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

Authors

  • Stanley B. Cohen,

    Corresponding author
    1. Metroplex Clinical Research Center, Dallas, Texas
    • Metroplex Clinical Research Center, 5939 Harry Hines Boulevard, Suite 441, Dallas, TX 75235
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    • 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 companies 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.

  • Robin K. Dore,

    1. Anaheim, California
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    • 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 companies 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.

  • Nancy E. Lane,

    1. University of California, Davis Medical Center, Sacramento, California
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    • 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 companies 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.

  • Peter A. Ory,

    1. University of Washington, Seattle
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    • 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 companies 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.

  • Charles G. Peterfy,

    1. Synarc Inc., San Francisco, California
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    • 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 companies 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.

  • John T. Sharp,

    1. University of Washington, Seattle
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    • 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 companies 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.

  • Désirée van der Heijde,

    1. Leiden University Medical Center, Leiden, The Netherlands
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    • 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 companies 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.

  • Lifen Zhou,

    1. Amgen Inc., Thousand Oaks, California
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    • 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 companies 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.

  • Wayne Tsuji,

    1. Amgen Inc., Thousand Oaks, California
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    • 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 companies 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.

  • Richard Newmark

    1. Amgen Inc., Thousand Oaks, California
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  • ClinicalTrials.gov identifier: NCT00095498.

Abstract

Objective

RANKL is essential for osteoclast development, activation, and survival. Denosumab is a fully human monoclonal IgG2 antibody that binds RANKL, inhibiting its activity. The aim of this multicenter, randomized, double-blind, placebo-controlled, phase II study was to evaluate the effects of denosumab on structural damage in patients with rheumatoid arthritis (RA) receiving methotrexate treatment.

Methods

RA patients received subcutaneous placebo (n = 75), denosumab 60 mg (n = 71), or denosumab 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 suppression 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.

Conclusion

Addition of twice-yearly injections of denosumab to ongoing methotrexate treatment inhibited structural damage in patients with RA for up to 12 months, with no increase in the rates of adverse events as compared with placebo.

Ancillary