Background Rheumatoid arthritis (RA) is commonly treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs); however, joint destruction is not always fully suppressed. We evaluated the efficacy of denosumab that was added to csDMARD therapy for RA patients. Methods This randomised, double-blind, parallel-group, placebo-controlled phase 3 study was conducted at 104 hospitals in Japan. We enrolled RA patients aged ≥20 years receiving csDMARDs, with erosive disease and elevated acute phase reactants. Participants were randomly assigned (1:1:1) to subcutaneously receive denosumab 60 mg every 3 months (Q3M), a matching placebo every 3 months, and denosumab 60 mg or the placebo every other 3 months (Q6M). The primary endpoint was the change in the modified total Sharp score (mTSS) from baseline to 12 months and analysed using the van Elteren stratified rank test adjusted for randomised strata. The effect of denosumab on bone mineral density (BMD) was also evaluated. Findings In total, 654 patients received treatments (218 had placebo; 217 had denosumab Q6M; and 219 had denosumab Q3M). Compared with the placebo group, both denosumab groups showed significantly less progression of joint destruction. The mean changes in the mTSS were 1·49±3·76 in the placebo group, 0·99±3·77 in the Q6M group (p=0·0235), and 0·72±2·32 in the Q3M group (p=0·0055). The percentage changes in lumbar spine (L1-L4) BMD from baseline in the placebo, Q6M, and Q3M groups were -1·03%, 3·99% (p<0·0001) and 4·88% (p<0·0001), respectively. No major differences were observed between the safety profiles of denosumab and placebo. Interpretation Denosumab inhibits the progression of joint destruction, increases BMD, and is generally well tolerated in RA patients taking csDMARD. This offers a potentially novel therapeutic option for preventing the onset and progress of structural damage and increasing BMD in RA patients treated with csDMARD. Trial Registration Number: This study is registered with ClinicalTrials.gov, number NCT01973569. Funding Daiichi Sankyo Co., Ltd. Declaration of Interest: TT has received research grants from Astellas, Chugai, Daiichi Sankyo, Takeda, AbbVie, Asahi Kasei, Mitsubishi Tanabe, Pfizer, Eisai, AYUMI, Nippon Kayaku, and Novartis, has received consulting fees from Astra Zeneca, Eli Lilly, Novartis, Mitsubishi Tanabe, AbbVie, Nippon Kayaku, Janssen, Astellas, Taiho, Chugai, Taisho Toyama, GlaxoSmithKline, and UCB, and has served on speakers’ fees for AbbVie, Bristol-Myers Squibb, Chugai, Mitsubishi Tanabe, Pfizer, Astellas, Daiichi Sankyo, Eisai, Sanofi, Teijin, Takeda, and Novartis. YT has received research grants from Mitsubishi Tanabe, Takeda, Bristol-Myers Squibb, Chugai, Astellas, AbbVie, MSD, Daiichi Sankyo, Pfizer, Kyowa Hakko Kirin, Eisai and Ono, and has served on speakers’ bureaus for Daiichi Sankyo, Astellas, Pfizer, Mitsubishi Tanabe, Bristol-Myers Squibb, Chugai, YL Biologics, Eli Lilly, Sanofi, Janssen, and UCB. SS has received grant/research support from Chugai and Daiichi Sankyo, and has served on speakers’ bureaus for Asahi-Kasei Pharma, Astellas, MSD, Daiichi Sankyo, Takeda, Chugai, Teijin Pharma, Pfizer, Eli-Lilly Japan, and Mitsubishi-Tanabe. HY has received research grants from MSD, Astellas, AbbVie, BMS, Kaken, UCB, Ono, AYUMI, Eisai, Daiichi Sankyo, Takeda, Mitsubishi Tanabe, Chugai, Teijin, Torii, Nippon Shinyaku and Pfizer, and has received consulting fees from Pfizer, YL Biologics, Takeda, Teijin, BMS, Nippon Kayaku, Chugai, Mitsubishi Tanabe, Daiichi Sankyo, and Astellas. TY has received Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT #17H04377), and has received consulting fees from Daiichi Sankyo. ST has acted as a consultant for Amgen, Astellas, MSD, AbbVie, Daiichi Sankyo, Eli-Lilly, Ono, Asahi Kasei Pharma, and Teijin Pharma. TN is an employee of Daiichi Sankyo. NO is a shareholder and employee of Daiichi Sankyo. HKG. has received consulting fees from Daiichi Sanyo, Pfizer, Amgen, Bioclinica, Eli Lilly, Janssen, Servier, Novartis, l Takeda, Merck, Biomarin, Clementia, Agnovos, Regeneron and Medimmune. DvdH. has received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda and UCB, and is the director of Imaging Rheumatology BV. Ethical Approval: The study was approved by the institutional review boards of all participating sites and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants.