Received: 27 January 2021 Revised: 8 May 2021
DOI: 10.1002/ptr.7204
REVIEW
Effectiveness of Curcuma longa extract versus placebo for the
treatment of knee osteoarthritis: A systematic review and
meta-analysis of randomized controlled trials
Wenli Dai1 | Wenqiang Yan1 |
Yingfang Ao1
1
Institute of Sports Medicine, Beijing Key
Laboratory of Sports Injuries, Peking
University Third Hospital, Beijing, China
2
Medical Imaging Center, The First Affiliated
Hospital of Guangzhou University of Chinese
Medicine, Guangzhou, China
Correspondence
Yingfang Ao, Institute of Sports Medicine,
Beijing Key Laboratory of Sports Injuries,
Peking University Third Hospital, 49 North
Garden Road, Haidian District, Beijing 100191,
China.
Email: aoyingfang@126.com
Funding information
Beijing Natural Science Foundation, Grant/
Award Numbers: 7171014, 7174361,
7182175; Beijing Municipal Science and
Technology Commission, Grant/Award
Number: Z171100001017085; National
Natural Science Foundation of China, Grant/
Award Numbers: 81672212, 81802153,
81902205
1 | I N T RO DU CT I O N
Osteoarthritis (OA) of the knee is one of the most common degen-
erative joint diseases influencing the quality of life of patients
(Cross et al., 2014; Haywood et al., 2003). Pain and loss of function
are the main clinical features that lead to treatment (Dieppe &
Lohmander, 2005; Johnson & Hunter, 2014). Although knee
arthroplasty provides an effective solution for severe knee OA
(Carr et al., 2012), for younger and middle-aged patients with earlier
stages of knee OA, conservative nonsurgical therapies have
been proposed to treat the painful joint (Bijlsma, Berenbaum, &
Wenli Dai and Wenqiang Yan contributed equally to this study.
Phytotherapy Research. 2021;1–15.
Accepted: 17 June 2021
Xi Leng2 | Jing Chen1 | Xiaoqing Hu1 |
The aim of this systematic review was to evaluate the efficacy and safety of all types
of Curcuma longa extract versus placebo for knee osteoarthritis (OA) treatment. The
research was conducted by using the databases of PubMed, Embase, Scopus, and
Cochrane Library through April 2021. Randomized controlled trials (RCTs) that com-
pared the effect of Curcuma longa extract with placebo for patients with knee OA
were considered eligible. The pooled results were expressed as mean differences or
relative risks with 95% confidence intervals. A total of 10 RCTs with 783 patients
were eligible for this meta-analysis. The pooled analysis showed that Curcuma longa
extract was associated with significantly better pain relief and functional improve-
ment compared with placebo for knee OA. Moreover, the smallest effect sizes of
VAS for pain and WOMAC total score exceeded the minimum clinically important
differences (MCIDs). Current evidence indicates that, compared with placebo,
Curcuma longa extract has more benefit in pain relief and functional improvement for
symptomatic knee OA. However, considering the potential heterogeneity in the
included studies, more future high-quality RCTs with large sample sizes are necessary
to confirm the benefits of Curcuma longa extract on knee OA.
KEYWORDS
Curcuma longa extract, knee osteoarthritis, phytotherapy, placebo, systematic review, turmeric
Lafeber, 2011; Richmond et al., 2010). The first-line pharmacological
therapy is the use of nonsteroidal antiinflammatory drugs (NSAIDs)
and paracetamol. However, these drugs have a low transient analge-
sic effect on knee OA, and several studies have observed the occur-
rence of adverse events mainly in elderly patients with
comorbidities (Bhala et al., 2013; da Costa et al., 2017; Machado
et al., 2015; Persson et al., 2020; Ungprasert, Cheungpasitporn,
Crowson, & Matteson, 2015). Particularly, the safety profiles of
NSAIDs remain a concern, and caution is recommended before
selecting an NSAID and dose regimen for a patient (Hochberg
et al., 2012). The unfavorable safety profiles of commonly pre-
scribed knee OA treatments have led researchers to explore safer
alternatives.
wileyonlinelibrary.com/journal/ptr © 2021 John Wiley & Sons Ltd. 1
2 DAI ET AL.
More recently, Curcuma longa extract, an antiinflammatory and
antioxidative agent, which has been used in both Ayurveda and tradi-
tional Chinese medicine to treat arthritis, has become an attractive
treatment option to improve the status of the joint for OA patients
(Alghadir, Miraj, & Ali, 2020; Heidari-Beni et al., 2020; Kunnumakkara
et al., 2017; Prasad, Tyagi, & Aggarwal, 2014). Preclinical studies have
found that Curcuma longa extract regulates various biochemical path-
ways by modulating several molecular targets, including cytokines,
enzymes, transcription factors, as well as genes regulating cell apopto-
sis (Ahmad et al., 2020; Gupta, Patchva, Koh, & Aggarwal, 2012).
Inhibitory influence of curcumin, the principal component of Curcuma
longa extract, has been demonstrated on mediators like collagenase,
elastase, cyclooxygenase, and hyaluronidase-related inflammation
process (Gupte et al., 2019). Curcumin has also shown inhibitory
effects on pro-inflammatory cytokines, including tumor necrosis
factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 (Bengmark, 2006;
Kang, Jung, Hyeon, Seon, & Lee, 2020; Kim et al., 2012; Yang, Wu,
Mao, Wang, & Tai, 2013). This agent was established to be non-toxic
even after using up to 8,000 mg per day for 3 months and was consid-
ered a harmless composite by the Food and Drug Administrations of
the United States (Chainani-Wu, 2003; Hatamipour, Sahebkar,
Alavizadeh, Dorri, & Jaafari, 2019; Soleimani, Sahebkar,
Hosseinzadeh, 2018).
Despite these promising preclinical data, limited evidence exists
regarding the efficacy, safety, optimal administration dosage, and fre-
quency of Curcuma longa extract for the treatment of knee OA in
humans. In addition, due to small sample sizes, these studies were not
