Hunt RM. Histochemical localization of calcium in the fracture callus with potassium pyroantimonate. Possible role of chondrocyte mitochondrial calcium in callus calcification. J Bone Joint Surg Am. 1986;68(5):703–15.CrossRefPubMedGoogle Scholar
  17. 17.
    Einhorn TA, Hirschman A, Kaplan C, Nashed R, Devlin VJ, Warman J. Neutral protein-degrading enzymes in experimental fracture callus: a preliminary report. J Orthop Res. 1989;7(6):792–805.CrossRefPubMedGoogle Scholar
  18. 18.
    Ford JL, Robinson DE, Scammell BE. The fate of soft callus chondrocytes during long bone fracture repair. J Orthop Res. 2003;21(1):54–61.CrossRefPubMedGoogle Scholar
  19. 19.
    Claes L, Recknagel S, Ignatius A. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol. 2012;8(3):133–43.  https://doi.org/10.1038/nrrheum.2012.1.CrossRefPubMedGoogle Scholar
  20. 20.
    Pountos I, Georgouli T, Calori GM, Giannoudis PV. Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis. Sci World J. 2012;2012:606404.CrossRefGoogle Scholar
  21. 21.
    Lindaman LM. Bone healing in children. Clin Podiatr Med Surg. 2001;18:97–108.PubMedGoogle Scholar
  22. 22.
    Wilkins KE. Principles of fracture remodeling in children. Injury. 2005;36(Suppl 1):A3–11.CrossRefPubMedGoogle Scholar
  23. 23.
    Aho AJ. Electron microscopic and histologic studies on fracture repair in old and young rats. Acta Chir Scand Suppl. 1966;357:162–5.PubMedGoogle Scholar
  24. 24.
    Parker MJ. Prediction of fracture union after internal fixation of intracapsular femoral neck fractures. Injury. 1994;25(Suppl 2):B3–6.PubMedGoogle Scholar
  25. 25.
    Robinson CM, Court-Brown CM, McQueen MM, Wakefield AE. Estimating the risk of nonunion following nonoperative treatment of a clavicular fracture. J Bone Joint Surg Am. 2004;86-A(7):1359–65.CrossRefPubMedGoogle Scholar
  26. 26.
    Zura R, Braid-Forbes MJ, Jeray K, Mehta S, Einhorn TA, Watson JT, Della Rocca GJ, Forbes K, Steen RG. Bone fracture nonunion rate decreases with increasing age: A prospective inception cohort study. Bone. 2017;95:26–32.CrossRefPubMedGoogle Scholar
  27. 27.
    Hayda RA, Brighton CT, Esterhai JL Jr. Pathophysiology of delayed healing. Clin Orthop Relat Res. 1998;(355 Suppl):S31–40.Google Scholar
  28. 28.
    Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol. 2015;11(1):45–54.CrossRefPubMedGoogle Scholar
  29. 29.
    Einhorn TA, Bonnarens F, Burstein AH. The contributions of dietary protein and mineral to the healing of experimental fractures. A biomechanical study. J Bone Joint Surg Am. 1986;68(9):1389–95.CrossRefPubMedGoogle Scholar
  30. 30.
    Brinker MR, Bailey DE Jr. Fracture healing in tibia fractures with an associated vascular injury. J Trauma. 1997;42(1):11–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Bibbo C, Lin SS, Beam HA, Behrens FF. Complications of ankle fractures in diabetic patients. Orthop Clin North Am. 2001;32(1):113–33.CrossRefPubMedGoogle Scholar
  32. 32.
    Gorter EA, Krijnen P, Schipper IB. Vitamin D status and adult fracture healing. J Clin Orthop Trauma. 2017;8(1):34–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Kowalewski K, Yong S. Bone and urinary hydroxyproline in normal and hypothyroid rat with a long bone fracture. Acta Endocrinol. 1967;56(3):547–53.PubMedCrossRefGoogle Scholar
  34. 34.
    Bilous RW, Tunbridge WM. The epidemiology of hypothyroidism-an update. Bailliere Clin Endocrinol Metab. 1988;2(3):531–40.CrossRefGoogle Scholar
  35. 35.
    Dix B, Grant-McDonald L, Catanzariti A, Saltrick K. Preoperative Anemia in Hindfoot and Ankle Arthrodesis. Foot Ankle Spec. 2017;10(2):109–15.CrossRefPubMedGoogle Scholar
  36. 36.
