Osteoarthritis is a major contributor to pain and disability worldwide. Inflammation plays an important role in the development of osteoarthritis, and anti-inflammatory drugs may slow disease progression. This exploratory analysis of a randomized trial examined whether colchicine reduces incident total knee and hip replacements.
Abstract
Background:
Osteoarthritis is a major contributor to pain and disability worldwide. Given that inflammation plays an important role in the development of osteoarthritis, anti-inflammatory drugs may slow disease progression.
Objective:
To examine whether colchicine, 0.5 mg daily, reduces incident total knee replacements (TKRs) and total hip replacements (THRs).
Design:
Exploratory analysis of the LoDoCo2 (Low-Dose Colchicine 2) randomized, controlled, double-blind trial. (Australian New Zealand Clinical Trials Registry: ACTRN12614000093684)
Setting:
43 centers in Australia and the Netherlands.
Patients:
5522 patients with chronic coronary artery disease.
Intervention:
Colchicine, 0.5 mg, or placebo once daily.
Measurements:
The primary outcome was time to first TKR or THR since randomization. All analyses were performed on an intention-to-treat basis.
Results:
A total of 2762 patients received colchicine and 2760 received placebo during a median follow-up of 28.6 months. During the trial, TKR or THR was performed in 68 patients (2.5%) in the colchicine group and 97 (3.5%) in the placebo group (incidence rate, 0.90 vs. 1.30 per 100 person-years; incidence rate difference, −0.40 [95% CI, −0.74 to −0.06] per 100 person-years; hazard ratio, 0.69 [CI, 0.51 to 0.95]). In sensitivity analyses, similar results were obtained when patients with gout at baseline were excluded and when joint replacements that occurred in the first 3 and 6 months of follow-up were omitted.
Limitation:
LoDoCo2 was not designed to investigate the effect of colchicine in osteoarthritis of the knee or hip and did not collect information specifically on osteoarthritis.
Conclusion:
In this exploratory analysis of the LoDoCo2 trial, use of colchicine, 0.5 mg daily, was associated with a lower incidence of TKR and THR. Further investigation of colchicine therapy to slow disease progression in osteoarthritis is warranted.
Primary Funding Source:
None.
References
- 1.
Cross M ,Smith E ,Hoy D ,et al . The global burden of hip and knee osteoarthritis: estimates from the Global Burden of Disease 2010 Study. Ann Rheum Dis. 2014;73:1323-1330. [PMID: 24553908] doi:10.1136/annrheumdis-2013-204763 CrossrefMedlineGoogle Scholar - 2. Osteoarthritis Research Society International. Osteoarthritis: A Serious Disease. 1 December 2016. Accessed at https://oarsi.org/education/oarsi-resources/oarsi-white-paper-oa-serious-disease on 18 August 2022. Google Scholar
- 3.
Lohmander LS ,Roos EM . Disease modification in OA - will we ever get there? Nat Rev Rheumatol. 2019;15:133-135. [PMID: 30733580] doi:10.1038/s41584-019-0174-1 CrossrefMedlineGoogle Scholar - 4.
Kapoor M ,Martel-Pelletier J ,Lajeunesse D ,et al . Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7:33-42. [PMID: 21119608] doi:10.1038/nrrheum.2010.196 CrossrefMedlineGoogle Scholar - 5.
Schieker M ,Conaghan PG ,Mindeholm L ,et al . Effects of interleukin-1β inhibition on incident hip and knee replacement: exploratory analyses from a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2020;173:509-515. [PMID: 32744862] doi:10.7326/M20-0527 LinkGoogle Scholar - 6.
Leung YY, Yao Hui LL ,Kraus VB . Colchicine—update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015;45:341-350. [PMID: 26228647] doi:10.1016/j.semarthrit.2015.06.013 CrossrefMedlineGoogle Scholar - 7.
