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Intermittently administered parathyroid hormone 1–34 reverses bone loss and structural impairment in orchiectomized adult rats

Osteoporosis International volume 16, pages 1436–1443 (2005)Cite this article

Abstract

Male osteoporosis is emerging as a central theme in bone research. As in females, hypogonadism appears as a principal risk factor in men that leads to bone loss and increased fracture incidence. Intermittently administered parathyroid hormone (PTH) reverses bone loss in sex hormone-deprived women and female animals and increases bone mass in elderly men and normal male animals. This study was carried out to assess whether the PTH anabolic activity is also effective in adult castrated males and to gain insight into the underlying tissue processes. Bilateral orchiectomy (ORX) or sham-ORX was performed in 13-week old rats. Five weeks later, the ORX rats were treated intermittently with human PTH(1–34), 80 μg/kg/day or vehicle for 6 weeks. Femora were evaluated by quantitative micro-computed tomography followed by dynamic histomorphometry. The trabecular bone volume density showed 40% and 56% ORX-induced loss in the distal metaphysis at 6 weeks and 12 weeks post-ORX, respectively. PTH(1–34) induced supraphysiologic recovery of this bone loss (155% recovery) consequent to a vast increase in trabecular thickness (174% over sham-ORX controls) and a partial reversal (62%) of the decrease in trabecular number. As compared with the results in 12-week, orchiectomized vehicle-administered rats, the PTH(1–34) treatment induced a significant decrease in osteoclast number (20%) and twofold increase in bone formation rate. While ORX did not affect the femoral diaphysis, PTH(1–34) induced marked cortical thickening via the stimulation of endosteal mineral appositional rate (154% over ORX rats). These data portray PTH(1–34) as a highly potent bone anabolic agent in adult ORX rats, mainly by increasing both the trabecular and cortical thicknesses through its effect on osteoblasts and osteoclasts. The adult ORX rat is useful for investigating the processes involved in bone anabolic activity in castrated osteoporotic males and for the development of bone anabolic agents for treating this condition.

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References

  1. Melton LJ 3rd, Alothman KI, Khosla S, Achenbach SJ, Oberg AL, Zincke H (2003) Fracture risk following bilateral orchiectomy. J Urol 169:1747–1750

    PubMed  Google Scholar 

  2. Dawson NA (2003) Therapeutic benefit of bisphosphonates in the management of prostate cancer-related bone disease. Expert Opin Pharmacother 4:705–716

    Google Scholar 

  3. Smith MR (2003) Management of treatment-related osteoporosis in men with prostate cancer. Cancer Treat Rev 29:211–218

    Google Scholar 

  4. Smith MR (2003) Bisphosphonates to prevent osteoporosis in men receiving androgen deprivation therapy for prostate cancer. Drugs Aging 20:175–183

    Google Scholar 

  5. Iwamoto J, Takeda T, Katsumata T, Tanaka T, Ichimura S, Toyama Y (2002) Effect of etidronate on bone in orchiectomized and sciatic neurectomized adult rats. Bone 30:360–367

    Google Scholar 

  6. Vandenput L, Boonen S, Van Herck E, Swinnen JV, Bouillon R, Vanderschueren D (2002) Evidence from the aged orchiectomized male rat model that 17beta-estradiol is a more effective bone-sparing and anabolic agent than 5alpha-dihydrotestosterone. J Bone Miner Res 17:2080–2086

    CAS  PubMed  Google Scholar 

  7. Cosman F, Lindsay R (1998) Is parathyroid hormone a therapeutic option for osteoporosis? A review of the clinical evidence. Calcif Tissue Int 62:475–480

    Google Scholar 

  8. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM (2003) The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 349:1216–1226

    Article  CAS  PubMed  Google Scholar 

  9. 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  CAS  PubMed  Google Scholar 

  10. Alexander JM, Bab I, Fish S, Müller R, Uchiyama T, Gronowicz G, Nahounou M, Zhao Q, White DW, Chorev M, Gazit D, Rosenblatt M (2001) Human parathyroid hormone 1–34 reverses bone loss in ovariectomized mice. J Bone Miner Res 16:1665–1673

    Google Scholar 

  11. Hock JM, Gera I, Fonseca J, Raisz LG (1988) Human parathyroid hormone (1–34) increases bone mass in ovariectomized and orchiectomized rats. Endocrinology 6:2899–2904