    Gruson KI, Aharonoff GB, Egol KA, Zuckerman JD, Koval KJ. The relationship between admission hemoglobin level and outcome after hip fracture. J Orthop Trauma. 2002;16(1):39–44.CrossRefPubMedGoogle Scholar
  37. 37.
    Chakkalakal DA, Novak JR, Fritz ED, Mollner TJ, McVicker DL, Lybarger DL, McGuire MH, Donohue TM Jr. Chronic ethanol consumption results in deficient bone repair in rats. Alcohol Alcohol. 2002;37(1):13–20.CrossRefPubMedGoogle Scholar
  38. 38.
    Hazan EJ, Hornicek FJ, Tomford W, Gebhardt MC, Mankin HJ. The effect of adjuvant chemotherapy on osteoarticular allografts. Clin Orthop Relat Res. 2001;385:176–81.CrossRefGoogle Scholar
  39. 39.
    Hausman MR, Schaffler MB, Majeska RJ. Prevention of fracture healing in rats by an inhibitor of angiogenesis. Bone. 2001;29(6):560–4.CrossRefGoogle Scholar
  40. 40.
    Aaron JE, Francis RM, Peacock M, Makins NB. Contrasting microanatomy of idiopathic and corticosteroid-induced osteoporosis. Clin Orthop Relat Res. 1989;243:294–305.Google Scholar
  41. 41.
    Pountos I, Georgouli T, Blokhuis TJ, Pape HC, Giannoudis PV. Pharmacological agents and impairment of fracture healing: what is the evidence? Injury. 2008;39(4):384–94.CrossRefPubMedGoogle Scholar
  42. 42.
    Pountos I, Giannoudis PV. Effect of methotrexate on bone and wound healing. Expert Opin Drug Saf. 2017;16(5):535–45.CrossRefPubMedGoogle Scholar
  43. 43.
    Gerster JC, Bossy R, Dudler J. Bone non-union after osteotomy in patients treated with methotrexate. J Rheumatol. 1999;26:2695–7.PubMedGoogle Scholar
  44. 44.
    Neal BC, Rodgers A, Clark T, Gray H, Reid IR, Dunn L, MacMahon SW. A systematic survey of 13 randomized trials of non-steroidal anti-inflammatory drugs for the prevention of heterotopic bone formation after major hip surgery. Acta Orthop Scand. 2000;71(2):122–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Miller GK. Editorial Commentary: The Efficacy of Nonsteroidal Anti-inflammatory Drugs for Prophylaxis of Heterotopic Ossification in Hip Arthroscopy-Do We Treat Patients or X-rays? Arthroscopy. 2016;32(3):526–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Jeffcoach DR, Sams VG, Lawson CM, Enderson BL, Smith ST, Kline H, Barlow PB, Wylie DR, Krumenacker LA, McMillen JC, Pyda J, Daley BJ, University of Tennessee Medical Center, Department of Surgery. Nonsteroidal anti-inflammatory drugs' impact on nonunion and infection rates in long-bone fractures. J Trauma Acute Care Surg. 2014;76(3):779–83.CrossRefPubMedGoogle Scholar
  47. 47.
    Perry AC, Prpa B, Rouse MS, Piper KE, Hanssen AD, Steckelberg JM, Patel R. Levofloxacin and trovafloxacin inhibition of experimental fracture-healing. Clin Orthop Relat Res. 2003;414:95–100.CrossRefGoogle Scholar
  48. 48.
    Miclau T, Edin ML, Lester GE, Lindsey RW, Dahners LE. Bone toxicity of locally applied aminoglycosides. J Orthop Trauma. 1995;9(5):401–6.CrossRefPubMedGoogle Scholar
  49. 49.
    Pilge H, Fröbel J, Prodinger PM, Mrotzek SJ, Fischer JC, Zilkens C, Bittersohl B, Krauspe R. Enoxaparin and rivaroxaban have different effects on human mesenchymal stromal cells in the early stages of bone healing. Bone Joint Res. 2016;5(3):95–100.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Street JT, McGrath M, O'Regan K, Wakai A, McGuinness A, Redmond HP. Thromboprophylaxis using a low molecular weight heparin delays fracture repair. Clin Orthop Relat Res. 2000;(381):278–89.Google Scholar
  51. 51.
