Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Non-union bone fractures

Abstract

The human skeleton has remarkable regenerative properties, being one of the few structures in the body that can heal by recreating its normal cellular composition, orientation and mechanical strength. When the healing process of a fractured bone fails owing to inadequate immobilization, failed surgical intervention, insufficient biological response or infection, the outcome after a prolonged period of no healing is defined as non-union. Non-union represents a chronic medical condition not only affecting function but also potentially impacting the individual’s psychosocial and economic well-being. This Primer provides the reader with an in-depth understanding of our contemporary knowledge regarding the important features to be considered when faced with non-union. The normal mechanisms involved in bone healing and the factors that disrupt the normal signalling mechanisms are addressed. Epidemiological considerations and advances in the diagnosis and surgical therapy of non-union are highlighted and the need for greater efforts in basic, translational and clinical research are identified.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Traditional non-union classification.
Fig. 2: Influence of the mechanical conditions on fracture healing.
Fig. 3: Alterations in non-union.
Fig. 4: Treatment of humerus atrophic non-union.
Fig. 5: Tibial oligotrophic non-union.
Fig. 6: Examples of hypertrophic non-unions.
Fig. 7: Factors involved in the treatment of non-unions.

References

  1. 1.

    Brinker, M. R., Hanus, B. D., Sen, M. & O’Connor, D. P. The devastating effects of tibial nonunion on health-related quality of life. J. Bone Joint Surg. Am. 95, 2170–2176 (2013).

    Google Scholar 

  2. 2.

    Brinker, M. R., Trivedi, A. & O’Connor, D. P. Debilitating effects of femoral nonunion on health-related quality of life. J. Orthop. Trauma 31, e37–e42 (2017). A cohort study looking at femoral non-union, the impact of this disease is similar to end-stage hip arthrosis and tibial non-union, and worse than other medical conditions.

    Google Scholar 

  3. 3.

    Mills, L. A., Aitken, S. A. & Simpson, A. The risk of non-union per fracture: current myths and revised figures from a population of over 4 million adults. Acta Orthop. 88, 434–439 (2017). This paper showed that the analysis of non-union incidence revealed the overall peak incidence at an age between 30 and 40 years, with more frequent non-unions in upper limbs than in lower limbs.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Zura, R. et al. Epidemiology of fracture nonunion in 18 human bones. JAMA Surg. 151, e162775 (2016). This paper is a large cohort study identifying patient-specific risk factors for the development of non-union.

    Google Scholar 

  5. 5.

    Taylor, J. C. in Campbell’s Operative Orthopaedics (eds Crenshaw, A. H., Daugherty, K. & Campbell, W. C.) 1287–1345 (Mosby, 1992).

  6. 6.

    Brinker, M. R. & O’Connor, D. P. in Skeletal Trauma (eds Browner, B., Jupiter, J., Krettek, C. & Anderson, P.) 743–834 (Elsevier, 2020).

  7. 7.

    Weber, B. G. & Cech, O. Pseudarthrosis: Pathophysiology, Biomechanics, Therapy, Results (Grune & Stratton, 1976). This book describes the classification of non-union types, which is still used today.

  8. 8.

    Schottel, P. C., O’Connor, D. P. & Brinker, M. R. Time trade-off as a measure of health-related quality of life: long bone nonunions have a devastating impact. J. Bone Joint Surg. Am. 97, 1406–1410 (2015).

    Google Scholar 

  9. 9.

    Hak, D. J. et al. Delayed union and nonunions: epidemiology, clinical issues, and financial aspects. Injury 45 (Suppl. 2), S3–S7 (2014).

    Google Scholar 

  10. 10.

    Ekegren, C. L., Edwards, E. R., de Steiger, R. & Gabbe, B. J. Incidence, costs and predictors of non-union, delayed union and mal-union following long bone fracture. Int J. Environ. Res Public Health 15, 2845 (2018). This is an analysis of the Victorian Orthopaedic Trauma Outcomes Registry showing that older age and tibia or femoral shaft fracture are risk factors for the development of non-union.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Özkan, S., Nolte, P. A., van den Bekerom, M. P. J. & Bloemers, F. W. Diagnosis and management of long-bone nonunions: a nationwide survey. Eur. J. Trauma Emerg. Surg. 45, 3–11 (2019).

    Google Scholar 

  12. 12.

    Mathieu, L. et al. Management of the complications of traditional bone setting for upper extremity fractures: the experiences of a French Forward Surgical Team in Chad. Chirur. Main. 33, 137–143 (2014).

    CAS  Google Scholar 

  13. 13.

    Reynolds, T. A. et al. The impact of trauma care systems in low- and middle-income countries. Annu. Rev. Public. Health 38, 507–532 (2017).

    Google Scholar 

  14. 14.

    Bhandari, M. et al. A lack of consensus in the assessment of fracture healing among orthopaedic surgeons. J. Orthop. Trauma 16, 562–566 (2002).

    Google Scholar 

  15. 15.

    Tian, R. et al. Prevalence and influencing factors of nonunion in patients with tibial fracture: systematic review and meta-analysis. J. Orthop. Surg. Res. 15, 377 (2020).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Tzioupis, C. & Giannoudis, P. V. Prevalence of long-bone non-unions. Injury 38 (Suppl. 2), S3–S9 (2007).

    Google Scholar 

  17. 17.

    Keating, J. F., O’Brien, P. I., Blachut, P., Meek, R. N. & Broekhuyse, H. M. Reamed interlocking intramedullary nailing of open fractures of the tibia. Clin. Orthop. Relat. Res. 338, 182–191 (1997).

    Google Scholar 

  18. 18.

    O’Halloran, K. et al. Will my tibial fracture heal? predicting nonunion at the time of definitive fixation based on commonly available variables. Clin. Orthop. Relat. Res. 474, 1385–1395 (2016).

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Ross, K. A. et al. Prediction of tibial nonunion at the 6-week time point. Injury 49, 2075–2082 (2018).

    Google Scholar 

  20. 20.

    Canadian Orthopaedic Trauma Society.Nonunion following intramedullary nailing of the femur with and without reaming: results of a multicenter randomized clinical trial. J. Bone Joint Surg. Am. 85, 2093–2096 (2003).

    Google Scholar 

  21. 21.

    Metsemakers, W. J., Roels, N., Belmans, A., Reynders, P. & Nijs, S. Risk factors for nonunion after intramedullary nailing of femoral shaft fractures: remaining controversies. Injury 46, 1601–1607 (2015).

    Google Scholar 

  22. 22.

    Rommens, P. M., Blum, J. & Runkel, M. Retrograde nailing of humeral shaft fractures. Clin. Orthop. Relat. Res. 350, 26–39 (1998).

    Google Scholar 

  23. 23.

    Sarmiento, A., Zagorski, J. B., Zych, G. A., Latta, L. L. & Capps, C. A. Functional bracing for the treatment of fractures of the humeral diaphysis. J. Bone Joint Surg. Am. 82, 478–486 (2000).

    CAS  Google Scholar 

  24. 24.

    Singh, A. et al. Gustilo IIIB open tibial fractures: an analysis of infection and nonunion rates. Indian J. Orthop. 52, 406–410 (2018).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Calori, G. M., Albisetti, W., Agus, A., Iori, S. & Tagliabue, L. Risk factors contributing to fracture non-unions. Injury 38 (Suppl. 2), S11–S18 (2007).

    Google Scholar 

  26. 26.

    Taitsman, L. A., Lynch, J. R., Agel, J., Barei, D. P. & Nork, S. E. Risk factors for femoral nonunion after femoral shaft fracture. J. Trauma 67, 1389–1392 (2009).

    Google Scholar 

  27. 27.

