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Cited by 33Curcumin's Biomedical ApplicationsOsteoarthritis Treatment and MechanismsGinger and Zingiberaceae research

Efficacy and safety of curcuminoids alone in alleviating pain and dysfunction for knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials

Open access
Feng, Jie, Li, Zhao, Tian, Linling, Mu, Panyun, Hu, Yimei, Xiong, Feng, Ma, Xu·2022·BMC Complementary Medicine and Therapies
DOI 10.1186/s12906-022-03740-9PMC PMC9580113
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Abstract

Background: Curcuminoids (CURs) are the principal ingredients of Curcuma longa L. [Zingiberaceae] (CL)—an herbal plant used in east Asia to alleviate pain and inflammation. Thus far, the therapeutic effects of CURs for knee osteoarthritis (OA) uncovered by multiple reviews remained uncertain due to broadly involving trials with different agents-combined or CURs-free interventions. Therefore, we formed stringent selection criteria and assessment methods to summarize current evidence on the efficacy and safety of CURs alone in the treatment of knee OA. Methods: A series of databases were searched for randomized controlled trials (RCTs) evaluating the efficacy and safety of CURs for knee OA. Clinical outcomes were evaluated using meta-analysis and the minimum clinically important difference (MCID) for both statistical and clinical significance. Results: Fifteen studies with 1670 patients were included. CURs were significantly more effective than placebo in the improvements of VAS for pain ( WMD: − 1.77, 95% CI: − 2.44 to − 1.09), WOMAC total score ( WMD: − 7.06, 95% CI: − 12.27 to − 1.84), WOMAC pain score ( WMD: − 1.42, 95% CI: − 2.41 to − 0.43), WOMAC function score ( WMD: − 5.04, 95% CI: − 7.65 to − 2.43), and WOMAC stiffness score ( WMD: − 0.54, 95% CI: − 1.03 to − 0.05). Meanwhile, CURs were not inferior to NSAIDs in the improvements of pain- and function-related outcomes. Additionally, CURs did not significantly increase the incidence of adverse events (AEs) compared with placebo ( RR: 1.03, 95% CI: 0.69 to 1.53, P = 0.899, I 2 = 23.7%) and NSAIDs (RR: 0.71 0.65, 95% CI: 0.57 0.41 to 0.90 1.03). Conclusions: CURs alone can be expected to achieve considerable analgesic and functional promotion effects for patients with symptomatic knee OA in short term, without inducing an increase of adverse events. However, considering the low quality and substantial heterogeneity of present studies, a cautious and conservative recommendation for broader clinical use of CURs should still be made. Further high-quality studies are necessary to investigate the impact of different dosages, optimization techniques and administration approaches on long-term safety and efficacy of CURs, so as to strengthen clinical decision making for patients with symptomatic knee OA.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review and meta-analysis of 15 RCTs (1,670 patients) found that oral curcuminoids alone reduced knee osteoarthritis pain and improved function versus placebo, and were not inferior to NSAIDs, without a significant increase in adverse events. The authors caution that low study quality and substantial heterogeneity warrant conservative interpretation.

Key findings

  • Versus placebo, curcuminoids significantly improved VAS for pain (WMD −1.77, 95% CI −2.44 to −1.09, P < 0.001, I² = 86.8%), WOMAC total score (WMD −10.47, 95% CI −15.65 to −5.3, P < 0.001, I² = 0.0%), WOMAC pain (WMD −1.94, 95% CI −2.91 to −0.97), WOMAC function (WMD −6.36, 95% CI −8.94 to −3.78), and WOMAC stiffness (WMD −0.54, 95% CI −1.03 to −0.05, P = 0.031). Note: the abstract reports different pooled values for WOMAC total (−7.06), pain (−1.42), and function (−5.04) than the Results section.
  • No significant difference was found between curcuminoids and NSAIDs for VAS pain (WMD −0.3, 95% CI −0.63 to 0.04, P = 0.082), WOMAC total (−0.68), pain (0.24), function (−0.57), or stiffness (0.19).
  • Using minimum clinically important difference (MCID) thresholds, only VAS for pain (−1.77 vs MCID 1.18) and WOMAC total score (−10.47 vs MCID 8.97) exceeded MCID in the placebo comparison; WOMAC pain, function, and stiffness did not.
  • Adverse events did not differ significantly from placebo (RR 1.07, 95% CI 0.70–1.65, P = 0.745, I² = 32.6%) or NSAIDs (RR 0.65, 95% CI 0.41–1.03, P = 0.065); total AE incidence was 25.06% with curcuminoids vs 35.57% in controls. Sensitivity analysis excluding Gupte et al. made the NSAID comparison significant (RR 0.63, 95% CI 0.41–0.95, P = 0.026).