    Melhus H, Michaëlsson K, Holmberg L, Wolk A, Ljunghall S. Smoking, antioxidant vitamins, and the risk of hip fracture. J Bone Miner Res. 1999;14(1):129–35.CrossRefPubMedGoogle Scholar
  52. 52.
    Porter SE, Hanley EN Jr. The musculoskeletal effects of smoking. J Am Acad Orthop Surg. 2001;9(1):9–17.CrossRefPubMedGoogle Scholar
  53. 53.
    Castillo RC, Bosse MJ, MacKenzie EJ, Patterson BM, LEAP Study Group. Impact of smoking on fracture healing and risk of complications in limb-threatening open tibia fractures. J Orthop Trauma. 2005;19(3):151–7.CrossRefPubMedGoogle Scholar
  54. 54.
    Saville PD. Changes in bone mass with age and alcoholism. J Bone Joint Surg Am. 1965;47:492–9.CrossRefPubMedGoogle Scholar
  55. 55.
    Arlot ME, Bonjean M, Chavassieux PM, Meunier PJ. Bone histology in adults with aseptic necrosis. Histomorphometric evaluation of iliac biopsies in seventy-seven patients. J Bone Joint Surg Am. 1983;65:1319–27.CrossRefPubMedGoogle Scholar
  56. 56.
    Nogueira-Filho Gda R, Cadide T, Rosa BT, Neiva TG, Tunes R, Peruzzo D, Nociti FH Jr, César-Neto JB. Cannabis sativa smoke inhalation decreases bone filling around titanium implants: a histomorphometric study in rats. Implant Dent. 2008;17(4):461–70.CrossRefPubMedGoogle Scholar
  57. 57.
    Dimitriou R, Kanakaris N, Soucacos PN, Giannoudis PV. Genetic predisposition to non-union: evidence today. Injury. 2013;44(Suppl 1):S50–3.CrossRefPubMedGoogle Scholar
  58. 58.
    Zeckey C, Hildebrand F, Glaubitz LM, Jürgens S, Ludwig T, Andruszkow H, Hüfner T, Krettek C, Stuhrmann M. Are polymorphisms of molecules involved in bone healing correlated to aseptic femoral and tibial shaft non-unions? J Orthop Res. 2011;29(11):1724–31.  https://doi.org/10.1002/jor.21443.CrossRefPubMedGoogle Scholar
  59. 59.
    Dimitriou R, Carr IM, West RM, Markham AF, Giannoudis PV. Genetic predisposition to fracture non-union: a case control study of a preliminary single nucleotide polymorphisms analysis of the BMP pathway. BMC Musculoskelet Disord. 2011;12:44.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Rhinelander FW, Baragry RA. Microangiography in bone healing: Undisplaced closed fractures. J Bone Joint Surg. 1962;44A:1273.CrossRefGoogle Scholar
  61. 61.
    Fong K, Truong V, Foote CJ, Petrisor B, Williams D, Ristevski B, et al. Predictors of nonunion and reoperation in patients with fractures of the tibia: an observational study. BMC Musculoskelet Disord. 2013;14:103.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Claes L, Augat P, Suger G, Wilke HJ. Influence of size and stability of the osteotomy gap on the success of fracture healing. J Orthop Res. 1997 Jul;15(4):577–84.CrossRefPubMedGoogle Scholar
  63. 63.
    Claes L, Eckert-Hübner K, Augat P. The fracture gap size influences the local vascularization and tissue differentiation in callus healing. Langenbeck's Arch Surg. 2003;388(5):316–22.CrossRefGoogle Scholar
  64. 64.
    Riehl JT, Connolly K, Haidukewych G, Koval K. Fractures Due to Gunshot Wounds: Do Retained Bullet Fragments Affect Union? Iowa Orthop J. 2015;35:55–61.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Claes L, Maurer-Klein N, Henke T, Gerngross H, Melnyk M, Augat P. Moderate soft tissue trauma delays new bone formation only in the early phase of fracture healing. J Orthop Res. 2006;24(6):1178–85.CrossRefPubMedGoogle Scholar
  66. 66.
    Lu C, Miclau T, Hu D, Marcucio RS. Ischemia leads to delayed union during fracture healing: a mouse model. J Orthop Res. 2007;25(1):51–61.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Reverte MM, Dimitriou R, Kanakaris NK, Giannoudis PV. What is the effect of compartment syndrome and fasciotomies on fracture healing in tibial fractures? Injury. 2011;42(12):1402–7.CrossRefPubMedGoogle Scholar
  68. 68.
    Claes LE, Heigele CA, Neidlinger-Wilke C, Kaspar D, Seidl W, Margevicius KJ, Augat P. Effects of mechanical factors on the fracture healing process. Clin Orthop Relat Res. 1998;(355 Suppl):S132–47.Google Scholar
  69. 69.
    Mavčič B, Antolič V. Optimal mechanical environment of the healing bone fracture/osteotomy. Int Orthop. 2012;36(4):689–95.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Hu X, Xu S, Lu H, Chen B, Zhou X, He X, Dai J, Zhang Z, Gong S. Minimally invasive plate osteosynthesis vs conventional fixation techniques for surgically treated humeral shaft fractures: a meta-analysis. J Orthop Surg Res. 2016;11(1):59.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Duan X, Li T, Mohammed AQ, Xiang Z. Reamed intramedullary nailing versus unreamed intramedullary nailing for shaft fracture of femur: a systematic literature review. Arch Orthop Trauma Surg. 2011;131(10):1445–52.CrossRefPubMedGoogle Scholar
  72. 72.
    Krettek C, Haas N, Tscherne H. The role of supplemental lag-screw fixation for open fractures of the tibial shaft treated with external fixation. J Bone Joint Surg Am. 1991;73(6):893–7.CrossRefPubMedGoogle Scholar
  73. 73.
    Claes L, Grass R, Schmickal T, Kisse B, Eggers C, Gerngross H, Mutschler W, Arand M, Wintermeyer T, Wentzensen A. Monitoring and healing analysis of 100 tibial shaft fractures. Langenbeck's Arch Surg. 2002;387(3–4):146–52.CrossRefGoogle Scholar
  74. 74.
    Pountos I, Panteli M, Georgouli T, Giannoudis PV. Neoplasia following use of BMPs: is there an increased risk? Expert Opin Drug Saf. 2014;13(11):1525–34.CrossRefPubMedGoogle Scholar
  75. 75.
    Giannoudis PV, Einhorn TA, Marsh D. Fracture healing: the diamond concept. Injury. 2007;38(Suppl 4):S3–6.CrossRefPubMedGoogle Scholar
  76. 76.
    Crist BD, Stoker AM, Stannard JP, Cook JL. Analysis of relevant proteins from bone graft harvested using the reamer irrigator and aspirator system (RIA) versus iliac crest (IC) bone graft and RIA waste water. Injury. 2016;47(8):1661–8.CrossRefPubMedGoogle Scholar
  77. 77.
    Marchand LS, Rothberg DL, Kubiak EN, Higgins TF. Is This Autograft Worth It?: The Blood Loss and Transfusion Rates Associated With Reamer Irrigator Aspirator Bone Graft Harvest. J Orthop Trauma. 2017;31(4):205–9.CrossRefPubMedGoogle Scholar
  78. 78.
    Pountos I, Georgouli T, Kontakis G, Giannoudis PV. Efficacy of minimally invasive techniques for enhancement of fracture healing: evidence today. Int Orthop. 2010;34(1):3–12.CrossRefPubMedGoogle Scholar
  79. 79.
    Kanakaris NK, Calori GM, Verdonk R, Burssens P, De Biase P, Capanna R, Vangosa LB, Cherubino P, Baldo F, Ristiniemi J, Kontakis G, Giannoudis PV. Application of BMP-7 to tibial non-unions: a 3-year multicenter experience. Injury. 2008;39(Suppl 2):S83–90.CrossRefPubMedGoogle Scholar
  80. 80.
    Anitua E, Andia I, Ardanza B, Nurden P, Nurden AT. Autologous platelets as a source of proteins for healing and tissue regeneration. Thromb Haemost. 2004;91(1):4–15.PubMedGoogle Scholar
  81. 81.
    Sheth U, Simunovic N, Klein G, Fu F, Einhorn TA, Schemitsch E, Ayeni OR, Bhandari M. Efficacy of autologous platelet-rich plasma use for orthopaedic indications: a meta-analysis. J Bone Joint Surg Am. 2012;94(4):298–307.CrossRefPubMedGoogle Scholar
  82. 82.