adequately powered to detect the effect of Curcuma longa extract on
knee OA patients. The purpose of this study was to (a) evaluate the
efficacy and safety of all types of Curcuma longa extract versus pla-
cebo for knee OA treatment, (b) compare the efficacy and safety of
different dosages of Curcuma longa extract treatment, and (c) evaluate
the efficacy and safety of different durations of Curcuma longa extract
treatment.
2 | METHODS
We followed the recommendations of the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins & Green, 2011) to carry
out the study and we followed the PRISMA (Preferred Reporting
Items for Systematic Reviews and Meta-Analyses) statement (Moher,
Liberati, Tetzlaff, & Altman, 2009) to report our meta-analysis
(Table S1). This systematic review was registered prospectively in the
PROSPERO database (registration number CRD42020215753).
2.1 | Search strategy
A systematic literature search was conducted in PubMed, Embase,
Scopus, and the Cochrane Library from inception to April 23, 2021, to
identify randomized controlled trials (RCTs) that evaluated the effi-
cacy and safety of Curcuma longa extract versus placebo for knee OA
treatment. Electronic searches were performed with the use of Medi-
cal Subject Headings (MeSH) terms and corresponding keywords. The
search terms used were (MeSH “Curcuma”, “Curcumin” and keywords
“curcuma”, “turmeric”, “curcumin”, “curcuminoid”), and (MeSH
“Arthritis”, “Osteoarthritis”, “Osteoarthritis, Knee” and keywords
“arthritis”, “osteoarthritis”, “gonarthrosis”). The full electronic search
strategy on PubMed was presented in Table S2. Similar strategies
were used with other databases. We also searched ClinicalTrial.gov
and manually checked the bibliographies of identified articles, includ-
ing relevant reviews and meta-analyses to identify additional eligible
studies.
2.2 | Selection criteria
Two reviewers independently carried out the initial search, removed
duplicate records, screened the titles and abstracts for relevance, and
identified them as included, excluded, or uncertain. In case of uncer-
tainty, the full text of the article was reviewed to determine eligibility.
Discrepancies were resolved through discussion.
We included RCTs in this study based on the following criteria:
& (a) population (P): patients diagnosed with knee OA based on the
criteria described by the American College of Rheumatology (Altman
et al., 1986); (b) intervention (I): oral administration of Curcuma longa
extract; (c) comparison (C): oral administration of placebo; and (d) one
or more of the following outcomes (O): visual analog scale for pain
(VAS for pain) (Hawker, Mian, Kendzerska, & French, 2011), Western
Ontario and McMaster Universities Osteoarthritis Index (WOMAC)
total score, WOMAC sub-scores (WOMAC pain, function, and stiff-
ness scores) (McConnell, Kolopack, & Davis, 2001), and adverse
events. Adverse events were defined as any untoward event occur-
ring during the trial, regardless of its relation to treatment, such as
allergy, anorectal or gastrointestinal problems, headache, nausea, joint
pain, or infection. Observational studies, reviews, language other than
English, topical administration of Curcuma longa extract, and those
had not sufficient data on main parameters were excluded from this
meta-analysis.
2.3 | Data extraction
Data were extracted by two independent reviewers using a standard-
ized electronic form. Disagreements were resolved through discussion
with the help of a chief investigator and the consensus was reached in
all cases. The following data were extracted: first author, the year of
publication, country, the number of participants, age, sex, body mass
index (BMI), the severity of OA, intervention, the method of adminis-
tration, and outcomes data. Predefined primary outcomes were VAS
for pain and WOMAC total score. Secondary outcomes included
WOMAC pain score, WOMAC function score, WOMAC stiffness
score, and adverse events. When the same patients were reported in
several publications, we retained only the largest study, to avoid the
duplication of information. We also sought Data S1 of the included
DAI ET AL.
studies or contacted corresponding authors to verify extracted data
or to request missing data. To resolve any possible discrepancies
between the two reviewers, the final agreement was calculated by
Cohen's kappa statistics, and κ > 0.6 was assumed as substantial con-
sistency (Landis & Koch, 1977).
2.4 | Risk of bias assessment
Two independent reviewers used the Cochrane Risk of Bias tool
(Higgins & Green, 2011) to assess the risk of bias in the RCTs. Each
study was reviewed and scored as high, low, or unclear risk of bias
according to the following domains: random sequence generation,
allocation concealment, blinding of participants and personnel,
blinding of outcome assessment, incomplete outcome data, selective
reporting, and other bias. Discrepancies between the reviewers were
resolved by discussion until consensus was achieved.
2.5 | Quality of evidence
The GRADEpro GDT software online version (http://www.
guidelinedevelopment.org/ [accessed April 2021]) was used to evalu-
ate the overall quality of evidence. According to the GRADE guide-
lines, RCT evidence is initially allocated ‘high quality’, but can be
downgraded up to three levels to ‘moderate quality’, ‘low quality’, or
‘very low quality’ due to five categories of limitations. High quality
indicates that we are very confident that the true effect lies close to
that of the estimated effect; moderate quality indicates that the true
effect is likely to be close to the estimated effect, but there is a possi-
bility that it is substantially different; low quality indicates that the
true effect may be substantially different from the estimated effect;