Conaghan PG ,Cook AD ,Hamilton JA ,et al . Therapeutic options for targeting inflammatory osteoarthritis pain. Nat Rev Rheumatol. 2019;15:355-363. [PMID: 31068673] doi:10.1038/s41584-019-0221-y CrossrefMedlineGoogle Scholar - 8.
Liu W ,Wang H ,Su C ,et al . The evaluation of the efficacy and safety of oral colchicine in the treatment of knee osteoarthritis: a meta-analysis of randomized controlled trails. Biomed Res Int. 2022;2022:2381828. [PMID: 35132374] doi:10.1155/2022/2381828 CrossrefMedlineGoogle Scholar - 9.
Nidorf SM ,Fiolet ATL ,Mosterd A ,et al ; LoDoCo2 Trial Investigators. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383:1838-1847. [PMID: 32865380] doi:10.1056/NEJMoa2021372 CrossrefMedlineGoogle Scholar - 10.
Nidorf SM ,Fiolet ATL ,Eikelboom JW ,et al ; LoDoCo2 Investigators. The effect of low-dose colchicine in patients with stable coronary artery disease: the LoDoCo2 trial rationale, design, and baseline characteristics. Am Heart J. 2019;218:46-56. [PMID: 31706144] doi:10.1016/j.ahj.2019.09.011 CrossrefMedlineGoogle Scholar - 11. Rothman K, Greenland S, Lash T. Modern Epidemiology. 3rd ed. Lippincott Williams & Wilkins; 2008. Google Scholar
- 12.
Bruyere O ,Pavelka K ,Rovati LC ,et al . Total joint replacement after glucosamine sulphate treatment in knee osteoarthritis: results of a mean 8-year observation of patients from two previous 3-year, randomised, placebo-controlled trials. Osteoarthritis Cartilage. 2008;16:254-260. [PMID: 17681803] CrossrefMedlineGoogle Scholar - 13.
Dougados M ,Nguyen M ,Berdah L ,et al ;ECHODIAH Investigators Study Group . Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip. Arthritis Rheum. 2001;44:2539-2547. [PMID: 11710710] CrossrefMedlineGoogle Scholar - 14.
Spencer CM ,Wilde MI . Diacerein. Drugs. 1997;53:98-106. [PMID: 9010651] CrossrefMedlineGoogle Scholar - 15.
Yu H ,Huang T ,Lu WW ,et al . Osteoarthritis pain. Int J Mol Sci. 2022;23. [PMID: 35563035] doi:10.3390/ijms23094642 CrossrefMedlineGoogle Scholar - 16.
Singh A ,Molina-Garcia P ,Hussain S ,et al . Efficacy and safety of colchicine for the treatment of osteoarthritis: a systematic review and meta-analysis of intervention trials. Clin Rheumatol. 2023;42:889-902. [PMID: 36224305] doi:10.1007/s10067-022-06402-w CrossrefMedlineGoogle Scholar - 17.
Das SK ,Ramakrishnan S ,Mishra K ,et al . A randomized controlled trial to evaluate the slow-acting symptom-modifying effects of colchicine in osteoarthritis of the knee: a preliminary report. Arthritis Rheum. 2002;47:280-284. [PMID: 12115158] CrossrefMedlineGoogle Scholar - 18.
Das SK ,Mishra K ,Ramakrishnan S ,et al . A randomized controlled trial to evaluate the slow-acting symptom modifying effects of a regimen containing colchicine in a subset of patients with osteoarthritis of the knee. Osteoarthritis Cartilage. 2002;10:247-252. [PMID: 11950246] CrossrefMedlineGoogle Scholar - 19.
Aran S ,Malekzadeh S ,Seifirad S . A double-blind randomized controlled trial appraising the symptom-modifying effects of colchicine on osteoarthritis of the knee. Clin Exp Rheumatol. 2011;29:513-518. [PMID: 21640042] MedlineGoogle Scholar - 20.