    Google Scholar 

  12. Orwoll ES, Scheele WH, Paul S, Adami S, Syversen U, Diez-Perez A, Kaufman JM, Clancy AD, Gaich GA (2003) The effect of teriparatide [human parathyroid hormone (1–34)] therapy on bone density in men with osteoporosis. J Bone Miner Res 18:9–17

    CAS  PubMed  Google Scholar 

  13. Iwamoto J, Yeh JK, Takeda T (2003) Effect of vitamin K2 on cortical and cancellous bones in orchidectomized and/or sciatic neurectomized rats. J Bone Miner Res 18:776–783

    Google Scholar 

  14. Li M, Jee WS, Ke HZ, Tang LY, Ma YF, Liang XG, Setterberg RB (1995) Prostaglandin E2 administration prevents bone loss induced by orchidectomy in rats. J Bone Miner Res 10:66–73

    Google Scholar 

  15. Hildebrand T, Laib A, Müller R, Dequeker J, Rüegsegger P (1999) Direct three-dimensional morphometric analysis of human cancellous bone: Microstructural data from spine, femur, iliac crest, and calcaneus. J Bone Miner Res 14:1167–1174

    CAS  PubMed  Google Scholar 

  16. Yang R, Davies CM, Archer CW, Richards RG (2003) Immunohistochemistry of matrix markers in Technovit 9100 New-embedded undecalcified bone sections. Eur Cell Mater 31:57–71

    Google Scholar 

  17. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610

    CAS  PubMed  Google Scholar 

  18. Li M, Shen Y, Wronski TJ (1997) Time course of femoral neck osteopenia in ovariectomized rats. Bone 20:55–61

    Article  CAS  PubMed  Google Scholar 

  19. Mo A, Yao W, Li C, Tian X, Su M, Ling Y, Zhang Q, Setterberg RB, Jee WS (2002) Bipedal stance exercise and prostaglandin E2 (PGE2) and its synergistic effect in increasing bone mass and in lowering the PGE2 dose required to prevent ovariectomized-induced cancellous bone loss in aged rats. Bone 31:402–406

    Google Scholar 

  20. Mosekilde L, Danielsen CC, Sogaard CH, McOsker JE, Wronski TJ (1995) The anabolic effects of parathyroid hormone on cortical bone mass, dimensions and strength-assessed in a sexually mature, ovariectomized rat model. Bone 16:223–230

    Google Scholar 

  21. Oxlund H, Andreassen TT (2004) Simvastatin treatment partially prevents ovariectomy-induced bone loss while increasing cortical bone formation. Bone 34:609–618

    Google Scholar 

  22. Gunness M, Orwoll E (1995) Early induction of alterations in cancellous and cortical bone histology after orchiectomy in mature rats. J Bone Miner Res 10:1735–1744

    Google Scholar 

  23. Stewart AF, Cain RL, Burr DB, Jacob D, Turner CH, Hock JM (2000) Six-month daily administration of parathyroid hormone and parathyroid hormone-related protein peptides to adult ovariectomized rats markedly enhances bone mass and biomechanical properties: a comparison of human parathyroid hormone 1–34, parathyroid hormone-related protein 1–36, and SDZ-parathyroid hormone 893. J Bone Miner Res 15:1517–1525

    Google Scholar 

  24. Sato M, Westmore M, Ma YL, Schmidt A, Zeng QQ, Glass EV, Vahle J, Brommage R, Jerome CP, Turner CH (2004) Teriparatide [PTH(1–34)] strengthens the proximal femur of ovariectomized nonhuman primates despite increasing porosity. J Bone Miner Res 19:623–629

    Google Scholar 

  25. Rixon RH, Whitfield JF, Gagnon L, Isaacs RJ, Maclean S, Chakravarthy B, Durkin JP, Neugebauer W, Ross V, Sung W, Willick GE (1994) Parathyroid hormone fragments may stimulate bone growth in ovariectomized rats by activating adenylyl cyclase. J Bone Miner Res 9:1179–1789

    Google Scholar 

  26. Meng XW, Liang XG, Birchman R, Wu DD, Dempster DW, Lindsay R, Shen V (1996) Temporal expression of the anabolic action of PTH in cancellous bone of ovariectomized rats. J Bone Miner Res 11:421–429