    Winquist, R. A., Hansen, J. S. T. & Clawson, D. K. Closed intramedullary nailing of femoral fractures. A report of five hundred and twenty cases. 1984. J. Bone Joint Surg. Am. 83, 1912–1912 (2001).

    CAS  Google Scholar 

  28. 28.

    Ma, Y.-G., Hu, G.-L., Hu, W. & Liang, F. Surgical factors contributing to nonunion in femoral shaft fracture following intramedullary nailing. Chin. J. Traumatol. 19, 109–112 (2016).

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Mills, L. A. & Simpson, A. H. R. W. The relative incidence of fracture non-union in the Scottish population (5.17 million): a 5-year epidemiological study. BMJ Open 3, e002276 (2013).

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Zura, R. et al. Bone fracture nonunion rate decreases with increasing age: a prospective inception cohort study. Bone 95, 26–32 (2017).

    Google Scholar 

  31. 31.

    Scolaro, J. A. et al. Cigarette smoking increases complications following fracture. J. Bone Joint Surg. Am. 96, 674–681 (2014).

    Google Scholar 

  32. 32.

    Hernigou, J. & Schuind, F. Smoking as a predictor of negative outcome in diaphyseal fracture healing. Int. Orthop. 37, 883–887 (2013).

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Jeffcoach, D. R. et al. Nonsteroidal anti-inflammatory drugs’ impact on nonunion and infection rates in long-bone fractures. J. Trauma Acute Care Surg. 76, 779–783 (2014).

    CAS  Google Scholar 

  34. 34.

    Moghaddam, A. et al. Cigarette smoking influences the clinical and occupational outcome of patients with tibial shaft fractures. Injury 42, 1435–1442 (2011).

    Google Scholar 

  35. 35.

    Pearson, R. G., Clement, R. G. E., Edwards, K. L. & Scammell, B. E. Do smokers have greater risk of delayed and non-union after fracture, osteotomy and arthrodesis? A systematic review with meta-analysis. BMJ Open 6, e010303 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Zura, R., Mehta, S., Della Rocca, G. J. & Steen, R. G. Biological risk factors for nonunion of bone fracture. JBJS Rev. 4, 1 (2016).

    Google Scholar 

  37. 37.

    Dodwell, E. R. et al. NSAID exposure and risk of nonunion: a meta-analysis of case–control and cohort studies. Calcif. Tissue Int. 87, 193–202 (2010).

    CAS  Google Scholar 

  38. 38.

    Hernandez, R. K., Do, T. P., Critchlow, C. W., Dent, R. E. & Jick, S. S. Patient-related risk factors for fracture-healing complications in the United Kingdom general practice research database. Acta Orthop. 83, 653–660 (2012).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Burrus, M. T., Werner, B. C. & Yarboro, S. R. Obesity is associated with increased postoperative complications after operative management of tibial shaft fractures. Injury 47, 465–470 (2015).

    Google Scholar 

  40. 40.

    Gortler, H. et al. Diabetes and healing outcomes in lower extremity fractures: a systematic review. Injury 49, 177–183 (2018).

    Google Scholar 

  41. 41.

    van Wunnik, B. P. W., Weijers, P. H. E., van Helden, S. H., Brink, P. R. G. & Poeze, M. Osteoporosis is not a risk factor for the development of nonunion: a cohort nested case–control study. Injury 42, 1491–1494 (2011).

    Google Scholar 

  42. 42.

    Brinker, M. R., O’Connor, D. P., Monla, Y. T. & Earthman, T. P. Metabolic and endocrine abnormalities in patients with nonunions. Curr. Orthop. Pract. 19, 430–442 (2008).

    Google Scholar 

  43. 43.

    Dimitriou, R., Carr, I. M., West, R. M., Markham, A. F. & Giannoudis, P. V. Genetic predisposition to fracture non-union: a case control study of a preliminary single nucleotide polymorphisms analysis of the BMP pathway. BMC Musculoskelet. Disord. 12, 44–44 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Guimarães, J. M. et al. Polymorphisms in BMP4 and FGFR1 genes are associated with fracture non-union: polymorphisms and non-union. J. Orthop. Res. 31, 1971–1979 (2013).

    Google Scholar 

  45. 45.

    Sathyendra, V. M. D. et al. Single nucleotide polymorphisms in osteogenic genes in atrophic delayed fracture-healing. J. Bone Joint Surg. Am. 96, 1242–1248 (2014).

    Google Scholar 

  46. 46.

    Zeckey, C. et al. Are polymorphisms of molecules involved in bone healing correlated to aseptic femoral and tibial shaft non-unions? J. Orthop. Res. 29, 1724–1731 (2011).

    CAS  Google Scholar 

  47. 47.

    McCoy, J. T. H. et al. Genomewide association study of fracture nonunion using electronic health records. JBMR 3, 23–28 (2019).

    Google Scholar 

  48. 48.

    Aslan, A. et al. Surgical treatment of osteopetrosis-related femoral fractures: two case reports and literature review. Case Rep. Orthop. 2014, 891963 (2014).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Rovira Martí, P. & Ullot Font, R. Orthopaedic disorders of pycnodysostosis: a report of five clinical cases. Int. Orthop. 40, 2221–2231 (2016).

    Google Scholar 

  50. 50.

    Azzam, K. A., Rush, E. T., Burke, B. R., Nabower, A. M. & Esposito, P. W. Mid-term results of femoral and tibial osteotomies and Fassier-Duval nailing in children with osteogenesis imperfecta. J. Pediatr. Orthop. 38, 331–336 (2018).

    Google Scholar 

  51. 51.

    Mills, L., Tsang, J., Hopper, G., Keenan, G. & Simpson, A. H. R. W. The multifactorial aetiology of fracture nonunion and the importance of searching for latent infection. Bone Joint Res. 5, 512–519 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Hofmann, A. et al. Cell viability, osteoblast differentiation, and gene expression are altered in human osteoblasts from hypertrophic fracture non-unions. Bone 42, 894–906 (2008).

    CAS  Google Scholar 

  53. 53.

    Ding, Z. C., Lin, Y. K., Gan, Y. K. & Tang, T. T. Molecular pathogenesis of fracture nonunion. J. Orthop. Transl. 14, 45–56 (2018).

    Google Scholar 

  54. 54.

    Hellwinkel, J. E., Miclau, T. 3rd, Provencher, M. T., Bahney, C. S. & Working, Z. M. The life of a fracture: biologic progression, healing gone awry, and evaluation of union. JBJS Rev. 8, e1900221 (2020).

    Google Scholar 

  55. 55.

    Tsiridis, E., Upadhyay, N. & Giannoudis, P. Molecular aspects of fracture healing: which are the important molecules? Injury 38 (Suppl. 1), S11–S25 (2007).

    Google Scholar 

  56. 56.

    Zhou, X. et al. Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLoS Genet. 10, e1004820 (2014).

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Berendsen, A. D. & Olsen, B. R. Bone development. Bone 80, 14–18 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Kronenberg, H. M. Developmental regulation of the growth plate. Nature 423, 332–336 (2003).

    CAS  Google Scholar 

  59. 59.

    Boudin, E., Fijalkowski, I., Hendrickx, G. & Van Hul, W. Genetic control of bone mass. Mol. Cell. Endocrinol. 432, 3–13 (2016).

    CAS  Google Scholar 

  60. 60.

    Bonewald, L. F. The amazing osteocyte. J. Bone Min. Res. 26, 229–238 (2011).

    CAS  Google Scholar 

  61. 61.

    Einhorn, T. A. & Gerstenfeld, L. C. Fracture healing: mechanisms and interventions. Nat. Rev. Rheumatol. 11, 45–54 (2015). This paper is a review on the cellular and molecular processes during fracture healing and the role of the immune system and vascularization but also discusses the impact of the injury and treatment options.

