Calcified Tissue International

, Volume 74, Issue 4, pp 351–356

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

  • T. T. Andreassen
  • G. E. Willick
  • P. Morley
  • J. F. Whitfield


The influence of intermittent hPTH(l-34)NH2, hPTH(1-31)NH2, and monocyclic [Leu27]cyclo(Glu22-Lys26)hPTH(1-31)NH2 treatment on callus formation, mechanical strength, and callus tissue mechanical quality of tibial fractures in rats was investigated after 8 and 16 weeks of healing. In the 8 weeks of healing animals, the PTH-peptides were injected subcutaneously during the entire observation period (15 nmol/kg/day [hPTH(1-34)NH2: 15 nmol = 60 µg]), and control animals with fractures were given vehicle. In the 16 weeks of healing animals, the PTH-peptides were injected only during the first 8 weeks of healing (15 nmol/kg/day), after which the animals were left untreated during the rest of the healing period. After the first 8 weeks of healing, increased fracture strength and callus volume were seen in the PTH-treated rats (ultimate load 66%, ultimate stiffness 58%, callus volume 28%), and the three peptides were equally effective. No difference in callus tissue mechanical quality was found between PTH and vehicle animals. After 16 weeks of healing, no differences in fracture strength, callus volume, or callus tissue mechanical quality were seen between PTH and vehicle. When comparing PTH-treated animals at 8 and 16 weeks, fracture strength and callus tissue mechanical quality continued to increase after the withdrawal of PTH (ultimate load 23%, ultimate stress 88%, elastic modulus 87%) and external callus volume declined during this period (27%).


