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Reaming in treatment of non-unions in long bones: cytokine expression course as a tool for evaluation of non-union therapy

  • Trauma Surgery
  • Published:
Archives of Orthopaedic and Trauma Surgery Aims and scope Submit manuscript

Abstract

The analysis of peripheral serum cytokine expression patterns has been shown to be a possible method for demonstrating changes in bone metabolism. The aim of this study is to evaluate the effectiveness of this method within the treatment of long bone non-union with intramedullary reaming, a well-established non-union treatment concept.

Materials and methods

Three groups were added to this study: group one (G1) suffered from long bone non-unions, treated successfully with intramedullary reaming; group two (G2) consisted of long bone fractures with proper fracture healing; and group three (G3) included long bone fractures resulting in non-unions. We took blood samples on day 2, and after week 1, 4, 6, month 3 and 6 after initial treatment. Clinical and radiological follow-up were provided for 6 months. We measured transforming growth factor ß-1 (TGFß-1), platelet-derived growth factor (PDGF-AB), and insulin like growth factor-1 (IGF-1) at all-time points.

Results

TGF-ß1 levels in G1 and G2 increased from day 2 to 6 weeks after surgery. In general, G1 and G2 showed parallel TGF-ß1 expression patterns, and G3 had a significant peak during first week compared to G1 (p = 0.023). PDGF peaked in G3 during first week after treatment, whereas G1 had its maximum after 4 weeks and G2 after 6 weeks. We were able to detect a significantly lower PDGF concentration at 3 months in G1 compared to G3 (p = 0.029). IGF-1 showed a peak concentration in G1 during the first 4 weeks. Afterwards, concentration levels in both G1 and G2 were higher.

Conclusions

Our study was able to show that the cytokine expression pattern in physiological bone healing is similar to that in successful non-union treatment with intramedullary reaming. Our results show that the effect of non-union therapy could be observed objectively by measuring cytokine expression patterns in peripheral blood even in a small group of patients.

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References

  1. Andrew JG, Hoyland J, Freemont AJ, Marsh D (1993) Insulinlike growth factor gene expression in human fracture callus. Calcif Tissue Int 53(2):97–102

    Article  CAS  PubMed  Google Scholar 

  2. Andrew JG, Hoyland JA, Freemont AJ, Marsh DR (1995) Platelet-derived growth factor expression in normally healing human fractures. Bone 16(4):455–460

    CAS  PubMed  Google Scholar 

  3. Bensamoun SF, Hawse JR, Subramaniam M et al (2006) TGFbeta inducible early gene-1 knockout mice display defects in bone strength and microarchitecture. Bone 39(6):1244–1251

    Article  CAS  PubMed  Google Scholar 

  4. Bhandari M, Guyatt GH, Tong D, Adili A, Shaughnessy SG (2000) Reamed versus nonreamed intramedullary nailing of lower extremity long bone fractures: a systematic overview and meta-analysis. J Orthop Trauma 14(1):2–9

    Article  CAS  PubMed  Google Scholar 

  5. Boonen S, Mohan S, Dequeker J et al (1999) Down-regulation of the serum stimulatory components of the insulin-like growth factor (IGF) system (IGF-I, IGF-II, IGF binding protein [BP]-3, and IGFBP-5) in age-related (type II) femoral neck osteoporosis. J Bone Miner Res Off J Am Soc Bone Miner Res 14(12):2150–2158

    Article  CAS  Google Scholar 

  6. Canalis E (1993) Insulin like growth factors and the local regulation of bone formation. Bone 14(3):273–276

    Article  CAS  PubMed  Google Scholar 

  7. Caplan AI, Correa D (2011) PDGF in bone formation and regeneration: new insights into a novel mechanism involving MSCs. J Orthop Res Off Publ Orthop Res Soc 29(12):1795–1803

    Article  CAS  Google Scholar 

  8. Devescovi V, Leonardi E, Ciapetti G, Cenni E (2008) Growth factors in bone repair. La Chirurgia degli organi di movimento 92(3):161–168

    Article  PubMed  Google Scholar 

  9. el Moumni M, Leenhouts PA, ten Duis HJ, Wendt KW (2009) The incidence of non-union following unreamed intramedullary nailing of femoral shaft fractures. Injury 40(2):205–208

    Article  PubMed  Google Scholar 

  10. Fayaz HC, Giannoudis PV, Vrahas MS et al (2011) The role of stem cells in fracture healing and nonunion. Int Orthop 35(11):1587–1597

