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.