Case Studies in Fracture Healing and Nonunions

  • Joseph BorrelliJr.
  • Brent L. Norris


Fracture healing is a complex biological and biomechanical process that depends upon a sequence of factors to take place in an often-forgotten about biomechanical environment. Generally, fracture healing proceeds in one of two ways. When fracture fragments are brought directly into contact with each other and stabilized in a manner that limits motion, healing generally takes place by primary/direct bone healing. Primary bone healing includes both contact and gap healing, and in these scenarios fracture healing generally does not include callus formation. Secondary/indirect fracture healing generally occurs when the biomechanical environment during healing allows some motion at the fracture site. Secondary bone healing, unlike primary bone healing, includes the development of a soft callus comprised mostly of cartilage, followed by ossification of this soft callus, and eventually complete fracture healing and remodeling. When fractures fail to heal in the expected time frame, they are considered to be a nonunion. The multiple clinical examples in this chapter highlight the relationship between the biomechanical environment provided by external and internal means of fracture stabilization and the type of fracture healing to be expected. This chapter also includes a description of these types of fracture healing as well as a couple of examples of the approach and treatment of fracture nonunion.


Primary/direct bone healing Secondary/indirect bone healing Nonunion Mesenchymal stem cells (MSC) Inflammation Callus Angiogenesis Fracture 