    Article  PubMed Central  PubMed  Google Scholar 

  11. Gaebler C, McQueen MM, Vecsei V, Court-Brown CM (2011) Reamed versus minimally reamed nailing: a prospectively randomised study of 100 patients with closed fractures of the tibia. Injury 42(Suppl 4):S17–S21

    Article  PubMed  Google Scholar 

  12. Gao KD, Huang JH, Li F et al (2009) Treatment of aseptic diaphyseal nonunion of the lower extremities with exchange intramedullary nailing and blocking screws without open bone graft. Orthop Surg 1(4):264–268

    Article  PubMed  Google Scholar 

  13. Giannoudis PV, Einhorn TA, Schmidmaier G, Marsh D (2008) The diamond concept–open questions. Injury 39(Suppl 2):S5–S8

    Article  PubMed  Google Scholar 

  14. Grotendorst GR (1984) Alteration of the chemotactic response of NIH/3T3 cells to PDGF by growth factors, transformation, and tumor promoters. Cell 36(2):279–285

    Article  CAS  PubMed  Google Scholar 

  15. Hak DJ, Lee SS, Goulet JA (2000) Success of exchange reamed intramedullary nailing for femoral shaft nonunion or delayed union. J Orthop Trauma 14(3):178–182

    Article  CAS  PubMed  Google Scholar 

  16. Henle P, Zimmermann G, Weiss S (2005) Matrix metalloproteinases and failed fracture healing. Bone 37(6):791–798

    Article  CAS  PubMed  Google Scholar 

  17. Hering S, Isken E, Knabbe C et al (2001) TGFbeta1 and TGFbeta2 mRNA and protein expression in human bone samples. Exp Clin Endocrinol Diabetes Off J Ger Soc Endocrinol Ger Diabetes Assoc 109(4):217–226

    Article  CAS  Google Scholar 

  18. Hill PA, Tumber A, Meikle MC (1997) Multiple extracellular signals promote osteoblast survival and apoptosis. Endocrinology 138(9):3849–3858

    CAS  PubMed  Google Scholar 

  19. Hollinger JO, Hart CE, Hirsch SN, Lynch S, Friedlaender GE (2008) Recombinant human platelet-derived growth factor: biology and clinical applications. J Bone Joint Surg Am 90(Suppl 1):48–54

    Article  PubMed  Google Scholar 

  20. Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG (1991) Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 88(20):9267–9271

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Mills LA, Simpson AH (2013) The relative incidence of fracture non-union in the Scottish population (5.17 million): a 5-year epidemiological study. BMJ Open, 3(2)

  22. Moghaddam-Alvandi A, Zimmermann G, Buchler A et al (2012) Results of nonunion treatment with bone morphogenetic protein 7 (BMP-7). Der Unfallchirurg 115(6):518–526

    Article  CAS  PubMed  Google Scholar 

  23. Moghaddam A, Muller U, Roth HJ, Wentzensen A, Grutzner PA, Zimmermann G (2011) TRACP 5b and CTX as osteological markers of delayed fracture healing. Injury 42(8):758–764

    Article  CAS  PubMed  Google Scholar 

  24. Moghaddam A, Weiss S, Wolfl CG et al (2010) Cigarette smoking decreases TGF-b1 serum concentrations after long bone fracture. Injury 41(10):1020–1025

    Article  CAS  PubMed  Google Scholar 

  25. Schmidmaier G, Herrmann S, Green J et al (2006) Quantitative assessment of growth factors in reaming aspirate, iliac crest, and platelet preparation. Bone 39(5):1156–1163

    Article  CAS  PubMed  Google Scholar 

  26. Schmidmaier G, Wildemann B, Ostapowicz D (2004) Long-term effects of local growth factor (IGF-I and TGF-beta 1) treatment on fracture healing. A safety study for using growth factors. J Orthop Res Off Publ Orthop Res Soc 22(3):514–519

    Article  CAS  Google Scholar 

  27. Sheng MH, Lau KH, Baylink DJ (2014) Role of osteocyte-derived insulin-like growth factor I in developmental growth, modeling, remodeling, and regeneration of the bone. J Bone Metab 21(1):41–54

    Article  PubMed Central  PubMed  Google Scholar 

  28. Sledge SL, Johnson KD, Henley MB, Watson JT (1989) Intramedullary nailing with reaming to treat non-union of the tibia. J Bone Joint Surg Am 71(7):1004–1019

