Skip to main content

Advertisement

SpringerLink
Log in

Sequential Treatment with Intermittent Low-Dose Human Parathyroid Hormone (1-34) and Bisphosphonate Enhances Large-Size Skeletal Reconstruction by Vascularized Bone Transplantation

  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Vascularized bone transplantation enables reconstruction of large skeletal defects, but this process needs a long time. Since short-term intermittent parathyroid hormone (PTH) enhances rat fracture healing, we investigated the effects of 4-week intermittent low-dose (10 μg/kg/day) or high-dose (100 μg/kg/day) PTH followed by 4-week vehicle, low-dose or high-dose intermittent PTH, or zoledronic acid (ZOL, 2 μg/kg/week), a potent bisphosphonate, on large skeletal reconstruction by vascularized tibial grafting in rats. Compared to 8-week vehicle, 8-week low-dose PTH did not significantly increase the serum osteocalcin level as well as the urinary deoxypyridinoline level, while 4-week low-dose or high-dose PTH followed by 4-week ZOL decreased both of these levels. Eight-week PTH increased the bone mass of the graft and strength of the reconstructed skeleton in a dose-dependent manner; notably, the reconstructed skeleton showed an obviously higher response to PTH compared to the contralateral nonoperated femur. In contrast, 4-week PTH followed by 4-week vehicle reduced these effects and caused local bone loss at the host-graft junctions. Four-week PTH followed by 4-week ZOL did not induce such bone loss; however, 4-week high-dose PTH followed by 4-week ZOL caused a large callus in the distal cortical junction. Four-week PTH followed by 4-week ZOL increased the bone mass and strength similarly to 8-week PTH. These preliminary findings suggest, for the first time, that sequential treatment with short-term intermittent low-dose PTH and bisphosphonate as well as long-term intermittent low-dose PTH treatment enhance large skeletal reconstruction by vascularized bone transplantation, though early timing of sequential antiresorptive treatment could result in delay of bone repair.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Taylor GI, Miller GD, Ham FJ (1975) The free vascularized bone graft: a clinical extension of microvascular techniques. Plast Reconstr Surg 55:533–544

    Article  PubMed  CAS  Google Scholar 

  2. Doi K, Kawai S, Shigetomi M (1996) Congenital tibial pseudoarthrosis treated with vascularised bone allograft. Lancet 347:970–971

    Article  PubMed  CAS  Google Scholar 

  3. Wood MB (2007) Free vascularized fibular grafting-25 years’ experience: tips, techniques, and pearls. Orthop Clin North Am 38:1–12

    Article  PubMed  Google Scholar 

  4. Bishop AT, Pelzer M (2007) Vascularized bone allotransplantation: current state and implications for future reconstructive surgery. Orthop Clin North Am 38:109–122

    Article  PubMed  Google Scholar 

  5. Aspenberg P (2005) Drugs and fracture repair. Acta Orthop 76:741–748

    Article  PubMed  Google Scholar 

  6. Simpson AHRW, Mills L, Noble B (2006) The role of growth factors and related agents in accelerating fracture healing. J Bone Joint Surg Br 88:701–705

    Article  PubMed  CAS  Google Scholar 

  7. William Axelrad T, Kakar S, Einhorn TA (2007) New technologies for the enhancement of skeletal repair. Injury 38(suppl 1):S49–S62

    Article  PubMed  Google Scholar 

  8. Reeve J, Hesp R, Williams D, Hulme P, Klenerman L, Zanelli JM, Darby AJ, Tregear GW, Parsons JA (1976) Anabolic effect of low doses of a fragment of human parathyroid hormone on the skeleton in postmenopausal osteoporosis. Lancet 1:1035–1038

    Article  PubMed  CAS  Google Scholar 

  9. Reeve J (2002) Recombinant human parathyroid hormone: osteoporosis is proving amenable to treatment. BMJ 324:435–436

    Article  PubMed  Google Scholar 

  10. Tashjian AH Jr, Gagel RF (2006) Teriparatide [human PTH (1-34)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis. J Bone Miner Res 21:354–365

    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. 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 

  13. Nakajima A, Shimoji N, Shiomi K, Shimizu S, Moriya H, Einhorn TA, Yamazaki M (2002) Mechanisms of 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 

  14. Andreassen TT, Willick GE, Morley P, Whitfield JF (2004) Treatment of 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. 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 

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

    Article  PubMed  Google Scholar 

  17. Seebach C, Skripitz R, Andreassen TT, Aspenberg P (2004) Intermittent parathyroid hormone (1-34) enhances mechanical strength and density of new bone after distraction osteogenesis in rats. J Orthop Res 22:472–478

    Article  PubMed  CAS  Google Scholar 

  18. Skripitz R, Bohling S, Ruther W, Aspenberg P (2005) Stimulation of implant fixation by parathyroid hormone (1–34): a histomorphometric comparison of PMMA cement and stainless steel. J Orthop Res 23:1266–1270

    PubMed  CAS  Google Scholar 

  19. Gabet Y, Muller R, Levy J, Dimarchi R, Chorev M, Bab I, Kohavi D (2006) Parathyroid hormone 1-34 enhances titanium implant anchorage in low-density trabecular bone: a correlative micro-computed tomographic and biomechanical analysis. Bone 39:276–282