and very low quality indicates that the true effect is likely to be sub-
stantially different from the estimated effect. Limitations considered
are (a) risk of bias (i.e., whether limitations in the study design and
execution would bias the effect estimate), (b) inconsistency of results
(i.e., high, unexplained heterogeneity), (c) indirectness of evidence
(e.g., if effects of Curcuma longa extract on knee OA had to be inferred
from indirect evidence amongst those without knee OA),
(d) imprecision (i.e., wide confidence intervals [CIs], including poten-
tially covering appreciable benefit and harm), and (e) other consider-
ations (i.e., selective publication of studies leading to a systematic bias
in the effect estimate) (Andrews et al., 2013).
2.6 | Statistical analysis
Outcomes were analyzed on an intention-to-treat basis with random-
effects models, as these models provide a more conservative estimate
than the fixed-effect model by incorporating both within- and
between-study variation (Berkey, Hoaglin, Mosteller, & Colditz, 1995).
In each study and for the outcome measures (VAS for pain, WOMAC
total, pain, function, and stiffness scores), we calculated the treatment
3
effect from the difference between the pre-intervention and post-
intervention changes in the treatment and control groups. For dichot-
omous outcome data (adverse events), we calculated relative risks
(RRs) with 95% CIs. For continuous outcome data, we calculated mean
differences (MDs) with 95% CIs. We applied the Hartung–Knapp
adjustment (Hartung & Knapp, 2001; IntHout, Ioannidis, &
Borm, 2014) to account for uncertainty in the estimation of between-
study variance in the random-effects meta-analysis. This variance is
imprecisely estimated when few studies are included and when some
studies are small, leading to 95% CIs that are much wider than for the
fixed-effect analysis. For the primary outcomes (VAS for pain and
WOMAC pain score), the pooled effect sizes were compared with
their minimum clinically important differences (MCID)—defined as the
smallest difference perceived as important by the average patient
(Doganay Erdogan, Leung, Pohl, Tennant, & Conaghan, 2016). When
the magnitude of the treatment effect equals or exceeds the MCID,
the management of a patient should be changed unless there are
adverse side effects or excessive costs (Jaeschke, Singer, &
Guyatt, 1989). Based on the previous work, the MCID for changes in
VAS for pain and WOMAC total score was set at 15% (Angst, Aes-
chlimann, Michel, & Stucki, 2002; Angst, Aeschlimann, & Stucki, 2001;
Hmamouchi et al., 2012; Tubach et al., 2012). Heterogeneity across
studies was tested by using the I2 statistic. I2 values of 25, 50, and
75% were considered to indicate low, moderate, and high heterogene-
ity, respectively (Higgins, Thompson, Deeks, & Altman, 2003). In addi-
tion, the 95% CIs for I2 were also calculated (Higgins &
Thompson, 2002). Bias secondary to small study effects was investi-
gated using funnel plots and the Egger test (Egger, Davey Smith,
Schneider, & Minder, 1997; Sterne & Egger, 2001). All analyses were
conducted using Stata statistical software version 16 (StataCorp). The
results were considered statistically significant at two-sided
p-values < .05.
2.7 | Primary sensitivity analyses
To check the effect of various factors on the efficacy and safety of
Curcuma longa extract, we did sensitivity analyses for the VAS for
pain, WOMAC function score, and adverse events, including studies
with different doses (≥1,000 mg Curcuma longa extract per day or
<1,000 mg Curcuma longa extract per day) of Curcuma longa extract
for knee OA. We did an additional sensitivity analysis for VAS for pain,
WOMAC function score, and adverse events with studies that
included different durations (<12 weeks of treatment duration or
≥12 weeks of treatment duration) of Curcuma longa extract treatment.
2.8 | Secondary sensitivity analyses
We did secondary sensitivity analyses for high-quality studies regard-
ing the VAS for pain, WOMAC function score, and adverse events.
According to the Cochrane Risk of Bias tool, studies were considered
high quality when all domains were judged to be at low risk of bias
4 DAI ET AL.
(Higgins & Green, 2011). We did additional sensitivity analyses with
studies conducted in Asian or Western populations, to account for
the efficacy and safety of Curcuma longa extract in different races.
3 | RESULTS
3.1 | Literature search
In the initial search, we identified 2,898 records. By removing dupli-
cate records, 1,537 studies remained for reading title and abstract.
Afterward, 1,468 studies were excluded after reading the titles and
abstracts and 69 studies finally remained for reading the full text.
After full-text examination, 59 studies were excluded due to the fol-
lowing reasons: wrong population or outcome (n = 30), commentary,
editorial, observational study, laboratory study, or review (n = 23), no
placebo (n = 4), or combining Curcuma longa extract with other agents
as an intervention group (n = 2). Finally, 10 RCTs were included
in this meta-analysis (Atabaki, Shariati-Sarabi, Tavakkol-Afshari, &
Mohammadi, 2020; Haroyan et al., 2018; Hashemzadeh, Davoudian,
Jaafari, & Mirfeizi, 2020; Henrotin et al., 2019; Madhu, Chanda, &
Saji, 2013; Nakagawa et al., 2014; Panahi et al., 2014; Panda,
Nirvanashetty, Parachur, Mohanty, & Swain, 2018; Srivastava,
Saksena, Khattri, Kumar, & Dagur, 2016; Wang et al., 2020). The study
flow diagram is shown in Figure 1. The 59 studies excluded from this
meta-analysis are listed in Data S1.
3.2 | Study characteristics
The study characteristics are presented in Table 1. These studies were
published between 2013 and 2020. The sample size of the studies
F I G U R E 1 Flowchart
illustrating the literature search
 DAI ET AL.