    Google Scholar 

  62. 62.

    Claes, L., Recknagel, S. & Ignatius, A. Fracture healing under healthy and inflammatory conditions. Nat. Rev. Rheumatol. 8, 133–143 (2012). This review summarizes the cellular processes during fracture healing, the involvement of the immune system and vascularization, and the importance of biomechanical conditions.

    CAS  Google Scholar 

  63. 63.

    Loi, F. et al. Inflammation, fracture and bone repair. Bone 86, 119–130 (2016). This paper summarizes the factors influencing bone healing and discusses possibilities to enhance bone repair by the modulation of the inflammatory phase.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Perren, S. M. 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. 84, 1093–1110 (2002).

    Google Scholar 

  65. 65.

    Choy, M. H. V. et al. How much do we know about the role of osteocytes in different phases of fracture healing? A systematic review. J. Orthop. Transl. 21, 111–121 (2020).

    Google Scholar 

  66. 66.

    Kolar, P. et al. The early fracture hematoma and its potential role in fracture healing. Tissue Eng. B Rev. 16, 427–434 (2010).

    Google Scholar 

  67. 67.

    Kovtun, A. et al. The crucial role of neutrophil granulocytes in bone fracture healing. Eur. Cell Mater. 32, 152–162 (2016).

    CAS  Google Scholar 

  68. 68.

    Sinder, B. P., Pettit, A. R. & McCauley, L. K. Macrophages: their emerging roles in bone. J. Bone Miner. Res. 30, 2140–2149 (2015).

    Google Scholar 

  69. 69.

    Schlundt, C. et al. Individual effector/regulator T cell ratios impact bone regeneration. Front. Immunol. 10, 1954 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Schmidt-Bleek, K., Kwee, B. J., Mooney, D. J. & Duda, G. N. Boon and bane of inflammation in bone tissue regeneration and its link with angiogenesis. Tissue Eng. B Rev. 21, 354–364 (2015).

    CAS  Google Scholar 

  71. 71.

    Bahney, C. S. et al. Cellular biology of fracture healing. J. Orthop. Res. 37, 35–50 (2019). This paper gives an overview of the cellular and molecular processes during fracture healing.

    Google Scholar 

  72. 72.

    Claes, L. E. et al. Effects of mechanical factors on the fracture healing process. Clin. Orthop. Relat. Res. 355 (Suppl.), S132–S147 (1998).

    Google Scholar 

  73. 73.

    Claes, L. E. & Heigele, C. A. Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. J. Biomech. 32, 255–266 (1999).

    CAS  Google Scholar 

  74. 74.

    Perren, S. M. & Boitzy, A. Cellular differentiation and bone biomechanics during the consolidation of a fracture. Anat. Clin. 28, 13–28 (1978). This is an animal study investigating the effects of force and motion on bone healing, which provides important insights into the effects of compression and interfragmentary movement on the healing process.

    Google Scholar 

  75. 75.

    Perren, S. M. & Rahn, B. A. Biomechanics of fracture healing. Can. J. Surg. 23, 228–232 (1980).

    CAS  Google Scholar 

  76. 76.

    Elliott, D. S. et al. A unified theory of bone healing and nonunion: BHN theory. Bone Joint J. 98-B, 884–891 (2016). This article presents a theory combining knowledge from biological and mechanical aspects of bone formation and healing with the bone-healing unit, which is disturbed in non-unions due to mechanical conditions.

    CAS  Google Scholar 

  77. 77.

    Colnot, C., Zhang, X. & Knothe Tate, M. L. Current insights on the regenerative potential of the periosteum: molecular, cellular, and endogenous engineering approaches. J. Orthop. Res. 30, 1869–1878 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Bassett, C. A. & Herrmann, I. Influence of oxygen concentration and mechanical factors on differentiation of connective tissues in vitro. Nature 190, 460–461 (1961).

    CAS  Google Scholar 

  79. 79.

    Grimes, R., Jepsen, K. J., Fitch, J. L., Einhorn, T. A. & Gerstenfeld, L. C. The transcriptome of fracture healing defines mechanisms of coordination of skeletal and vascular development during endochondral bone formation. J. Bone Min. Res. 26, 2597–2609 (2011).

    CAS  Google Scholar 

  80. 80.

    Aghajanian, P. & Mohan, S. The art of building bone: emerging role of chondrocyte-to-osteoblast transdifferentiation in endochondral ossification. Bone Res. 6, 19 (2018).

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Claes, L. et al. Metaphyseal fracture healing follows similar biomechanical rules as diaphyseal healing. J. Orthop. Res. 29, 425–432 (2011).

    Google Scholar 

  82. 82.

    Sandberg, O. H. & Aspenberg, P. Inter-trabecular bone formation: a specific mechanism for healing of cancellous bone. Acta Orthop. 87, 459–465 (2016).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Giannoudis, P. V., Einhorn, T. A. & Marsh, D. Fracture healing: the diamond concept. Injury 38 (Suppl. 4), S3–S6 (2007). This paper highlights the importance of the mechanical environment, growth factors, scaffolds and osteogenic cells for successful bone healing and is used for planning the management of fractures.

    Google Scholar 

  84. 84.

    Andrzejowski, P. & Giannoudis, P. V. The ‘diamond concept’ for long bone non-union management. J. Orthop. Traumatol. 20, 21 (2019).

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Claes, L. Improvement of clinical fracture healing — what can be learned from mechano-biological research? J. Biomech. 115, 110148 (2021).

    Google Scholar 

  86. 86.

    Augat, P. et al. Shear movement at the fracture site delays healing in a diaphyseal fracture model. J. Orthop. Res. 21, 1011–1017 (2003).

    Google Scholar 

  87. 87.

    Claes, L. E. & Meyers, N. The direction of tissue strain affects the neovascularization in the fracture-healing zone. Med. Hypotheses 137, 109537 (2020).

    CAS  Google Scholar 

  88. 88.

    Bhandari, M. et al. Predictors of reoperation following operative management of fractures of the tibial shaft. J. Orthop. Trauma 17, 353–361 (2003).

    Google Scholar 

  89. 89.

    Perren, S. M. Physical and biological aspects of fracture healing with special reference to internal fixation.Clin. Orthop. Relat. Res. 138, 175–196 (1979).

    Google Scholar 

  90. 90.

    Stewart, S., Darwood, A., Masouros, S., Higgins, C. & Ramasamy, A. Mechanotransduction in osteogenesis. Bone Joint Res. 9, 1–14 (2020).

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Huang, C. & Ogawa, R. Mechanotransduction in bone repair and regeneration. FASEB J. 24, 3625–3632 (2010).

    CAS  Google Scholar 

  92. 92.

    Wehrle, E. et al. The impact of low-magnitude high-frequency vibration on fracture healing is profoundly influenced by the oestrogen status in mice. Dis. Model. Mech. 8, 93–104 (2015).

    CAS  Google Scholar 

  93. 93.

    Borgiani, E. et al. Age-related changes in the mechanical regulation of bone healing are explained by altered cellular mechanoresponse. J. Bone Miner. Res. 34, 1923–1937 (2019).

    CAS  Google Scholar 

  94. 94.

    Maruyama, M. et al. Modulation of the inflammatory response and bone healing. Front. Endocrinol. 11, 386 (2020).

    Google Scholar 

  95. 95.

    Clark, D., Nakamura, M., Miclau, T. & Marcucio, R. Effects of aging on fracture healing. Curr. Osteoporos. Rep. 15, 601–608 (2017).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    George, M. D. et al. Risk of nonunion with nonselective NSAIDs, COX-2 inhibitors, and opioids. J. Bone Joint Surg. Am. 102, 1230–1238 (2020).

