Skip to main content
SpringerLink
Log in

Parathyroid Hormone, Its Fragments and Their Analogs for the Treatment of Osteoporosis

  • Review Article
  • Published:
Treatments in Endocrinology

Abstract

The susceptibility to traumatic fracturing of osteopenic bones, and the spontaneous fracturing of osteoporotic bones by normal body movements caused by the microstructural deterioration and loss of bone, are currently treated with antiresorptive drugs, such as the bisphosphonates, calcitonin, estrogens, and selective estrogen receptor modulators. These antiresorptive agents target osteoclasts and, as their name indicates, reduce or stop bone resorption. They cannot directly stimulate bone formation, increase bone mass above normal values in ovariectomized rat models, or improve microstructure.

However, there is a family of agents — the parathyroid hormone (PTH) and some of its fragments and their analogs —which directly stimulate bone growth and improve microstructure independently from impairing osteoclasts. These drugs are about to make their clinical debut in treating patients with osteoporosis and, probably not too far in the future, for accelerating fracture healing. They stimulate osteoblast accumulation and bone formation in three ways via signals from the type 1 PTH/PTH-related protein (PTHR1) receptors on proliferatively inactive preosteoblasts, osteoblasts, osteocytes and bone-lining cells. The receptor signals shut down the proliferative machinery in preosteoblasts and push their maturation to osteoblasts, cause the osteo-blastic cells to make and secrete several factors that stimulate the extensive proliferation of osteoprogenitors without PTHR1 receptors, stimulate the reversion of bone-lining cells to osteoblasts, and extend osteoblast lifespan and productivity by preventing them from suicidally initiating apoptosis.

The first of the PTHs to reach the clinic will be teriparatide [recombinant human (h)PTH-(1–34)], which was recommended for approval in 2001 by the US Food and Drug Administration Endocrinology and Metabolic Drugs Advisory Committee for the treatment of postmenopausal osteoporosis. Teriparatide has been shown to considerably increase cancellous and cortical bone mass, improve bone microstructure, prevent fractures and thus provide benefits that cannot be provided by current antiresorptive drugs, when administered subcutaneously at a daily dose of 20µg for no longer than 2 years to patients with osteoporosis.

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

Table I
Table II
Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bilezikian JP, Marcus MA, Levine MA. The parathyroid hormone. 2nd ed. San Diego (CA): Academic Press, 2001

    Google Scholar 

  2. Bilezikian JP, Raisz LG, Rodan GA. Bone biology. 2nd ed. Vols 1 and 2. San Diego (CA): Academic Press, 2002

    Google Scholar 

  3. Whitfield JF. The parathyroid hormones (PTHs): anabolic tools for mending fractures and treating osteoporosis. Medscape Available from URL: http://www.medscape.com/viewprogram/604 [Accessed Jun 6]

  4. Whitfield JF, Morley P, Willick GE. The bone-building action of the parathyroid hormone. Drugs Aging 1999; 15: 117–29

    Article  PubMed  CAS  Google Scholar 

  5. Whitfield JF, Morley P, Willick GE. The parathyroid hormone: an unexpected bone builder for treating osteoporosis. Austin (TX): Landes Bioscience, 1998

    Google Scholar 

  6. Whitfield JF, Morley P, Willick GE. The control of bone growth by parathyroid hormone (PTH), leptin and statins. Crit Rev Euk Gene Expression 2002; 12: 23–51

    Article  CAS  Google Scholar 

  7. Whitfield JF, Morley P, Willick GE. Bone growth stimulators: new tools for treating bone loss and mending fractures. Vitamins and hormones. Vol. 64. San Diego (CA): Academic Press, 2002: Chapter 1

    Google Scholar 

  8. Parikka V, Lehenkari P, Sassi M-L, et al. Estrogen reduces the depth of resorption pits by disturbing the organic bone matrix degradation activity of mature osteoclasts. Endocrinology 2001; 142: 5371–8

    Article  PubMed  CAS  Google Scholar 

  9. Taylor D, O’Brien F, Prima-Mello A, et al. Compression data on bovine bone confirms that a “stressed volume” principle explains the variability of strength results. J Biomech 1999; 32(11): 1199–203

    Article  PubMed  CAS  Google Scholar 

  10. Weibull W. Fatigue testing and analysis of results. New York: Pergamon Press, 1961

    Google Scholar 

  11. Frost HM. Intermediate organization of the skeleton. Vol 1. Boca Raton (FL): CRC Press, 1986

    Google Scholar 

  12. Noble BS, Reeve J. Osteocyte function, osteocyte death and bone fracture resistance. Mol Cell Endocrinol 2000; 159: 7–13

    Article  PubMed  CAS  Google Scholar 

  13. Burger EH, Klein-Nulend J. Mechanotrasduction in bone: role of the lacuno-canalicular network. FASEB J 1999; 13: S101–12

