Efficacy and safety of denosumab in the treatment of rheumatoid arthritis: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

WANG Mingxia ¹ , FENG Yuchen ² , WANG Hongxia ¹ , YU Yakun ¹ , HAO Jiayao ¹ ,  SHEN Haili ²

1. Second Clinical College of Lanzhou University, Lanzhou 730030, P. R. China;
2. Lanzhou University Second Hospital, Lanzhou 730030, P. R. China;

Corresponding author：

SHEN Haili, Email: 1261082557@qq.com

Keywords：

Rheumatoid arthritis; Denosumab; Efficacy; Safety; Meta-analysis

DOI：

10.7507/1672-2531.202208030

Video：

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Objective To systematically review the efficacy and safety of denosumab in the treatment of rheumatoid arthritis. Methods The PubMed, EMbase, Web of Science, The Cochrane Library, CNKI, WanFang Data, and VIP databases were searched to collect randomized controlled trials (RCTs) of denosumab in the treatment of rheumatoid arthritis. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of the included studies. Meta-analysis was then performed using RevMan 5.4 software. Results A total of 7 RCTs including 2 346 patients were included. The results of meta-analysis showed that administering 60 mg densuzumab every 6 months (Q6M) was superior to placebo in increasing the bone mineral density (BMD) of the lumbar spine, the hip, the femoral neck, and improving the modified total Sharp score. Administering 60 mg denosumab every 3 months (Q3M) and 60 mg Q6M were both superior to the placebo group at improving erosion score; in addition, the 60 mg Q3M group was superior to the 60 mg Q6M group. There was no significant difference between denosumab and the placebo in improving joint space narrowing score, the American College of Rheumatology 20%, 50%, or 70% responses, health assessment questionnaire disability index, or disease activity score. In terms of safety, there was no significant difference between denosumab and the placebo group. Conclusion Densuzumab can delay the progression of rheumatoid arthritis bone erosion, and its safety is acceptable. Due to the limited quantity and quality of the included studies, more high-quality studies are needed to verify the above conclusion.

Citation： WANG Mingxia, FENG Yuchen, WANG Hongxia, YU Yakun, HAO Jiayao, SHEN Haili. Efficacy and safety of denosumab in the treatment of rheumatoid arthritis: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2023, 23(1): 27-33. doi: 10.7507/1672-2531.202208030 Copy