    Google Scholar 

  97. 97.

    Miclau, K. R. et al. Stimulating fracture healing in ischemic environments: does oxygen direct stem cell fate during fracture healing? Front. Cell Dev. Biol. 5, 45 (2017).

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Santolini, E. et al. Femoral and tibial blood supply: a trigger for non-union? Injury 45, 1665–1673 (2014).

    Google Scholar 

  99. 99.

    Hankenson, K. D., Dishowitz, M., Gray, C. & Schenker, M. Angiogenesis in bone regeneration. Injury 42, 556–561 (2011).

    PubMed  PubMed Central  Google Scholar 

  100. 100.

    Weiss, S., Zimmermann, G., Pufe, T., Varoga, D. & Henle, P. The systemic angiogenic response during bone healing. Arch. Orthop. Trauma Surg. 129, 989–997 (2009).

    Google Scholar 

  101. 101.

    Garcia, P. et al. Rodent animal models of delayed bone healing and non-union formation: a comprehensive review. Eur. Cell Mater. 26, 1–12 (2013).

    CAS  Google Scholar 

  102. 102.

    Reed, A. A., Joyner, C. J., Brownlow, H. C. & Simpson, A. H. Human atrophic fracture non-unions are not avascular. J. Orthop. Res. 20, 593–599 (2002).

    CAS  Google Scholar 

  103. 103.

    Schwabe, P., Simon, P., Kronbach, Z., Schmidmaier, G. & Wildemann, B. A pilot study investigating the histology and growth factor content of human non-union tissue. Int. Orthop. 38, 2623–2629 (2014).

    Google Scholar 

  104. 104.

    Duchamp de Lageneste, O. et al. Periosteum contains skeletal stem cells with high bone regenerative potential controlled by periostin. Nat. Commun. 9, 773 (2018).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Abou-Khalil, R. et al. Role of muscle stem cells during skeletal regeneration. Stem Cell 33, 1501–1511 (2015).

    CAS  Google Scholar 

  106. 106.

    Bajada, S., Marshall, M. J., Wright, K. T., Richardson, J. B. & Johnson, W. E. Decreased osteogenesis, increased cell senescence and elevated Dickkopf-1 secretion in human fracture non union stromal cells. Bone 45, 726–735 (2009).

    CAS  Google Scholar 

  107. 107.

    El-Jawhari, J. J. et al. Defective proliferation and osteogenic potential with altered immunoregulatory phenotype of native bone marrow-multipotential stromal cells in atrophic fracture non-union. Sci. Rep. 9, 17340 (2019).

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Wagner, J. M. et al. Inflammatory processes and elevated osteoclast activity chaperon atrophic non-union establishment in a murine model. J. Transl. Med. 17, 416 (2019).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Solomon, D. H., Hochberg, M. C., Mogun, H. & Schneeweiss, S. The relation between bisphosphonate use and non-union of fractures of the humerus in older adults. Osteoporos. Int. 20, 895–901 (2009).

    CAS  Google Scholar 

  110. 110.

    Metsemakers, W. J. et al. Infection after fracture fixation: Current surgical and microbiological concepts. Injury 49, 511–522 (2018).

    CAS  Google Scholar 

  111. 111.

    Szczęsny, G. et al. Genetic factors responsible for long bone fractures non-union. Arch. Orthop. Trauma Surg. 131, 275–281 (2011).

    Google Scholar 

  112. 112.

    Dapunt, U. et al. Are atrophic long-bone nonunions associated with low-grade infections? Ther. Clin. Risk Manag. 11, 1843–1852 (2015).

    PubMed  PubMed Central  Google Scholar 

  113. 113.

    Seebach, E. & Kubatzky, K. F. Chronic implant-related bone infections — can immune modulation be a therapeutic strategy? Front. Immunol. 10, 1724 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Fisher, J. S., Kazam, J. J., Fufa, D. & Bartolotta, R. J. Radiologic evaluation of fracture healing. Skelet. Radiol. 48, 349–361 (2019).

    Google Scholar 

  115. 115.

    Morshed, S., Corrales, L., Genant, H. & Miclau, T. 3rd Outcome assessment in clinical trials of fracture-healing. J. Bone Joint Surg. Am. 90 (Suppl. 1), 62–67 (2008).

    Google Scholar 

  116. 116.

    Whelan, D. B. et al. Development of the radiographic union score for tibial fractures for the assessment of tibial fracture healing after intramedullary fixation. J. Trauma 68, 629–632 (2010). Development and reliability testing of non-union radiographic score to assess fracture healing.

    Google Scholar 

  117. 117.

    Litrenta, J. et al. Determination of radiographic healing: an assessment of consistency using RUST and modified RUST in metadiaphyseal fractures. J. Orthop. Trauma 29, 516–520 (2015).

    Google Scholar 

  118. 118.

    Oliver, W. M. et al. The Radiographic Union Score for HUmeral fractures (RUSHU) predicts humeral shaft nonunion. Bone Joint J. 101-B, 1300–1306 (2019).

    Google Scholar 

  119. 119.

    Henley, M. B. & Miller, A. Internally rotated oblique x-ray to assess healing of distal tibial shaft fractures. J. Orthop. Trauma https://doi.org/10.1097/BOT.0b013e3182645c1a (2012).

    Article  Google Scholar 

  120. 120.

    Bhattacharyya, T. et al. The accuracy of computed tomography for the diagnosis of tibial nonunion. J. Bone Joint Surg. Am. 88, 692–697 (2006).

    Google Scholar 

  121. 121.

    Oe, K. et al. Quantitative bone single-photon emission computed tomography imaging for uninfected nonunion: comparison of hypertrophic nonunion and non-hypertrophic nonunion. J. Orthop. Surg. Res. 16, 125 (2021).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Gholamrezanezhad, A. et al. Clinical nononcologic applications of PET/CT and PET/MRI in musculoskeletal, orthopedic, and rheumatologic imaging. AJR Am. J. Roentgenol. 210, W245–W263 (2018).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Moed, B. R. et al. Ultrasound for the early diagnosis of tibial fracture healing after static interlocked nailing without reaming: clinical results. J. Orthop. Trauma 12, 206–213 (1998).

    CAS  Google Scholar 

  124. 124.

    Cadet, E. R., Yin, B., Schulz, B., Ahmad, C. S. & Rosenwasser, M. P. Proximal humerus and humeral shaft nonunions. J. Am. Acad. Orthop. Surg. 21, 538–547 (2013).

    Google Scholar 

  125. 125.

    Nauth, A. et al. Principles of nonunion management: state of the art. J. Orthop. Trauma 32 (Suppl. 1), S52–S57 (2018). This paper gives an overview of the risk factors for the development of non-union, diagnosis of the cause and treatment options.

    Google Scholar 

  126. 126.

    Bell, A., Templeman, D. & Weinlein, J. C. Nonunion of the femur and tibia: an update. Orthop. Clin. North Am. 47, 365–375 (2016).

    Google Scholar 

  127. 127.

    Calori, G. M., Phillips, M., Jeetle, S., Tagliabue, L. & Giannoudis, P. V. Classification of non-union: need for a new scoring system? Injury 39 (Suppl. 2), S59–S63 (2008). This paper describes the development of a scoring system that is intended to facilitate decisions for the further treatment of non-unions.

    Google Scholar 

  128. 128.

    Rammelt, S. & Zwipp, H. Corrective arthrodeses and osteotomies for post-traumatic hindfoot malalignment: indications, techniques, results. Int. Orthop. 37, 1707–1717 (2013).