    PubMed  CAS  Google Scholar 

  14. Marotti G. The structure of bone tissues and the cellular control of their deposition. Ital J Anat Embryol 1996; 101: 25–79

    PubMed  CAS  Google Scholar 

  15. Martin RB. Toward a unifying theory of bone remodeling. Bone 2000; 26: 1–6

    Article  PubMed  CAS  Google Scholar 

  16. Martin RB. Does osteocyte formation cause the non-linear refilling of osteons? Bone 2000; 26: 71–8

    Article  PubMed  CAS  Google Scholar 

  17. Martin RB. Is all cortical bone remodeling initiated by microdamage? Bone 2002; 30: 8–13

    Article  PubMed  CAS  Google Scholar 

  18. Kufahl RH, Saha S. A theoretical model for stress-generated fluid flow in the canaliculi-lacunae network in bone tissue. J Biomech 1990; 23: 171–80

    Article  PubMed  CAS  Google Scholar 

  19. Tomkinson A, Gevers EF, Wit JM, et al. The role of estrogen in the control of osteocyte apoptosis. J Bone Miner Res 1998; 13: 12143–50

    Article  Google Scholar 

  20. Tomkinson A, Reeve J, Shaw RW, et al. The death of osteocytes via apoptosis accompanies estrogen withdrawal in human bone. J Clin Endocrinol Metab 1997; 82(9): 3128–35

    Article  PubMed  CAS  Google Scholar 

  21. Seeman E, Delmas PD. Reconstructing the skeleton with intermittent parathyroid hormone. Trends Endocrinol Metab 2001; 12: 281–3

    Article  PubMed  CAS  Google Scholar 

  22. Boivin GY, Chevassieux PM, Santora AC, et al. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone 2000; 27: 687–94

    Article  PubMed  CAS  Google Scholar 

  23. Delmas PD. Different effects of antiresorptive therapies on vertebral and non-vertebral fractures in postmenopausal osteoporosis. Bone 2002; 30: 14–7

    Article  PubMed  CAS  Google Scholar 

  24. Schneider BS. FDA Center for Drug Evaluation and Research, Endocrinology and Metabolic Drugs Advisory Committee Meeting July 27,2001: 150. Availalble from URL: http://www.fdavideo.com [Accessed 2002 Jun 6]

  25. Center for Drug Evaluation and Research, Endocrinology and Metabolic Drugs Advisory Committee Meeting July 27, 2001:150. Availalble from URL: http://www.fdavideo.com [Accessed 2002 Jun 6]

  26. Shimizu N, Carter PH, Khatri A, et al. Enhanced activity in parathyroid hormone-(1–14) and -(1–1 l):novel peptides for probing ligand-receptor interactions. Endocrinology 2001; 142: 3068–74

    Article  PubMed  CAS  Google Scholar 

  27. Shimizu N, Guo J, Gardella TJ. Parathyroid hormone (PTH)-(1–14) and -(1–11) analogs conformationally constrained by α-aminoisobutyric acid mediate full agonist responses via the juxtamembrane region of the PTH-1 receptor. J Biol Chem 2001; 276: 49003–12

    Article  PubMed  CAS  Google Scholar 

  28. Dempster DW, Cosman F, Parisien M, et al. Anabolic action of parathyroid hormone. Endocrine Revs 1993; 14: 690–709

    CAS  Google Scholar 

  29. Morley P, Whitfield JF, Willick GE. Therapeutic prospects for parathyroid hormone and parathyroid hormone analogs. Curr Med Chem-Immunol Endocr Metabol Agents 2001; 1: 269–87

    Article  CAS  Google Scholar 

  30. Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1–34) on bone histomorphometry and serum chemistry in rats. Endocrinology 1997; 138: 4607–12

    Article  PubMed  CAS  Google Scholar 

  31. Tam CS, Heersche JN, Murray TM, et al. Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration. Endocrinology 1882; 110: 506–12

    Article  Google Scholar 

  32. Zhou H, Shen V, Dempster DW, et al. Continuous parathyroid hormone and estrogen administration increases vertebral cancellous bone volume and cortical width in the estrogen-deficient rat. J Bone Miner Res 2001; 16: 1300–7

    Article  PubMed  CAS  Google Scholar 

  33. Andreassen TT, Ejersted C, Oxlund H. Intermittent parathyroid hormone (1–34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res 1999; 14: 960–8

    Article  PubMed  CAS  Google Scholar 

  34. Andreassen TT, Willick GE, Morley P, et al. Treatment with parathyroid hormone fragments increases fracture strength and callus amount and strength normalizes after treatment withdrawal [abstract]. J Bone Miner Res 2001; 16: S425

    Google Scholar 

  35. Bonadio J. Tissue engineering via local gene delivery; update and future prospects for enhancing the technology. Adv Drug Del Rev 2000; 44: 185–94

