Sustained antiresorptive effects after a single treatment with human recombinant osteoprotegerin (OPG): a pharmacodynamic and pharmacokinetic analysis in rats.
Osteoprotegerin (OPG) is a naturally occurring negative regulator of osteoclast differentiation, activation, and survival. We created a recombinant form of human OPG (rhOPG), with a sustained serum half-life, to achieve prolonged antiresorptive activity. This study describes the rapid and sustained antiresorptive effects that are achieved with a single treatment with rhOPG. Male Sprague-Dawley rats (10 weeks old) were given a single bolus intravenous injection of vehicle (PBS) or rhOPG (5 mg/kg). PBS- and rhOPG-treated rats (n = 6/group) were killed at 0, 0.5, 1, 2, 5, 10, 20, and 30 days post-treatment. rhOPG-treated rats were compared with their age-matched controls. The main pharmacologic effect of rhOPG was a rapid (24 h) reduction in osteoclast surface in the tibia, which reached a nadir on days 5 and 10 (95% reduction vs. vehicle controls). Osteoclast surface remained significantly reduced 30 days after the single treatment with rhOPG. Tibial cancellous bone volume was significantly increased within 5 days of rhOPG treatment (23%) and reached a peak increase of 58% on day 30. Femoral bone mineral density was significantly increased in rhOPG-treated rats on days 10 and 20. Pharmacokinetic analysis revealed that serum concentrations of rhOPG remained at measurable levels throughout the 30-day study. These data show that a single intravenous injection of rhOPG in young growing rats causes significant gains in bone volume and density, which are associated with rapid and sustained suppression of osteoclastic bone resorption.
Capparelli
Charles
C
Metabolic Disorders Research, Amgen, Inc., Thousand Oaks, California 91320, USA.
Morony
Sean
S
Warmington
Kelly
K
Adamu
Stephen
S
Lacey
David
D
Dunstan
Colin R
CR
Stouch
Brian
B
Martin
Steven
S
Kostenuik
Paul J
PJ
D000818:Animals; D001862:Bone Resorption; D005260:Female; D006023:Glycoproteins / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D053244:Osteoprotegerin; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C506030:TNFRSF11B protein, human; C506032:Tnfrsf11b protein, rat