    PubMed  PubMed Central  Google Scholar 

  129. 129.

    Peschiera, V., Staletti, L., Cavanna, M., Saporito, M. & Berlusconi, M. Predicting the failure in distal femur fractures. Injury 49 (Suppl. 3), S2–S7 (2018).

    Google Scholar 

  130. 130.

    Driesman, A. S., Fisher, N., Karia, R., Konda, S. & Egol, K. A. Fracture site mobility at 6 weeks after humeral shaft fracture predicts nonunion without surgery. J. Orthop. Trauma 31, 657–662 (2017).

    Google Scholar 

  131. 131.

    Nicholson, J. A. et al. Displaced midshaft clavicle fracture union can be accurately predicted with a delayed assessment at 6 weeks following injury: a prospective cohort study. J. Bone Joint Surg. Am. 102, 557–566 (2020).

    Google Scholar 

  132. 132.

    Nicholson, J. A., Oliver, W. M., MacGillivray, T. J., Robinson, C. M. & Simpson, A. Sonographic bridging callus at six weeks following displaced midshaft clavicle fracture can accurately predict healing. Bone Joint Res. 10, 113–121 (2021).

    PubMed  PubMed Central  Google Scholar 

  133. 133.

    Brinker, M. R. & O’Connor, D. P. Management of aseptic tibial and femoral diaphyseal nonunions without bony defects. Orthop. Clin. North Am. 47, 67–75 (2016).

    Google Scholar 

  134. 134.

    Rupp, M. et al. Diaphyseal long bone nonunions - types, aetiology, economics, and treatment recommendations. Int. Orthop. 42, 247–258 (2018). This paper provides an overview of the epidemiology, costs, aetiology, classification and treatment options of non-unions.

    Google Scholar 

  135. 135.

    Reed, A. A., Joyner, C. J., Isefuku, S., Brownlow, H. C. & Simpson, A. H. Vascularity in a new model of atrophic nonunion. J. Bone Joint Surg. Br. 85, 604–610 (2003).

    CAS  Google Scholar 

  136. 136.

    Panteli, M., Pountos, I., Jones, E. & Giannoudis, P. V. Biological and molecular profile of fracture non-union tissue: current insights. J. Cell. Mol. Med. 19, 685–713 (2015).

    PubMed  PubMed Central  Google Scholar 

  137. 137.

    Ramoutar, D. N., Rodrigues, J., Quah, C., Boulton, C. & Moran, C. G. Judet decortication and compression plate fixation of long bone non-union: Is bone graft necessary? Injury 42, 1430–1434 (2011).

    CAS  Google Scholar 

  138. 138.

    Amorosa, L. F. et al. A single-stage treatment protocol for presumptive aseptic diaphyseal nonunions: a review of outcomes. J. Orthop. Trauma 27, 582–586 (2013).

    Google Scholar 

  139. 139.

    Kothari, A., Monk, P. & Handley, R. Percutaneous strain reduction screws-a safe and simple surgical option for problems with bony union. a technical trick. J. Orthop. Trauma 33, e151–e157 (2019).

    Google Scholar 

  140. 140.

    Wolff, J. Das Gesetz der Transformation der Knochen (Hirschwald, 1892).

  141. 141.

    Frost, H. M. Bone “mass” and the “mechanostat”: a proposal. Anat. Rec. 219, 1–9 (1987).

    CAS  Google Scholar 

  142. 142.

    Cheal, E. J., Mansmann, K. A., DiGioia, A. M. 3rd, Hayes, W. C. & Perren, S. M. Role of interfragmentary strain in fracture healing: ovine model of a healing osteotomy. J. Orthop. Res. 9, 131–142 (1991).

    CAS  Google Scholar 

  143. 143.

    Palomares, K. T. et al. Mechanical stimulation alters tissue differentiation and molecular expression during bone healing. J. Orthop. Res. 27, 1123–1132 (2009).

    PubMed  PubMed Central  Google Scholar 

  144. 144.

    Judet, P. R. & Patel, A. Muscle pedicle bone grafting of long bones by osteoperiosteal decortication. Clin. Orthop. Relat. Res. 87, 74–80 (1972).

    CAS  Google Scholar 

  145. 145.

    Somford, M. P., van den Bekerom, M. P. & Kloen, P. Operative treatment for femoral shaft nonunions, a systematic review of the literature. Strateg. Trauma Limb Reconstr. 8, 77–88 (2013).

    Google Scholar 

  146. 146.

    Bhan, K., Tyagi, A., Kainth, T., Gupta, A. & Umar, M. Reamed exchange nailing in nonunion of tibial shaft fractures: a review of the current evidence. Cureus 12, e9267 (2020).

    PubMed  PubMed Central  Google Scholar 

  147. 147.

    Hierholzer, C. & Bühren, V. in Intramedullary Nailing, a comprehensive Guide Vol. 1 (eds Rommens, P. M. & Hessmann, M. H.) Ch. 25, 419–452 (Springer, 2015).

  148. 148.

    Glatt, V., Evans, C. H. & Stoddart, M. J. Regenerative rehabilitation: the role of mechanotransduction in orthopaedic regenerative medicine. J. Orthop. Res. 37, 1263–1269 (2019).

    PubMed  PubMed Central  Google Scholar 

  149. 149.

    Ilizarov, G. A. The principles of the Ilizarov method. Bull. Hosp. Joint Dis. Orthop. Inst. 48, 1–11 (1988).

    CAS  Google Scholar 

  150. 150.

    Aktuglu, K., Erol, K. & Vahabi, A. Ilizarov bone transport and treatment of critical-sized tibial bone defects: a narrative review. J. Orthop. Traumatol. 20, 22 (2019).

    PubMed  PubMed Central  Google Scholar 

  151. 151.

    Glatt, V., Tepic, S. & Evans, C. Reverse dynamization: a novel approach to bone healing. J. Am. Acad. Orthop. Surg. 24, e60–e61 (2016).

    Google Scholar 

  152. 152.

    Glatt, V., Samchukov, M., Cherkashin, A. & Iobst, C. Reverse dynamization accelerates bone-healing in a large-animal osteotomy model. J. Bone Joint Surg. Am. 103, 257–263 (2021).

    Google Scholar 

  153. 153.

    Gebauer, D., Mayr, E., Orthner, E. & Ryaby, J. P. Low-intensity pulsed ultrasound: effects on nonunions. Ultrasound Med. Biol. 31, 1391–1402 (2005).

    Google Scholar 

  154. 154.

    Rutten, S., Nolte, P. A., Guit, G. L., Bouman, D. E. & Albers, G. H. Use of low-intensity pulsed ultrasound for posttraumatic nonunions of the tibia: a review of patients treated in the Netherlands. J. Trauma 62, 902–908 (2007).

    Google Scholar 

  155. 155.

    Elster, E. A. et al. Extracorporeal shock wave therapy for nonunion of the tibia. J. Orthop. Trauma 24, 133–141 (2010).

    Google Scholar 

  156. 156.

    Alkhawashki, H. M. Shock wave therapy of fracture nonunion. Injury 46, 2248–2252 (2015).

    Google Scholar 

  157. 157.

    Maazouz, Y. et al. In vitro measurement of the chemical changes occurring within beta-tricalcium phosphate bone graft substitutes. Acta Biomater. 102, 440–457 (2020).

    CAS  Google Scholar 

  158. 158.

    Zhang, J. et al. Cells responding to surface structure of calcium phosphate ceramics for bone regeneration. J. Tissue Eng. Regen. Med. 11, 3273–3283 (2017).

    CAS  Google Scholar 

  159. 159.