    Article  CAS  Google Scholar 

  36. Bonadio J, Smiley E, Patil P, et al. Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration. Nat Med 1999; 5: 753–9

    Article  PubMed  CAS  Google Scholar 

  37. Fang J, Zhu YY, Smiley E, et al. Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc Natl Acad Sci USA 1996; 93: 5753–8

    Article  PubMed  CAS  Google Scholar 

  38. Goldstein SA, Bonadio J. Potential role for direct gene transfer in the enhancement of fracture healing. Clin Orthop 1998; 355: S154–62

    PubMed  Google Scholar 

  39. Péhu M, Policard A, Dufort A. L’Ostéopetrose ou maladie des os marmoréens. Presse Med 1931; 53: 999–1003

    Google Scholar 

  40. Walker D. The induction of osteopetrotic changes in hypophysectomized, thyroparathyroidectomized, and intact rats of various ages. Endocrinology 1971; 89: 1389–406

    Article  PubMed  CAS  Google Scholar 

  41. Hodsman AB, Steer BM. Early histomorphometric changes in response to parathyroid hormone therapy in osteoporosis: evidence for de novo bone formation in quiescent cancellous surfaces. Bone 1993; 14: 523–7

    Article  PubMed  CAS  Google Scholar 

  42. Selye H. On the stimulation of new bone formation with parathyroid extract and irradiated ergosterol. Endocrinology 1932; 16: 547–58

    Article  CAS  Google Scholar 

  43. Watson PH, Fraher LJ, Kisiel M, et al. Enhanced osteoblast development after continuous infusion of hPTH-(1–84) in the rat. Bone 1999; 24: 89–94

    Article  PubMed  CAS  Google Scholar 

  44. Aubin JE. The role of osteoblasts. In: Henderson JE, Goltzman D, editors. The osteoporosis primer. Cambridge: Cambridge University, 2000: 18–35

    Chapter  Google Scholar 

  45. Aubin JE. Regulation of osteoblast formation and function. Rev Endocrine Metab Dis 2001; 2: 81–94

    Article  CAS  Google Scholar 

  46. Burr DB, Hirano T, Turner CH. Intermittently administered human parathyroid hormone (1–34) treatment increases intracortical bone turnover and porosity without reducing bone strength in the humerus of ovariectomized cynomolgus monkeys. J Bone Miner Res 2001; 16: 157–65

    Article  PubMed  CAS  Google Scholar 

  47. Hirano T, Burr DB, Cain RL, et al. Changes in geometry and cortical porosity in adult ovary-intact rabbits after 5 months treatment with LY333334 (hPTH 1–34). Calcif Tissue Int 2000; 66: 456–60

    Article  PubMed  CAS  Google Scholar 

  48. Miller SC, Wronsky TJ. Long-term osteopenic changes in cancellous bone structure in ovariectomized rats. Anat Rec 1993; 236: 433–41

    Article  PubMed  CAS  Google Scholar 

  49. Jerome CP, Burr DB, Van Bibber T, et al. Treatment with human parathyroid hormone (1–34) for 18 months increases cancellous bone volume and improves trabecular architecture in ovariectomized cynomolgus monkeys (Macaca fascicularis). Bone 2001; 28: 150–9

    Article  PubMed  CAS  Google Scholar 

  50. Reeve J, Hesp R, Williams D, et al. Anabolic effect of low doses of a fragment of human parathyroid hormone fragment on the skeleton in postmenopausal osteoporosis. Lancet 1976; I: 1035–6

    Article  Google Scholar 

  51. Reeve J Tregear GW, Parsons JA. Preliminary trial of low doses of human parathyroid hormone fragment 1-34 in treatment of osteoporosis. Clin Endocrinol 1976; 21: 469–77

    Google Scholar 

  52. Reeve J, Meunier PJ, Parsons JA, et al. Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicenter trial. BMJ 1980; 280: 1340–4

    Article  PubMed  CAS  Google Scholar 

  53. Hesp R, Hulme P, Williams D, et al. The relationship between changes in femoral bone density and calcium balance in patients with involutional osteoporosis treated with human PTH fragment 1–34. Metab Bone Dis Rel Res 1981; 2: 331–4

    Article  Google Scholar 

  54. Reeve J, Arlot M, Bernat M, et al. Calcium-47 kinetic measurements of bone turnover compared to bone histomorphometry in osteoporosis: the influence of human parathyroid (hPTH 1–34) therapy. Metab Bone Dis Rel Res 1981; 3: 23–30

    Article  CAS  Google Scholar 

  55. Slovik DM, Neer RM, Potts JT. Short-term effects of synthetic human parathyroid hormone-(1–34) administration on bone mineral metabolism in osteoporotic patients. J Clin invest 1981; 68: 1261–71

