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Experimental Stimulation of Bone Healing with Teriparatide: Histomorphometric and Microhardness Analysis in a Mouse Model of Closed Fracture

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Abstract

Fracture consolidation is a crucial goal to achieve as early as possible, but pharmacological stimulation has been neglected so far. Teriparatide has been considered for this purpose for its anabolic properties. We set up a murine model of closed tibial fracture on which different doses of teriparatide were tested. Closed fracture treatment avoids any bias introduced by surgical manipulations. Teriparatide’s effect on callus formation was monitored during the first 4 weeks from fracture. Callus evolution was determined by histomorphometric and microhardness assessment. Daily administration of 40 μg/kg of teriparatide accelerated callus mineralization from day 9 onward without significant increase of sizes, and at day 15 the microhardness properties of treated callus were similar to those of bone tissue. Teriparatide considerably improved callus consolidation in the very early phases of bone healing.

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References

  1. Matos MA, Tannuri U, Guarniero R (2010) The effect of zoledronate during bone healing. J Orthop Traumatol 11:7–12

    Article  PubMed  Google Scholar 

  2. Rowshan HH, Parham MA, Baur DA, McEntee RD, Cauley E, Carriere DT, Wood JC, Demsar WJ, Pizarro JM (2010) Effect of intermittent systemic administration of recombinant parathyroid hormone (1–34) on mandibular fracture healing in rats. J Oral Maxillofac Surg 68:260–267

    Article  PubMed  Google Scholar 

  3. Yu YY, Lieu S, Lu C, Colnot C (2010) Bone morphogenetic protein 2 stimulates endochondral ossification by regulating periosteal cell fate during bone repair. Bone 47:65–73

    Article  PubMed  CAS  Google Scholar 

  4. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH (2001) Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441

    Article  PubMed  CAS  Google Scholar 

  5. Jiang Y, Zhao J, Liao EY, Dai RC, Wu XP, Genant HK (2005) Application of micro-CT assessment of 3-D bone microstructure in preclinical and clinical studies. J Bone Miner Metab 23(Suppl):122–131

    Article  PubMed  Google Scholar 

  6. Aspenberg P, Genant HK, Johansson T, Nino AJ, See K, Krohn K, Garcia-Hernandez PA, Recknor CP, Einhorn TA, Dalsky GP, Mitlak BH, Fierlinger A, Lakshmanan MC (2010) Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J Bone Miner Res 25:404–414

    Article  PubMed  CAS  Google Scholar 

  7. Rubery PT, Bukata SV (2010) Teriparatide may accelerate healing in delayed unions of type iii odontoid fractures: a report of 3 cases. J Spinal Disord Tech 23:151–155

    Article  PubMed  Google Scholar 

  8. Yu CT, Wu JK, Chang CC, Chen CL, Wei JC (2008) Early callus formation in human hip fracture treated with internal fixation and teriparatide. J Rheumatol 35:2082–2083

    PubMed  Google Scholar 

  9. Bonnarens F, Einhorn TA (1984) Production of a standard closed fracture in laboratory animal bone. J Orthop Res 2:97–101

    Article  PubMed  CAS  Google Scholar 

  10. Skripitz R, Andreassen TT, Aspenberg P (2000) Strong effect of PTH(1–34) on regenerating bone: a time sequence study in rats. Acta Orthop Scand 71:619–624

    Article  PubMed  CAS  Google Scholar 

  11. Andreassen TT, Ejersted C, Oxlund H (1999) Intermittent parathyroid hormone (1–34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res 14:960–968

    Article  PubMed  CAS  Google Scholar 

  12. Nakazawa T, Nakajima A, Shiomi K, Moriya H, Einhorn TA, Yamazaki M (2005) Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1–34) on chondrogenesis in a model of experimental fracture healing. Bone 37:711–719

    Article  PubMed  CAS  Google Scholar 

  13. Holzer G, Majeska RJ, Lundy MW, Hartke JR, Einhorn TA (1999) Parathyroid hormone enhances fracture healing. A preliminary report. Clin Orthop Relat Res 366:258–263

    Article  PubMed  Google Scholar 

  14. Andreassen TT, Willick GE, Morley P, Whitfield JF (2004) Treatment with parathyroid hormone hPTH(1–34), hPTH(1–31), and monocyclic hPTH(1–31) enhances fracture strength and callus amount after withdrawal fracture strength and callus mechanical quality continue to increase. Calcif Tissue Int 74:351–356

    Article  PubMed  CAS  Google Scholar 

  15. Nakajima A, Shimoji N, Shiomi K, Shimizu S, Moriya H, Einhorn TA, Yamazaki M (2002) Mechanisms for the enhancement of fracture healing in rats treated with intermittent low-dose human parathyroid hormone (1–34). J Bone Miner Res 17:2038–2047

    Article  PubMed  CAS  Google Scholar 

  16. Komatsubara S, Mori S, Mashiba T, Nonaka K, Seki A, Akiyama T, Miyamoto K, Cao Y, Manabe T, Norimatsu H (2005) Human parathyroid hormone (1–34) accelerates the fracture healing process of woven to lamellar bone replacement and new cortical shell formation in rat femora. Bone 36:678–687

    Article  PubMed  CAS  Google Scholar 

  17. Alkhiary YM, Gerstenfeld LC, Krall E, Westmore M, Sato M, Mitlak BH, Einhorn TA (2005) Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1–34). J Bone Joint Surg Am 87:731–741