Erden M ,Ediz L ,Hiz Ö ,et al . Effect of colchicine on total antioxidant capacity, antioxidant enzymes and oxidative stress markers in patients with knee osteoarthritis. Int J Clin Med. 2012;3:377-382. doi:10.4236/ijcm.2012.35071 CrossrefGoogle Scholar - 21.
Srivastava R ,Das SK ,Goel G ,et al . Does long term colchicine prevent degradation of collagen fiber network in osteoarthritis? Int J Rheum Dis. 2018;21:114-117. [PMID: 28261974] doi:10.1111/1756-185X.13022 CrossrefMedlineGoogle Scholar - 22.
Leung YY ,Haaland B ,Huebner JL ,et al . Colchicine lack of effectiveness in symptom and inflammation modification in knee osteoarthritis (COLKOA): a randomized controlled trial. Osteoarthritis Cartilage. 2018;26:631-640. [PMID: 29426008] doi:10.1016/j.joca.2018.01.026 CrossrefMedlineGoogle Scholar - 23.
Davis CR ,Ruediger CD ,Dyer KA ,et al . Colchicine is not effective for reducing osteoarthritic hand pain compared to placebo: a randomised, placebo-controlled trial (COLAH). Osteoarthritis Cartilage. 2021;29:208-214. [PMID: 33232804] doi:10.1016/j.joca.2020.11.002 CrossrefMedlineGoogle Scholar - 24. U.S. Food and Drug Administration. Osteoarthritis: Structural Endpoints for the Development of Drugs, Devices, and Biological Products for Treatment. Guidance for Industry. August 2018. Google Scholar
- 25. OECD iLibrary. Health at a Glance 2017: OECD Indicators. 10 November 2017. Accessed at www.oecd-ilibrary.org/social-issues-migration-health/health-at-a-glance-2017_health_glance-2017-en on 18 April 2023. Google Scholar
- 26.
Altman RD ,Abadie E ,Avouac B ,et al ; Group for Respect of Excellence and Ethics in Science (GREES). Total joint replacement of hip or knee as an outcome measure for structure modifying trials in osteoarthritis. Osteoarthritis Cartilage. 2005;13:13-19. [PMID: 15639632] CrossrefMedlineGoogle Scholar - 27.
Maillefert JF ,Hawker GA ,Gossec L ,et al ;OMERACT 7 Special Interest Group . Concomitant therapy: an outcome variable for musculoskeletal disorders? Part 2: total joint replacement in osteoarthritis trials. J Rheumatol. 2005;32:2449-2451. [PMID: 16331784] MedlineGoogle Scholar - 28.
Hawker GA . Who, when, and why total joint replacement surgery? The patient's perspective. Curr Opin Rheumatol. 2006;18:526-530. [PMID: 16896295] CrossrefMedlineGoogle Scholar - 29.
Reginster JY ,Reiter-Niesert S ,Bruyère O ,et al . Recommendations for an update of the 2010 European regulatory guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis and reflections about related clinically relevant outcomes: expert consensus statement. Osteoarthritis Cartilage. 2015;23:2086-2093. [PMID: 26187570] doi:10.1016/j.joca.2015.07.001 CrossrefMedlineGoogle Scholar - 30. LROI. Online LROI-report 2016. Accessed at www.lroi-report.nl/previous-reports on 21 April 2023. Google Scholar
- 31. Australian Orthopaedic Association National Joint Replacement Registry. 2016 Annual Report. Hip, Knee & Shoulder Arthroplasty: September 1999 to December 2015. Accessed at https://aoanjrr.sahmri.com/annual-reports-2016 on 21 April 2023. Google Scholar
Author, Article, and Disclosure Information
Michelle W.J. Heijman,
Department of Research, Sint Maartenskliniek, and Department of Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands (M.W.J.H., C.H.M.E.)
Department of Cardiology, University Medical Center Utrecht, and Dutch Network for Cardiovascular Research (WCN), Utrecht, the Netherlands (A.T.L.F.)