Methods

  • Systematic review and meta-analysis (PROSPERO CRD42021266888) of RCTs of oral curcuminoids alone versus placebo or conventional agents (ibuprofen, diclofenac, paracetamol) in ACR-diagnosed knee OA; eight databases plus ClinicalTrials.gov searched to August 2022, without time or language restriction.
  • Fifteen studies with 1,670 patients (published 2009–2022; sample sizes 30–331; follow-up ≤ 6 months) were included; five were active-controlled and ten placebo-controlled.
  • Random-effects meta-analysis in Stata 14 and RevMan 5.4, reporting WMD or RR with 95% CI; heterogeneity by Q-test and I²; MCID (20% of baseline) used as a clinical-significance threshold; pre-planned subgroup analyses (dose, total dose, follow-up duration, bio-optimized vs pure extracts, region); risk of bias via Cochrane tool; GRADE for evidence quality.

Limitations

  • Stated by the authors: original studies were of low quality with substantial heterogeneity from varied dosages, follow-up durations, regions, preparations, and baseline values; heterogeneity persisted after subgroup analyses; follow-up was limited to 6 months, leaving long-term effectiveness equivocal; and although Egger's tests were non-significant, funnel plot asymmetry suggested potential publication bias, with small numbers of studies per comparison.
  • Evident from the text: the abstract and Results section report inconsistent pooled effect estimates for several WOMAC outcomes; several subgroup analyses rested on only two studies each; and the NSAID comparison became statistically significant only after omitting one trial, indicating fragility of that result.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s12906-022-03740-9

Cites

86 of 86 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

18 of 34 cited sources checked · 8 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Evidence to reveal the clinical significance of CURs alone for knee OA is insufficient.

    “Thus far, the therapeutic effects of CURs for knee osteoarthritis (OA) uncovered by multiple reviews remained uncertain due to broadly involving trials with different agents-combined or CURs-free interventions [8, 24–26], and evidence to reveal the clinical significance of CURs alone for knee OA is insufficient.”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [8] Bannuru RR, Osani MC, Al-Eid F, Wang C. Efficacy of curcumin and Boswellia for knee osteoarthritis: Systematic review and meta-analysis. Semin Arthritis Rheum. 2018;48(3):416–29. source
    • cites [24] Wang Z, Singh A, Jones G, Winzenberg T, Ding C, Chopra A, Das S, Danda D, Laslett L, Antony B. Efficacy and safety of turmeric extracts for the treatment of knee osteoarthritis: a systematic review and meta-analysis of randomised controlled trials. Curr Rheumatol Rep. 2021;23(2):11. source

      The Background and rationale and Objectives sections describe a planned review of turmeric extracts for knee OA, but do not assess whether evidence for curcumin alone is clinically sufficient. The Characteristics of interventions section includes curcumin and some combination therapies; it does not say that combining different interventions made earlier reviews' findings uncertain. Searches for clinical significance, curcumin alone, and uncertainty did not locate that assessment in our copy. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [25] Wenli D, Wenqiang Y, Xi L, Jing C, Xiaoqing H, Yingfang A. Effectiveness of Curcuma longa extract versus placebo for the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials. Phytotherapy research: PTR; 2021.

      Not checked in the free run.

    • cites [26] Zeng L, Yu G, Hao W, Yang K, Chen H. The efficacy and safety of Curcuma longa extract and curcumin supplements on osteoarthritis: A systematic review and meta-analysis. Biosci Rep. 2021;41(6):BSR20210817. source

      The Introduction says earlier evidence was too limited for definite clinical recommendations, but the paper presents its updated analysis as addressing that gap. In Results > Primary outcomes, curcumin or Curcuma longa extract alone reduced pain versus placebo; the Conclusion recommends supplementation for patients with OA. Thus, the paper does not present evidence for these interventions alone as insufficient, although its conclusion addresses OA generally rather than knee OA specifically. (LLM, conf=0.82)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    CURs postpone joint contracture progress by inhibiting myofibroblast proliferation from the joint capsule.