    Google Scholar 

  27. Zhang KQ, Chen JW, Li QN, Li GF, Tian XY, Huang LF, Bao LH, Wang ML (2002) Effect of intermittent injection of recombinant human parathyroid hormone on bone histomorphometry of ovariectomized rats. Acta Pharmacol Sin 23:659–662

    Google Scholar 

  28. Lane NE, Kimmel DB, Nilsson MH, Cohen FE, Newton S, Nissenson RA, Strewler GJ (1996) Bone-selective analogs of human PTH(1–34) increase bone formation in an ovariectomized rat model. J Bone Miner Res 11:614–625

    Google Scholar 

  29. Sato M, Ma YL, Hock JM, Westmore MS, Vahle J, Villanueva A, Turner CH (2002) Skeletal efficacy with parathyroid hormone in rats was not entirely beneficial with long-term treatment. J Pharmacol Exp Ther 302:304–313

    Google Scholar 

  30. Hock JM, Gera I (1992) Effects of continuous and intermittent administration and inhibition of resorption on the anabolic response of bone to parathyroid hormone. J Bone Miner Res 7:65–72

    Google Scholar 

  31. Li M, Wronski TJ (1995) Response of femoral neck to estrogen depletion and parathyroid hormone in aged rats. Bone 16:551–557

    Article  CAS  PubMed  Google Scholar 

  32. Qin L, Raggatt LJ, Partridge NC (2004) Parathyroid hormone: a double-edged sword for bone metabolism. Trends Endocrinol Metab 15:60–65

    Google Scholar 

  33. Andreassen TT, Oxlund H (2000) The influence of combined parathyroid hormone and growth hormone treatment on cortical bone in aged ovariectomized rats. J Bone Miner Res 15:2266–2275

    CAS  PubMed  Google Scholar 

  34. Moriyama I, Iwamoto J, Takeda T, Toyama Y (2002) Comparative effects of intermittent administration of human parathyroid hormone (1–34) on cancellous and cortical bone loss in tail-suspended and sciatic neurectomized young rats. J Orthop Sci 7:379–385

    Google Scholar 

  35. Sato M, Zeng GQ, Turner CH (1997) Biosynthetic human parathyroid hormone (1–34) effects on bone quality in aged ovariectomized rats. Endocrinology 138:4330–4337

    Google Scholar 

  36. Ma Y, Jee WS, Yuan Z, Wei W, Chen H, Pun S, Liang H, Lin C (1999) Parathyroid hormone and mechanical usage have a synergistic effect in rat tibial diaphyseal cortical bone. J Bone Miner Res 14:439–448

    Google Scholar 

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Acknowledgments

We thank O. Lahat for expert technical support. This work was supported by a grant from the Elyahu Penn Foundation to I.B. and by ECTS Exchange Scholarship Grant and Boehringer Ingelheim Fonds travel allowance to Y.G. Purchase of the μCT system was supported in part by an ISF grant (9007/01) to I.B.

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Affiliations

  1. Bone Laboratory, The Hebrew University of Jerusalem, Jerusalem, Israel

    Yankel Gabet & Itai Bab

  2. Dental Implantology Center, Hebrew University-Hadassah School of Dental Medicine, Jerusalem, Israel

    David Kohavi

  3. Institute for Biomedical Engineering, Swiss Federal Institute of Technology (ETH) and University of Zürich, Zürich, Switzerland

    Ralph Müller

  4. Laboratory for Translational Research, Harvard Medical School, 600 One Kendall Square, 3rd Floor, Cambridge, MA, 02139, USA

    Michael Chorev

Authors
  1. Yankel Gabet
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  2. David Kohavi
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  3. Ralph Müller
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  4. Michael Chorev
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  5. Itai Bab
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Correspondence to Michael Chorev.

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Gabet, Y., Kohavi, D., Müller, R. et al. Intermittently administered parathyroid hormone 1–34 reverses bone loss and structural impairment in orchiectomized adult rats. Osteoporos Int 16, 1436–1443 (2005). https://doi.org/10.1007/s00198-005-1876-6

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  • DOI: https://doi.org/10.1007/s00198-005-1876-6

Keywords

  • Bone anabolic agents
  • Bone loss
  • Orchiectomy
  • Osteoporosis
  • Parathyroid hormone