    CAS  PubMed  Google Scholar 

  29. Tang Y, Wu X, Lei W et al (2009) TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med 15(7):757–765

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Tzeng DY, Deuel TF, Huang JS, Senior RM, Boxer LA, Baehner RL (1984) Platelet-derived growth factor promotes polymorphonuclear leukocyte activation. Blood 64(5):1123–1128

    CAS  PubMed  Google Scholar 

  31. Vulpiani MC, Vetrano M, Conforti F et al (2012) Effects of extracorporeal shock wave therapy on fracture nonunions. Am J Orthop 41(9):E122–E127

    PubMed  Google Scholar 

  32. Wan M, Li C, Zhen G et al (2012) Injury-activated transforming growth factor beta controls mobilization of mesenchymal stem cells for tissue remodeling. Stem Cells 30(11):2498–2511

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Watanabe Y, Matsushita T, Bhandari M, Zdero R, Schemitsch EH (2010) Ultrasound for fracture healing: current evidence. J Orthop Trauma 24(Suppl 1):S56–S61

    Article  PubMed  Google Scholar 

  34. Weiss S, Henle P, Bidlingmaier M, Moghaddam A, Kasten P, Zimmermann G (2008) Systemic response of the GH/IGF-I axis in timely versus delayed fracture healing. Growth Horm IGF Res 18(3):205–212

    Article  PubMed  Google Scholar 

  35. Weiss S, Zimmermann G, Baumgart R, Kasten P, Bidlingmaier M, Henle P (2005) Systemic regulation of angiogenesis and matrix degradation in bone regeneration–distraction osteogenesis compared to rigid fracture healing. Bone 37(6):781–790

    Article  CAS  PubMed  Google Scholar 

  36. Weiss S, Zimmermann G, Pufe T, Varoga D, Henle P (2009) The systemic angiogenic response during bone healing. Arch Orthop Trauma Surg 129(7):989–997

    Article  PubMed  Google Scholar 

  37. Zimmermann G, Henle P, Kusswetter M et al (2005) TGF-beta1 as a marker of delayed fracture healing. Bone 36(5):779–785

    Article  CAS  PubMed  Google Scholar 

  38. Zimmermann G, Wagner C, Schmeckenbecher K, Wentzensen A, Moghaddam A (2009) Treatment of tibial shaft non-unions: bone morphogenetic proteins versus autologous bone graft. Injury 40(Suppl 3):S50–S53

    Article  PubMed  Google Scholar 

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Acknowledgments

We would like to thank the Medical Faculty of the University of Heidelberg and its “Friedrich Fischer Nachlass” funding programme, which provided support for this study with 7.500 Euros. Furthermore, we want to thank our lab technician Sandra Speth for performing the ELISA analysis, Christopher Child for the support of the statistical analysis, Axel Büchler for sample collection, and Tyler Swing, Michael Tanner, and Sebastian Korff for proofreading.

Conflict of interest

The authors have revealed all financial and personal relationships to other people or organisations that could inappropriately influence this work. Conflicts of interest include employment, stock ownership, honoraria, paid expert testimony, patents, grants, funding, or consultancies.

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Authors and Affiliations

  1. Trauma and Reconstructive Surgery, Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, HTRG-Heidelberg Trauma Research Group, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118, Heidelberg, Germany

    Fabian Westhauser, Sanaz Moghaddam, Gerhard Schmidmaier & Arash Moghaddam

  2. Department for Trauma Surgery, Theresienkrankenhaus und St. Hedwigs-Klinik GmbH, Bassermannstr. 1, 68165, Mannheim, Germany

    Gerald Zimmermann

  3. Institute for Medical Biometry and Informatics, Heidelberg University Hospital, Im Neuenheimer Feld 305, 69121, Heidelberg, Germany

    Tom Bruckner

  4. BG Trauma Centre Ludwigshafen, Ludwig-Guttmann-Str. 13, 67071, Ludwigshafen, Germany

    Bahram Biglari

Authors
  1. Fabian Westhauser
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  2. Gerald Zimmermann
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  3. Sanaz Moghaddam
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  4. Tom Bruckner
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  6. Bahram Biglari
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  7. Arash Moghaddam
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Correspondence to Arash Moghaddam.

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Westhauser, F., Zimmermann, G., Moghaddam, S. et al. Reaming in treatment of non-unions in long bones: cytokine expression course as a tool for evaluation of non-union therapy. Arch Orthop Trauma Surg 135, 1107–1116 (2015). https://doi.org/10.1007/s00402-015-2253-3

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