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Sustained Antiresorptive Effects After a Single Treatment With Human Recombinant Osteoprotegerin (OPG): A Pharmacodynamic and Pharmacokinetic Analysis in Rats
Author(s) -
Capparelli Charles,
Morony Sean,
Warmington Kelly,
Adamu Stephen,
Lacey David,
Dunstan Colin R,
Stouch Brian,
Martin Steven,
Kostenuik Paul J
Publication year - 2003
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2003.18.5.852
Subject(s) - osteoprotegerin , osteoclast , medicine , endocrinology , pharmacokinetics , bone mineral , resorption , bone resorption , cancellous bone , ovariectomized rat , osteoporosis , bone remodeling , pharmacodynamics , receptor , activator (genetics) , surgery , hormone
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.