1.	Coutant F, Miossec P. Evolving concepts of the pathogenesis of rheumatoid arthritis with focus on the early and late stages. Curr Opin Rheumatol, 2020, 32(1): 57-63.
2.	Schett G. Autoimmunity as a trigger for structural bone damage in rheumatoid arthritis. Mod Rheumatol, 2017, 27(2): 193-197.
3.	Meednu N, Zhang H, Owen T, et al. Production of RANKL by memory B cells: a link between B cells and bone erosion in rheumatoid arthritis. Arthritis Rheumatol, 2016, 68(4): 805-816.
4.	Tanaka Y, Ohira T. Mechanisms and therapeutic targets for bone damage in rheumatoid arthritis, in particular the RANK-RANKL system. Curr Opin Pharmacol, 2018, 40: 110-119.
5.	Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med, 2009, 361(8): 756-765.
6.	Hasegawa T, Kaneko Y, Izumi K, et al. Efficacy of denosumab combined with bDMARDs on radiographic progression in rheumatoid arthritis. Joint Bone Spine, 2017, 84(3): 379-380.
7.	Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum, 1988, 31(3): 315-324.
8.	Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum, 2010, 62(9): 2569-2581.
9.	van der Heijde D, Simon L, Smolen J, et al. How to report radiographic data in randomized clinical trials in rheumatoid arthritis: guidelines from a roundtable discussion. Arthritis Rheum, 2002, 47(2): 215-218.
10.	张正付, 李萌, 燕娟, 等. 药物临床试验中不良事件的案例收集与评判. 中国临床药理学杂志, 2020, 36(23): 3957-3961.
11.	Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions. Available at: http://handbook.cochrane.org.
12.	So H, Cheng IT, Lau SL, et al. Effects of RANKL inhibition on promoting healing of bone erosion in rheumatoid arthritis using HR-pQCT: a 2-year, randomised, double-blind, placebo-controlled trial. Ann Rheum Dis, 2021, 80(8): 981-988.
13.	Mochizuki T, Yano K, Ikari K, et al. Effects of romosozumab or denosumab treatment on the bone mineral density and disease activity for 6 months in patients with rheumatoid arthritis with severe osteoporosis: an open-label, randomized, pilot study. Osteoporos Sarcopenia, 2021, 7(3): 110-114.
14.	Tanaka Y, Soen S, Ishiguro N, et al. Identifying the preferable rheumatoid arthritis subgroups for intervention with the anti-RANKL antibody denosumab to reduce progression of joint destruction. RMD Open, 2020, 6(2): e001249.
15.	Takeuchi T, Tanaka Y, Soen S, et al. Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial. Ann Rheum Dis, 2019, 78(7): 899-907.
16.	Takeuchi T, Tanaka Y, Ishiguro N, et al. Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)-a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial. Ann Rheum Dis, 2016, 75(6): 983-990.
17.	Deodhar A, Dore RK, Mandel D, et al. Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients. Arthritis Care Res (Hoboken), 2010, 62(4): 569-574.
18.	Cohen SB, Dore RK, Lane NE, et al. 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. Arthritis Rheum, 2008, 58(5): 1299-1309.
19.	Tanaka S, Tanaka Y. RANKL as a therapeutic target of rheumatoid arthritis. J Bone Miner Metab, 2021, 39(1): 106-112.
20.	Tateiwa D, Yoshikawa H, Kaito T. Cartilage and bone destruction in arthritis: pathogenesis and treatment strategy: a literature review. Cells, 2019, 8(8): 818.
21.	Tsukasaki M, Takayanagi H. Osteoimmunology: evolving concepts in bone-immune interactions in health and disease. Nat Rev Immunol, 2019, 19(10): 626-642.
22.	Danks L, Komatsu N, Guerrini MM, et al. RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation. Ann Rheum Dis, 2016, 75(6): 1187-1195.
23.	Deschner J, Wypasek E, Ferretti M, et al. Regulation of RANKL by biomechanical loading in fibrochondrocytes of meniscus. J Biomech, 2006, 39(10): 1796-1803.
24.	Pettit AR, Ji H, von Stechow D, et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol, 2001, 159(5): 1689-1699.
25.	Matzelle MM, Gallant MA, Condon KW, et al. Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. Arthritis Rheum, 2012, 64(5): 1540-1550.
26.	Quiñonez-Flores CM, González-Chávez SA, Pacheco-Tena C. Hypoxia and its implications in rheumatoid arthritis. J Biomed Sci, 2016, 23(1): 62.
27.	Avouac J, Koumakis E, Toth E, et al. Increased risk of osteoporosis and fracture in women with systemic sclerosis: a comparative study with rheumatoid arthritis. Arthritis Care Res (Hoboken), 2012, 64(12): 1871-1878.
28.	Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis, 2020, 79(6): 685-699.
29.	Deeks ED. Denosumab: a review in postmenopausal osteoporosis. Drugs Aging, 2018, 35(2): 163-173.
30.	Clézardin P, Coleman R, Puppo M, et al. Bone metastasis: mechanisms, therapies, and biomarkers. Physiol Rev, 2021, 101(3): 797-855.