Fracture healing PTH peptides Withdrawal Mechanical strength 


  1. 1.
    Shen, V, Dempster, DW, Mellish, RWE, Birchman, R, Horbert, W, Lindsay, R 1992Effects of combined and separate intermittent administration of low-dose human parathyroid hormone fragment (1–34) and 17β-estradiol on bone histomorphometry in ovariectomized rats with established osteopenia.Calcif Tissue Int50214220PubMedGoogle Scholar
  2. 2.
    Oxlund, H, Ejersted, C, Andreassen, TT, Tørring, O, Nilsson, MHL 1993Parathyroid hormone (1–34) and (1–84) stimulate cortical bone formation both from periosteum and endosteum.Calcif Tissue Int53394399Google Scholar
  3. 3.
    Wronski, TJ, Yen, C-F, Qi, H, Dann, LM 1993Parathyroid hormone is more effective than estrogen or bisphosphonates for restoration of lost bone mass in ovariectomized rats.Endocrinology132823831Google Scholar
  4. 4.
    Mosekilde, L, Danielsen, CC, Gasser, J 1994The effect on vertebral bone mass and strength of long-term treatment with antiresorptive agents (estrogen and calcitonin), human parathyroid hormone-(1-38), and combination therapy, assessed in aged ovariectomized rats.Endocrinology13421262134Google Scholar
  5. 5.
    Ejersted, C, Andreassen, TT, Nilsson, MHL, Oxlund, H 1994Human parathyroid hormone (1–34) increases bone formation and strength of cortical bone in aged rats.Eur J Endocrinol130201207Google Scholar
  6. 6.
    Mosekilde, L, Danielsen, CC, Søgaard, CH, McOsker, JE, Wronski, TJ 1995The anabolic effects of parathyroid hormone on cortical bone mass, dimensions and strength - assessed in a sexually mature, ovariectomized rat model.Bone16223230CrossRefPubMedGoogle Scholar
  7. 7.
    Dobnig, H, Turner, RT 1995Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells.Endocrinology13636323638Google Scholar
  8. 8.
    Whitfield, JF, Morley, P, Willick, G, Maclean, S, Ross, V, Isaacs, RJ, Barbier, J-R 1998Comparison of the abilities of human parathyroid hormone (hPTH)-(1-34) and [Leu27]-cyclo(Glu22-Lys26)-hPTH-(1-31)NH2 to stimulate femoral trabecular bone growth in ovariectomized rats.Calcif Tissue Int63423428CrossRefPubMedGoogle Scholar
  9. 9.
    Andreassen, TT, Oxlund, H 2000The influence of combined parathyroid hormone and growth hormone treatment on cortical bone in aged ovariectomized rats.J Bone Miner Res1522662275Google Scholar
  10. 10.
    Ejersted, C, Andreassen, TT, Oxlund, H, Jørgensen, PH, Bak, B, Häggblad, J, Tørring, O, Nilsson, MHL 1993Human parathyroid hormone (1-34) and (1-84) increase the mechanical strength and thickness of cortical bone in rats.J Bone Miner Res810971101PubMedGoogle Scholar
  11. 11.
    Sato, M, Zeng, GQ, Turner, CH 1997Biosynthetic human parathyroid hormone (1-34) effects on bone quality in aged ovariectomized rats.Endocrinology13843304337PubMedGoogle Scholar
  12. 12.
    Ejersted, C, Oxlund, H, Eriksen, EF, Andreassen, TT 1998Withdrawal of parathyroid hormone treatment causes rapid resorption of newly formed vertebral cancellous and endocortical bone in old rats.Bone234352CrossRefPubMedGoogle Scholar
  13. 13.
    Shen, V, Birchman, R, Liang, XG, Wu, DD, Dempster, DW, Lindsay, R 1998Accretion of bone mass and strength with parathyroid hormone prior to the onset of estrogen deficiency can provide temporary beneficial effects in skeletally mature rats.J Bone Miner Res13883890Google Scholar
  14. 14.
    Morley, P, Whitfield, JF, Willick, GE, Ross, V, Maclean, S, Barbier, J-R, Isaacs, RJ, Andreassen, TT 2001The effect of monocyclic and bicyclic analogs of human parathyroid hormone (hPTH)-(1-31)NH2 on bone formation and mechanical strength in ovariectomized rats.Calcif Tissue Int6895101PubMedGoogle Scholar
  15. 15.
    Yamamoto, N, Takahashi, HE, Tanizawa, T, Fujimoto, R, Hara, T, Tanaka, S 1993Maintenance of bone mass by physical exercise after discontinuation of intermittent hPTH(1-34) administration.Bone Miner23333342Google Scholar
  16. 16.
    Takano, Y, Tanizawa, T, Mashiba, T, Endo, N, Nishida, S, Takahashi, HE 1996Maintaining bone mass by bisphosphonate incadronate disodium (YM175) sequential treatment after discontinuation of intermittent human parathyroid hormone (1-34) administration in ovariectomized rats.J Bone Miner Res11169177Google Scholar
  17. 17.
    Ejersted, C, Oxlund, H, Andreassen, TT 1998Bisphosphonate maintains parathyroid hormone (1-34)-induced cortical bone mass and mechanical competence in old rats.Calcif Tissue Int62316322CrossRefPubMedGoogle Scholar
  18. 18.
    Andreassen, TT, Ejersted, C, Oxlund, H 1999Intermittent parathyroid hormone (1-34) treatment increases callus formation and mechanical strength of healing rat fractures.J Bone Miner Res14960968Google Scholar
  19. 19.
    Holzer, G, Majeska, RJ, Lundy, MW, Hartke, JR, Einhorn, TA 1999Parathyroid hormone enhances fracture healing. A preliminary report.Clin Orthop366258263CrossRefPubMedGoogle Scholar