Dutch Network for Cardiovascular Research (WCN), Utrecht, the Netherlands, and Department of Cardiology, Meander Medical Center, Amersfoort, the Netherlands (A.M.)
Department of Cardiology, Amsterdam University Medical Center, Amsterdam, the Netherlands, and Cardialysis BV, Rotterdam, the Netherlands (J.G.P.T.)
Department of Pharmacy, Sint Maartenskliniek, and Department of Pharmacy, Radboud University Medical Center, Nijmegen, the Netherlands (B.J.F.B.)
Dutch Network for Cardiovascular Research (WCN), Utrecht, the Netherlands (A.S.)
Department of Medicine, McMaster University, Hamilton, Ontario, Canada (J.W.E.)
Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia, and GenesisCare Western Australia and Heart and Vascular Research Institute of Sir Charles Gairdner Hospital, Perth, Western Australia, Australia (P.L.T.)
GenesisCare Western Australia and Heart and Vascular Research Institute of Sir Charles Gairdner Hospital, Perth, Western Australia, Australia (S.M.N.)
Department of Rheumatology, Radboud University Medical Center, and Department of Rheumatology, Sint Maartenskliniek, Nijmegen, the Netherlands (C.D.P.)
Dutch Network for Cardiovascular Research (WCN), Utrecht, the Netherlands; Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands; and Department of Cardiology, Northwest Clinics, Alkmaar, the Netherlands (J.H.C.).
Financial Support: The authors received no financial support for research, authorship, or publication of this article.
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-0289.
Data Sharing Statement: The authors have indicated they will not be sharing data. Relevant data (for example, partial data sets) will be made accessible for analyses approved by the LoDoCo2 Steering Committee. All requests for data can be made to the LoDoCo2 Steering Committee (e-mail, a.
Corresponding Author: Michelle W.J. Heijman, MSc, Department of Research, Sint Maartenskliniek, Hengstdal 3, 6574 NA, Ubbergen, the Netherlands; e-mail, m.
Author Contributions: Conception and design: M.W.J. Heijman, J.G.P. Tijssen, C.H.M. van den Ende, C.D. Popa, J.H. Cornel.
Analysis and interpretation of the data: M.W.J. Heijman, A.T.L. Fiolet, A. Mosterd, J.G.P. Tijssen, B.J.F. van den Bemt, J.W. Eikelboom, P.L. Thompson, C.H.M. van den Ende, S.M. Nidorf, C.D. Popa, J.H. Cornel.
Drafting of the article: M.W.J. Heijman, J.G.P. Tijssen, B.J.F. van den Bemt, C.H.M. van den Ende, S.M. Nidorf, C.D. Popa, J.H. Cornel.
Critical revision for important intellectual content: M.W.J. Heijman, A.T.L. Fiolet, A. Mosterd, J.G.P. Tijssen, B.J.F. van den Bemt, A. Schut, P.L. Thompson, S.M. Nidorf, C.D. Popa, J.H. Cornel.
Final approval of the article: M.W.J. Heijman, A.T.L. Fiolet, A. Mosterd, J.G.P. Tijssen, B.J.F. van den Bemt, A. Schut, J.W. Eikelboom, P.L. Thompson, C.H.M. van den Ende, S.M. Nidorf, C.D. Popa, J.H. Cornel.
Provision of study materials or patients: A.T.L. Fiolet, J.H. Cornel.
Statistical expertise: A.T.L. Fiolet, J.G.P. Tijssen.
Obtaining of funding: J.H. Cornel.
Administrative, technical, or logistic support: M.W.J. Heijman, A.T.L. Fiolet, A. Schut, C.D. Popa.
Collection and assembly of data: A.T.L. Fiolet, A. Mosterd, J.G.P. Tijssen, A. Schut, S.M. Nidorf, J.H. Cornel.
This article was published at Annals.org on 30 May 2023.
* Drs. Popa and Cornel contributed equally to this work.
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