    Pountos I, Georgouli T, Henshaw K, Bird H, Jones E, Giannoudis PV. The effect of bone morphogenetic protein-2, bone morphogenetic protein-7, parathyroid hormone, and platelet-derived growth factor on the proliferation and osteogenic differentiation of mesenchymal stem cells derived from osteoporotic bone. J Orthop Trauma. 2010;24(9):552–6.CrossRefPubMedGoogle Scholar
  83. 83.
    DiGiovanni CW, Lin SS, Baumhauer JF, Daniels T, Younger A, Glazebrook M, Anderson J, Anderson R, Evangelista P, Lynch SE, North American Orthopedic Foot and Ankle Study Group. Recombinant human platelet-derived growth factor-BB and beta-tricalcium phosphate (rhPDGF-BB/β-TCP): an alternative to autogenous bone graft. J Bone Joint Surg Am. 2013;95(13):1184–92.CrossRefPubMedGoogle Scholar
  84. 84.
    Tzioupis CC, Giannoudis PV. The Safety and Efficacy of Parathyroid Hormone (PTH) as a Biological Response Modifier for the Enhancement of Bone Regeneration. Curr Drug Saf. 2006;1(2):189–203.CrossRefPubMedGoogle Scholar
  85. 85.
    Peichl P, Holzer LA, Maier R, Holzer G. Parathyroid hormone 1-84 accelerates fracture-healing in pubic bones of elderly osteoporotic women. J Bone Joint Surg Am. 2011;93(17):1583–7.CrossRefPubMedGoogle Scholar
  86. 86.
    Aspenberg P, Johansson T. Teriparatide improves early callus formation in distal radial fractures. Acta Orthop. 2010;81(2):234–6.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Türker M, Aslan A, Çırpar M, Kochai A, Tulmaç ÖB, Balcı M. Histological and biomechanical effects of zoledronate on fracture healing in an osteoporotic rat tibia model. Eklem Hastalik Cerrahisi. 2016;27(1):9–15.CrossRefPubMedGoogle Scholar
  88. 88.
    Kiely P, Ward K, Bellemore CM, Briody J, Cowell CT, Little DG. Bisphosphonate rescue in distraction osteogenesis: a case series. J Pediatr Orthop. 2007;27(4):467–71.CrossRefPubMedGoogle Scholar
  89. 89.
    Kuzyk PR, Schemitsch EH. The science of electrical stimulation therapy for fracture healing. Indian J Orthop. 2009;43(2):127–31.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Korenstein R, Somjen D, Fischler H, Binderman I. Capacitative pulsed electric stimulation of bone cells. Induction of cyclic-AMP changes and DNA synthesis. Biochim Biophys Acta. 1984;803(4):302–7.CrossRefPubMedGoogle Scholar
  91. 91.
    Mollon B, da Silva V, Busse JW, Einhorn TA, Bhandari M. Electrical stimulation for long-bone fracture-healing: a meta-analysis of randomized controlled trials. J Bone Joint Surg Am. 2008;90(11):2322–30.CrossRefPubMedGoogle Scholar
  92. 92.
    Pounder NM, Harrison AJ. Low intensity pulsed ultrasound for fracture healing: a review of the clinical evidence and the associated biological mechanism of action. Ultrasonics. 2008;48(4):330–8.CrossRefPubMedGoogle Scholar
  93. 93.
    Schandelmaier S, Kaushal A, Lytvyn L, Heels-Ansdell D, Siemieniuk RA, Agoritsas T, Guyatt GH, Vandvik PO, Couban R, Mollon B, Busse JW. Low intensity pulsed ultrasound for bone healing: systematic review of randomized controlled trials. BMJ. 2017;356:j656.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Vulpiani MC, Vetrano M, Conforti F, Minutolo L, Trischitta D, Furia JP, Ferretti A. Effects of extracorporeal shock wave therapy on fracture nonunions. Am J Orthop (Belle Mead NJ). 2012;41(9):E122–7.Google Scholar
  95. 95.
    Zelle BA, Gollwitzer H, Zlowodzki M, Bühren V. Extracorporeal shock wave therapy: current evidence. J Orthop Trauma. 2010;24(Suppl 1):S66–70.CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Academic Department of Trauma and Orthopaedics, School of MedicineUniversity of LeedsLeedsUK
  2. 2.NIHRLeedsUK
  3. 3.Musculoskeletal Biomedical Research Center, Chapel Allerton HospitalLeedsUK

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