    “And CURs were shown to postpone joint contracture progress via inhibiting the proliferation of myofibroblasts from the joint capsule [18].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Zhuang Z, Yu D, Chen Z, Liu D, Yuan G, Yirong N, Sun L, Liu Y, He R, Wang K. Curcumin Inhibits Joint Contracture through PTEN Demethylation and Targeting PI3K/Akt/mTOR Pathway in Myofibroblasts from Human Joint Capsule. Evid Based Complement Alternat Med. 2019;2019:4301238. source

      Results §3.1.2 reports that curcumin inhibited proliferation of myofibroblasts isolated from the joint capsule. The Discussion §4 says this may be beneficial in the early phases of arthrofibrosis, but does not show that curcumin postponed the progression of joint contracture. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Animal studies have demonstrated that CURs administered via nano-scale drug carriers have potent anti-inflammatory and anti-arthritic activity for knee OA.

    “Several animal studies have assessed the efficacy of CURs administered via nano-scale drug carriers for knee OA, demonstrating that CURs have potent anti-inflammatory and anti-arthritic activity, both with and without biological materials [19–23].”
    Quote in the paperNot a substantial claim1 of 5 sources checked
    • cites [19] Yeh CC, Su YH, Lin YJ, Chen PJ, Shi CS, Chen CN, Chang HI. Evaluation of the protective effects of curcuminoid (curcumin and bisdemethoxycurcumin)-loaded liposomes against bone turnover in a cell-based model of osteoarthritis. Drug Des Devel Ther. 2015;9:2285–300.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [20] Ratanavaraporn J, Soontornvipart K, Shuangshoti S, Shuangshoti S, Damrongsakkul S. Localized delivery of curcumin from injectable gelatin/Thai silk fibroin microspheres for anti-inflammatory treatment of osteoarthritis in a rat model. Inflammopharmacology. 2017;25(2):211–21. source
    • cites [21] Wang J, Wang X, Cao Y, Huang T, Song DX, Tao HR. Therapeutic potential of hyaluronic acid/chitosan nanoparticles for the delivery of curcuminoid in knee osteoarthritis and an in vitro evaluation in chondrocytes. Int J Mol Med. 2018;42(5):2604–14. source
    • cites [22] Crivelli B, Bari E, Perteghella S, Catenacci L, Sorrenti M, Mocchi M, Farago S, Tripodo G, Prina-Mello A, Torre ML. Silk fibroin nanoparticles for celecoxib and curcumin delivery: ROS-scavenging and anti-inflammatory activities in an in vitro model of osteoarthritis. Eur J Pharm Biopharm. 2019;137:37–45. source
    • cites [23] Kang C, Jung E, Hyeon H, Seon S, Lee D. Acid-activatable polymeric curcumin nanoparticles as therapeutic agents for osteoarthritis. Nanomedicine. 2020;23: 102104. source
  • Premisecitation

    The therapeutic effects of CURs for knee OA uncovered by multiple reviews remained uncertain because reviews broadly involved trials with different agents-combined or CURs-free interventions.

    “Thus far, the therapeutic effects of CURs for knee osteoarthritis (OA) uncovered by multiple reviews remained uncertain due to broadly involving trials with different agents-combined or CURs-free interventions [8, 24–26], and evidence to reveal the clinical significance of CURs alone for knee OA is insufficient.”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [8] Bannuru RR, Osani MC, Al-Eid F, Wang C. Efficacy of curcumin and Boswellia for knee osteoarthritis: Systematic review and meta-analysis. Semin Arthritis Rheum. 2018;48(3):416–29. source

      The Introduction (page unavailable) says earlier meta-analyses had methodological flaws, and the Results describe this review’s inclusion of curcuminoid-only, boswellia-only, and combination trials. But the paper does not attribute uncertainty about curcuminoids specifically to earlier reviews’ inclusion of combined or curcuminoid-free interventions; it names outdated trial data, pooling methods, and irreproducible results as flaws instead. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [24] Wang Z, Singh A, Jones G, Winzenberg T, Ding C, Chopra A, Das S, Danda D, Laslett L, Antony B. Efficacy and safety of turmeric extracts for the treatment of knee osteoarthritis: a systematic review and meta-analysis of randomised controlled trials. Curr Rheumatol Rep. 2021;23(2):11. source

      The Background and rationale and Characteristics of interventions sections discuss turmeric-extract trials and allow some combination therapies. They do not assess earlier reviews or say that their findings were uncertain because they included combined-agent or turmeric-free interventions; searches for those limitations found no such passage. No page numbers are available in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [25] Wenli D, Wenqiang Y, Xi L, Jing C, Xiaoqing H, Yingfang A. Effectiveness of Curcuma longa extract versus placebo for the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials. Phytotherapy research: PTR; 2021.