TABLE 1 Characteristics of included studies

Number of Mean age,

patients years Female/male
Target Treatment Study
Study Country CL Placebo CL Placebo CL Placebo population Intervention Comparator duration design Outcomes
Wang Australia 36 34 61.3 62.4 18/18 21/13 Knee OA 500 mg CL, Placebo, 12 weeks RCT, VAS for pain, MRI, WOMAC pain,
et al. (2020) patients BID BID DB function, and stiffness scores,
cartilage composition values, and
adverse events
Atabaki Iran 15 15 49.1 48.3 15/0 15/0 Knee OA 80 mg CL, Placebo, 12 weeks RCT, VAS for pain and laboratory tests
et al. (2020) patients QD QD DB
Hashemzadeh Iran 40 40 54.1 56.5 32/8 35/5 Knee OA 40 mg CL, Placebo, 6 weeks RCT, WOMAC pain, function, stiffness, and
et al. (2020) patients BID BID DB total scores
Henrotin Belgium 49 47 61.4 63.3 40/9 34/13 Knee OA 93 mg CL, Placebo, 12 weeks RCT, VAS for pain, KOOS score, laboratory
et al. (2019) patients BID BID DB tests, NSAID consumption, adverse
events, and patient's satisfaction
Panda India 25 25 55.2 53.1 - - Knee OA 500 mg CL, Placebo, 8.6 weeks RCT VAS for pain, WOMAC pain, function,
et al. (2018) patients QD QD stiffness, and total scores,
laboratory tests, and adverse events
Haroyan Armenia 66 68 54.7 56 60/6 65/3 Knee OA 333 mg CL, Placebo, 12 weeks RCT, WOMAC pain, function, stiffness, and
et al. (2018) patients TID TID DB total scores, OA physical
performance measures, laboratory
tests, and adverse events
Srivastava India 78 82 50.2 50.3 53/25 50/32 Knee OA 500 mg CL, Placebo, 16 weeks RCT VAS for pain, WOMAC pain, function,
et al. (2016) patients BID BID and stiffness scores, laboratory
tests, and adverse events
Panahi Iran 27 26 57.3 57.6 22/5 22/4 Knee OA 500 mg CL, Placebo, 6 weeks RCT VAS for pain, WOMAC pain, function,
et al. (2014) patients TID TID stiffness, and total scores,
Lequesne's pain functional index,
and adverse events
Nakagawa Japan 25 25 71.9 66.1 21/4 20/5 Knee OA 540 mg CL, Placebo, 8 weeks RCT VAS for pain, Japanese knee
et al. (2014) patients BID BID osteoarthritis measure, and NSAID
consumption
Madhu India 30 30 56.6 56.8 17/13 17/13 Knee OA 500 mg CL, Placebo, 6 weeks RCT VAS for pain, WOMAC total score,
et al. (2013) patients BID BID and adverse events

Abbreviations: BID, twice per day; CL, Curcuma longa extract; DB, double-blind; KOOS, Knee injury and Osteoarthritis Outcome Score; MRI, magnetic resonance imaging; NSAID, nonsteroidal antiinflammatory
drugs; OA, osteoarthritis; QD, once per day; RCT, randomized controlled trial; TID, three times per day; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.
5
6 DAI ET AL.

ranged from 30 to 160, with a total of 783 patients comprising 391 in

the Curcuma longa extract group, and 392 in the placebo group. The
severity of OA was classified by the Kellgren and Lawrence grading
scale (K-L) in eight studies (Atabaki et al., 2020; Haroyan et al., 2018;
Hashemzadeh et al., 2020; Henrotin et al., 2019; Madhu et al., 2013;
Nakagawa et al., 2014; Panda et al., 2018; Srivastava et al., 2016),
with five studies (Atabaki et al., 2020; Hashemzadeh et al., 2020;
Madhu et al., 2013; Nakagawa et al., 2014; Panda et al., 2018) includ-
ing patients with a K-L grade of 2 or 3, one study (Haroyan
et al., 2018) including patients with a K-L grade from 1 to 3, and two
studies (Henrotin et al., 2019; Srivastava et al., 2016) including
patients with a K-L grade from 1 to 4 before treatment. The Cohen κ
statistic for agreement on data screening and selection was 0.86.

3.3 | Risk of bias

Among the 10 studies, five studies (Atabaki et al., 2020; Haroyan

et al., 2018; Hashemzadeh et al., 2020; Henrotin et al., 2019; Wang
et al., 2020) were judged to be at low risk of bias while five (Madhu
et al., 2013; Nakagawa et al., 2014; Panahi et al., 2014; Panda et al., 2018;
Srivastava et al., 2016) were found to have a high risk of bias (Figure 2).

3.4 | MCID

Based on the previous work, the MCID for changes in the VAS for pain,
WOMAC total score was set at 15% (Angst et al., 2001; Angst et al., 2002;
Hmamouchi et al., 2012; Tubach et al., 2012). Thus, in the present study,
based on the baseline value of each outcome in the included studies, the
value of MCID for the VAS for pain was calculated as 0.97, and that for
the WOMAC total score was calculated as 5.93.

3.5 | Primary outcomes

3.5.1 | VAS for pain
A total of eight studies provided relevant data on the VAS for pain. The
pooled analysis showed that Curcuma longa extract was significantly
more efficacious in pain relief compared with placebo (MD: 2.21,
95% CI: 3.15 to 1.28, p < .0001, Figure 3), with significant hetero-
geneity (I = 94%, 95% CI: 91–96%). Moreover, for the difference of
2
VAS for pain between Curcuma longa extract and placebo, the smallest
treatment effect ( 1.28) exceeded the MCID (0.97 for VAS for pain).
F I G U R E 2 Risk of bias summary: review authors' judgments
about each risk of bias item for each included study. +: low risk of
bias; -: high risk of bias; ?: unclear risk of bias [Colour figure can be
viewed at wileyonlinelibrary.com]
Figure S1A), with significant heterogeneity (I2 = 81%, 95% CI: 57–
92%). Moreover, for the difference of WOMAC total score between
Curcuma longa extract and placebo, the smallest treatment effect
( 7.23) exceeded the MCID (5.93 for WOMAC total score).

3.6 | Secondary outcomes

3.5.2 | WOMAC total score
3.6.1 | WOMAC pain score
A total of five studies provided relevant data on the WOMAC total
score. The pooled analysis showed that Curcuma longa extract was A total of six studies provided relevant data on the WOMAC pain
significantly more efficacious in function improvement compared score. The pooled analysis showed that Curcuma longa extract was
with placebo (MD: 11.93, 95% CI: 16.63 to 7.23, p < .0001, significantly more efficacious in pain relief compared with placebo
DAI ET AL. 7

F I G U R E 3 Forest plot of
comparison: Curcuma longa
extract versus placebo. Outcome:
VAS for pain. CL, Curcuma longa
extract [Colour figure can be
viewed at wileyonlinelibrary.com]

(MD: 1.94, 95% CI: 2.80 to 1.09, p < .0001, Figure S1B), with sig- effect showed a significantly better VAS for pain (MD: 1.91, 95%
nificant heterogeneity (I2 = 76%, 95% CI: 47–89%). CI: 2.76 to 1.06, p < .0001, I2 = 83% [95% CI for I2: 62–93%],
Figure 4A) and WOMAC function score (MD: 6.01, 95% CI:
9.84 to 2.19, p < .0001, I2 = 66% [95% CI for I2: 0–90%],
3.6.2 | WOMAC function score Figure 4B) for Curcuma longa extract compared with placebo when
the dosage of Curcuma longa extract was ≥1,000 mg per day.
A total of six studies provided relevant data on the WOMAC function Moreover, there was no significant difference between Curcuma
score. The pooled analysis showed that Curcuma longa extract was longa extract and placebo regarding adverse events when the dos-
significantly more efficacious in function improvement compared with age of Curcuma longa extract was ≥1,000 mg per day (RR: 0.87,
placebo (MD: 6.45, 95% CI: 9.10 to 3.80, p < .0001, Figure S1C), 95% CI: 0.49–1.55, p = .64, I2 = 19% [95% CI for I2: 0–85%],
with significant heterogeneity (I = 83%, 95% CI: 64–92%).
2
Figure 4C).
A total of five studies reported the effect of Curcuma longa
extract for OA patients with dosage <1,000 mg per day. The overall
3.6.3 | WOMAC stiffness score pooled effect showed a significantly better VAS for pain (MD:
2.72, 95% CI: 4.96 to 0.48, p = .02, I2 = 98% [95% CI for I2:
A total of six studies provided relevant data on the WOMAC stiffness 96–99%], Figure 4A) and WOMAC function score (MD: 6.82,
score. The pooled analysis showed that Curcuma longa extract was 95% CI: 11.12 to 2.52, p < .0001, I2 = 88% [95% CI for I2: 68–
significantly more efficacious in function improvement compared with 96%], Figure 4B) for Curcuma longa extract compared with placebo
placebo (MD: 0.53, 95% CI: 0.95 to 0.11, p = .01, Figure S1D), when the dosage of Curcuma longa extract was <1,000 mg per day.
with significant heterogeneity (I2 = 77%, 95% CI: 49–90%). Moreover, there was no significant difference between Curcuma
longa extract and placebo regarding adverse events when the dos-
age of Curcuma longa extract was <1,000 mg per day (RR: 1.56,
3.6.4 | Adverse events 95% CI: 0.80–3.07, p = .19, I2 = 0% [95% CI for I2: 0–90%],
Figure 4C).
A total of seven studies compared the risk of adverse events in
Curcuma longa extract versus placebo. The pooled analysis showed
that there was no significant difference between Curcuma longa 3.7.2 | Duration of Curcuma longa extract treatment
extract and placebo (RR: 1.08, 95% CI: 0.69–1.70, p = .74) with low
heterogeneity (I2 = 19%, 95% CI: 0–71%). A total of five studies reported the effect of Curcuma longa extract for
OA patients with treatment duration ≥12 weeks. The overall pooled
effect showed a significantly better VAS for pain (MD: -2.16, 95% CI:
3.7 | Primary sensitivity analyses 4.03 to 0.29, p = 0.02, I2 = 97% [95% CI for I2: 95–98%],
Figure 5A) and WOMAC function score (MD: 4.01, 95% CI: 5.69
3.7.1 | Dosage of Curcuma longa extract to 2.33, p < .0001, I2 = 28% [95% CI for I2: 0–74%], Figure 5B) for
Curcuma longa extract compared with placebo when the treatment
A total of five studies reported the effect of Curcuma longa extract duration of Curcuma longa extract was ≥12 weeks. Moreover, there
for OA patients with dosage ≥1,000 mg per day. The overall pooled was no significant difference between Curcuma longa extract and
8 DAI ET AL.

F I G U R E 4 Forest plot of comparison: different dosages of Curcuma longa extract (≥1,000 mg per day or <1,000 mg per day) versus placebo.
Outcome: (A) VAS for pain; (B) Western Ontario and McMaster Universities Osteoarthritis Index function score; (C) adverse events. CL, Curcuma
longa extract [Colour figure can be viewed at wileyonlinelibrary.com]
DAI ET AL. 9

F I G U R E 5 Forest plot of comparison: Curcuma longa extract versus placebo in studies with different treatment durations (≥12 weeks or
<12 weeks). Outcome: (A) VAS for pain; (B) Western Ontario and McMaster Universities Osteoarthritis Index function score; (C) adverse events.
CL, Curcuma longa extract [Colour figure can be viewed at wileyonlinelibrary.com]
10
placebo regarding adverse events in a treatment duration ≥12 weeks
(RR: 1.00, 95% CI: 0.55–1.80, p = .99, I2 = 36% [95% CI for I2: 0–
78%], Figure 5C).
A total of five studies reported the effect of Curcuma longa
extract for OA patients with treatment duration <12 weeks. The over-
all pooled effect showed a significantly better VAS for pain (MD:
2.28, 95% CI: 3.04 to 1.52, p < .0001, I2 = 71% [95% CI for I2:
18–90%], Figure 5A) and WOMAC function score (MD: 8.96, 95%
CI: 10.56 to 7.37, p < .0001, I2 = 6% [95% CI for I2: 0–90%],
Figure 5B) for Curcuma longa extract compared with placebo when
the treatment duration of Curcuma longa extract was <12 weeks.
Moreover, there was no significant difference between Curcuma longa
extract and placebo regarding adverse events in a treatment duration
<12 weeks (RR: 1.48, 95% CI: 0.64 to 3.42, p = .36, I2 = 1% [95% CI
2
for I : 0–90%], Figure 5C).
3.8 | Secondary sensitivity analyses
In the five high quality studies, Curcuma longa extract was associated
with significantly better VAS for pain (MD: 2.45, 95% CI:
0.40, p = .02, I2 = 96% [95% CI for I2: 91–98%]) and WOMAC func-
tion score (MD: 5.29, 95% CI: 9.38 to 1.20, p = .01, I = 74%
2
[95% CI for I2: 13–92%]) compared with placebo. Moreover, there
was no significant difference between Curcuma longa extract and pla-
cebo regarding adverse events (RR: 1.06, 95% CI: 0.58 to 1.92,
p = .85, I = 36% [95% CI for I : 0–79%]).
2 2
In the eight studies conducted in Asian populations, Curcuma
longa extract was associated with significantly better VAS for pain
(MD: 2.56, 95% CI: 3.68 to 1.44, p < .0001, I2 = 94% [95% CI
2
for I : 90–97%]) and WOMAC function score (MD: 6.83, 95% CI:
9.88 to 3.78, p < .0001, I2 = 86% [95% CI for I2: 69–94%]) com-
pared with placebo. Moreover, there was no significant difference
between Curcuma longa extract and placebo regarding adverse events
(RR: 1.33, 95% CI: 0.68–2.62, p = .41, I = 11% [95% CI for I : 0–
2 2
79%]). Similarly, in the two studies conducted in Western populations,
Curcuma longa extract was associated with significantly better VAS
for pain (MD: 1.28, 95% CI: 1.88 to 0.69, p < .0001, I2 = 37%
2
[95% CI for I : 0–80%]) compared with placebo. Moreover, there was
no significant difference between Curcuma longa extract and placebo
regarding adverse events (RR: 0.98, 95% CI: 0.47–2.04, p = .96,
I2 = 51% [95% CI for I2: 0–88%]). We could not pool the WOMAC
function score for Western populations because only one study pro-
vided the data.
3.9 | Quality of the evidence
The GRADE evidence profile for the primary and secondary outcomes
is shown in Table 2. The quality of evidence was assessed as high for
adverse events, moderate for VAS for pain, WOMAC pain score, and
WOMAC function score, low for WOMAC total score and WOMAC
stiffness score.
DAI ET AL.
3.10 | Publication bias
For comparisons involving five or more studies, visual inspection of
funnel plots revealed minimal asymmetry (Data S2), suggesting the
absence of significant publication bias (p = .108 using the Egger test).
4 | DI SCU SSION
The principal findings of this study show that Curcuma longa extract is
associated with significantly better pain relief and functional improve-
ment compared with placebo. The effect sizes of VAS for pain and
WOMAC pain score exceeded the MCID. Moreover, a similar
improvement in pain and function was seen in favor of Curcuma longa
extract treatment compared with placebo in different Curcuma
longa extract dosages and treatment durations. We also found that
Curcuma longa extract did not increase the risk of adverse events
compared with placebo.
Our findings are consistent with those of previous observational
studies and clinical trials on the efficacy of Curcuma longa extract for
4.50 to knee OA. A large observational study with 820 patients on the effi-
cacy of Curcuma longa extract reported a significant improvement in
articular mobility, pain, and quality of life at 6 months of follow-up
(Appelboom, Maes, & Albert, 2014). A 6-week, single-blind RCT
reported a significant improvement in clinical symptoms and a reduc-
tion in the use of rescue medication for Curcuma longa extract com-
pared with placebo (Madhu et al., 2013). A 12-week placebo-
controlled, double-blind RCT showed Curcuma longa extract was more
effective than placebo for knee pain (Wang et al., 2020). An RCT with
bio-optimized Curcuma longa extract showed positive trends in mea-
surements of patients' global assessment of disease activity over
12 weeks (Henrotin et al., 2019). We did not find any difference in
the number of adverse events between Curcuma longa extract and
placebo, indicating that Curcuma longa extract was safe and modestly
effective in treating knee OA.
According to recent laboratory studies, one of the mechanisms
for the protective effects of Curcuma longa extract for OA is its
antiinflammatory properties (Aggarwal, Gupta, & Sung, 2013;
Chin, 2016; Panahi, Sahebkar, Parvin, & Saadat, 2012). By inhibiting
nuclear factor kappa-B (NF-κB), Curcuma longa extract can lead to the
reduction of several key regulators of inflammation such as activator
protein-1, MAPK, JNK, cyclooxygenase-II, and PI3K/Akt (Shakibaei,
John, Schulze-Tanzil, Lehmann, & Mobasheri, 2007). Curcuma longa
extract can effectively reduce the release of pro-inflammatory cyto-
kines such as TNF- α, IL-1β, IL-6, prostaglandin E2, and macrophage
chemotactic protein-1 in chondrocytes (Chowdhury, Salter, Bader, &
Lee, 2008; Csaki, Mobasheri, & Shakibaei, 2009; Mathy-Hartert
et al., 2009). Furthermore, the inhibition of NF-κB by Curcuma longa
extract inhibits the catabolic actions of matrix metalloproteinase
(MMP) enzymes. Because of the inhibition of MMPs, Curcuma longa
extract can promote extracellular matrix synthesis and prevent carti-
lage degradation (Buhrmann et al., 2011; Clutterbuck, Mobasheri,
Shakibaei, Allaway, & Harris, 2009; Csaki et al., 2009; Mathy-Hartert
 DAI ET AL.

TABLE 2 GRADE quality grading evaluation of the systematic review

Quality assessment Number of patients

Number of Risk Other Curcuma longa

studies Design of bias Inconsistency Indirectness Imprecision considerations extract Placebo Effect GRADE Importance

VAS for pain

8 RCT No Serious1 No serious No serious None 285 284 MD 2.21 ( 3.15 to ⨁⨁⨁◯ CRITICAL
serious 1.28) MODERATE

WOMAC total score

5 RCT No Serious1 No serious No serious Reporting bias2 188 189 MD 11.93 ( 16.63 to ⨁⨁◯◯ CRITICAL
serious 7.23) LOW

WOMAC pain score

6 RCT No Serious1 No serious No serious None 272 275 MD 1.94 ( 2.80 to ⨁⨁⨁◯ CRITICAL
serious 1.09) MODERATE

WOMAC function score

6 RCT No Serious1 No serious No serious None 272 275 MD 6.45 ( 9.10 to ⨁⨁⨁◯ CRITICAL
serious 3.80) MODERATE

WOMAC stiffness score

6 RCT No Serious1 Serious3 No serious None 272 275 MD 0.53 ( 0.95 to ⨁⨁◯◯ IMPORTANT
serious 0.11) LOW

Adverse events

7 RCT No No serious No serious No serious None 45/316 (14.2%) 40/312 RR 1.08 (0.69 to 1.70) ⨁⨁⨁⨁ CRITICAL
serious (12.8%) HIGH

Abbreviations: GRADE, GRADE working group grades of evidence; MD, mean difference; RCT, randomized controlled trial; RR: relative risk; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.
(Reasons for grading are as follows: 1, there is severe heterogeneity; 2, small sample bias may exist; and 3, indirectness).
11
12
et al., 2009; Shakibaei et al., 2007). In addition, a study has also found
that Curcuma longa extract could increase chondrocyte survival
through down-regulation of inflammation-induced apoptosis (Csaki
et al., 2009).
In addition to its antiinflammatory function, Curcuma longa extract is
a potent antioxidant and has been shown to modulate oxidative stress
through various mechanisms. The study has observed that reactive oxy-
gen species can enhance the expression of MMP, damage the cartilage
matrix hemostasis, promote chondrocytes apoptosis, as well as increase
pain-related mediators (Abramson, 2008; Panahi et al., 2014). Because of
the phenolic hydroxyl groups in the chemical structure, Curcuma longa
extract can scavenge free radicals, which results in decreasing lipid per-
oxidation and oxidative damage to proteins and DNA (Panahi
et al., 2014). Moreover, Curcuma longa extract inhibits the activity of the
enzymes, such as 5-lipoxygenase, COX-II, and nitric oxide synthase, to
prevent the synthesis of free radicals, and enhances the intra-cellular
antioxidant defense by stimulating the nuclear factor-erythroid-2-related
factor 2 (Nrf-2) (Ak & Gülçin, 2008). In our study, Curcuma longa extract
was significantly more effective in pain relief and functional improvement
compared with placebo in patients with knee OA, which is in line with
the previous laboratory studies.
Over the last 25 years, the concept of a minimal clinically impor-
tant difference (MCID) has emerged in the outcomes literature. A clin-
ically important difference is defined as a change or difference in the
outcome measure that would be perceived as important and benefi-
cial by the clinician or the patient (Gazendam, Ekhtiari, Bozzo, Phil-
lips, & Bhandari, 2021; Saltzman et al., 2017). An MCID is, therefore, a
threshold value for such change. In Outcome Measures in Rheumatol-
ogy (OMERACT) meetings 5–7, the anchor-based method was rec-
ommended as the method of choice (Crosby, Kolotkin, &
Williams, 2003; Wells et al., 2001; Wells et al., 2001). The MICD aids
clinicians as a tool in evaluating therapeutic options and determining
whether significant outcomes will have clinically meaningful implica-
tions (Zlowodzki & Bhandari, 2009). In our study, the effect sizes of
primary outcomes (VAS for pain and WOMAC total score) were com-
pared with their MCID. Our meta-analysis shows that Curcuma longa
extract was associated with better pain relief and function improve-
ment compared with placebo because the smallest treatment effect
was greater than the MCID (i.e., the lower limit of the CI of VAS for
pain and WOMAC total score was greater than the MCID).
Despite the promising effect of Curcuma longa extract to prevent
OA progression, the optimal administration dosage and treatment
duration for humans remains unknown. Theoretically, a higher dosage
may further increase the antiinflammatory and anti-oxidant effects of
the agent, which may result in better pain relief for OA patients. How-
ever, the probability of adverse events may also increase. In contrast,
a lower dosage may result in a lower adverse events rate, but the
antiinflammatory and anti-oxidant effects may decrease. In our study,
a similar improvement in pain and function was seen in favor of differ-
ent dosages of Curcuma longa extract treatment compared with pla-
cebo. Higher pain relief and functional improvement were also
observed after different treatment durations of Curcuma longa extract
compared with placebo. Moreover, there was no significant difference
DAI ET AL.
in adverse events between Curcuma longa extract and placebo in dif-
ferent dosages and durations of Curcuma longa extract treatment.
Due to the lack of rigorous regulation, the need for the manufac-
turer of the nutraceutical to prove efficacy, safety, and quality of a
marketed product is less strongly enforced than in the pharmaceutical
sector. Therefore, many available products might be ineffective. How-
ever, systematic reviews and meta-analyses are at the top in the hier-
archy of clinical evidence and can be very useful on these kinds of
topics in that they help with a comprehensive conclusion, which can
give the ultimate idea of whether or not to use a specific nutraceutical
as an effective medicinal agent (Izzo, Hoon-Kim, Radhakrishnan, &
Williamson, 2016; Williamson, Liu, & Izzo, 2020).
Some limitations of our study need to be mentioned. First, the
studies included were heterogeneous in terms of the preparation of
Curcuma longa extract. This factor may lead to potentially differing
biological activity of Curcuma longa extract that can result in different
physiological responses in patients. In addition, there was also sub-
stantial heterogeneity among the patients, such as patient age, sex,
BMI, activity level, and OA grade. These factors could also affect the
pain and function-related outcomes. Second, none of the included
studies reported on knee survivorship—that is, the number of patients
who ultimately failed the therapy and went on to require a total knee
arthroplasty. Third, several studies we included in the analysis suf-
fered from important methodological limitations. The potential risk of
bias that those studies pose has weakened our inference of the treat-
ment effects.
5 | CONC LU SIONS
Current evidence indicates that, compared with placebo, Curcuma
longa extract has more benefit in pain relief and functional improve-
ment in patients with symptomatic knee OA. However, considering
the potential heterogeneity in the included RCTs, these results need
to be interpreted with caution. More future high-quality RCTs with
large sample sizes are necessary to confirm the benefits of Curcuma
longa extract on knee OA.
ACKNOWLEDG MENTS
The authors thank information specialist He Xiao from Nanfang Hos-
pital, Guangzhou, China, for assistance in the literature search. This
work was supported by grants from the National Natural Science
Foundation of China (Nos. 81672212, 81802153, and 81902205), the
Beijing Natural Science Foundation (Nos. 7171014, 7174361, and
7182175), and the Beijing Municipal Science and Technology Com-
mission (No. Z171100001017085).
CONFLIC T OF INT ER E ST
The authors declare no conflict of interest.
AUT HOR S' CONT R IBUT IONS
Yingfang Ao and Xiaoqing Hu conceived and designed the study. Xi
Leng, Wenqiang Yan, and Wenli Dai searched and selected studies,
DAI ET AL.
analyzed the data, wrote and revised the paper. Jing Chen, Xi Leng,
and Wenli Dai prepared the figures and tables. All authors read and
agreed with the final statement.
DATA AVAI LAB ILITY S TATEMENT
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
ORCID
Yingfang Ao https://orcid.org/0000-0001-8103-5050
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SUPPORTING INF ORMATION
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Supporting Information section at the end of this article.
How to cite this article: Dai, W., Yan, W., Leng, X., Chen, J.,
Hu, X., & Ao, Y. (2021). 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, 1–15. https://doi.org/10.1002/
ptr.7204