    Article  PubMed  CAS  Google Scholar 

  56. Slovik DM, Rosenthal DI, Doppelt S, et al. Restoration of spinal bone in osteoporotic men by treatment with human parathyroid hormone (1–34) and 1,25-dihydroxyvitamin D. J Bone Miner Res 1986; 1: 377–81

    Article  PubMed  CAS  Google Scholar 

  57. Reeve J, Arlot M, Price TR, et al. Periodic courses of human 1–34 parathyroid peptide alternating with calcitriol paradoxically reduce bone remodeling in spinal osteoporosis. Eur J Clin Invest 1987; 17: 421–8

    Article  PubMed  CAS  Google Scholar 

  58. Neer RM, Slovik D, Doppelt S, et al. The use of parathyroid hormone plus 1,25-dihydroxyvitamin D to increase trabecular bone in osteoporotic men and postmenopausal women. In: Cristiansen C, Johansen JS, Riis BJ, editors. Osteoporosis. Copenhagen: Osteopress APS, 1987: 829–35

    Google Scholar 

  59. Hesch RD, Busch U, Prokop M, et al. Increase of vertebral density by combination therapy with pulsatile 1–38 hPTH and sequential addition of calcitonin nasal spray in osteoporotic patients. Calcif Tissue Int 1989; 44: 176–80

    Article  PubMed  CAS  Google Scholar 

  60. Reeve J, Davies UM, Hesp R, et al. Treatment of osteoporosis with human parathyroid peptide and observations on the effect of sodium fluoride. BMJ 1990; 301: 314–8

    Article  PubMed  CAS  Google Scholar 

  61. Hodsman AB, Fraher LJ. Biochemical responses to sequential human parathyroid hormone (1–38) and calcitonin in osteoporotic patients. Bone Miner 1990; 9: 137–52

    Article  PubMed  CAS  Google Scholar 

  62. Reeve J, Bradbeer JN, Arlot M, et al. hPTH 1–34 treatment of osteoporosis with added hormone replacement therapy: biochemical, kinetic and histological responses. Osteop Int 1991; 1: 162–70

    Article  CAS  Google Scholar 

  63. Hodsman AB, Steer BM, Fraher LJ, et al. Bone densitometric and histomorphometric responses to sequential human parathyroid hormone(1–38) and salmon calcitonin in osteoporotic patients. Bone Miner 1991; 14: 67–83

    Article  PubMed  CAS  Google Scholar 

  64. Neer R, Slovik D, Daly M, et al. Treatment of postmenopausal osteoporosis with daily plus calcitriol [abstract]. J Endocrinol Invest 1991; 14Suppl. 3: 50

    Google Scholar 

  65. Bradbeer JN, Arlot ME, Meunier PJ, et al. Treatment of osteoporosis with parathyroid peptide (hPTH 1–34) and oestrogen: Increase in volumetric density of iliac cancellous bone may depend on reduced trabecular spacing as well as increased thickness of packets of newly formed bone. Clin Endocrinol 1992; 37: 282–9

    Article  CAS  Google Scholar 

  66. Hodsman AB, Fraher LJ, Ostbye T, et al. An evaluation of several biochemical markers of bone formation and resorption in a protocol utilizing cyclical parathyroid hormone and calcitonin in therapy of osteoporosis. J Clin Invest 1993; 91: 1138–48

    Article  PubMed  CAS  Google Scholar 

  67. Reeve J, Arlot ME, Bradbeer JN, et al. Human parathyroid peptide treatment of vertebral osteoporosis. Osteop Int 1993; 3: S199–203

    Article  Google Scholar 

  68. Finkelstein IS, Klibanski A, Schaefer EH, et al. Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency. N Engl J Med 1994; 331: 1618

    Article  PubMed  CAS  Google Scholar 

  69. Lindsay R, Cosman F, Nieves J, et al. Controlled clinical trial of the effects of 1-hPTH in estrogen treated osteoporotic women [abstract]. J Bone Miner Res 1995;8: S130

    Google Scholar 

  70. Sone T, Fukunaga M, Ono S, et al. Small dose of human parathyroid hormone (1-increased bone mass in the lumbar vertebrae in patients with senile osteoporosis. Min Electrol Metab 1995; 21: 232–5

    CAS  Google Scholar 

  71. Hodsman AB, Fraher LJ, Watson PH, et al. A randomized controlled trial to compare the efficacy of cyclical parathyroid hormone versus cyclical parathyroid hormone and sequential calcitonin to improve bone mass in post-menopausal women with osteoporosis. J Clin Endocrinol Metab 1997; 82: 620–8

    Article  PubMed  CAS  Google Scholar 

  72. Lindsay R, Nieves J, Formica C, et al. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 1997; 350: 550–5

    Article  PubMed  CAS  Google Scholar 

  73. Lindsay R, Hodsman A, Genant H, et al. A randomized controlled multicenter study of 1–84h PTH for treatment of postmenopausal osteoporosis [abstract]. Bone 1998; 23: 175