    Article  PubMed  Google Scholar 

  18. Andreassen TT, Fledelius C, Ejersted C, Oxlund H (2001) Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone. Acta Orthop Scand 72:304–307

    Article  PubMed  CAS  Google Scholar 

  19. Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K, Nakamura K, Taniguchi T (2000) T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature 408:600–605

    Article  PubMed  CAS  Google Scholar 

  20. Young N, Mikhalkevich N, Yan Y, Chen D, Zheng WP (2005) Differential regulation of osteoblast activity by Th cell subsets mediated by parathyroid hormone and IFN-gamma. J Immunol 175:8287–8295

    PubMed  CAS  Google Scholar 

  21. Xing Z, Lu C, Hu D, Yu YY, Wang X, Colnot C, Nakamura M, Wu Y, Miclau T, Marcucio RS (2010) Multiple roles for CCR2 during fracture healing. Dis Model Mech 3:451–458

    Article  PubMed  CAS  Google Scholar 

  22. Thompson Z, Miclau T, Hu D, Helms JA (2002) A model for intramembranous ossification during fracture healing. J Orthop Res 20:1091–1098

    Article  PubMed  CAS  Google Scholar 

  23. McDonald M, Tagil M, Morse A, Godfrey C, Amanat N, Little D (2008) PTH(1–34) treatment increases fracture callus size and strength more effectively in closed than open fractures. Bone 42(Suppl 1):S78–S79

    Article  Google Scholar 

  24. Boivin G, Bala Y, Doublier A, Farlay D, Ste-Marie LG, Meunier PJ, Delmas PD (2008) The role of mineralization and organic matrix in the microhardness of bone tissue from controls and osteoporotic patients. Bone 43:532–538

    Article  PubMed  CAS  Google Scholar 

  25. Iida-Klein A, Hughes C, Shen V, Moreno A, Lu SS, Dempster DW, Cosman F, Lindsay R (2006) Effects of cyclic vs. daily PTH regimens on bone strength in association with bone density, biochemical markers and bone structure in mice. J Bone Miner Res 21:274–282

    Article  PubMed  CAS  Google Scholar 

  26. Boivin G, Meunier PJ (1993) Histomorphometric methods applied to bone. In: Grupe G, Garland AN (eds) Histology of ancient human bone. Springer Verlag, Berlin, pp 137–156

    Google Scholar 

  27. Grundnes O, Gjerdet NR, Utvåg SE, Reikerås O (1998) Vascular and structural changes in rat femora following nailing and intramedullary occlusion. J Orthop Res 16:293–299

    Article  PubMed  CAS  Google Scholar 

  28. Le AX, Miclau T, Hu D, Helms JA (2001) Molecular aspects of healing in stabilized and non-stabilized fractures. J Orthop Res 19:78–84

    Article  PubMed  CAS  Google Scholar 

  29. Bala Y, Farlay DF, Delmas PD, Meunier PJ, Boivin G (2010) Time sequence of secondary mineralization and microhardness in cortical and cancellous bone from ewes. Bone 46:1204–1212

    Article  PubMed  Google Scholar 

  30. Kakar S, Einhorn TA, Vora S, Miara LJ, Hon G, Wigner NA, Toben D, Jacobsen KA, Al-Sebaei MO, Song M, Trackman PC, Morgan EF, Gerstenfeld LC, Barnes GL (2007) Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures. J Bone Miner Res 22:1903–1912

    Article  PubMed  CAS  Google Scholar 

  31. Little DG, Ramachandran M, Schindeler A (2007) The anabolic and catabolic responses in bone repair. J Bone Joint Surg Br 89:425–433

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Prof. A. Angeli for enthusiastically encouraging this study, Eli Lilly for providing teriparatide, and Dr. B. Peracino for assistance in confocal microscopy.

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Authors and Affiliations

  1. Department of Clinical and Biological Sciences, University of Turin, Reg. Gonzole 10, 10043, Orbassano, TO, Italy

    Barbara Mognetti, Silvia Marino, Alessandro Barberis, Francesco Di Carlo & Michele Portigliatti Barbos

  2. INSERM, UMR 1033, Team “Bone Quality & Biological Markers, 69008, Lyon, France

    Anne-Sophie Bravo Martin, Yohann Bala & Georges Boivin

  3. Université de Lyon, UMR 1033, Team “Bone Quality & Biological Markers,”, 69008, Lyon, France

    Anne-Sophie Bravo Martin, Yohann Bala & Georges Boivin

Authors
  1. Barbara Mognetti
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  2. Silvia Marino
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  3. Alessandro Barberis
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  4. Anne-Sophie Bravo Martin
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  5. Yohann Bala
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  6. Francesco Di Carlo
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  7. Georges Boivin
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  8. Michele Portigliatti Barbos
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Correspondence to Michele Portigliatti Barbos.

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The authors have stated that they have no conflict of interest.

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Mognetti, B., Marino, S., Barberis, A. et al. Experimental Stimulation of Bone Healing with Teriparatide: Histomorphometric and Microhardness Analysis in a Mouse Model of Closed Fracture. Calcif Tissue Int 89, 163–171 (2011). https://doi.org/10.1007/s00223-011-9503-3

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  • DOI: https://doi.org/10.1007/s00223-011-9503-3

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