    Zhang, Y., Cheng, X., Jansen, J. A., Yang, F. & van den Beucken, J. Titanium surfaces characteristics modulate macrophage polarization. Mater. Sci. Eng. C. Mater. Biol. Appl. 95, 143–151 (2019).

    CAS  Google Scholar 

  160. 160.

    Schmal, H. et al. Nonunion - consensus from the 4th annual meeting of the Danish Orthopaedic Trauma Society. EFORT Open Rev. 5, 46–57 (2020).

    PubMed  PubMed Central  Google Scholar 

  161. 161.

    Cox, G., Jones, E., McGonagle, D. & Giannoudis, P. V. Reamer-irrigator-aspirator indications and clinical results: a systematic review. Int. Orthop. 35, 951–956 (2011).

    PubMed  PubMed Central  Google Scholar 

  162. 162.

    Carragee, E. J., Hurwitz, E. L. & Weiner, B. K. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 11, 471–491 (2011).

    PubMed  PubMed Central  Google Scholar 

  163. 163.

    James, A. W. et al. A review of the clinical side effects of bone morphogenetic protein-2. Tissue Eng. Part B Rev. 22, 284–297 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Liu, X. et al. Delivery of growth factors using a smart porous nanocomposite scaffold to repair a mandibular bone defect. Biomacromolecules 15, 1019–1030 (2014).

    CAS  Google Scholar 

  165. 165.

    Quinlan, E. et al. Development of collagen-hydroxyapatite scaffolds incorporating PLGA and alginate microparticles for the controlled delivery of rhBMP-2 for bone tissue engineering. J. Control. Rel. 198, 71–79 (2015).

    CAS  Google Scholar 

  166. 166.

    Walsh, D. P. et al. Rapid healing of a critical-sized bone defect using a collagen-hydroxyapatite scaffold to facilitate low dose, combinatorial growth factor delivery. J. Tissue Eng. Regen. Med. 13, 1843–1853 (2019).

    CAS  Google Scholar 

  167. 167.

    Glatt, V. et al. Improved healing of large segmental defects in the rat femur by reverse dynamization in the presence of bone morphogenetic protein-2. J. Bone Joint Surg. Am. 94, 2063–2073 (2012).

    Google Scholar 

  168. 168.

    Canintika, A. F. & Dilogo, I. H. Teriparatide for treating delayed union and nonunion: a systematic review. J. Clin. Orthop. Trauma 11, S107–S112 (2020).

    Google Scholar 

  169. 169.

    Sato, M. et al. Expression of bone matrix proteins mRNA during distraction osteogenesis. J. Bone Min. Res. 13, 1221–1231 (1998).

    CAS  Google Scholar 

  170. 170.

    Sato, M. et al. Mechanical tension-stress induces expression of bone morphogenetic protein (BMP)-2 and BMP-4, but not BMP-6, BMP-7, and GDF-5 mRNA, during distraction osteogenesis. J. Bone Min. Res. 14, 1084–1095 (1999).

    CAS  Google Scholar 

  171. 171.

    Rauch, F. et al. Temporal and spatial expression of bone morphogenetic protein-2, -4, and -7 during distraction osteogenesis in rabbits. Bone 27, 453–459 (2000).

    CAS  Google Scholar 

  172. 172.

    Radomisli, T. E., Moore, D. C., Barrach, H. J., Keeping, H. S. & Ehrlich, M. G. Weight-bearing alters the expression of collagen types I and II, BMP 2/4 and osteocalcin in the early stages of distraction osteogenesis. J. Orthop. Res. 19, 1049–1056 (2001).

    CAS  Google Scholar 

  173. 173.

    Aspenberg, P., Basic, N., Tagil, M. & Vukicevic, S. Reduced expression of BMP-3 due to mechanical loading: a link between mechanical stimuli and tissue differentiation. Acta Orthop. Scand. 71, 558–562 (2000).

    CAS  Google Scholar 

  174. 174.

    Daluiski, A. et al. Bone morphogenetic protein-3 is a negative regulator of bone density. Nat. Genet. 27, 84–88 (2001).

    CAS  Google Scholar 

  175. 175.

    Wozney, J. M. & Rosen, V. in Physiology and Pharmacology of Bone 725–748 (Springer, 1993).

  176. 176.

    Hernigou, P., Poignard, A., Beaujean, F. & Rouard, H. Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J. Bone Joint Surg. Am. 87, 1430–1437 (2005). This paper demonstrates the clinical potential of naive bone marrow progenitor cells.

    Google Scholar 

  177. 177.

    Garnavos, C., Mouzopoulos, G. & Morakis, E. Fixed intramedullary nailing and percutaneous autologous concentrated bone-marrow grafting can promote bone healing in humeral-shaft fractures with delayed union. Injury 41, 563–567 (2010).

    Google Scholar 

  178. 178.

    Gomez-Barrena, E. et al. Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial. Biomaterials 196, 100–108 (2019).

    CAS  Google Scholar 

  179. 179.

    Ismail, H. D. et al. Mesenchymal stem cell implantation in atrophic nonunion of the long bones: a translational study. Bone Joint Res. 5, 287–293 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Liu, S. et al. Manufacturing differences affect human bone marrow stromal cell characteristics and function: comparison of production methods and products from multiple centers. Sci. Rep. 7, 46731 (2017).

    PubMed  PubMed Central  Google Scholar 

  181. 181.

    Murao, H., Yamamoto, K., Matsuda, S. & Akiyama, H. Periosteal cells are a major source of soft callus in bone fracture. J. Bone Miner. Metab. 31, 390–398 (2013).

    CAS  Google Scholar 

  182. 182.

    Colnot, C. Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration. J. Bone Min. Res. 24, 274–282 (2009). This paper identified the source and preferred healing pathways of skeletal progenitor cells.

    Google Scholar 

  183. 183.

    Bragdon, B. C. & Bahney, C. S. Origin of reparative stem cells in fracture healing. Curr. Osteoporos. Rep. 16, 490–503 (2018).

    PubMed  PubMed Central  Google Scholar 

  184. 184.

    Manzini, B. M., Machado, L. M. R., Noritomi, P. Y. & Da Silva, J. V. L. Advances in bone tissue engineering: a fundamental review. J. Biosci. 46, 17 (2021).

    Google Scholar 

  185. 185.

    Perez, J. R. et al. Tissue engineering and cell-based therapies for fractures and bone defects. Front. Bioeng. Biotechnol. 6, 105 (2018).

    PubMed  PubMed Central  Google Scholar 

  186. 186.

    Kon, T. et al. Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J. Bone Min. Res. 16, 1004–1014 (2001).

    CAS  Google Scholar 

  187. 187.

    Schlundt, C. et al. Macrophages in bone fracture healing: their essential role in endochondral ossification. Bone 106, 78–89 (2018).

    CAS  Google Scholar 

  188. 188.

    Reinke, S. et al. Terminally differentiated CD8+ T cells negatively affect bone regeneration in humans. Sci. Transl. Med. 5, 177ra136 (2013). Combination of clinical and preclinical studies identifying a special T cell subtype in impaired bone healing, which might be useful as a possible prognostic marker and therapeutic target.

    Google Scholar 

  189. 189.

    Julier, Z. et al. Enhancing the regenerative effectiveness of growth factors by local inhibition of interleukin-1 receptor signaling. Sci. Adv. 6, eaba7602 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Martino, M. M. et al. Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration. Nat. Commun. 7, 11051 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    World Health Organization. WHO/WHOQOL: Measuring Quality of Life (2020).

  192. 192.

    Johnson, L. et al. Physical health and psychological outcomes in adult patients with long-bone fracture non-unions: evidence today. J. Clin. Med. 8, 1998 (2019).

    PubMed  PubMed Central  Google Scholar 

  193. 193.

