Infrequent delivery of a long-acting PTH-Fc fusion protein has potent anabolic effects on cortical and cancellous bone.

Abstract

UNLABELLED:

Skeletal anabolism with PTH is achieved through daily injections that result in brief exposure to the peptide. We hypothesized that similar anabolic effects could be achieved with less frequent but more sustained exposures to PTH. A PTH-Fc fusion protein with a longer half-life than PTH(1-34) increased cortical and cancellous BMD and bone strength with once- or twice-weekly injections.

INTRODUCTION:

The anabolic effects of PTH are currently achieved with, and thought to require, daily injections that result in brief exposure to the peptide. We hypothesized that less frequent but more sustained exposures to PTH could also be anabolic for bone, provided that serum levels of PTH were not constant.

MATERIALS AND METHODS:

PTH(1-34) was fused to the Fc fragment of human IgG1 to increase the half-life of PTH. Skeletal anabolism was examined in mice and rats treated once or twice per week with this PTH-Fc fusion protein.

RESULTS:

PTH-Fc and PTH(1-34) had similar effects on PTH/PTHrP receptor activation, internalization, and signaling in vitro. However, PTH-Fc had a 33-fold longer mean residence time in the circulation of rats compared with that of PTH(1-34). Subcutaneous injection of PTH-Fc once or twice per week resulted in significant increases in bone volume, density, and strength in osteopenic ovariectomized mice and rats. These anabolic effects occurred in association with hypercalcemia and were significantly greater than those achievable with high concentrations of daily PTH(1-34). PTH-Fc also significantly improved cortical bone volume and density under conditions where daily PTH(1-34) did not. Antiresorptive co-therapy with estrogen further enhanced the ability of PTH-Fc to increase bone mass and strength in ovariectomized rats.

CONCLUSIONS:

These results challenge the notion that brief daily exposure to PTH is essential for its anabolic effects on cortical and cancellous bone. PTH-derived molecules with a sustained circulating half-life may represent a powerful and previously undefined anabolic regimen for cortical and cancellous bone.

• Authors: Paul J Kostenuik, Serge Ferrari, Dominique Pierroz, Mary Bouxsein, Sean Morony, Kelly S Warmington, Steven Adamu, Zhaopo Geng, Mario Grisanti, Victoria Shalhoub, Steve Martin, Gloria Biddlecome, Grant Shimamoto, Tom Boone, Victor Shen, David Lacey
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 22 Issue 10 Pg. 1534-47 (Oct 2007) ISSN: 0884-0431 [Print] United States
• PMID: 17576164 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anabolic Agents
• Arrestins
• Estrogens
• Immunoglobulin Fc Fragments
• Parathyroid Hormone
• Receptor, Parathyroid Hormone, Type 1
• Recombinant Proteins
• beta-Arrestins

Topics

• Aging (physiology)
• Anabolic Agents (administration & dosage, pharmacokinetics, pharmacology)
• Animals
• Arrestins (metabolism)
• Bone and Bones (drug effects, metabolism)
• Cell Line
• Cricetinae
• Dose-Response Relationship, Drug
• Estrogens (pharmacology)
• Half-Life
• Humans
• Immunoglobulin Fc Fragments (administration & dosage)
• Male
• Mice
• Ovariectomy
• Parathyroid Hormone (administration & dosage, pharmacokinetics, pharmacology)
• Protein Transport
• Rats
• Receptor, Parathyroid Hormone, Type 1 (metabolism)
• Recombinant Proteins (administration & dosage, pharmacokinetics, pharmacology)
• Time Factors
• beta-Arrestins