    Article  PubMed  CAS  Google Scholar 

  20. Gunness-Hey M, Hock JM (1989) Loss of the anabolic effect of parathyroid hormone on bone after discontinuation of hormone in rats. Bone 10:447–452

    Article  PubMed  CAS  Google Scholar 

  21. Ejersted C, Oxlund H, Eriksen EF, Andreassen TT (1998) Withdrawal of parathyroid hormone treatment causes rapid resorption of newly formed vertebral cancellous and endocortical bone in old rats. Bone 23:43–52

    Article  PubMed  CAS  Google Scholar 

  22. Ejersted C, Oxlund H, Andreassen TT (1998) Bisphosphonate maintains parathyroid hormone (1-34)-induced cortical bone mass and mechanical strength in old rats. Calcif Tissue Int 62:316–322

    Article  PubMed  CAS  Google Scholar 

  23. Rhee Y, Won Y-Y, Baek M-H, Lim S-K (2004) Maintenance of increased bone mass after recombinant human parathyroid hormone (1-84) with sequential zoledronate treatment in ovariectomized rats. J Bone Miner Res 19:931–937

    Article  PubMed  CAS  Google Scholar 

  24. Hodsman AB, Bauer DC, Dempster DW, Dian L, Hanley DA, Harris ST, Kendler DL, McClung MR, Miller PD, Olszynski WP, Orwoll E, Yuen CK (2005) Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev 26:688–703

    Article  PubMed  CAS  Google Scholar 

  25. Cranney A, Papanioannou A, Zytaruk N, Hanley D, Adachi J, Goltzman D, Murray T, Hodsman A, for the Clinical Guidelines Committee of Osteoporosis Canada (2006) Parathyroid hormone for the treatment of osteoporosis: a systematic review. CMAJ 175:52–59

    PubMed  Google Scholar 

  26. Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, Widmer A, Devogelaer JP, Kaufman JM, Jaeger P, Body JJ, Brandi ML, Broell J, Di Micco R, Genazzani AR, Felsenberg D, Happ J, Hooper MJ, Ittner J, Leb G, Mallmin H, Murray T, Ortolani S, Rubinacci A, Saaf M, Samsioe G, Verbruggen L, Meunier PJ (2002) Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 346:653–661

    Article  PubMed  CAS  Google Scholar 

  27. Hornby SB, Evans GP, Hornby SL, Pataki A, Glatt M, Green JR (2003) Long-term zoledronic acid treatment increases bone structure and mechanical strength of long bones of ovariectomized adult rats. Calcif Tissue Int 72:519–527

    Article  PubMed  CAS  Google Scholar 

  28. Glatt M, Pataki A, Evans GP, Hornby SB, Green JR (2004) Loss of vertebral bone and mechanical strength in estrogen-deficient rats is prevented by long-term administration of zoledronic acid. Osteoporos Int 15:707–715

    Article  PubMed  CAS  Google Scholar 

  29. Crawford BA, Kam C, Pavlovic J, Byth K, Handelsman DJ, Angus PW, McCaughan GW (2006) Zoledronic acid prevents bone loss after liver transplantation: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 144:239–248

    PubMed  CAS  Google Scholar 

  30. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR, for the HORIZON Pivotal Fracture Trial (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822

    Article  PubMed  CAS  Google Scholar 

  31. Shigetomi M, Doi K, Kuwata N, Muramatsu K, Yamamoto K, Kawai S (1994) Experimental study on vascularized bone allografts for reconstruction of massive bone defects. Microsurgery 15:663–670

    Article  PubMed  CAS  Google Scholar 

  32. Merida L, Shigetomi M, Ihara K, Tsubone T, Ikeda K, Yamaguchi A, Sugiyama T, Kawai S (2002) Effects of vitamin D analog, 22-oxa-1,25 dihydroxyvitamin D3, on bone reconstruction by vascularized bone allograft. Bone 30:422–427

    Article  PubMed  CAS  Google Scholar 

  33. Ohno T, Shigetomi M, Ihara K, Matsunaga T, Hashimoto T, Kawano H, Sugiyama T, Kawai S (2003) Skeletal reconstruction by vascularized allogenic bone transplantation: effects of statin in rats. Transplantation 76:869–871

    Article  PubMed  CAS  Google Scholar 

  34. Tsubone T, Shigetomi M, Ihara K, Ikeda K, Merida L, Ohno T, Sugiyama T, Kawai S (2003) Hypertrophy of vascularized bone isograft in rats treated with cyclosporine A. Calcif Tissue Int 73:393–399

    Article  PubMed  CAS  Google Scholar 

  35. Ikeda K, Shigetomi M, Ihara K, Tsubone T, Hashimoto T, Kawano H, Sugiyama T, Kawai S (2004) Effects of cessation of immunosuppression on skeleton reconstructed by vascularized bone allograft in rats. J Orthop Res 22:388–394