    Kanakaris, N. K. & Giannoudis, P. V. The health economics of the treatment of long-bone non-unions. Injury 38 (Suppl. 2), S77–S84 (2007).

    Google Scholar 

  194. 194.

    Zeckey, C. et al. The aseptic femoral and tibial shaft non-union in healthy patients - an analysis of the health-related quality of life and the socioeconomic outcome. Open. Orthop. J. 5, 193–197 (2011).

    PubMed  PubMed Central  Google Scholar 

  195. 195.

    Antonova, E., Le, T. K., Burge, R. & Mershon, J. Tibia shaft fractures: costly burden of nonunions. BMC Musculoskelet. Disord. 14, 42 (2013).

    PubMed  PubMed Central  Google Scholar 

  196. 196.

    Tay, W. H., de Steiger, R., Richardson, M., Gruen, R. & Balogh, Z. J. Health outcomes of delayed union and nonunion of femoral and tibial shaft fractures. Injury 45, 1653–1658 (2014).

    Google Scholar 

  197. 197.

    Wichlas, F. et al. Long-term functional outcome and quality of life after successful surgical treatment of tibial nonunions. Int. Orthop. 39, 521–525 (2015).

    Google Scholar 

  198. 198.

    Stewart, S. K. Fracture non-union: a review of clinical challenges and future research needs. Malays. Orthop. J. 13, 1–10 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199.

    Lian, J. B. et al. MicroRNA control of bone formation and homeostasis. Nat. Rev. Endocrinol. 8, 212–227 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200.

    Garmilla-Ezquerra, P. et al. Analysis of the bone microRNome in osteoporotic fractures. Calcif. Tissue Int. 96, 30–37 (2015).

    CAS  Google Scholar 

  201. 201.

    Weilner, S. et al. Differentially circulating miRNAs after recent osteoporotic fractures can influence osteogenic differentiation. Bone 79, 43–51 (2015).

    CAS  Google Scholar 

  202. 202.

    Murata, K. et al. Inhibition of miR-92a enhances fracture healing via promoting angiogenesis in a model of stabilized fracture in young mice. J. Bone Min. Res. 29, 316–326 (2014).

    CAS  Google Scholar 

  203. 203.

    Weilner, S. et al. Secreted microvesicular miR-31 inhibits osteogenic differentiation of mesenchymal stem cells. Aging Cell 15, 744–754 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Ernst, M., Richards, R. G. & Windolf, M. Smart implants in fracture care - only buzzword or real opportunity? Injury 52 (Suppl. 2), S101–S105 (2021).

    Google Scholar 

  205. 205.

    Ernst, M. et al. Clinical feasibility of fracture healing assessment through continuous monitoring of implant load. J. Biomech. 116, 110188 (2021).

    Google Scholar 

  206. 206.

    Li, Z. et al. Pro-osteogenic effects of WNT in a mouse model of bone formation around femoral implants. Calcif. Tissue Int. 108, 240–251 (2021).

    CAS  Google Scholar 

  207. 207.

    Salmon, B. et al. WNT-activated bone grafts repair osteonecrotic lesions in aged animals. Sci. Rep. 7, 14254 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. 208.

    Burska, A. N. et al. Dynamics of early signalling events during fracture healing and potential serum biomarkers of fracture non-union in humans. J. Clin. Med. 9, 492 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. 209.

    Kaiser, K. et al. Pharmacological inhibition of IL-6 trans-signaling improves compromised fracture healing after severe trauma. Naunyn Schmiedebergs Arch. Pharmacol. 391, 523–536 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210.

    Dai, Y. et al. Differentially expressed microRNAs as diagnostic biomarkers for infected tibial non-union. Injury 52, 11–18 (2021).

    Google Scholar 

  211. 211.

    Cheah, E., Wu, Z., Thakur, S. S., O’Carroll, S. J. & Svirskis, D. Externally triggered release of growth factors - a tissue regeneration approach. J. Control. Rel. 332, 74–95 (2021).

    CAS  Google Scholar 

  212. 212.

    Rämö, L. et al. Effect of surgery vs functional bracing on functional outcome among patients with closed displaced humeral shaft fractures: the FISH randomized clinical trial. JAMA 323, 1792–1801 (2020).

    PubMed  PubMed Central  Google Scholar 

  213. 213.

    Ding, L., He, Z., Xiao, H., Chai, L. & Xue, F. Factors affecting the incidence of aseptic nonunion after surgical fixation of humeral diaphyseal fracture. J. Orthop. Sci. 19, 973–977 (2014).

    Google Scholar 

  214. 214.

    Ekholm, R., Tidermark, J., Törnkvist, H., Adami, J. & Ponzer, S. Outcome after closed functional treatment of humeral shaft fractures. J. Orthop. Trauma 20, 591–596 (2006).

    Google Scholar 

  215. 215.

    Thakore, R. V. et al. The Gustilo–Anderson classification system as predictor of nonunion and infection in open tibia fractures. Eur. J. Trauma Emerg. Surg. 43, 651–656 (2017).

    CAS  Google Scholar 

  216. 216.

    Dailey, H. L., Wu, K. A., Wu, P.-S., McQueen, M. M. & Court-Brown, C. M. Tibial fracture nonunion and time to healing after reamed intramedullary nailing: risk factors based on a single-center review of 1003 patients. J. Orthop. Trauma 32, e263–e269 (2018).

    Google Scholar 

  217. 217.

    Lian, H. & Huang, J. Effectiveness comparison of different operative methods in treatment of closed fracture of tibial shaft. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 29, 1067–1071 (2015).

    Google Scholar 

  218. 218.

    Gaebler, C., McQueen, M. M., Vécsei, V. & Court-Brown, C. M. Reamed versus minimally reamed nailing: a prospectively randomised study of 100 patients with closed fractures of the tibia. Injury 42, S17–S21 (2011).

    Google Scholar 

  219. 219.

    Ostrum, R. F., DiCicco, J., Lakatos, R. & Poka, A. Retrograde intramedullary nailing of femoral diaphyseal fractures. J. Orthop. Trauma 12, 464–468 (1998).

    CAS  Google Scholar 

  220. 220.

    Löffler, J. et al. Compromised bone healing in aged rats is associated with impaired M2 macrophage function. Front. Immunol. 10, 2443 (2019).

    PubMed  PubMed Central  Google Scholar 

  221. 221.

    Waki, T. et al. Profiling microRNA expression in fracture nonunions: potential role of microRNAs in nonunion formation studied in a rat model. Bone Joint J. 97-B, 1144–1151 (2015).

    CAS  Google Scholar 

  222. 222.

    Meesters, D. M. et al. Deficiency of inducible and endothelial nitric oxide synthase results in diminished bone formation and delayed union and nonunion development. Bone 83, 111–118 (2016).

    CAS  Google Scholar 

  223. 223.

    Fajardo, M., Liu, C.-J. & Egol, K. Levels of expression for BMP-7 and several BMP antagonists may play an integral role in a fracture nonunion: a pilot study. Clin. Orthop. Relat. Res. 467, 3071 (2009).

    PubMed  PubMed Central  Google Scholar 

  224. 224.

    Zimmermann, G. et al. TGF-β1 as a marker of delayed fracture healing. Bone 36, 779–785 (2005).

    CAS  Google Scholar 

  225. 225.

    Tsuji, K. et al. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat. Genet. 38, 1424–1429 (2006).

    CAS  Google Scholar 

  226. 226.

    Makino, T., Hak, D. J., Hazelwood, S. J., Curtiss, S. & Reddi, A. H. Prevention of atrophic nonunion development by recombinant human bone morphogenetic protein-7. J. Orthop. Res. 23, 632–638 (2005).

    CAS  Google Scholar 

  227. 227.

    Wildemann, B. et al. Local BMP-2 application can rescue the delayed osteotomy healing in a rat model. Injury 42, 746–752 (2011).

    CAS  Google Scholar 

  228. 228.

    Zhang, W. et al. The intracellular NADH level regulates atrophic nonunion pathogenesis through the CtBP2-p300-Runx2 transcriptional complex. Int. J. Biol. Sci. 14, 2023–2036 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. 229.

    Chen, X. et al. NSM00158 Specifically disrupts the CtBP2-p300 interaction to reverse CtBP2-mediated transrepression and prevent the occurrence of nonunion. Mol. Cell 43, 517–529 (2020).

    CAS  Google Scholar 

  230. 230.

    Baht, G. S. et al. Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin. Nat. Commun. 6, 7131 (2015).

    CAS  Google Scholar 

  231. 231.

    Burgers, T. A. et al. Mice with a heterozygous Lrp6 deletion have impaired fracture healing. Bone Res. 4, 16025 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. 232.

    Liu, Y. et al. Effects of sclerostin antibody on the healing of femoral fractures in ovariectomised rats. Calcif. Tissue Int. 98, 263–274 (2016).

    CAS  Google Scholar 

  233. 233.

    Haffner-Luntzer, M. et al. Inhibition of midkine augments osteoporotic fracture healing. PLoS ONE 11, e0159278 (2016).

    PubMed  PubMed Central  Google Scholar 

  234. 234.

    McKenzie, J. A. et al. Activation of hedgehog signaling by systemic agonist improves fracture healing in aged mice. J. Orthop. Res. 37, 51–59 (2019).

    CAS  Google Scholar 

  235. 235.

    Weiss, S. et al. Systemic response of the GH/IGF-I axis in timely versus delayed fracture healing. Growth Horm. IGF Res. 18, 205–212 (2008).

    Google Scholar 

  236. 236.

    Aspenberg, P. et al. Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J. Bone Min. Res. 25, 404–414 (2010).

    CAS  Google Scholar 

  237. 237.

    Kumabe, Y. et al. Triweekly administration of parathyroid hormone (1–34) accelerates bone healing in a rat refractory fracture model. BMC Musculoskelet. Disord. 18, 545 (2017).

    PubMed  PubMed Central  Google Scholar 

  238. 238.

    Bostrom, M. P. G. et al. Parathyroid hormone-related protein analog RS-66271 is an effective therapy for impaired bone healing in rabbits on corticosteroid therapy. Bone 26, 437–442 (2000).

    CAS  Google Scholar 

  239. 239.

    Minkwitz, S., Fassbender, M., Kronbach, Z. & Wildemann, B. Longitudinal analysis of osteogenic and angiogenic signaling factors in healing models mimicking atrophic and hypertrophic non-unions in rats. PLoS ONE 10, e0124217 (2015).

    PubMed  PubMed Central  Google Scholar 

  240. 240.

    Garcia, P. et al. Temporal and spatial vascularization patterns of unions and nonunions: role of vascular endothelial growth factor and bone morphogenetic proteins. J. Bone Joint Surg. Am. 94, 49–58 (2012).

    CAS  Google Scholar 

  241. 241.

    Goel, P. N. et al. Suppression of notch signaling in osteoclasts improves bone regeneration and healing. J. Orthop. Res. 37, 2089–2103 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. 242.

    Schipani, E., Maes, C., Carmeliet, G. & Semenza, G. L. Regulation of osteogenesis-angiogenesis coupling by HIFs and VEGF. J. Bone Min. Res. 24, 1347–1353 (2009).

    CAS  Google Scholar 

Download references

Acknowledgements

M.J.S. and R.G.R. thank the support from the AO Foundation. A.I. is supported by the Collaborative Research Center CRC1149 (DFG, German Research Foundation; Project number 251293561).

Author information

Affiliations

Authors

Contributions

Introduction (J.B.J.); Epidemiology (F.L.); Mechanisms/pathophysiology (B.W. and A.I.); Diagnosis, screening and prevention (L.A.T. and J.B.J.); Management (R.M.S., M.J.S. and R.G.R.); Quality of life (R.P.); Outlook (J.B.J. and M.J.S.); Overview of Primer (J.B.J. and B.W.).

Corresponding authors

Correspondence to Britt Wildemann or Jesse B. Jupiter.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Disease Primers thanks P. Kloen, P. Leucht, A. Nauth, M. Poeze, S. Rammelt, P. M. Rommens and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Callus

Healing tissue that connects the bone ends.

Sequestrum

Necrotic tissue separated from the surrounding tissue.

Interfragmentary movement

Axial compression, tension and shear movements in the callus area.

Progenitor cells

Cells with the potential to differentiate in a more specific cell type.

Remodelling

Physiological process of bone resorption and formation that occurs in mature bone and during healing.

Intramembranous ossification

Direct transformation of mesenchymal tissue into bone.

Endochondral ossification

Bone formation via an intermediate cartilage template.

Chondrocytes

Cells of mesenchymal origin that produce cartilaginous matrix.

Osteoblasts

Bone-forming cells of mesenchymal origin that produce extracellular matrix and are responsible for mineralization.

Osteoclasts

Bone-resorbing cells of haematopoietic origin.

Osteocytes

Terminally differentiated osteoblasts embedded in the mineralized tissue that are important for bone homeostasis.

Diaphysis

Shaft of a long bone, mainly cortical bone.

Metaphysis

Neck portion of a long bone, mainly trabecular bone.

Primary bone healing

Direct healing without an intermediate cartilage template and without callus formation.

Osteocyte-lacuno-canalicular network

Communication network in bone.

Haversian systems

Canals that contain capillaries and nerve fibres, surrounded by concentric layers of mineralized tissue (lamella) forming osteons (substructures of bone tissue).

Secondary bone healing

Indirect healing with callus formation and intramembranous as well as endochondral ossification.

Macrophages

Differentiated monocytes that phagocytize dying and dead cells and cell debris and modulate the inflammatory milieu.

Healing phases

Fracture, haematoma formation, inflammation, repair with soft and hard callus formation, remodelling.

Angiogenesis

Formation of new blood vessels from existing vessels.

Soft callus

Fibrous and cartilaginous tissue.

Interfragmentary strain

Axial interfragmentary movement divided by the fracture gap size.

Periosteum

Cell-rich membrane covering the outer bone surface, important for bone healing.

Monocytes

Type of white blood cell, part of the innate immune system.

Cortical bone

Dense structure that forms the outer shell of long bones.

Trabecular bone

Porous bone formed from an interconnective network of rods and plates that are alined along the lines of stress.

Delayed union

Delay in healing of a fractured bone within the expected time.

Primary cilia

Immotile tubules that project from the cell surface like antennas.

Hard callus

Mineralized tissue.

Pseudoarthrosis

False joint, special form of non-union.

Osteonecrosis

Avascular death (necrosis) of bone.

Deformity

A bone without normal shape or size owing to congenital, developmental or post-traumatic reasons.

Judet decortication

Part of the surgical procedure and local approach to non-unions in which the surface of the local bone is peeled up in thin flakes with an osteotome in continuity with overlying soft tissue to enhance the bleeding area and, therefore, bone formation.

Critical-size defect

Substantial bone loss that does not heal spontaneously despite surgical stabilization.

Ilizarov technique

A surgical procedure based on the application of a ring external fixator to the bone, which can provide mechanical support together with the ability to progressively change the position of the rings and bone to move bone in space.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wildemann, B., Ignatius, A., Leung, F. et al. Non-union bone fractures. Nat Rev Dis Primers 7, 57 (2021). https://doi.org/10.1038/s41572-021-00289-8

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing