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

Authors

  • A. F. Stewart M.D.,

    Corresponding author
    1. University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
    • Division of Endocrinology, BST E-1140, University of Pittsburgh School of Medicine, 3550 Terrace Street, Pittsburgh, PA 15213, U.S.A.
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  • R. L. Cain,

    1. Lilly Research Laboratories, Indianapolis, Indiana, U.S.A.
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  • D. B. Burr,

    1. Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.
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  • D. Jacob,

    1. Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.
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  • C. H. Turner,

    1. Indiana University School of Medicine, Indianapolis, Indiana, U.S.A.
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  • J. M. Hock,

    1. Lilly Research Laboratories, Indianapolis, Indiana, U.S.A.
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  • Marc K. Drezner M.D.

    Editor-in-ChiefSearch for more papers by this author
    • The electronic/computer revolution continues to surprise all of us as use of techniques changes our business and personal lives. Consequently, we constantly strive to use the advances and not surrender to ignorance. In this issue of the Journal, we have chosen to introduce a novel addition to our publication. As you will see, in the article by Stewart et al. entitled 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 we have succumbed to space limitations and eliminated potentially valuable data (in the eyes of a subset of our readers) but used the advances of today to make this information available on our web site, linked to the published electronic version of the article. In this way, we have kept space open for a greater number of original articles while providing outstanding data communication. Clearly, this is just the beginning of the evolution/revolution in the JBMR format. With our move to self-publication, such changes beckon and we will continue to respond. We hope that you are pleased and look forward to any suggestions that you may have. In any case, keep the challenges coming.


Abstract

Daily administration of parathyroid hormone (PTH) and PTH-related protein (PTHrP) peptides has been shown to increase bone mass and strength in animals and, for PTH, to increase bone mass in humans. Long-term direct comparison of multiple members of the PTH/PTHrP family in vivo has not been reported. We therefore selected three PTH/PTHrP molecules for direct comparison in vivo in an adult rat model of postmenopausal osteoporosis: PTH(1-34), PTHrP(1-36), and the PTH analog, SDZ-PTH 893 {Leu8, Asp10, Lys11, Ala16, Gln18, Thr33, Ala34 human PTH 1–34 [hPTH(1-34)]}. A 6-month study was performed in which adult (6-month-old) vehicle-treated ovariectomized (OVX) and sham OVX rats were compared with OVX rats receiving 40 μg/kg per day of either PTH(1-34), PTHrP(1-36), or PTH-SDZ-893. Bone mass, as assessed by ash weight and densitometry, bone histomorphometry, biomechanical properties at trabecular and cortical sites, and indices of bone formation markedly increased in all three PTH/PTHrP peptide-treated groups as compared with controls. In general, this improvement followed a rank order of SDZ-PTH-893 > PTH > PTHrP. The adverse effect profile also was greatest with SDZ-PTH-893; these rats developed moderate hypercalcemia, marked renal calcium accumulation, and displayed a 13% mortality. These studies show that PTH(1-34), PTHrP(1-36), and PTH-SDZ-893 significantly and progressively increase bone mass and bone strength in this rat model of postmenopausal osteoporosis. The adverse effect profile correlates in general terms with efficacy. All three peptides show promise as skeletal anabolic agents. Further studies in humans will be required to define optimal efficacy-to-adverse effect ratios and relative efficacy for each peptide in human osteoporosis.

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