Can metformin relieve tibiofemoral cartilage volume loss and knee symptoms in overweight knee osteoarthritis patients? Study protocol for a randomized, double-blind, and placebo-controlled trial

Guangfeng Ruan, Shiwen Yuan, Aiju Lou, Yingqian Mo, Yuan Qu, Dongmei Guo, Shangqi Guan, Yan Zhang, Xiaoyong Lan, Jun Luo, Yifang Mei, Hongwei Zhang, Weirong Wu, Lie Dai, Qinghong Yu, Xiaoyan Cai, Changhai Ding, Guangfeng Ruan, Shiwen Yuan, Aiju Lou, Yingqian Mo, Yuan Qu, Dongmei Guo, Shangqi Guan, Yan Zhang, Xiaoyong Lan, Jun Luo, Yifang Mei, Hongwei Zhang, Weirong Wu, Lie Dai, Qinghong Yu, Xiaoyan Cai, Changhai Ding

Abstract

Background: Osteoarthritis (OA) is the most common joint disease, and is most frequently seen in the knees. However, there is no effective therapy to relieve the progression of knee OA. Metformin is a safe, well-tolerated oral medication that is extensively used as first-line therapy for type 2 diabetes. Previous observational studies and basic researches suggested that metformin may have protective effects on knee OA, which needs to be verified by clinical trials. This study, therefore, aims to examine the effects of metformin versus placebo on knee cartilage volume loss and knee symptoms in overweight knee OA patients by a randomized controlled trial over 24 months.

Methods: This protocol describes a multicenter, randomized, double-blind, and placebo-controlled clinical trial aiming to recruit 262 overweight knee OA patients. Participants will be randomly allocated to the two arms of the study, receiving metformin hydrochloride sustained-release tablets or identical inert placebo for 24 months (start from 0.5 g/day for the first 2 weeks, and increase to 1 g/day for the second 2 weeks, and further increase to 2 g/day for the remaining period if tolerated). Primary outcomes will be changes in tibiofemoral cartilage volume and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score over 24 months. Secondary outcomes will be changes in visual analogue scale (VAS) knee pain, tibiofemoral cartilage defects, effusion-synovitis volume, and tibiofemoral bone marrow lesions maximum size over 24 months. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per-protocol analyses will be performed as the secondary analyses.

Discussion: If metformin is proved to slow knee cartilage volume loss and to relieve knee symptoms among overweight knee OA patients, it will have the potential to become a disease modifying drug for knee OA. Metformin is a convenient intervention with low cost, and its potential effects on slowing down the structural progression and relieving the symptoms of knee OA would effectively reduce the disease burden worldwide.

Trial registration: ClinicalTrials. gov NCT05034029 . Registered on 30 Sept 2021.

Keywords: Knee osteoarthritis; Metformin; Randomized controlled trial.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Flowchart of the trial. #MRI, questionnaires, and body composition will be acquired. ☩262 participants will be enrolled and equally allocated to the two groups (131 per group) in this trial; however, the number of participants actually enrolled may vary slightly. *The follow-up will be carried out at 3, 6, 12, and 24 months, with questionnaires and body composition being acquired at 3, 6, 12, and 24 months, hematological measurements being acquired at 6, 12, and 24 months, and MRI being acquired at 24 months