1. Coutant F, Miossec P. Evolving concepts of the pathogenesis of rheumatoid arthritis with focus on the early and late stages. Curr Opin Rheumatol, 2020, 32(1): 57-63.
2. Schett G. Autoimmunity as a trigger for structural bone damage in rheumatoid arthritis. Mod Rheumatol, 2017, 27(2): 193-197.
3. Meednu N, Zhang H, Owen T, et al. Production of RANKL by memory B cells: a link between B cells and bone erosion in rheumatoid arthritis. Arthritis Rheumatol, 2016, 68(4): 805-816.
4. Tanaka Y, Ohira T. Mechanisms and therapeutic targets for bone damage in rheumatoid arthritis, in particular the RANK-RANKL system. Curr Opin Pharmacol, 2018, 40: 110-119.
5. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med, 2009, 361(8): 756-765.
6. Hasegawa T, Kaneko Y, Izumi K, et al. Efficacy of denosumab combined with bDMARDs on radiographic progression in rheumatoid arthritis. Joint Bone Spine, 2017, 84(3): 379-380.
7. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum, 1988, 31(3): 315-324.
8. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum, 2010, 62(9): 2569-2581.
9. van der Heijde D, Simon L, Smolen J, et al. How to report radiographic data in randomized clinical trials in rheumatoid arthritis: guidelines from a roundtable discussion. Arthritis Rheum, 2002, 47(2): 215-218.
10. 张正付, 李萌, 燕娟, 等. 药物临床试验中不良事件的案例收集与评判. 中国临床药理学杂志, 2020, 36(23): 3957-3961.
11. Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions. Available at: http://handbook.cochrane.org.
12. So H, Cheng IT, Lau SL, et al. Effects of RANKL inhibition on promoting healing of bone erosion in rheumatoid arthritis using HR-pQCT: a 2-year, randomised, double-blind, placebo-controlled trial. Ann Rheum Dis, 2021, 80(8): 981-988.
13. Mochizuki T, Yano K, Ikari K, et al. Effects of romosozumab or denosumab treatment on the bone mineral density and disease activity for 6 months in patients with rheumatoid arthritis with severe osteoporosis: an open-label, randomized, pilot study. Osteoporos Sarcopenia, 2021, 7(3): 110-114.
14. Tanaka Y, Soen S, Ishiguro N, et al. Identifying the preferable rheumatoid arthritis subgroups for intervention with the anti-RANKL antibody denosumab to reduce progression of joint destruction. RMD Open, 2020, 6(2): e001249.
15. Takeuchi T, Tanaka Y, Soen S, et al. Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial. Ann Rheum Dis, 2019, 78(7): 899-907.
16. Takeuchi T, Tanaka Y, Ishiguro N, et al. Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)-a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial. Ann Rheum Dis, 2016, 75(6): 983-990.
17. Deodhar A, Dore RK, Mandel D, et al. Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients. Arthritis Care Res (Hoboken), 2010, 62(4): 569-574.
18. Cohen SB, Dore RK, Lane NE, et al. 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. Arthritis Rheum, 2008, 58(5): 1299-1309.
19. Tanaka S, Tanaka Y. RANKL as a therapeutic target of rheumatoid arthritis. J Bone Miner Metab, 2021, 39(1): 106-112.
20. Tateiwa D, Yoshikawa H, Kaito T. Cartilage and bone destruction in arthritis: pathogenesis and treatment strategy: a literature review. Cells, 2019, 8(8): 818.
21. Tsukasaki M, Takayanagi H. Osteoimmunology: evolving concepts in bone-immune interactions in health and disease. Nat Rev Immunol, 2019, 19(10): 626-642.
22. Danks L, Komatsu N, Guerrini MM, et al. RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation. Ann Rheum Dis, 2016, 75(6): 1187-1195.
23. Deschner J, Wypasek E, Ferretti M, et al. Regulation of RANKL by biomechanical loading in fibrochondrocytes of meniscus. J Biomech, 2006, 39(10): 1796-1803.
24. Pettit AR, Ji H, von Stechow D, et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol, 2001, 159(5): 1689-1699.
25. Matzelle MM, Gallant MA, Condon KW, et al. Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. Arthritis Rheum, 2012, 64(5): 1540-1550.
26. Quiñonez-Flores CM, González-Chávez SA, Pacheco-Tena C. Hypoxia and its implications in rheumatoid arthritis. J Biomed Sci, 2016, 23(1): 62.
27. Avouac J, Koumakis E, Toth E, et al. Increased risk of osteoporosis and fracture in women with systemic sclerosis: a comparative study with rheumatoid arthritis. Arthritis Care Res (Hoboken), 2012, 64(12): 1871-1878.
28. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis, 2020, 79(6): 685-699.
29. Deeks ED. Denosumab: a review in postmenopausal osteoporosis. Drugs Aging, 2018, 35(2): 163-173.
30. Clézardin P, Coleman R, Puppo M, et al. Bone metastasis: mechanisms, therapies, and biomarkers. Physiol Rev, 2021, 101(3): 797-855.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of denosumab in the treatment of rheumatoid arthritis: a meta-analysis

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