    Google Scholar 

  74. Fujita T, Inoue T, Morii H, et al. Effect of intermittent weekly dose of human parathyroid hormone (1–34) on osteoporosis: a randomized double-masked prospective study using three dose levels. Osteop Int 1999; 9: 296–306

    Article  CAS  Google Scholar 

  75. Cann CE, Roe EB, Sanchez SD, et al. PTH effects in the femur: envelope-specific responses by 3DQCT in postmenopausal women (abstract). J Bone Miner Res 1999; 14: S137

    Google Scholar 

  76. Roe EB, Sanchez SD, del Puerto GA, et al. Parathyroid hormone 1–34 (hPTH 1–34) and estrogen produce dramatic bone density increases in postmenopausal osteoporosis: results from a placebo-controlled randomized trial [abstract]. J Bone Miner Res 1999; 14: S137

    Google Scholar 

  77. Rittmaster RS, Bolognese M, Ettinger MP, et al. Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab 2000; 85: 2129–34

    Article  PubMed  CAS  Google Scholar 

  78. Cosman F, Nieves J, Woelfert L, et al. Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. J Bone Miner Res 2001; 16: 925–31

    Article  PubMed  CAS  Google Scholar 

  79. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporsis. N Engl J Med 2001; 344: 1434–41

    Article  PubMed  CAS  Google Scholar 

  80. Bilezekian JP, Kurland ES. Therapy of male osteoporosis with parathyroid hormone. Calcif Tissue Int 2001; 69: 248–51

    Article  Google Scholar 

  81. Dempster DW, Cosman F, Kurland ES, et al. Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J Bone Miner Res 2001; 16: 1846–53

    Article  PubMed  CAS  Google Scholar 

  82. Reeve J, Mitchell A, Tellez M, et al. Treatment with parathyroid peptides and estrogen replacement for sever postmenopausal vertebral osteoporsis; prediction of long-term responses in spine and femur. J Bone Miner Metab 2001; 19: 102–14

    Article  PubMed  CAS  Google Scholar 

  83. Kurland EH, Cosman F, MaMahon DJ, et al. Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J Clin Endocrinol Metab 2000; 85: 3069–76

    Article  PubMed  CAS  Google Scholar 

  84. Chimeh F, Holick MF. Novel use for PTH(1–34): an effective safe topical therapy for treating psoriasis [abstract]. J Bone Miner Res 2000; 15: S232

    Google Scholar 

  85. Calvi LM, Sims NA, Hunzelman JL, et al. Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. J Clin Invest 2001; 107: 277–86

    Article  PubMed  CAS  Google Scholar 

  86. Gardella TJ, Jüppner H. Interactions of PTH and PTHrP with their receptors. Rev Endo Metab Dis 2000; 1: 317–29

    Article  CAS  Google Scholar 

  87. Hoare SRJ, Usdin TB. Molecular mechanisms of ligand recognition by parathyroid 1 (PTH1)andPTH2 receptors. CurrPharma Design 2001;7: 698–713

    Google Scholar 

  88. Mahon MJ, Donowitz M, Segre GV. Direct binding of the PTH/PTHrP receptor (PTH1R) to the Na-H exchange regulatory factor 2 (NHERF2) selectively transfers signaling from adenylate cyclase to phospholipase C pathways [abstract]. J Bone Miner Res 2001; 16: S159

    Google Scholar 

  89. Suh P-G, Hwang J-I, Ryu SH, et al. The roles of PDZ-containing proteins in PLC-β-mediated signaling. Biochem Biophys Res Commun 2001; 288: 1–7

    Article  PubMed  CAS  Google Scholar 

  90. Rixon RH, Whitfield JF, Gagnon L, et al. Parathyroid hormone fragments may stimulate bone growth in ovariectomized rats by activating adenylyl cyclase. J Bone Miner Res 1994; 9: 1179–89

    Article  PubMed  CAS  Google Scholar 

  91. Vilardaga J-P, Krasel C, Chauvin S, et al. Internalization determinants of the parathyroid hormone receptor differentially regulate β-arrestin/receptor association. J Biol Chem 2002; 277: 8121–9

    Article  PubMed  CAS  Google Scholar 

  92. Keenan SM, Baldassare JJ. Molecular scaffold protein and cellular responses. Trends Endocrinol Metab 2001; 12: 184–6

    Article  PubMed  CAS  Google Scholar 

  93. Luttrell LM, Roudabush FL, Choy EW, et al. Activation and targeting of extracellular signal-regulated kinases by β-arrestin scaffolds. Proc Natl Acad Sci USA 2001; 98: 2449–54

    Article  PubMed  CAS  Google Scholar 

  94. Miller WE, McDonald PH, Cai SF, et al. Identification of a motif in the carboxyl terminus of β-arrestin-2 responsible for activation of JNK3. J Biol Chem 2001; 276: 27770–7

    Article  PubMed  CAS  Google Scholar 

  95. Pouysségur J. Signal transduction: an arresting start for MAPK. Science 2000; 290: 1515–8

    Article  PubMed  Google Scholar 

  96. Onyia JE, Gelbert L, Zhang M, et al. Analysis of gene expression by DNA microarray reveals novel clues to the mechanism of the catabolic and anabolic actions of PTH in bone [abstract]. J Bone Miner Res 2001; 16: S227

    Google Scholar 

  97. Ali AA, O’Brien CA, Weinstein RS, et al. An inverse relationship between prevalence of osteoblast apoptosis and rate of bone formation with intermittent, but not sustained, elevation of PTH in mice [abstract]. J Bone Miner Res 2001; 16: S178

    Google Scholar 

  98. Han Z, Boyle DL, Chang L, et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 2001; 108: 73–81

    PubMed  CAS  Google Scholar 

  99. Hurley MM, Marcello K, Abrue C, et al. Transcriptional regulation of the collagenase gene by basic fibroblast growth factor in osteoblastic MC3T3-E1 cells. Biochem Biophys Res Commun 1995; 214: 331–9

    Article  PubMed  CAS  Google Scholar 

  100. Onyia JE, Ma YL, Galbreath E, et al. ADAMTS-1: a cellular disintegren and metalloprotease with thrombospondin motifs is essential for normal bone growth and PTH regulated bone metabolism [abstract]. J Bone Miner Res 2001; 16: S158

    Google Scholar 

  101. Ma YL, Cain RL, Halladay DL, et al. Catabolic effects of continuous human PTH (1–38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation. Endocrinology 2001; 142: 4047–54

    Article  PubMed  CAS  Google Scholar 

  102. Tintut Y, Parhami F, Le V, et al. Inhibition of osteoblast-specific transcription factor Cbfa1 by the cAMP pathway in osteoblastic cells. Ubiquitin/proteasome-dependent regulation. J Biol Chem 1999; 274: L28875–9

    Article  Google Scholar 

  103. Mizuna M, Kuboki Y. Osteoblast gerne expression of bone marrow cells during the osteoblastic differentiation induced by type I collagen. J Biochem (Tokyo) 2001; 129: 133–8

    Article  Google Scholar 

  104. McCauley LK, Koh AJ, Beecher CA, et al. PTH/PTHrP receptor is temporally regulated during osteoblast differentiation and is associated with collagen synthesis. J Cell Biochem 1996; 61: 638–47

    Article  PubMed  CAS  Google Scholar 

  105. Stein GS, Lian JB, Stein JL, et al. Transcriptional control of osteoblast growth and differentiation. Physiol Rev 1996; 76: 593–629

    PubMed  CAS  Google Scholar 

  106. Raouf A, Seth A. Discovery of osteoblast-associated genes using cDNA microarrays. Bone 2002; 30: 463–41

    Article  PubMed  CAS  Google Scholar 

  107. Iacopetti P, Barsacchi G, Tirone F, et al. Developmental expression of the PC3 gene is correlated with neuronal cell birthday. Mech Devel 1994; 47: 127–37

    Article  CAS  Google Scholar 

  108. Iacopetti P, Michelini M, Stuckman I, et al. Expression of the antiproliferative gene TIS21 at the onset of neurogenesis identifies single neuroepithelial cells that switch from proliferative to neuron-generating division. Proc Natl ACad SCi USA 1999; 96: 4639–44

    Article  PubMed  CAS  Google Scholar 

  109. Cornish J, Callon KE, Lin C, et al. Stimulation of osteoblast proliferation by C-terminal fragments of parathyroid hormone-related protein. J Bone Miner Res 1999; 14: 915–22

    Article  PubMed  CAS  Google Scholar 

  110. Cornish J, Callon KE, Nicholson GC, et al. Parathyroid hormone-related protein-(107–139) inhibits bone resorption in vivo. Endocrinology 1997; 138: 1299–304

    Article  PubMed  CAS  Google Scholar 

  111. Esbrit P, Alvarez-Arroyo MV, De Miguel F, et al. C-terminal parathyroid hormone-related protein increases vascular endothelial growth factor in human osteoblastic cells. J Am Soc Nephrol 2000; 11: 1085–92

    PubMed  CAS  Google Scholar 

  112. Fenton AJ, Kemp BE, Hammonds RG, et al. A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein, PTHrP[107–111]. Endocrinology 1991; 129: 3424–6

    Article  PubMed  CAS  Google Scholar 

  113. Zheng MH, McCaughan HB, Paradimitriou JM, et al. Tartrate resistant acid phosphatase activity in rat cultured osteoclasts is inhibited by a carboxyl terminal peptide (osteostatin) from parathyroid hormone-related protein. J Cell Biochem 1994; 54: 145–53

