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Regional Bone Center, Helen Hayes Hospital, New York State Department of Health West Haverstraw, New York 10993
Department of Medicine, Columbia University College of Physicians and Surgeons New York, New York 10032
Department of Pathology, Columbia University College of Physicians and Surgeons New York, New York 10032
Correspondence: Address requests for reprints to: Robert Lindsay, M.D., Ph.D., Helen Hayes Hospital, Regional Bone Center, Route 9W, West Haverstraw, New York 10993.
Abstract
I. Introduction: PHYSICIANS have traditionally considered PTH to be an agent that is catabolic to the skeleton. However, as early as 60 yr ago, Albright and his colleagues (1) and later Selye (2) noted that the peptide extract could also be anabolic to the skeleton, producing increases in bone tissue in animals. The potential for an agent that can increase bone mass and hence reverse the skeletal defect in patients with osteoporosis is great, particularly if in doing so it also repairs microarchitectural damage. The agents currently available in the United States for treatment of osteoporosis, estrogens and salmon calcitonin, primarily stabilize bone mass and prevent further loss of bone, although a transient small increment in mass is often reported, particularly in patients with elevated levels of bone remodeling. This increase is not a true anabolic effect but is related to the temporal effects on turnover in which resorption declines initially followed by a reduction in formation that may take several months. Fluoride, in contrast, does increase bone mass by a true anabolic action, but there is controversy about the quality of the bone formed. Two recent controlled studies failed to find a reduction in fracture recurrence (3, 4), although the dose may have been excessive, and consequently, fluoride is currently not approved for treatment of osteoporosis in the United States. Thus, if PTH is capable of improving bone mass and quality, the peptide will have a potential therapeutic role in osteoporosis. This review summarizes the data available to date, starting at the cellular level.
Footnotes
* Supported in part by U.S. Public Health Service Grants AM-39191, AR-41386, DK-46381, and DK-42892
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R. T. Turner, G. L. Evans, J. M. Cavolina, B. Halloran, and E. Morey-Holton Programmed Administration of Parathyroid Hormone Increases Bone Formation and Reduces Bone Loss in Hindlimb-Unloaded Ovariectomized Rats Endocrinology, October 1, 1998; 139(10): 4086 - 4091. [Abstract] [Full Text] [PDF]
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 J. S. Finkelstein, A. Klibanski, A. L. Arnold, T. L. Toth, M. D. Hornstein, and R. M. Neer Prevention of Estrogen Deficiency-Related Bone Loss With Human Parathyroid Hormone-(1-34): A Randomized Controlled Trial JAMA, September 23, 1998; 280(12): 1067 - 1073. [Abstract] [Full Text] [PDF]
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A. Bisello, A. E. Adams, D. F. Mierke, M. Pellegrini, M. Rosenblatt, L. J. Suva, and M. Chorev Parathyroid Hormone-Receptor Interactions Identified Directly by Photocross-linking and Molecular Modeling Studies J. Biol. Chem., August 28, 1998; 273(35): 22498 - 22505. [Abstract] [Full Text] [PDF]
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H. Plotkin, C. Gundberg, M. Mitnick, and A. F. Stewart Dissociation of Bone Formation from Resorption during 2-Week Treatment with Human Parathyroid Hormone-Related Peptide-(1-36) in Humans: Potential as an Anabolic Therapy for Osteoporosis J. Clin. Endocrinol. Metab., August 1, 1998; 83(8): 2786 - 2791. [Abstract] [Full Text]
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H. A. Simmons, C. M. Pirie, D. D. Thompson, and H. Z. Ke Parathyroid Hormone (1-34) Increased Total Body Bone Mass in Aged Female Rats J. Pharmacol. Exp. Ther., July 1, 1998; 286(1): 341 - 344. [Abstract] [Full Text]
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B.-Y. Liu, J. Guo, B. Lanske, P. Divieti, H. M. Kronenberg, and F. R. Bringhurst Conditionally Immortalized Murine Bone Marrow Stromal Cells Mediate Parathyroid Hormone-Dependent Osteoclastogenesis in Vitro Endocrinology, April 1, 1998; 139(4): 1952 - 1964. [Abstract] [Full Text] [PDF]
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F. Cosman, J. Nieves, L. Woelfert, S. Gordon, V. Shen, and R. Lindsay Parathyroid Responsivity in Postmenopausal Women with Osteoporosis During Treatment with Parathyroid Hormone J. Clin. Endocrinol. Metab., March 1, 1998; 83(3): 788 - 790. [Abstract] [Full Text]
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S. Rihani-Bisharat, G. Maor, and D. Lewinson In Vivo Anabolic Effects of Parathyroid Hormone (PTH) 28-48 and N-Terminal Fragments of PTH and PTH-Related Protein on Neonatal Mouse Bones Endocrinology, March 1, 1998; 139(3): 974 - 981. [Abstract] [Full Text] [PDF]
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L. K. McCauley, A. J. Koh, C. A. Beecher, and T. J. Rosol Proto-Oncogene c-fos Is Transcriptionally Regulated by Parathyroid Hormone (PTH) and PTH-Related Protein in a Cyclic Adenosine Monophosphate-Dependent Manner in Osteoblastic Cells Endocrinology, December 1, 1997; 138(12): 5427 - 5433. [Abstract] [Full Text] [PDF]