    Article  PubMed  Google Scholar 

  36. Oxlund H, Ortoft G, Thomsen JS, Danielsen CC, Ejersted C, Andreassen TT (2006) The anabolic effect of PTH on bone is attenuated by simultaneous glucocorticoid treatment. Bone 39:244–252

    Article  PubMed  CAS  Google Scholar 

  37. Nakazawa T, Nakajima A, Shinomi 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 

  38. Mori S (2003) Fracture healing with anti-resorptive agents. J Musculoskelet Neuronal Interact 3:314–316

    PubMed  CAS  Google Scholar 

  39. Morris CD, Einhorn TA (2005) Bisphosphonates in orthopaedic surgery. J Bone Joint Surg Am 87:1609–1618

    Article  PubMed  Google Scholar 

  40. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY (2005) Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 90:1294–1301

    Article  PubMed  CAS  Google Scholar 

  41. Armamento-Villareal R, Napoli N, Panwar V, Novack D (2006) Suppressed bone turnover during alendronate therapy for high-turnover osteoporosis. N Engl J Med 355:2048–2050

    Article  PubMed  CAS  Google Scholar 

  42. Li J, Mori S, Kaji Y, Kawanishi J, Akiyama T, Norimatsu H (2000) Concentration of bisphosphonate (incadronate) in callus area and its effects on fracture healing in rats. J Bone Miner Res 15:2042–2051

    Article  PubMed  CAS  Google Scholar 

  43. Li J, Mori S, Kaji Y, Mashiba T, Kawanishi J, Norimatsu H (1999) Effect of bisphosphonate (incadronate) on fracture healing of long bones in rats. J Bone Miner Res 14:969–979

    Article  PubMed  CAS  Google Scholar 

  44. Li CY, Mori S, Li JL, Kaji Y, Akiyama T, Kawanishi J, Norimatsu H (2001) Long-term effect of incadronate disodium (YM-175) on fracture healing of femoral shaft in growing rats. J Bone Miner Res 16:429–436

    Article  PubMed  CAS  Google Scholar 

  45. Cao Y, Mori S, Mashiba T, Westmore MS, Ma L, Sato M, Akiyama T, Shi L, Komatsubara S, Miyamoto K, Norimatsu H (2002) Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats. J Bone Miner Res 17:2237–2246

    Article  PubMed  CAS  Google Scholar 

  46. Matsunaga T, Shigetomi M, Hashimoto T, Suzuki H, Gondo T, Tanaka H, Sugiyama T, Taguchi T (2007) Effects of bisphosphonate treatment on bone repair under immunosuppression using cyclosporine A in adult rats. Osteoporos Int. doi:10.1007/s00198-007-0387-z

  47. Manabe T, Mori S, Mashiba T, Kaji Y, Iwata K, Komatsubara S, Seki A, Sun Y-X, Yamamoto T (2007) Human parathyroid hormone (1-34) accelerates natural fracture healing process in the femoral osteotomy model of cynomolgus monkeys. Bone 40:1475–1482

    Article  PubMed  CAS  Google Scholar 

  48. Chalidis B, Tzioupis C, Tsiridis E, Giannoudis PV (2007) Enhancement of fracture healing with parathyroid hormone: preclinical studies and potential clinical applications. Expert Opin Investig Drugs 16:441–449

    Article  PubMed  CAS  Google Scholar 

  49. Civitelli R, Napoli N, Armamento-Villareal R (2007) Use of intravenous bisphosphonates in osteoporosis. Curr Osteoporos Rep 5:8–13

    Article  PubMed  Google Scholar 

  50. Compston J (2007) Treatments for osteoporosis: looking beyond the HORIZON. N Engl J Med 356:1878–1880

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Shinya Kawai (Yamaguchi University School of Medicine) for support of this project. This study was partly supported by a grant from Novartis Pharma K.K. (Kabushiki Kaisya) (Japan, Tokyo). T. S. is the recipient of a research fellowship from the Uehara Memorial Foundation.

Author information

Author notes

  1. Toshihiro Sugiyama

    Present address: Department of Veterinary Basic Sciences, The Royal Veterinary College, University of London, Royal College Street, London, NW1 0TU, UK

Authors and Affiliations

  1. Department of Orthopedic Surgery, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Yamaguchi, 755-8505, Japan

    Takahiro Hashimoto, Mitsunori Shigetomi, Teruyasu Ohno, Tsunemitsu Matsunaga, Keiichi Muramatsu, Hiroshi Tanaka, Toshihiro Sugiyama & Toshihiko Taguchi

Authors
  1. Takahiro Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mitsunori Shigetomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Teruyasu Ohno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tsunemitsu Matsunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keiichi Muramatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroshi Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Toshihiro Sugiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Toshihiko Taguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshihiro Sugiyama.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hashimoto, T., Shigetomi, M., Ohno, T. et al. Sequential Treatment with Intermittent Low-Dose Human Parathyroid Hormone (1-34) and Bisphosphonate Enhances Large-Size Skeletal Reconstruction by Vascularized Bone Transplantation. Calcif Tissue Int 81, 232–239 (2007). https://doi.org/10.1007/s00223-007-9056-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-007-9056-7

Keywords

Search

Navigation