    Article  PubMed  CAS  Google Scholar 

  114. Aarts MM, Davidson D, Corluka A, et al., Parathyroid hormone-related protein promotes quiescence and survival of serum-deprived chondrocytes by inhibiting rRNA synthesis. J Biol Chem 2001; 276: 37934–43

    PubMed  CAS  Google Scholar 

  115. Aarts MM, Rix A, Guo J, et al. The nucleolar targeting signal (NTS) of parathyroid hormone-related protein mediates endocytosis and nucleolar translocation. J Bone Miner Res 1999; 14: 1493–503

    Article  PubMed  CAS  Google Scholar 

  116. Lam MHC, Thomas RJ, Martin TJ, et al. Nuclear and nucleolar localization of parathyroid hormone-related protein. Immunol Cell Biol 2000; 78: 395–402

    Article  PubMed  CAS  Google Scholar 

  117. Watson PH, Fraher LJ, Natale BV, et al. Nuclear localization of the type 1 parathyroid/parathyroid hormone-related peptide receptor in MC3T3-E1 cells: association with serum-induced cell proliferation. Bone 2000; 26: 221–5

    Article  PubMed  CAS  Google Scholar 

  118. Candeliere GA, Liu F, Aubin JE. Individual osteoblasts in the developing calvaria express different gene repertoires. Bone 2001; 28: 351–61

    Article  PubMed  CAS  Google Scholar 

  119. Allison TN, Derynck R. Transforming growth factor-β in skeletal development and maintenance. In: Canalis E, editor. Skeletal growth factors. Philadelphia (PA): Lippincott Williams & Wilkins, 2000: 233–49

    Google Scholar 

  120. Bikle DD, Harris J, Halloran BP, et al. Skeletal unloading induces resistance to insulin-like growth factor I. J Bone Miner Res 1994; 9: 1789–96

    Article  PubMed  CAS  Google Scholar 

  121. Hurley MM, Tetradis S, Huang YF, et al. Parathyroid hormone regulates the expression of fibroblast growth factor-2 mRNA and fibroblast growth factor receptor mRNA in osteoblastic cells. J Bone Miner Res 1999; 14: 776–83

    Article  PubMed  CAS  Google Scholar 

  122. KostenuikPJ, Harris J, Halloran BP, et al. Skeletal unloading causes resistance of osteoprogenitor cells to parathyroid hormone and to insulin-like growth factor-I. J Bone Miner Res 1999; 14: 21–31

    Article  Google Scholar 

  123. Miyakoshi N, Kasukawa Y, Linkhart TA, et al. Evidence that the anabolic effects of PTH on bone require IGF-I in growing mice. Endocrinology 2001; 142: 4349–56

    Article  PubMed  CAS  Google Scholar 

  124. Wu Y, Kumar R. Parathyroid hormone regulates transforming growth factor β1 and β2 synthesis in osteoblasts via divergent signaling pathways. J Bone Miner Res 2000; 15: 879–84

    Article  PubMed  CAS  Google Scholar 

  125. Ducy P. Cbfal: a molecular switch in osteoblast biology. Devel Dynamics 2000; 219: 461–71

    Article  CAS  Google Scholar 

  126. Walsh CA, Bowler WB, Bilbe G, et al. Effects of PTH on PTHrP gene expression in human osteoblasts: up-regulation with the kinetics of an immediate early gene. Biochem Biophys Res Commun 1997; 239: 155–9

    Article  PubMed  CAS  Google Scholar 

  127. Chilco PJ, Leopold V, Zajac JD. Differential regulation of the parathyroid hormone-related protein gene P1 and P3 promoters by cAMP. Mol Cell Endocrinol 1998; 138: 173–84

    Article  PubMed  CAS  Google Scholar 

  128. Goltzman D, White JH. Development and tissue-specific regulation of parathyroid hormone (PTH)/PTH-related peptide receptor gene expression. Crit Rev Euk Gene Express 2000; 12: 135–49

    Google Scholar 

  129. Miller SC, de Saint-Georges L, Bowman BM, et al. Bone lining cells: structure and function. Scanning Microscopy 1989; 3: 953–61

    PubMed  CAS  Google Scholar 

  130. Dobnig H, Turner RT. Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology 1995; 136: 3632–8

    Article  PubMed  CAS  Google Scholar 

  131. Leaffer D, Sweeney M, Kellerman LA, et al. Modulation of osteogenic cell ultra-structure by RS-2358 an analog of human parathyroid hormone (PTH)-related peptide-(1–34), and bovine PTH-(1–34). Endocrinology 1995; 136: 3624–31

    Article  PubMed  CAS  Google Scholar 

  132. Pugazhenthi S, Miller E, Sable C, et al. Insulin-like growth factor-I induces bcl-2 promoter through the transcription factor cAMP-responsive element-binding protein. J Biol Chem 1999; 274: 27529–34

    Article  PubMed  CAS  Google Scholar 

  133. Bellido T, Plotkin LI, Davis J, et al. Protein kinase A-dependent phosphorylation and inactivation of the pro-apoptotic protein Bad mediates the anti-apoptoic effect of PTH on osteoblastic cells [abstract]. J Bone Miner Res 2001; 16: F172

    Google Scholar 

  134. Virdee K, Parone PA, Tolkovsky AM. Phosphorylation of the pro-apoptosis protein BAD on serine 155, a novel site, contributes to cell survival. Curr Biol 2000; 10: 1151–4

    Article  PubMed  CAS  Google Scholar 

  135. Kubota K, Sakikawa C, Katsumata M, et al. Platelet-derived growth factor BB secreted from osteoclasts acts as an osteoblastogenesis inhibitory factor. J Bone Miner Res 2002; 17: 257–65

    Article  PubMed  CAS  Google Scholar 

  136. Greaves M. Cancer: the evolutionary legacy. Oxford: Oxford University Press, 2000

    Google Scholar 

  137. Samnegard E, Iwaniec UT, Cullen DM, et al. Maintenance of cortical bone in human parathyroid hormone (1–84)-treated ovariectomized rats. Bone 2001; 28: 251–60

    Article  PubMed  CAS  Google Scholar 

  138. Mosekilde L, Thomsen JS, McOsker JE. No loss of biomechanical effects after withdrawal of short-term PTH treatment in an aged, osteopenic, ovariectomized rat model. Bone 1997; 20: 429–37

    Article  PubMed  CAS  Google Scholar 

  139. Kostenuik PJ, Capparelli C, Morony S, et al. OPG and PTH-(1–34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats. Endocrinology 2001; 142: 4295–304

    Article  PubMed  CAS  Google Scholar 

  140. Potts Jr JT, Tregear GW, Keutman HT, et al. Synthesis of a biologically active N-terminal tetratriacontapeptide of parathyroid hormone. Proc Natl Acad Sci USA 1971; 68: 63–7

    Article  PubMed  CAS  Google Scholar 

  141. Divieti P, Inomata N, Chapin K, et al. Receptors for the carboxyl-terminal region of PTH (1–84) are highly expressed in osteocytic cells. Endocrinology 2001; 142: 916–25

    Article  PubMed  CAS  Google Scholar 

  142. Divieti P, John MR, Jüppner H, et al. Human PTH-(7–84) inhibits bone resorption in vitro via actions indepenedent of the type I PTH/PTHrP receptor. Endocrinology 2002; 143: 171–6

    Article  PubMed  CAS  Google Scholar 

  143. Nguyen-Yamamoto L, Rousseau L, Brossard J-H, et al. Synthetic carboxyl-terminal fragments of parathyroid hormone (PTH) decrease ionized calcium concentration in rats by acting on a receptor different from the PTH/PTH-related peptide receptor. Endocrinology 2001; 142: 1386–92

    Article  PubMed  CAS  Google Scholar 

  144. Whitfield JF, Morley P, Willick GE, et al. Comparison of the ability of recombinant human parathyroid hotmone rh PTH-(1–84) and hPTH-(1–31)NH2 to stimulate femoral trabecular bone growth in ovariectomized rats. Calci Tissue Int 1997; 60: 26–9

    Article  CAS  Google Scholar 

  145. Leone-Bay A, Sato M, Paton D, et al. Oral delivery of biologically active parathyroid hormone. Pharmaceutical Res 2001; 7: 964–70

    Article  Google Scholar 

  146. Mehta N, Stern W, Sturmer A, et al. Oral delivery of PTH analogs by a solid dosage formulation [abstract]. J Bone Miner Res 2001; 16: S540

    Google Scholar 

  147. Whitfield JF, Morley P, Willick G, et al. Stimulation of the growth of femoral trabecular bone in ovariectomized rats by the novel parathyroid hormone fragment hPTH-(1–31)NH2 (ostabolin). Calcif Tissue Int 1996; 58: 81–7

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors had no conflict of interest or funding in the writting of this article.

Author information

Authors and Affiliations

  1. Institute for Biological Sciences, National Research Council of Canada, Bldg M-54, Montreal Rd Campus, Ottawa, Ontario, K1A 0R6, Canada

    James F. Whitfield & Gordon E. Willick

  2. ParaTecH Therapeutics Inc., Ottawa, Ontario, Canada

    Paul Motley

Authors
  1. James F. Whitfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul Motley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gordon E. Willick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James F. Whitfield.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Whitfield, J.F., Motley, P. & Willick, G.E. Parathyroid Hormone, Its Fragments and Their Analogs for the Treatment of Osteoporosis. Mol Diag Ther 1, 175–190 (2002). https://doi.org/10.2165/00024677-200201030-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00024677-200201030-00005

Keywords

Search

Navigation