  20. 20.
    Jahng, JS, Kim, HW 2000Effect of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rats.Orthopedics2310891094PubMedGoogle Scholar
  21. 21.
    Andreassen, TT, Fledelius, C, Ejersted, C, Oxlund, H 2001Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone.Acta Orthop Scand72304307CrossRefPubMedGoogle Scholar
  22. 22.
    Nakajima, A, Shimoji, N, Shiomi, K, Shimizu, S, Moriya, H, Einhorn, TA, Yamazaki, M 2002Mechanisms for the enhancement of fracture healing in rats treated with intermittent low-dose human parathyroid hormone (1–34).J Bone Miner Res1720382047PubMedGoogle Scholar
  23. 23.
    Barbier, J-R, Neugebauer, W, Morley, P, Ross, V, Soska, M, Whitfield, JF, Willick, G 1997Bioactivities and secondary structures of constrained analogues of human parathyroid hormone: cyclic lactams of the receptor binding region.J Med Chem4013731380CrossRefPubMedGoogle Scholar
  24. 24.
    Turner, CH, Burr, DB 1993Basic biomechanical measurement of bone: a tutorial.Bone14595608PubMedGoogle Scholar
  25. 25.
    Jørgensen, PH, Bak, B, Andreassen, TT 1991Mechanical properties and biochemical composition of rat cortical femur and tibia after long-term treatment with biosynthetic human growth hormone.Bone12353359PubMedGoogle Scholar
  26. 26.
    Bak, B, Jørgensen, PH, Andreassen, TT 1991The stimulating effect of growth hormone on fracture healing is dependent on onset and duration of administration.Clin Orthop264295301PubMedGoogle Scholar
  27. 27.
    Fraher, LJ, Avram, R, Watson, PH, Hendy, GN, Henderson, JE, Chong, KL, Goltzman, D, Morley, P, Willick, GE, Whitfield, JF, Hodsman, AB 1999Comparison of the biochemical responses to human parathyroid hormone-(1-31)NH2 and hPTH-(1-34) in healthy humans.J Clin Endocrinol Metab8427392743PubMedGoogle Scholar
  28. 28.
    Mohan, S, Kutilek, S, Zhang, C, Shen, HG, Kodama, Y, Srivastava, AK, Wergedal, JE, Beamer, WG, Baylink, DJ 2000Comparison of bone formation responses to parathyroid hormone (1-34), (1-31), and (2-34) in mice.Bone27471478CrossRefPubMedGoogle Scholar
  29. 29.
    Bostrom, MPG, Gamradt, SC, Asnis, P, Vickery, BH, Hill, E, Avnur, Z, Waters, RV 2000Parathyroid hormone-related protein analog RS-66271 is an effective therapy for impaired bone healing in rabbits on corticosteroid therapy.Bone26437442CrossRefPubMedGoogle Scholar
  30. 30.
    Skripitz, R, Andreassen, TT, Aspenberg, P 2000Parathyroid hormone (1-34) increases the density of rat cancellous bone in a bone chamber.J Bone Joint Surg Br82-B138141Google Scholar
  31. 31.
    Skripitz, R, Andreassen, TT, Aspenberg, P 2000Strong effect of PTH (1-34) on regenerating bone: a time sequence study in rats.Acta Orthop Scand71619624CrossRefPubMedGoogle Scholar
  32. 32.
    Skripitz, R, Aspenberg, P 2001Implant fixation enhanced by intermittent treatment with parathyroid hormone.J Bone Joint Surg Br83-B437440CrossRefGoogle Scholar
  33. 33.
    Skripitz, R, Aspenberg, P 2001Early effect of parathyroid hormone (1-34) on implant fixation.Clin Orthop292427432Google Scholar
  34. 34.
    Lindsay, R, Nieves, J, Formica, C, Henneman, E, Woelfert, L, Shen, V, Dempster, D, Cosman, F 1997Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis.Lancet350550555PubMedGoogle Scholar
  35. 35.
    Rittmaster, RS, Bolognese, M, Ettinger, MP, Hanley, DA, Hodsman, AB, Kendler, DL, Rosen, CJ 2000Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate.J Clin Endocrinol Metab8521292134PubMedGoogle Scholar
  36. 36.
    Neer, RM, Arnaud, CD, Zanchetta, JR, Prince, R, Gaich, GA, Reginster, J-Y, Hodsman, AB, Eriksen, EF, Ish-Shalom, S, Genant, HK, Wang, O, Mitlak, BH 2001Effect of parathyroid hormone (1-34) on fractures and bone mineral densizty in postmenopausal women with osteoporosis.N Engl J Med34414341441PubMedGoogle Scholar
  37. 37.
    Orwoll, ES, Scheele, WH, Paul, S, Adami, S, Syversen, U, Diez-Perez, A, Kaufman, J-M, Clancy, AD, Gaich, GA 2003The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis.J Bone Miner Res18917PubMedGoogle Scholar
  38. 38.
    Marcus, R, Wang, O, Satterwhite, J, Mitlak, B 2003The skeletal response to teriparatide is largely independent of age, initial bone mineral density, and prevalent vertebral fractures in postmenopausal women with osteoporosis.J Bone Miner Res181823PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • T. T. Andreassen
    • 1
  • G. E. Willick
    • 2
  • P. Morley
    • 2
  • J. F. Whitfield
    • 2
  1. 1.Department of Connective Tissue Biology, Institute of AnatomyUniversity of Aarhus, AarhusDenmark
  2. 2.Institute for Biological ScienceNational Research Council of Canada, Ottawa, OntarioCanada

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