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H. Dobnig and R. T. Turner The Effects of Programmed Administration of Human Parathyroid Hormone Fragment (1-34) on Bone Histomorphometry and Serum Chemistry in Rats Endocrinology, November 1, 1997; 138(11): 4607 - 4612. [Abstract] [Full Text] [PDF]
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M. Sato, G. Q. Zeng, and C. H. Turner Biosynthetic Human Parathyroid Hormone (1-34) Effects on Bone Quality in Aged Ovariectomized Rats Endocrinology, October 1, 1997; 138(10): 4330 - 4337. [Abstract] [Full Text] [PDF]
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H. M. Kronenberg Editorial: Parathyroid Hormone and Osteocalcin--When Friends Become Strangers Endocrinology, August 1, 1997; 138(8): 3083 - 3084. [Full Text] [PDF]
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X.-P. Yu and S. Chandrasekhar Parathyroid Hormone (PTH 1-34) Regulation of Rat Osteocalcin Gene Transcription Endocrinology, August 1, 1997; 138(8): 3085 - 3092. [Abstract] [Full Text] [PDF]
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S.C. Miller, J. Hunziker, M. Mecham, and T.J. Wronski Intermittent Parathyroid Hormone Administration Stimulates Bone Formation in the Mandibles of Aged Ovariectomized Rats Journal of Dental Research, August 1, 1997; 76(8): 1471 - 1476. [Abstract] [PDF]
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J. G. Henry, M. Mitnick, P. R. Dann, and A. F. Stewart Parathyroid Hormone-Related Protein-(1-36) Is Biologically Active When Administered Subcutaneously to Humans J. Clin. Endocrinol. Metab., March 1, 1997; 82(3): 900 - 906. [Abstract] [Full Text] [PDF]
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A. B. Hodsman, L. J. Fraher, P. H. Watson, T. Ostbye, L. W. Stitt, J. D. Adachi, D. H. Taves, and D. Drost A Randomized Controlled Trial to Compare the Efficacy of Cyclical Parathyroid Hormone Versus Cyclical Parathyroid Hormone and Sequential Calcitonin to Improve Bone Mass in Postmenopausal Women with Osteoporosis J. Clin. Endocrinol. Metab., February 1, 1997; 82(2): 620 - 628. [Abstract] [Full Text] [PDF]
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Z. Huang, Y. Chen, S. Pratt, T.-H. Chen, T. Bambino, R. A. Nissenson, and D. M. Shoback The N-terminal Region of the Third Intracellular Loop of the Parathyroid Hormone (PTH)/PTH-related Peptide Receptor Is Critical for Coupling to cAMP and Inositol Phosphate/Ca2+ Signal Transduction Pathways J. Biol. Chem., December 27, 1996; 271(52): 33382 - 33389. [Abstract] [Full Text] [PDF]
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E. M. Greenfield, M. C. Horowitz, and S. A. Lavish Stimulation by Parathyroid Hormone of Interleukin-6 and Leukemia Inhibitory Factor Expression in Osteoblasts Is an Immediate-early Gene Response Induced by cAMP Signal Transduction J. Biol. Chem., May 3, 1996; 271(18): 10984 - 10989. [Abstract] [Full Text] [PDF]
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J. S. Finkelstein, A. Klibanski, E. H. Schaefer, M. D. Hornstein, I. Schiff, and R. M. Neer Parathyroid Hormone for the Prevention of Bone Loss Induced by Estrogen Deficiency N. Engl. J. Med., December 15, 1994; 331(24): 1618 - 1623. [Abstract] [Full Text]
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M. Shimizu, P. H. Carter, and T. J. Gardella Autoactivation of Type-1 Parathyroid Hormone Receptors Containing a Tethered Ligand J. Biol. Chem., June 23, 2000; 275(26): 19456 - 19460. [Abstract] [Full Text] [PDF]
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K. A. Buckley, S. C. Wagstaff, G. McKay, A. Gaw, R. A. Hipskind, G. Bilbe, J. A. Gallagher, and W. B. Bowler Parathyroid Hormone Potentiates Nucleotide-induced [Ca2+]i Release in Rat Osteoblasts Independently of Gq Activation or Cyclic Monophosphate Accumulation. A MECHANISM FOR LOCALIZING SYSTEMIC RESPONSES IN BONE J. Biol. Chem., March 16, 2001; 276(12): 9565 - 9571. [Abstract] [Full Text] [PDF]
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J. T. Swarthout, T. A. Doggett, J. L. Lemker, and N. C. Partridge Stimulation of Extracellular Signal-regulated Kinases and Proliferation in Rat Osteoblastic Cells by Parathyroid Hormone Is Protein Kinase C-dependent J. Biol. Chem., March 2, 2001; 276(10): 7586 - 7592. [Abstract] [Full Text] [PDF]
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N. Shimizu, J. Guo, and T. J. Gardella Parathyroid Hormone (PTH)-(1-14) and -(1-11) Analogs Conformationally Constrained by alpha -Aminoisobutyric Acid Mediate Full Agonist Responses via the Juxtamembrane Region of the PTH-1 Receptor J. Biol. Chem., December 21, 2001; 276(52): 49003 - 49012. [Abstract] [Full Text] [PDF]
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M. Shimizu, J. T. Potts Jr., and T. J. Gardella Minimization of Parathyroid Hormone. NOVEL AMINO-TERMINAL PARATHYROID HORMONE FRAGMENTS WITH ENHANCED POTENCY IN ACTIVATING THE TYPE-1 PARATHYROID HORMONE RECEPTOR J. Biol. Chem., July 14, 2000; 275(29): 21836 - 21843. [Abstract] [Full Text] [PDF]
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