      Not checked in the free run.

    • cites [26] Zeng L, Yu G, Hao W, Yang K, Chen H. The efficacy and safety of Curcuma longa extract and curcumin supplements on osteoarthritis: A systematic review and meta-analysis. Biosci Rep. 2021;41(6):BSR20210817. source

      The Introduction says earlier evidence was too limited for definite clinical recommendations, and the Methods (Selection criteria) allow curcumin either alone or combined with conventional therapy. But the paper does not say that reviews’ uncertainty was caused by including curcumin-free interventions; its own eligibility criteria require curcumin. Page numbers are unavailable in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Findingown data

    Larger effect sizes with clinical significance of both pain reduction and functional promotion were observed in trials performed in Asia compared with those in other countries.

    “Besides, larger effect sizes with clinical significance of both pain reduction and functional promotion were observed in trials performed in Asia compared with those in other countries, which was in accordance with the result of a recently published review by Wang et al. [24].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Wang Z, Singh A, Jones G, Winzenberg T, Ding C, Chopra A, Das S, Danda D, Laslett L, Antony B. Efficacy and safety of turmeric extracts for the treatment of knee osteoarthritis: a systematic review and meta-analysis of randomised controlled trials. Curr Rheumatol Rep. 2021;23(2):11. source

      The passages in our copy are from a review protocol, not reported results. Its Statistical analysis and Primary and secondary outcomes sections describe planned analyses of pain and physical function, but report no comparison of effect sizes between Asian trials and trials elsewhere (searched for geographic subgroup findings and clinical significance). No page numbers are available in the copy. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 14
  • May combine two claims. 28

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Curcuminoids (CURs) are the principal ingredients of Curcuma longa L., an herbal plant used in east Asia to alleviate pain and inflammation.

    “Analogues comprising curcumin, bisdemethoxycurcumin, demethoxycurcumin and cyclocurcumin are collectively referred to as curcuminoids (CURs) [12], which constitute the principal ingredients of CL—an herbal plant used in east Asia to alleviate pain and inflammation.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Cao Y, Xu RX, Liu Z. A high-throughput quantification method of curcuminoids and curcumin metabolites in human plasma via high-performance liquid chromatography/tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2014;949–950:70–8. source

      The Introduction identifies curcumin, demethoxycurcumin, and bisdemethoxycurcumin as curcuminoids extracted from Curcuma longa, supporting part of the definition to which the citation is attached. It does not include cyclocurcumin in that definition or state that the plant was used in East Asia to alleviate pain and inflammation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    The MCID threshold for VAS and WOMAC scores was defined as a 20% fluctuation from baseline of included studies according to previous research.

    “The MCID threshold for the VAS and WOMAC scores was defined as a 20% fluctuation from the baseline of the included studies according to previous researches [33–36], and calculated as follows: 1.18/10 for VAS for pain, 8.97/96 for WOMAC total score, 2.12/20 for WOMAC pain score, 6.62/68 for WOMAC function score, and 0.76/8 for WOMAC stiffness score.”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [33] Beaton DE. Understanding the relevance of measured change through studies of responsiveness. Spine (Phila Pa 1976). 2000;25(24):3192–9. source
    • cites [34] 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):384–91. source

      Not checked in the free run.

    • cites [35] Tubach F, Ravaud P, Martin-Mola E, Awada H, Bellamy N, Bombardier C, Felson DT, Hajjaj-Hassouni N, Hochberg M, Logeart I, et al. Minimum clinically important improvement and patient acceptable symptom state in pain and function in rheumatoid arthritis, ankylosing spondylitis, chronic back pain, hand osteoarthritis, and hip and knee osteoarthritis: Results from a prospective multinational study. Arthritis Care Res (Hoboken). 2012;64(11):1699–707. source

      The Discussion recommends 20% relative improvement from baseline as an MCII threshold for pain and function outcomes in five rheumatic diseases. It does not establish that threshold for WOMAC total, pain, function, and stiffness scores specifically, and it concerns improvement rather than fluctuation in either direction. The cited paper also does not supply the VAS and WOMAC score cutoffs listed in the citing sentence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [36] Dai WL, Lin ZM, Guo DH, Shi ZJ, Wang J. Efficacy and safety of Hylan versus hyaluronic acid in the treatment of knee osteoarthritis. J Knee Surg. 2019;32(3):259–68. source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The quality of evidence was classified using the GRADE system.