  1. 1.
    Mountziaris PM, Mikos AG. Modulation of the inflammatory response for enhanced bone tissue regeneration. Tissue Eng Part B Rev. 2008;14(2):179–86.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Xing Z, Ku 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
  3. 3.
    Pountos I, Giannoudis PV. Fracture healing: back to basics and latest advances. In: Giannoudis PV, editor. Fracture reduction and fixation techniques. Cham: Springer International; 2018.Google Scholar
  4. 4.
    Lane WAL. The operative treatment of fracture. 2nd ed. London: The Medical Publishing Co., Ltd; 1914.Google Scholar
  5. 5.
    Shapiro F. Cortical bone repair. The relationship of the lacunar-canalicular system and intercellular gap junctions to the repair process. J Bone Joint Surg Am. 1988;70(7):1067–81.CrossRefGoogle Scholar
  6. 6.
    Kaderly RE. Primary bone healing. Semin Vet Med Surg (Small Anim). 1991;6(1):21–5.Google Scholar
  7. 7.
    Kitaori T, Ito H, Schwarz EM, Tsutsumi R, Yoshitomi H, Oishi S, et al. Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheum. 2009;60(3):813–23.PubMedCrossRefGoogle Scholar
  8. 8.
    Rahn BA, Gallinaro P, Baltensperger A, Perren SM. Primary bone healing. An experimental study in the rabbit. J Bone Joint Surg Am. 1971;53(4):783–6.PubMedCrossRefGoogle Scholar
  9. 9.
    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
  10. 10.
    Parker MJ. Prediction of fracture union after internal fixation of intracapsular femoral neck fractures. Injury. 1994;25(Suppl 2):B3–6.PubMedGoogle Scholar
  11. 11.
    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(7):1359–65.PubMedCrossRefGoogle Scholar
  12. 12.
    Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and intervention. Nat Rev Rheumatol. 2015;11(1):45–54.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    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.PubMedCrossRefGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    Burke D, Dishowitz M, Sweetwyne M, Miedel E, Handkenson 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.PubMedCrossRefGoogle Scholar
  16. 16.
    Jeffcoach DR, Sams VG, Lawson CM, Enderson BL, Smith ST, Kline H, et al. Nonsteroidal anti-inflammatory drugs impact on nonunion and infection rates in long bone fractures. J Trauma Acute Care Surg. 2014;76(3):779–83.PubMedCrossRefGoogle Scholar
  17. 17.
    Goh SK, Yang KY, Koh JS, et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br. 2007;89(3):349–53.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Schilcher J, Michaelsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364(18):1728–37.PubMedCrossRefGoogle Scholar
  19. 19.
    Tyler W, Bukata S, O’Keefe R. Atypical femur fractures. Clin Geriatr Med. 2014;30(2):349–59.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Einhorn TA, O’Keefe RJ, Buchwalter JA, American Academy of Orthopaedic Surgeons. Orthopaedic basic science: foundations of clinical practice. 3rd ed. Rosemont: AAOS; 2007. p. 331–46.Google Scholar
  21. 21.
    Kwong FN, Harris MB. Recent developments in the biology of fracture repair. J Am Acad Orthop Surg. 2008;16(11):619–25.PubMedCrossRefGoogle Scholar
  22. 22.
    Gerstenfeld LC, Alkhiary YM, Krall EA, Nicholls FH, Stapleton SN, Fitch JL, et al. Three-dimensional reconstruction of fracture callus morphogenesis. J Histochem Cytochem. 2006;54(11):1215–28.PubMedCrossRefGoogle Scholar
  23. 23.
    Green E, Lubahn JD, Evans J. Risk factors, treatment, and outcomes associated with nonunion of the midshaft humerus fracture. J Surg Orthop Adv. 2005;14(2):64–72.PubMedGoogle Scholar
  24. 24.
    Pape HC, Giannoudis PV, Grimme K, van Griensven M, Krettek C. Effects of intramedullary femoral fracture fixation: what is the impact of experimental studies in regards to the clinical knowledge? Shock. 2002;18(4):291–300.PubMedCrossRefGoogle Scholar
  25. 25.
    Perren SM. Evolution of the internal fixation of long bone fractures. The scientific basis of biological internal fixation: choosing a new balance between stability and biology. J Bone Joint Surg Br. 2002;84(8):1093–110.CrossRefGoogle Scholar
  26. 26.
    Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA. Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem. 2003;88(5):873–84.PubMedCrossRefGoogle Scholar
  27. 27.
    Cho TJ, Gerstenfeld LC, Einhorn TA. Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res. 2002;17(3):513–20.CrossRefGoogle Scholar
  28. 28.
    Sfei C, Ho L, Doll BA, Azari K, Hollinger JO. Fracture repair. In: Lieberman JR, Friedlaender GE, editors. Bone regeneration and repair. Totowa: Humana Press; 2005. p. 21–44.CrossRefGoogle Scholar
  29. 29.
    Kon T, Cho TJ, Aizawa T, Yamazaki M, Nooh N, Graves D, et al. Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res. 2001;16(6):1004–14.CrossRefGoogle Scholar
  30. 30.
    Lee SK, Lorenzo J. Cytokines regulating osteoclast formation and function. Curr Opin Rheumatol. 2006;18(4):411–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Yang X, Ricciardi BF, Hernandez-Soria A, Shi Y, Pleshko CN, Bostrom MP. Callus mineralization and maturation are delayed during fracture healing in interleukin-6 knockout mice. Bone. 2007;41(6):928–36.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Bais MV, Wigner N, Young M, Toholka R, Graves DT, Morgan EF, et al. BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells. Bone. 2009;45(2):254–66.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Dimitriou R, Tsiridis E, Giannoudis PV. Current concepts of molecular aspects of bone healing. Injury. 2005;36(12):1392–404.PubMedCrossRefGoogle Scholar
  34. 34.
    Breur GJ, VanEnkevort BA, Farnum CE, Wilsman NJ. Linear relationship between the volume of hypertrophic chondrocytes and the rate of longitudinal bone growth in growth plates. J Orthop Res. 1991;9(3):348–59.PubMedCrossRefGoogle Scholar
  35. 35.
    Wendeberg B. Mineral metabolism of fractures of the tibia in man studied with external counting of Sr85. Acta Orthop Scand Suppl. 1961;52:1–79.PubMedCrossRefGoogle Scholar
  36. 36.
    Carano RA, Filvaroff EH. Angiogenesis and bone repair. Drug Discov Today. 2003;8(21):980–9.CrossRefGoogle Scholar
  37. 37.
    Rhinelander FW. Circulation in bone. In: Bourne GH, editor. The biochemistry and physiology of bone, vol. 2. New York, London: Academic Press; 1976.Google Scholar
  38. 38.
    Rhinelander FW. Tibial blood supply in relation to fracture healing. Clin Orthop Relat Res. 1974;105:34-81.CrossRefGoogle Scholar
  39. 39.
    Giannoudis PV, Einhorn TA, Marsh D. Fracture healing: the diamond concept. Injury. 2007;38(Suppl 4):S3–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Andrzejowski P, Giannoudis PV. The ‘diamond concept’ for long bone non-union management. J Orthop Traumatol. 2019;20(1):21.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Miska M, Findeisen S, Tanner M, Biglari B, Studier-Fischer S, Grutzner PA, et al. Treatment of nonunions in fractures of the humeral shaft according to the Diamond Concept. Bone Joint J. 2016;98-B(1):81–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Joseph BorrelliJr.
    • 1
    • 2
  • Brent L. Norris
    • 3
  1. 1.BayCare Health SystemLutzUSA
  2. 2.Department of Orthopedic Surgery and Sports Medicine, Morsani College of MedicineUniversity of South FloridaTampaUSA
  3. 3.Department of Orthopedic TraumaUniversity of OklahomaTulsaUSA

Personalised recommendations