References

    1. Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019;393(10182):1745–1759. doi: 10.1016/S0140-6736(19)30417-9.
    1. Oo WM, et al. Disease-modifying drugs in osteoarthritis: current understanding and future therapeutics. Expert Opin Emerg Drugs. 2018;23(4):331–347. doi: 10.1080/14728214.2018.1547706.
    1. Van Spil WE, et al. Osteoarthritis phenotypes and novel therapeutic targets. Biochem Pharmacol. 2019;165:41–48. doi: 10.1016/j.bcp.2019.02.037.
    1. Bondeson J, et al. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum. 2010;62(3):647–657. doi: 10.1002/art.27290.
    1. Peat G, Thomas MJ. Osteoarthritis year in review 2020: epidemiology & therapy. Osteoarthr Cartil. 2021;29(2):180–189. doi: 10.1016/j.joca.2020.10.007.
    1. Blanco FJ, Valdes AM, Rego-Pérez I. Mitochondrial DNA variation and the pathogenesis of osteoarthritis phenotypes. Nat Rev Rheumatol. 2018;14(6):327–340. doi: 10.1038/s41584-018-0001-0.
    1. Puig-Junoy J, Ruiz Zamora A. Socio-economic costs of osteoarthritis: a systematic review of cost-of-illness studies. Semin Arthritis Rheum. 2015;44(5):531–541. doi: 10.1016/j.semarthrit.2014.10.012.
    1. Aroda VR, et al. Metformin for diabetes prevention: insights gained from the diabetes prevention program/diabetes prevention program outcomes study. Diabetologia. 2017;60(9):1601–1611. doi: 10.1007/s00125-017-4361-9.
    1. Cabreiro F, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153(1):228–239. doi: 10.1016/j.cell.2013.02.035.
    1. Cameron AR, et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res. 2016;119(5):652–665. doi: 10.1161/CIRCRESAHA.116.308445.
    1. Teodoro JS, et al. Therapeutic options targeting oxidative stress, mitochondrial dysfunction and inflammation to hinder the progression of vascular complications of diabetes. Front Physiol. 2018;9:1857. doi: 10.3389/fphys.2018.01857.
    1. Apolzan JW, et al. Long-term weight loss with metformin or lifestyle intervention in the diabetes prevention program outcomes study. Ann Intern Med. 2019;170(10):682–690. doi: 10.7326/M18-1605.
    1. Song P, et al. Therapeutic applications of type 2 diabetes mellitus drug metformin in patients with osteoarthritis. Pharmaceuticals (Basel) 2021;14(2):152. doi: 10.3390/ph14020152.
    1. Feng X, et al. Metformin attenuates cartilage degeneration in an experimental osteoarthritis model by regulating AMPK/mTOR. Aging (Albany NY) 2020;12(2):1087–1103. doi: 10.18632/aging.102635.
    1. Wang C, et al. Metformin mitigates cartilage degradation by activating AMPK/SIRT1-mediated autophagy in a mouse osteoarthritis model. Front Pharmacol. 2020;11:1114. doi: 10.3389/fphar.2020.01114.
    1. Belenska-Todorova L, et al. Disease-modifying potential of metformin and alendronate in an experimental mouse model of osteoarthritis. Biomedicines. 2021;9(8):1017. doi: 10.3390/biomedicines9081017.
    1. He Y, et al. Rational engineering of ferritin nanocages for targeted therapy of osteoarthritis. Nanomedicine. 2020;28:102210. doi: 10.1016/j.nano.2020.102210.
    1. Li H, et al. Exploration of metformin as novel therapy for osteoarthritis: preventing cartilage degeneration and reducing pain behavior. Arthritis Res Ther. 2020;22(1):34. doi: 10.1186/s13075-020-2129-y.
    1. Na HS, et al. Metformin attenuates monosodium-Iodoacetate-induced osteoarthritis via regulation of pain mediators and the autophagy-Lysosomal pathway. Cells. 2021;10(3):681. doi: 10.3390/cells10030681.
    1. Li J, et al. Metformin limits osteoarthritis development and progression through activation of AMPK signalling. Ann Rheum Dis. 2020;79(5):635–645. doi: 10.1136/annrheumdis-2019-216713.
    1. Lu CH, et al. Combination COX-2 inhibitor and metformin attenuate rate of joint replacement in osteoarthritis with diabetes: a nationwide, retrospective, matched-cohort study in Taiwan. PLoS One. 2018;13(1):e0191242. doi: 10.1371/journal.pone.0191242.
    1. Wang Y, et al. Association between metformin use and disease progression in obese people with knee osteoarthritis: data from the osteoarthritis initiative-a prospective cohort study. Arthritis Res Ther. 2019;21(1):127. doi: 10.1186/s13075-019-1915-x.
    1. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med. 2010;7(3):e1000251. doi: 10.1371/journal.pmed.1000251.
    1. Altman R, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and therapeutic criteria Committee of the American Rheumatism Association. Arthritis Rheum. 1986;29(8):1039–1049. doi: 10.1002/art.1780290816.
    1. Altman RD, Gold GE. Atlas of individual radiographic features in osteoarthritis, revised. Osteoarthr Cartil. 2007;15 Suppl A:A1–56. doi: 10.1016/j.joca.2006.11.009.
    1. Ruan G, et al. Associations between diet quality and knee joint structures, symptoms and systemic abnormalities in people with symptomatic knee osteoarthritis. Clin Nutr. 2021;40(5):2483–2490. doi: 10.1016/j.clnu.2021.03.011.
    1. Cai G, et al. Effect of intravenous Zoledronic acid on Tibiofemoral cartilage volume among patients with knee osteoarthritis with bone marrow lesions: a randomized clinical trial. JAMA. 2020;323(15):1456–1466. doi: 10.1001/jama.2020.2938.
    1. Ruan G, et al. Associations between serum S100A8/S100A9 and knee symptoms, joint structures and cartilage enzymes in patients with knee osteoarthritis. Osteoarthr Cartil. 2019;27(1):99–105. doi: 10.1016/j.joca.2018.08.020.
    1. Angst F, Aeschlimann A, Stucki G. Smallest detectable and minimal clinically important differences of rehabilitation intervention with their implications for required sample sizes using WOMAC and SF-36 quality of life measurement instruments in patients with osteoarthritis of the lower extremities. Arthritis Rheum. 2001;45(4):384–391. doi: 10.1002/1529-0131(200108)45:4<384::AID-ART352>;2-0.
    1. Hochberg MC, et al. Effect of intra-articular Sprifermin vs placebo on Femorotibial joint cartilage thickness in patients with osteoarthritis: the FORWARD randomized clinical trial. JAMA. 2019;322(14):1360–1370. doi: 10.1001/jama.2019.14735.
    1. Hmamouchi I, et al. Clinically important improvement in the WOMAC and predictor factors for response to non-specific non-steroidal anti-inflammatory drugs in osteoarthritic patients: a prospective study. BMC Res Notes. 2012;5:58. doi: 10.1186/1756-0500-5-58.
    1. Angst F, et al. Minimal clinically important rehabilitation effects in patients with osteoarthritis of the lower extremities. J Rheumatol. 2002;29(1):131–138.
    1. Dai W, et al. Intra-articular Mesenchymal stromal cell injections are no different from placebo in the treatment of knee osteoarthritis: a systematic review and Meta-analysis of randomized controlled trials. Arthroscopy. 2021;37(1):340–358. doi: 10.1016/j.arthro.2020.10.016.
    1. Lv Z, Guo Y. Metformin and its benefits for various diseases. Front Endocrinol (Lausanne) 2020;11:191. doi: 10.3389/fendo.2020.00191.
    1. Drzewoski J, Hanefeld M. The current and potential therapeutic use of metformin-the good old drug. Pharmaceuticals (Basel) 2021;14(2):122. doi: 10.3390/ph14020122.
    1. Zhou Z, et al. Metformin inhibits advanced Glycation end products-induced inflammatory response in murine macrophages partly through AMPK activation and RAGE/NFκB pathway suppression. J Diabetes Res. 2016;2016:4847812.
    1. Zhang H, et al. Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2. Ann Rheum Dis. 2018;77(10):1524–1534. doi: 10.1136/annrheumdis-2018-213450.
    1. Francisco V, et al. Biomechanics, obesity, and osteoarthritis. The role of adipokines: when the levee breaks. J Orthop Res. 2018;36(2):594–604.
    1. Thijssen E, van Caam A, van der Kraan PM. Obesity and osteoarthritis, more than just wear and tear: pivotal roles for inflamed adipose tissue and dyslipidaemia in obesity-induced osteoarthritis. Rheumatology (Oxford) 2015;54(4):588–600. doi: 10.1093/rheumatology/keu464.
    1. Cao Y, et al. Vitamin D supplementation in the management of knee osteoarthritis: study protocol for a randomized controlled trial. Trials. 2012;13:131. doi: 10.1186/1745-6215-13-131.
    1. Aitken D, et al. A protocol for a multicentre, randomised, double-blind, placebo-controlled trial to compare the effect of annual infusions of zoledronic acid to placebo on knee structural change and knee pain over 24 months in knee osteoarthritis patients - ZAP2. BMC Musculoskelet Disord. 2018;19(1):217. doi: 10.1186/s12891-018-2143-2.
    1. Wluka AE, et al. The clinical correlates of articular cartilage defects in symptomatic knee osteoarthritis: a prospective study. Rheumatology (Oxford) 2005;44(10):1311–1316. doi: 10.1093/rheumatology/kei018.
    1. Guermazi A, et al. FRI0302 Worsening of HOFFA-synovitis and effusion-synovitis increase risk for total knee replacement. Ann Rheum Dis. 2013;71(Suppl 3):416. doi: 10.1136/annrheumdis-2012-eular.2759.
    1. Raynauld JP, et al. Risk factors predictive of joint replacement in a 2-year multicentre clinical trial in knee osteoarthritis using MRI: results from over 6 years of observation. Ann Rheum Dis. 2011;70(8):1382–8. doi: 10.1136/ard.2010.146407.
    1. Alahmari K, et al. Subjective and objective evaluation of pain for older adults with knee osteoarthritis in Saudi Arabia: a reliability study. Niger J Clin Pract. 2020;23(7):934–943. doi: 10.4103/njcp.njcp_270_19.

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