    “The quality of evidence was classified using the GRADE system [37] as high, moderate, low, or very low, with descending assignment of 4, 3, 2, or 1.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [37] Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–6. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The study was conducted by the guidance of the Cochrane Handbook for Systematic Review of Interventions and reported according to the PRISMA checklist.

    “The study was conducted by the guidance of the Cochran Handbook for Systematic Review of Interventions [28], and reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis checking list (Supplementary Table 1) [29].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [28] Cumpston M, Li T, Page MJ, Chandler J, Welch VA, Higgins JP, Thomas J. Updated guidance for trusted systematic reviews: a new edition of the cochrane handbook for systematic reviews of interventions. Cochrane Database Syst Rev. 2019;10:ED000142. source
    • cites [29] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Two reviewers applied the Cochrane Risk of Bias Tool 1 to assess risk of bias of included studies.

    “Two reviewers (L.L.T and Z.L.) applied the recommended Cochran Risk of Bias Tool 1 [31] to assess the risk of bias of the included studies.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [31] Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. source

  • May combine two claims.

    Findingown data

    Removing Haroyan et al. slightly decreased heterogeneity for WOMAC function score placebo-controlled group from 79.2% to 70.7%, with pooled WMD −7.21 (95% CI −9.71 to −4.72, P<0.001).

    “After excluding the study of Haroyan et al. [66], the inter-study heterogeneity in placebo-controlled group slightly decreased from 79.2% to 70.7%, but the pooled result (WMD: − 7.21, 95% CI: − 9.71 to − 4.72, P < 0.001) reached up to the magnitude exceeding the threshold (6.62) for clinical significance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All included studies were CURs-intervened trials aimed to evaluate clinical effectiveness of CURs and were published between 2009 and 2022.

    “All included studies were CURs-intervened trials aimed to evaluate the clinical effectiveness of CURs, and published between 2009 and 2022.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    A lower incidence of adverse events was observed in CURs group compared with NSAIDs group, but the pooled result was not statistically significant (RR 0.65, 95% CI 0.41 to 1.03, P=0.065, I2=55.8%).

    “while a lower incidence of AEs was observed in CURs group when compared with NSAIDs group, but the pooled results were not statistically significant ( RR: 0.65, 95% CI: 0.41 to 1.03, P = 0.065, I2 = 55.8%, Fig. 8).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Sample sizes of included studies ranged from 30 to 331.

    “Sample sizes of included studies were ranged from 30 to 331, and the follow-up durations were limited in 6 months.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Removing Panda et al. decreased heterogeneity for WOMAC stiffness score placebo-controlled group from 77.6% to 0.0%, with pooled WMD −0.31 (95% CI −0.56 to −0.05, P=0.018).

    “By excluding the study of Panda et al. [67], a decrease in heterogeneity from 77.6% to 0.0% in placebo-controlled group was observed, but the pooled result (WMD: − 0.31, 95% CI: − 0.56 to − 0.05, P = 0.018) was similar with the original analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Removing Srivastava et al. reduced heterogeneity for WOMAC pain score placebo-controlled group from 79.2% to 51.8%, with pooled WMD −2.28 (95% CI −3.05 to −1.52, P<0.001).

    “The study of Srivastava et al. [65] was considered to be the potential source of heterogeneity given that the I2 values in placebo-controlled group decreased from 79.2% to 51.8% after omitting their data, and the pooled result (WMD: − 2.28, 95% CI: − 3.05 to − 1.52, P < 0.001) reached up to the magnitude exceeding the threshold (2.12) for clinical significance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The present studies have low quality and substantial heterogeneity.

    “However, considering the low quality and substantial heterogeneity of present studies, a cautious and conservative recommendation for broader clinical use of CURs should still be made.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Follow-up durations of included studies were limited to 6 months.

    “Sample sizes of included studies were ranged from 30 to 331, and the follow-up durations were limited in 6 months.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Five trials applied active-controlled arms (ibuprofen, diclofenac, and paracetamol), and ten were placebo-controlled.

    “Five trials [56–60] applied active-controlled arms (ibuprofen, diclofenac, and paracetamol), and the other ten [61–72] were all placebo-controlled trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Removing Haroyan et al. reduced heterogeneity for WOMAC total score placebo-controlled group from 80.6% to 0.0%, with pooled WMD −12.88 (95% CI −14.79 to −10.98, P<0.001).

    “When the data of Haroyan et al. [66] was omitted, a significant reduction in heterogeneity from 80.6% to 0.0% in placebo-controlled group was observed, but the pooled result (WMD = − 12.88, 95% CI: − 14.79 to − 10.98, P < 0.001) of remained studies was similar with the original analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Removing the study of Atabaki et al. reduced heterogeneity for VAS for pain placebo-controlled group from 86.8% to 56.9%, with pooled WMD −1.36 (95% CI −1.76 to −0.97, P<0.001).

    “An obvious decrease from 86.8% to 56.9% in heterogeneity for placebo-controlled group was observed after removing the study of Atabaki et al. [70], with the intervention of CURs loaded nano-micelles, the pooled result ( WMD: − 1.36, 95% CI: − 1.76 to − 0.97, P < 0.001) was similar with the original analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    The MCID was exceeded by the effect sizes of all main outcomes in the time < 12 weeks subgroup, but the effect sizes of the WOMAC pain score and WOMAC function score in the time ≥ 12 weeks subgroup did not achieve clinical significance.

    “Besides, the MCID was exceeded by the effect sizes of all main outcomes in the time < 12 weeks subgroup, but the effect sizes of the WOMAC pain score and WOMAC function score in the time ≥ 12 weeks subgroup did not achieve clinical significance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CURs showed favorable improvement in VAS for pain, WOMAC pain score, and WOMAC function score compared to placebo at each time points (follow-up duration < or ≥ 12 weeks).

    “Thus, we removed the data of active-controlled trials in subgroup analyses, and found that CURs showed favorable improvement in VAS for pain, WOMAC pain score, and WOMAC function score compared to placebo at each time points (follow-up duration < or ≥ 12 weeks).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The bio-optimized extracts subgroup exceeded the MCID of WOMAC pain score, but the pure extracts subgroup was neither statistically nor clinically significant.

    “According to our study, we found that the result of the bio-optimized extracts subgroup increased to exceed the MCID of WOMAC pain score, but the result of the pure extracts subgroup was neither statistically nor clinically significant.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The effect sizes of VAS for pain, WOMAC pain score, and WOMAC function score in the low-dose (daily dose < 1,000 mg and total dose < 50 g) subgroup exceeded their MCID, while those in the high-dose (daily dose ≥ 1,000 mg and total dose ≥ 50 g) subgroup did not achieve clinical significance.

    “Actually, we found that the effect sizes of VAS for pain, WOMAC pain score and WOMAC function score in low-dose (daily dose < 1,000 mg and total dose < 50 g) subgroup exceeded their MCID, while those in high-dose (daily dose ≥ 1,000 mg and total dose ≥ 50 g) subgroup did not achieve clinical significance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Only VAS for pain and WOMAC total score achieved clinical significance by exceeding their MCID; WOMAC pain score, WOMAC function score, and WOMAC stiffness score did not.

    “The significance test of clinical benefits found that only VAS for pain and WOMAC total score achieved clinical significance by exceeding their MCID, while WOMAC pain score, WOMAC function score and WOMAC stiffness score did not.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The effect sizes of both VAS for pain and WOMAC function score in the bio-optimized extracts subgroup exceeded their MCID, while those in the pure extracts group did not.

    “Besides, the effect sizes of both VAS for pain and WOMAC function score in the bio-optimized extracts subgroup exceeded their MCID, while those in the pure extracts group did not.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CURs can reduce COX-2 synthesis tendentiously, which may result in better safety profiles than NSAIDs.

    “Normal NSAIDS are of critical safety concerns due to simultaneously inhibition of COX-1 and COX-2 enzymes in arthritis, while CURs can reduce the synthesis of COX-2 tendentiously [16], which may result in better safety profiles.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol Pharmacol. 2006;69(1):195–206. source

  • May combine two claims.

    Interpretationown data

    In time <12 weeks, daily dose <1,000 mg, total dose <50 g, bio-optimized extracts, and Asia subgroups, effect sizes increased to exceed the MCID for WOMAC pain score and WOMAC function score.

    “Conversely, in the time < 12 weeks, daily dose < 1,000 mg, total dose < 50 g, bio-optimized extracts, and Asia subgroups, we found that the effect sizes increased to exceed the MCID for WOMAC pain score and WOMAC function score.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Publication bias was detected using funnel plots and Egger's test for outcomes involving five or more comparisons.

    “Publication bias was detected using funnel plots and Egger’s test for outcomes involving five or more comparisons.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study was performed according to a pre-registered protocol (CRD42021266888, PROSPERO) with amendments in selection and assessment of outcomes.

    “The research was performed according to our pre-registered protocol (CRD42021266888, PROSPERO) with some amendments in the selection and assessment of outcomes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    For VAS for pain, the therapeutic effect of CURs versus placebo (−1.77) exceeded the MCID with both statistical and clinical significance.

    “However, the therapeutic effect (− 1.77) of CURs in placebo-controlled group exceeded the MCID with both statistical and clinical significance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Two independent reviewers removed duplicate publications and screened titles and abstracts to select studies.

    “To select relevant studies for further assessment, two independent reviewers (F.X. and X.M.) removed duplicate publications using Endnote X9, and identified each citation as eligible, ineligible and uncertain by screening titles and abstracts.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Pre-planned subgroup analyses were carried out for the placebo-controlled group based on daily dose, total dose, follow-up duration, type of CURs, and regions.

    “we carried out pre-planned subgroup analyses for the placebo-controlled group based on daily dose of CURs (dose < 1,000 mg, or dose ≥ 1,000 mg), total dose of CURs (dose < 50 g, or dose ≥ 50 g), follow-up duration (time < 12 weeks, or time ≥ 12 weeks), type of CURs (bio-optimized or pure extracts) and regions (Asia or non-Asia).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The robustness of the quantitative synthesis was tested by omitting the data of each citation in sensitivity analysis.

    “The robustness of the quantitative synthesis was tested by omitting the data of each citation in sensitivity analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    For WOMAC total score, the effect size of CURs versus placebo (−10.47) was larger than the MCID with both statistical and clinical significance.

    “For the comparison between CURs and NSAIDs, the therapeutic effect (− 0.68) did not exceed the MCID (8.97 for WOMAC total score), while the effect size (− 10.47) of CURs in placebo-controlled group was larger than the MCID with both statistical and clinical significance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    CURs alone can be expected to achieve considerable analgesic and functional promotion effects for patients with symptomatic knee OA in the short term, without inducing an increase of adverse events.

    “CURs alone can be expected to achieve considerable analgesic and functional promotion effects for patients with symptomatic knee OA in short term, without inducing an increase of adverse events.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    All data were extracted and recorded by two reviewers.

    “All data were extracted, and recorded in Excel spreadsheets prepared in advance by two reviewers (L.L.T and Z.L.).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The quality of the original studies was low, and substantial heterogeneity was detected among the included studies.

    “Firstly, the quality of the original studies was low, and substantial heterogeneity was detected among the included studies”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    CURs alone can be expected to achieve considerable analgesic and functional promotion effects for patients with symptomatic knee OA in short-term, without inducing an increase of adverse events.

    “CURs alone can be expected to achieve considerable analgesic and functional promotion effects for patients with symptomatic knee OA in short-term, without inducing an increase of adverse events.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The included trials are representative of patients with symptomatic knee OA in general.

  • May combine two claims.

    Interpretationreasoning

    Bio-optimized CURs may be sufficiently potent to lower dosage and shorten medication cycle.

    “Overall, in terms of alleviating pain and other symptoms, bio-optimized CURs may be sufficiently potent to lower dosage and shorten medication cycle.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The durations of follow-ups in main outcomes were limited to within 6 months, as a result, the long-term clinical effectiveness of CURs remains equivocal.

    “Thirdly, the durations of follow-ups in main outcomes were limited to within 6 months, as a result, the long-term clinical effectiveness of CURs remains equivocal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    All pain and function related outcomes were downgraded to have a moderate to very low quality of evidence due to inconsistency, risk of bias, and publication bias, while AEs were defined as high-quality evidence.

    “All pain and function related outcomes were downgraded to have a moderate to very low quality of evidence duo to inconsistency, risk of bias, and publication bias, while AEs were defined as high-quality evidence (Supplementary Table 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–6. source

      Not checked in the free run.

38 of 38

  • The paper relies on this without support.

    The included trials are representative of patients with symptomatic knee OA in general.

    “CURs alone can be expected to achieve considerable analgesic and functional promotion effects for patients with symptomatic knee OA in short-term, without inducing an increase of adverse events.”
1 of 1

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Abstract and results give different placebo-controlled WOMAC total effects

    Major

    The abstract reports a WMD of −7.06, while the results report −10.47 for the same comparison. The two estimates also fall on opposite sides of the paper's 8.97-point MCID.

  • WOMAC total placebo heterogeneity is reported as both 0% and 80.6%

    Major

    The initial placebo-controlled WOMAC total analysis reports I2 of 0.0%, but the sensitivity analysis says that omitting a study reduced that group's heterogeneity from 80.6% to 0.0%.

  • Abstract and results give different WOMAC function effects

    Major

    For the placebo comparison, the abstract reports a WMD of −5.04 but the results report −6.36.

  • Abstract and results give different WOMAC pain effects

    Major

    For the placebo comparison, the abstract reports a WMD of −1.42 but the results report −1.94.

  • Discussion denies significant dose-subgroup effects shown in Table 5

    Major

    The discussion says none of the dose subgroups differed significantly from placebo, but Table 5 shows effects with confidence intervals excluding zero, including the cited low-daily-dose VAS subgroup.

  • Abstract and results disagree on the placebo adverse-event estimate

    Major

    The abstract gives an RR of 1.03 and CI of 0.69-1.53; the adverse-events results give 1.07 and 0.70-1.65 for the placebo comparison.

  • Rescue-medication study list excludes a subsequently counted study

    Minor

    The stated list of eight studies reporting rescue-medication administration omits study [58], yet the next sentence includes [58] among five studies reporting rescue-medication users.

  • Gupte study has conflicting reference numbers

    Minor

    Table 1 identifies Gupte as [58], but Table 3 identifies it as [67]; Table 3 similarly swaps Panda's reference number.

  • Herotin intervention arm has an inconsistent sex breakdown

    Minor

    The reported 39 female and 15 male patients add to 54, not the stated arm size of 49.

    Reported 49 · recomputed 54

  • One study is classified as both low and high risk of bias

    Minor

    Study [56] appears in both the low-risk and high-risk lists.

10 of 10

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Sahebkar AH, Panahi Y, Sabouri A, Rahimnia A, Sharafi M, Alishiri GH. Efficacy and safety of supplementation with curcuminoids in the treatment of patients with osteoarthritis: a randomized controlled trial. Avicenna J Phytomedicine. 2015;5:15–6.
  2. Antony B, Wang Z, Winzenberg T, Cai G, Laslet L, Aitken D, Hopper I, Jones R, Ding C, Fripp J, et al. A randomised clinical trial of curcuma longa extract for treatng symptoms and efusion-synovits of knee osteoarthrits. Indian J Rheumatol. 2019;14(6):S173–4.
  3. Kertia N, Ahmad Husain Asdie A, Wasilah Rochmah W, Marsetyawan M. Anti-inflammatory activities and the safety of curcuminoid compared to diclofenac sodium for the treatment of osteoarthritis. Int J Rheum Dis 2013;16:37

Cited by

Sorted by citations

Related

Authors
Feng, J., Li, Z., Tian, L., Mu, P., Hu, Y., Xiong, F., & Ma, X.
Affiliations
Chengdu University of Traditional Chinese Medicine (CN)
Corresponding author
Hu, Yimei
ORCID
Venue
BMC Complementary Medicine and Therapies
Publisher
Springer Science and Business Media LLC
Published
2022-10-19
Volume
22
Issue
1
Pages
276-276
ISSN
2662-7671 (ISSN-L)
DOI
10.1186/s12906-022-03740-9
PMC
PMC9580113
OpenAlex
W4306784258
Semantic Scholar
06fa8d3e7f447669a7ff0be58e2dcc0c62c55c03
Cited by
33
References
86
Citations by year
2026: 11 · 2025: 9 · 2024: 12 · 2023: 1
FWCI
0.40
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Complementary Medicine and Therapies (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Sichuan Provincial Administration of Traditional Chinese Medicine (2021MS454)
  • the special fund for 100 Talents Program of the First Affiliated Hospital of Chengdu University of TCM (20-Y14)
  • the scientific research promotion plan of “Xinglin Scholars” Discipline Talents of Chengdu University of traditional Chinese Medicine (030058047)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Curcumin's Biomedical Applications
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Ginger and Zingiberaceae research
Keywords
curcuminoids, knee osteoarthritis, turmeric, herbal medicine, analgesia, functional improvement, WOMAC, adverse events, safety, minimal clinically important difference, anti-inflammatory agents, analgesics, placebo comparison, treatment safety
MeSH terms
Anti-Inflammatory Agents, Non-Steroidal, Humans, Pain, Randomized Controlled Trials as Topic, Osteoarthritis, Knee, Diarylheptanoids

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-05.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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