ARTHRITIS & RHEUMATISM Vol. 58, No. 5, May 2008, pp 1299–1309 DOI 10.1002/art.23417 © 2008, American College of Rheumatology Denosumab Treatment Effects on Structural Damage, Bone Mineral Density, and Bone Turnover in Rheumatoid Arthritis A Twelve-Month, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase II Clinical Trial Stanley B. Cohen, 1 Robin K. Dore, 2 Nancy E. Lane, 3 Peter A. Ory, 4 Charles G. Peterfy, 5 John T. Sharp, 4 De ´sire ´e van der Heijde, 6 Lifen Zhou, 7 Wayne Tsuji, 7 and Richard Newmark, 7 on behalf of the Denosumab Rheumatoid Arthritis Study Group Objective. RANKL is essential for osteoclast de- velopment, activation, and survival. Denosumab is a fully human monoclonal IgG2 antibody that binds RANKL, inhibiting its activity. The aim of this multi- center, randomized, double-blind, placebo-controlled, phase II study was to evaluate the effects of denosumab on structural damage in patients with rheumatoid ar- thritis (RA) receiving methotrexate treatment. Methods. RA patients received subcutaneous pla- cebo (n  75), denosumab 60 mg (n  71), or deno- sumab 180 mg (n  72) injections every 6 months for 12 months. The primary end point was the change from baseline in the magnetic resonance imaging (MRI) erosion score at 6 months. Results. At 6 months, the increase in the MRI erosion score from baseline was lower in the 60-mg denosumab group (mean change 0.13; P  0.118) and significantly lower in the 180-mg denosumab group (mean change 0.06; P  0.007) than in the placebo group (mean change 1.75). A significant difference in the modified Sharp erosion score was observed as early as 6 months in the 180-mg denosumab group (P  0.019) as compared with placebo, and at 12 months, both the 60-mg (P  0.012) and the 180-mg (P  0.007) denosumab groups were significantly different from the placebo group. Denosumab caused sustained suppres- sion of markers of bone turnover. There was no evidence of an effect of denosumab on joint space narrowing or on measures of RA disease activity. Rates of adverse events were comparable between the denosumab and placebo groups. ClinicalTrials.gov identifier: NCT00095498. Supported by Amgen Inc. Dr. Lane’s work was supported by a clinical research grant from Amgen. 1 Stanley B. Cohen, MD: Metroplex Clinical Research Center, Dallas, Texas; 2 Robin K. Dore, MD, Anaheim, California; 3 Nancy E. Lane, MD: University of California, Davis Medical Center, Sacramento, California; 4 Peter A. Ory, MD, John T. Sharp, MD: University of Washington, Seattle; 5 Charles G. Peterfy, MD, PhD: Synarc Inc., San Francisco, California; 6 De ´sire ´e van der Heijde, MD, PhD: Leiden Uni- versity Medical Center, Leiden, The Netherlands; 7 Lifen Zhou, MS, Wayne Tsuji, MD, Richard Newmark, PhD: Amgen Inc., Thousand Oaks, California. Dr. Cohen has received consulting fees and/or research grants from Merck, Sanofi-Aventis, Centocor, Scios, Bristol-Myers Squibb, and Wyeth-Ayerst (less than $10,000 each), and from Amgen, Genentech, Biogen Idec, Procter & Gamble, and Pfizer (more than $10,000 each). Dr. Dore has received consulting fees (less than $10,000 each) from Merck, Eli Lilly, and Roche, honoraria for service on the Speakers’ Bureaus for Merck, Procter & Gamble, Pfizer, and Sanofi-Aventis (less than $10,000 each), and for Eli Lilly, GlaxoSmithKline, and Roche (more than $10,000 each), and has been on the Advisory Boards for DMAb, Sclerostin, and Enbrel; she has received research grants (less than $10,000 each) from Amgen, Merck, Eli Lilly, and Roche. Dr. Lane has received speaking fees (less than $10,000 each) from Merck, Procter & Gamble, and Eli Lilly and has received research grants (more than $10,000 each) from Procter & Gamble. Dr. Ory has received consulting fees (more than $10,000 each) from Amgen, Abbott, and Targeted Genetics. Dr. Peterfy owns stock or stock options in Synarc, a company that provides centralized image and biochemical analysis services and subject recruitment for clinical trials to pharmaceutical, biotechnology, and medical devices companies, including Amgen, Bayer, Elan, Merck, Novartis, Pfizer, Roche, Servier, and others. Dr. Sharp has received consulting fees from Amgen and Abbott (more than $10,000 each), as well as from several other pharmaceutical compa- nies and pharmaceutical consulting firms (less than $10,000 each) not related to this study. Dr. van der Heijde has received consulting fees (less than $10,000) from Amgen, Abbott, Bristol-Myers Squibb, Centocor, Chugai, Merck, Roche, Schering-Plough, UCB, and Wyeth-Ayerst. Ms Zhou and Drs. Tsuji and Newmark own stock or stock options in Amgen. Address correspondence and reprint requests to Stanley B. Cohen, MD, Metroplex Clinical Research Center, 5939 Harry Hines Boulevard, Suite 441, Dallas, TX 75235. E-mail: Scohen@ arthdocs.com. Submitted for publication September 6, 2007; accepted in revised form January 11, 2008. 1299