Complementary Therapies in Medicine 63 (2021) 102775

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Complementary Therapies in Medicine

journal homepage: www.elsevier.com/locate/ctim

The efficacy of high- and low-dose curcumin in knee osteoarthritis: A

systematic review and meta-analysis
An-Fang Hsiao a, Yi-Chieh Lien b, I-Shiang Tzeng c, Chien-Ting Liu d, e, Sheng-Hsun Chou d,
Yi-Shiung Horng d, e, *
a
Department of Physical Medicine and Rehabilitation, Cheng Ching Hospital Chung Kang Branch, Taichung City, Taiwan, ROC
b
Department of Physical Medicine and Rehabilitation, Cardinal Tien Hospital An Kang Branch, New Taipei City, Taiwan, ROC
c
Department of Research, Taipei Tzu chi Hospital, Buddhist Tzu chi Medical Foundation, New Taipei City, Taiwan, ROC
d
Department of Physical Medicine and Rehabilitation, Taipei Tzu chi Hospital, Buddhist Tzu chi Medical Foundation, New Taipei City, Taiwan, ROC
e
Department of Medicine, Tzu Chi University, Hualien, Taiwan, ROC

A R T I C L E I N F O A B S T R A C T

Keywords: Objectives: The aim of this study was to critically appraise and evaluate effects of low- and high-dose curcumi­
Clinical trial noids on pain and functional improvement in patients with knee osteoarthritis (OA) and to compare adverse
Curcumin events (AEs) between curcuminoids and non-steroid anti-inflammatory drugs (NSAIDs).
Curcuminoid
Methods: We systematically reviewed all randomized controlled trials (RCTs) on curcuminoids in knee osteoar­
Knee osteoarthritis
Meta-analysis
thritis from the PubMed, Embase, Cochrane Library, AMED, Cinahl, ISI Web of Science, Chinese medical data­
Systematic review base, and Indian Scientific databases from inception to June 21, 2021.
Results: We included eleven studies with a total of 1258 participants with primary knee OA. The meta-analysis
results showed that curcuminoids were significantly more effective than comparators regarding visual
analogue scale (VAS) and Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain scores.
However, no significant difference in pain relief or AEs between the high-dose (daily dose ≥1000 mg or total
dose ≥42 gm) and low-dose (daily dose <1000 mg or total dose <42 gm) curcuminoid treatments was observed.
When comparing curcumininoids versus NSAIDs, a significant difference in VAS pain was found. For AE analysis,
three of our included studies used NSAIDs as comparators, with all reporting higher AE rates in the NSAID group,
though significance was reached in only one study.
Conclusions: The results of our meta-analysis suggest that low- and high-dose curcuminoids have similar pain
relief effects and AEs in knee OA. Curcuminoids are also associated with better pain relief than NSAIDs;
therefore, using curcuminoids as an adjunctive treatment in knee OA is recommended.

1. Introduction individuals with comorbidities may experience some adverse events

Osteoarthritis (OA) is a common degenerative disease that results in
pain, disability and poor quality of life. OA affects approximately 240
million people worldwide, approximately 10 % of men and 18 % of
women.1 Although the prevalence of knee OA is high worldwide, the
cause of OA remains uncertain, and there is no curative treatment for its
fundamental causes.2,3 Current treatments for knee OA include phar­
macological treatment, physiotherapy, bracing, prolotherapy and even
surgery, depending on the severity. The first-line medication for OA is
non-steroid anti-inflammatory drugs (NSAIDs)4–6; however, elderly
(AEs) associated with these drugs. Therefore, researchers have been
studying the effects of antioxidant supplements, such as curcuminoids,
on knee OA.7
Curcuminoids, especially curcumin, the extract of Jiang Huang
(Rhizoma Curcumae Longae, English name turmeric), are derived from
Chinese herbs and commonly used as food flavouring and colouring. The
major components of turmeric roots are volatile oils and curcuminoids8;
the latter includes diferuloylmethane (82 %), demethoxycurcumin (15
%), and bisdemethoxycurcumin (3%)”, three major components in
commercial curcumin.8 Curcuminoids have been shown to possess

* Corresponding author at: Department of Physical Medicine and Rehabilitation, Taipei Tzu chi Hospital, Buddhist Tzu chi Medical Foundation, No.289, Jianguo
Rd., Xindian Dist., New Taipei City 231, Taiwan, ROC.
E-mail address: yshorng2015@gmail.com (Y.-S. Horng).

https://doi.org/10.1016/j.ctim.2021.102775
Received 5 May 2021; Received in revised form 11 August 2021; Accepted 14 September 2021
Available online 16 September 2021
0965-2299/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
 A.-F. Hsiao et al.
Table 1
Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence profile for the role of curcuminoids in knee osteoarthritis of the eleven studies included in the meta-analysis.
Certainty assessment N◦ of patients Effect

N◦ of Study design Risk of Inconsistency Indirectness Imprecision Other Curcumin Placebo or Relative (95 % CI) Absolute (95 % CI) Certainty Importance
studies bias considerations NSAIDs

ADVERSE EVENTS
a
9 randomised serious not serious not serious not serious none 119/584 150/591 OR 0.770 46 fewer per 1000 (from ⨁⨁⨁x̂ CRITICAL
trials (20.4 %) (25.4 %) (0.491–1.207) 111 fewer to 37 more) MODERATE
VAS pain scale
a, c
9 randomised serious serious not serious not serious publication bias 626 632 SMD -1.658 (-2.558 – per 1000 (from – to –) ⨁x̂x̂x̂ VERY IMPORTANT
b
trials suspected d to -0.758) LOW
WOMAC total score
b, c
6 randomised serious serious not serious not serious none 365 362 SMD -0.793 (-1.350 – per 1000 (from – to –) ⨁⨁x̂x̂ LOW CRITICAL
e
trials to -0.237)
WOMAC pain
2

b, c
5 randomised serious serious not serious not serious none 365 362 SMD -0.787 (-1.317 – per 1000 (from – to –) ⨁⨁x̂x̂ LOW CRITICAL
e
trials to -0.257)
WOMAC physical function
b, c
5 randomised serious serious not serious not serious none 365 362 SMD 1.502 (-2.693 – per 1000 (from – to –) ⨁⨁x̂x̂ LOW IMPORTANT
e
trials to -0.310)
WOMAC stiffness
b, c
5 randomised serious serious not serious not serious none 365 362 SMD -1.203 (-2.313 – per 1000 (from – to –) ⨁⨁x̂x̂ LOW IMPORTANT
e
trials to -0.092)

CI: Confidence interval; OR: Odds ratio.

a
Three studies had performance bias due to incomplete blinding of participants and personnel.
b
Three studies had incomplete outcome data.

Complementary Therapies in Medicine 63 (2021) 102775

c
Statistically significant of heterogeneity with low p value and high I square.
d
Egger’s test of the VAS score was significant (p = 0.024), with substantial asymmetry in the funnel plot.
e
One study had performance bias due to incomplete blinding of participants and personnel.
A.-F. Hsiao et al.
Fig. 1. Flow chart of study selection.
multiple pharmacological effects, such as anti-inflammatory, anti-­
oxidative, anti-hyperlipidaemic, and anti-platelet effects, and also to
relieve pain and reduce swelling.9–11 These properties can be attributed
to curcumin acting as an inhibitor of the nuclear factor-kappa β (NF-κβ)
pathway and a scavenger of reactive oxygen and nitrogen species.12
Curcuminoids are employed as adjunctive treatment for rheumatoid
arthritis,13–15 degenerative neural disease,16 some cancers17–19 and
polycystic ovary disease.20 In general, curcumin’s side effects are not as
severe as those of NSAIDs; although some people might experience
nausea or diarrhoea after ingesting curcumin, these side effects are
self-limited and not dose-dependent.21
Recent randomized controlled trials (RCTs) have revealed that cur­
cumin has similar effects on pain relief and fewer gastrointestinal AEs
than NSAIDs, such as diclofenac and ibuprofen.22,23 Moreover, Ali
Mobasheri et al. reported that “curcumin synergistically potentiates the
growth-inhibitory and pro-apoptotic effects of the NSAID in OA-derived
synovial adherent cells”,8 suggesting that combination treatment with
curcumin and an NSAID may lower the NSAID dosage needed and
reduce its side effects. Additionally, a recent study by Shep et al. re­
ported less rescue medication use and fewer AEs in patients taking
combined curcuminoid and diclofenac than in those taking diclofenac
alone.23
Previous meta-analyses have shown that curcuminoids have benefi­
cial effects on knee OA.24–28 However, to the best of our knowledge, no
systematic review or meta-analysis has investigated curcuminoids with
regard to the daily or total dose on the effects of knee OA. Therefore, the
aim of this study was to critically appraise and evaluate the effects of low
and high doses of curcuminoids on pain and functional improvements in
patients with knee OA and to compare AEs between curcuminoids and
NSAIDs.
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Complementary Therapies in Medicine 63 (2021) 102775
2. Methods
2.1. Data sources/searches
We searched the PubMed, Embase, Cochrane Library, AMED, Cinahl,
ISI Web of Science, Chinese medical databases and Indian Scientific
databases. The search was conducted using appropriate English and
Chinese terms. The following keywords of Medical Sub Headings
(MeSH) were used as search terms: “curcumin,’’ “curcuma,’’
“turmeric,’’ “Curcuma domestica,’’ “Curcuma Longa,’’ “arthritis,’’
“osteoarthritis,’’ and “randomized.’’ RCTs were retrieved from the
available databases from inception to June 21, 2021 (Appendix 1).
2.2. Study selection
RCTs that assessed the effectiveness of curcuminoid formulations
against either a matching placebo or NSAIDs were included. Exclusion
criteria were as follows: non-RCTs involving concomitant medications
such as NSAIDs or other analgesics; medication not administered orally;
patients followed for fewer than 30 days; no thorough outcome mea­
sures; not written in English or Chinese; use of other interventions
concomitantly (such as additional nutraceuticals or herbal supplements
and invasive measurements); and no data available after contact with
authors electronically. RCTs in which NSAIDs or other analgesics were
used as rescue medications were included. RCTs containing more than
one intervention arm were included if the curcuminoid-only interven­
tion could be extracted in comparison with placebo. RCTs evaluating
compound medicines were excluded because it is difficult to differen­
tiate whether the effectiveness is due to curcuminoids or other
ingredients.
Three researchers independently searched using the MeSH terms
mentioned above. Two researchers screened each abstract according to
the inclusion and exclusion criteria. The abstracts selected underwent a
second screening while the full texts were obtained. Wherever addi­
tional information was required, we contacted the authors
electronically.
2.3. Outcome definitions
Outcomes of interest included pain scale scores evaluated by the
visual analogue scale (VAS) and Western Ontario and McMaster Uni­
versities Arthritis Index (WOMAC). WOMAC subscales of pain, physical
function and joint stiffness were used for subgroup analysis. AEs was
analysed as secondary outcomes.
2.4. Quality assessments
The Cochrane Risk of Bias Tool was employed to assess the included
RCTs. The following categories were examined: (1) method of
randomization, (2) allocation concealment, (3) blinding of participants
and personnel, (4) blinding of outcome assessment, (5) incomplete
outcome data, (6) selective outcome reporting, and (8) other bias. Each
domain was labelled as low risk of bias (+), high risk of bias (-) or un­
clear risk of bias (?). Two independent reviewers performed the quality
assessment and resolved disagreements via discussion.
2.5. Statistical analysis
The effects of curcumin were examined based on pre- to post-
intervention changes. We used the standardized mean difference
(SMD) and 95 % confidence intervals (CIs) for all continuous outcomes
and the odds ratio (OR) and 95 % CIs for AEs. A random-effects model
A.-F. Hsiao et al. Complementary Therapies in Medicine 63 (2021) 102775

Table 2
Characteristics of included studies.
Study author Year Patients Age (yrs) Duration Intervention Comparator Outcomes Rescue AEs (n) Funding
Country (n) Sex (% (weeks) medication -curcuminoids-
men) (daily dose) control

60.7 Curcuminoids Ibuprofen 39

Kuptniratsaikul, VAS on level
− 16
et al. 2009 107 6 2000 mg/day 800 mg/day walking and None None
19.6% − 23
Thailand (n = 52) (n = 55) stairs
P = 0.36
NA Curcuminoids VAS
Moharamzad, et al. Placebo (n =
67 10 600 mg/day (n WOMAC NA NA NA
2011 Iran NA 32)
= 35) QoL
56.7 Curcuminoids Placebo VAS Paracetamol 4
Madhu, et al. 2013
60 6 1000 mg/day 800 mg/day WOMAC (2000− 4000 − 2 NA
India 43.3%
(n = 30) (n = 30) CGIC* mg) − 2
57.5 Curcuminoids Placebo VAS Naproxen 11
Panahi, et al. 2014
53 6 1500 mg/day 1500 mg/day WOMAC − 7 None
Iran 23%
(n = 27) (n = 26) QoL − 4
68.7 Curcuminoids Placebo VAS Similar minor
Nakagawa, et al. Celecoxib (200
41 8 180 mg/day (n JKOM** adverse events in Manufacturer
2014 Japan 21.1% (n = 23) mg)
= 18) JOA*** both groups
60.6 Curcuminoids Ibuprofen Tramadol 120
Kuptniratsaikul, WOMAC 6-mi­
− 55
et al. 2014 367 4 1500 mg/day 1200 mg/day nutes walking None
10.% − 65
Thailand (n = 185) (n = 182) test
P = 0.222
50.3 Curcuminoids VAS Diclofenac 6
Srivastava, et al. Placebo (n =
160 16 500 mg/day (n − 2 Manufacturer
2016 India 35.6% 82) WOMAC (100 mg)
= 78) − 4
54.2 Curcuminoids VAS 5
Panda, et al. 2018 4 (30 Placebo (n = WOMAC Paracetamol − 3
50 500 mg/day (n Manufacturer
India NA days) 25) Lab data for (2000 mg)
= 25) − 2
safety concerns
55.4 Curcuminoids WOMAC 11
Haroyan, et al. Placebo (n = Physical − 7
134 12 999 mg/day (n NA Manufacturer
2018 Armenia 6.7% 68) performance
= 66) − 4
test
Paracetamol
52.6 Curcuminoids Diclofenac VAS 35
(500 mg)
Shep, et al. 2019
149 4 − 9 None
India 1500 mg/day 100 mg/day Ranitidine (150
66.9% KOOS**** − 26
(n = 74) (n = 75) mg)
P<0.01
61.8 Curcuminoids VAS 32
WOMAC − 14
Wang, et al. 2020 Placebo (n =
70 12 1000 mg/day Effusion volume Paracetamol − 18 Manufacturer
Australia 44.3% 34)
(n = 36) Cartilage 2 severe AEs in
composition placebo group
*
CGIC: Clinician Global Impression Change (CGIC) scale.
**
JKOM: Japanese Knee Osteoarthritis Measure.
***
JOA: Japanese Orthopedic Association.
****
KOOS: Knee Injury and Osteoarthritis Outcome Score.

was applied to pool SMDs or ORs across studies by Comprehensive Meta-
Analysis software (Version 3.0). Statistical heterogeneity was assessed
using the chi-squared test and I-squared values. I-squared >75 % indi­
cated moderate to substantial heterogeneity, 50% ≤ I-squared ≤75 %
mild heterogeneity, and 0% ≤ I-squared ≤50 % low or no heterogeneity.
Moreover, subgroup analyses were conducted on the basis of different
daily and total doses. Sensitivity analysis was used to evaluate the
impact of each individual study on the overall analysis by deleting one
study at a time and recalculating the pooled results from each subset of
the studies. To further analyse potential publication bias, funnel plots
are presented for clinical outcomes. Egger’s test was used to examine the
symmetry of funnel plots; P>0.05 indicates no publication bias. Due to
the small number of included studies, we also performed the random-
effects models with Hartung-Knapp adjustment for overall meta-
analyses using R software (version 4.0.0).
2.6. Evidence grading
To objectively measure the power of the included studies, we used
the modified Downs and Black quality score as an evaluation tool,29 with
27 domains, each scored as 1 for matched and 0 for not matched. The
corresponding quality levels were excellent (26− 28), good (20–25), fair
(15–19) or poor (≤14). Two reviewers evaluated quality independently
and resolved discrepancies via consensus. Most of our included studies
showed fair quality (scored between 15 and 25), except for one that
showed low quality (scored 4) because no full text was available (Ap­
pendix 2). We also used the Grading of Recommendations Assessment,
Development and Evaluation (GRADE) approach to evaluate the cer­
tainty of the outcomes, which rates certainty at one of four levels,
namely, high, moderate, low, and very low.30 As shown in Table 1, the
certainty of the AE was graded as moderate, and those of the WOMAC
and its subscales were graded as low.

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A.-F. Hsiao et al. Complementary Therapies in Medicine 63 (2021) 102775

3.1. Curcumin effectiveness for knee pain evaluated by VAS

Fig. 3 shows the results of nine RCTs using VAS pain as an outcome
assessment. Among them, two of the studies compared curcuminoids
with NSAIDs (n = 256), and seven studies compared curcuminoids with
placebo (n = 501). As shown in Fig. 3B, curcuminoids were significantly
more effective than NSAIDs even after Hartung-Knapp adjustment.

3.2. AEs for curcumin vs. placebo and curcumin vs. NSAIDs

Nine studies (n = 1150) reported AEs, which mainly comprised

gastrointestinal discomfort, such as abdominal pain or distension,
dyspepsia, nausea and vomiting. A small number of gastrointestinal
discomforts reported were bloating, diarrhoea and loose stool. Other
reported AEs include pitting oedema, dizziness, generalized body pain,
headache, dry mouth, skin rash and cough.
As shown in Fig. 4, there was no significant difference between the
curcuminoid and control groups according to the AE analysis. Among
the analysed studies, three (n = 623) employed NSAIDs as comparators,
and the other six studies used a placebo. Although the subgroup analysis
showed there was no statistical significance between curcuminoids and
NSAIDs, more AEs occurred in the NSAID group based on an investi­
gation of the clinical trials individually, but only one result reached
significance (Fig. 4B).

3.3. Curcumin effectiveness in knee pain and function evaluated by

WOMAC

Eight studies (n = 961) used the WOMAC as the assessment tool. Two
(n = 230) only evaluated WOMAC subscales, and two (n = 127) only
presented the WOMAC total scale as the outcome assessment. Analysis of
the six studies presenting the WOMAC total scale showed no significant
beneficial effects for curcuminoids (Fig. 5A). In the WOMAC subscale
analysis, curcuminoid exhibited significant beneficial effects in WOMAC
pain even after Hartung-Knapp adjustment, while the physical function
and stiffness subscales lost their significance after adjustment
(Fig. 5B–D).
Fig. 2. Risk of Bias Distribution Summary and Graph.

3.4. Curcumin effectiveness for pain: curcumin at low and high doses vs.
comparator
3. Results
To assess dose effects of curcuminoids, we defined a high dose as a
Our searches yielded 1516 references, and we excluded 1450 studies
daily dose ≥1000 mg or a total dose ≥42 gm. In nine studies that used
that were not clinical trials. Eleven RCTs were ultimately included in
VAS as an assessment tool, five (n = 439) involved a ≥1000 mg daily
accordance with the inclusion and exclusion criteria (Fig. 1). Eight RCTs
dose and seven (n = 666) a ≥42 gm total dose.
compared curcuminoids against placebo,31–38 and the other three RCTs
Before Hartung-Knapp adjustment, both low and high daily or total
compared curcuminoids against NSAIDs.22,39,40
doses of curcuminoids had beneficial effects on VAS pain, but the results
The characteristics of the RCTs included in our meta-analysis are
remained significant only in the high daily dose subgroup after adjust­
shown in Table 2. The studies were published between 2009 and 2020,
ment (Fig. 6A and B). However, pooled CIs between the low and high
and the total sample size ranged from 41 to 367. The treatment duration
doses overlapped, which indicated no significant difference in VAS pain
varied from 30 days to 4 months, and the daily and total dose ranged
reduction between the doses.
from 180 mg to 1500 mg and from 10.08 g to 84 g, respectively. Rescue
medications, namely, naproxen, celecoxib and acetaminophen, were
used in six of the studies. Eight studies used placebo as the comparator, 3.5. AEs: curcumin at low and high doses vs. comparator
two studies used ibuprofen, and one used diclofenac.
Fig. 2 describes the quality of studies and overall risk of bias distri­ In nine studies reporting AEs, six used a high daily dose, and 8 used a
high total dose. The analysis revealed no significance for AEs in the low
bution in our meta-analysis. The overall quality was relatively low for
detection bias, reporting bias and possibly sponsorship bias. vs. high dose analysis (Fig. 7A and B).

3.6. Sensitivity analysis

In the sensitivity analysis, we used a “leave-one-out” evaluation

5
A.-F. Hsiao et al.
Fig. 3. Forest Plot of the effects on VAS pain A) curcuminoids vs. comparator and B) comparator of placebo vs. comparator of NSAID.
procedure to assess the stability of the estimated measures. This was an
iterative procedure in which one trial was left out and a meta-analysis
was performed on the remaining subset of the studies at each itera­
tion. This analysis shows how each individual study affects the overall
estimate of the rest of the studies. As shown in Fig. 8, the pooled SMDs of
VAS and ORs of AEs revealed no significant influence on the overall
analysis by any individual study, indicating consistency in the pooled
results.
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Complementary Therapies in Medicine 63 (2021) 102775
3.7. Publication bias
The result of Egger’s test of the VAS score was significant (p =
0.024), with substantial asymmetry in the funnel plot, which may have
been caused by publication bias. However, funnel plots and Egger’s tests
of AEs, the WOMAC and its three subscales showed no publication bias
(Appendix 3).
A.-F. Hsiao et al.
Fig. 4. Forest Plot of the incidence of AEs A) curcuminoids vs. comparator and B) comparator of placebo vs. comparator of NSAID.
4. Discussion
Based on the results of our meta-analysis, curcuminoids were
significantly more effective than comparators with regard to pain relief
in patients with knee OA. After Hartung-Knapp adjustment, we found
very low to low certainty evidence for the effects of curcuminoids on
VAS pain, the WOMAC total score, and physical and stiffness scores,
although these effects were significant in the random-effects models
before adapting Hartung-Knapp correction. In contrast, the result for the
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Complementary Therapies in Medicine 63 (2021) 102775
WOMAC pain was still significantly favored curcuminoids even after
Hartung-Knapp adjustment (Fig. 5B). Moreover, while comparing cur­
cuminoids against NSAIDs, the results of the VAS pain score still showed
that curcuminoids were more effective in pain relief than NSAIDs even
after adjustment (Fig. 3B), which demonstrates the robustness of these
results. Our analyses also revealed no significant difference between
high and low curcuminoid doses in terms of pain relief and AEs. In AE
analysis, three of the included studies used NSAIDs as compara­
tors.22,39,40 All reported higher AEs in the NSAID group than in the
A.-F. Hsiao et al.
Fig. 5. Forest Plot of the effects on WOMAC A) WOMAC scales, B) WOMAC
pain, C) WOMAC physical function and D) WOMAC joint stiffness.
curcuminoid group, but only one reached statistical significance.22
Several previous meta-analyses have addressed the effectiveness of
curcumin in arthritis, such as OA and rheumatoid arthritis.24–28 Their
results revealed that curcumin is effective at reducing pain and
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Complementary Therapies in Medicine 63 (2021) 102775
inflammation-related symptoms in patients with OA,24 especially knee
OA.25–28 For example, the study by Bannuru et al. in 2018 compared
curcuminoid and boswellia formulations with both placebo and NSAIDs
in knee OA patients, and the results showed significant improvement in
pain and function and fewer gastrointestinal AEs with curcuminoids
compared with NSAIDs.27 In the most recent meta-analysis by Wang
et al. (2021), patients with a lower BMI and younger age had a better
response to curcuminoids, and larger effects of both pain and physical
function were noted in RCTs conducted in Asia than in other countries.28
Our results are not only concordant with previous meta-analyses but
also showed that there was no significant difference in VAS pain
reduction between high-dose (daily dose ≥1000 mg or total dose ≥42
gm) and low-dose (daily dose <1000 mg or total dose <42 gm) groups.
Using the GRADE approach, we evaluated the study quality and
rated the AEs as having a moderate certainty of evidence because three
included studies had performance bias, such as incomplete blinding
from the study investigator32 or assistants39 or not mention blinding to
the practitioners.22 We downgraded the WOMAC and its subscales to
having a low certainty of evidence due to the incomplete outcome data
and statistically significant heterogeneity with low p values and high
I-squared values. Heterogeneity may be caused by differences in treat­
ment duration, follow-up time, total doses, control groups, and
geographical differences. In addition, manufacturer sponsorship was
also noted in five studies; for example, Madhu et al. investigated the
product NR-INF-02, an extract from the rhizome of Curcuma longa,32
and Linn and Haroyan et al. used CuraMed,37 which was provided by
sponsors. Furthermore, publication bias was suspected in the VAS pain
score results since Egger’s test was statistically significant (p = 0.024)
with asymmetry in the funnel plot. Therefore, we further downgraded
the VAS pain score to having a very low certainty of evidence.
In addition to VAS and WOMAC scales, the included RCT by Wang
et al. also evaluated effusion-synovitis and cartilage composition of knee
joints by magnetic resonance imaging (MRI).38 However, the results
showed no improvement in MRI findings after curcumin usage, and
some other studies found no significant change in biomarkers related to
inflammation.41–43 Apart from the anti-inflammatory and anti-oxidative
effects of curcumin, Ean-Jeong Seo et al. reported that curcuminoid
acted as a nociceptin receptor antagonist that downregulated
opioid-related nociceptin receptor 1 gene (OPRL1) expression by
5.9-fold.44 As nociceptin increases pain sensation in supraspinal pain
transduction pathways, downregulating OPRL1 decreases production of
the nociception receptor, leading to pain relief.44 On the other hand, the
pain relief effects of NSAIDs can be attributed to inhibition of the
cyclooxygenase (COX) enzyme. There are two COX isoforms, COX-1 and
COX-2, and NSAID AEs are mainly caused by inhibition of COX-1; thus,
selective COX-2 inhibitors have fewer AEs than non-selective COX in­
hibitors.45 NF-κβ is a transcriptional regulator promoting COX-2
expression,46 and curcuminoids inhibit the NF-κβ pathway and further
decrease COX-2 synthesis.47 We believe this is the reason why curcu­
minoids have fewer AEs than non-selective NSAIDs. Regarding the safety
of curcuminoids versus NSAIDs, further RCTs comparing curcuminoids
with selective COX-2 inhibitors are warranted.
In the past, curcumin has been criticized because of its low
bioavailability and short half-life in clinical use, as its hydrophobic na­
ture results in poor blood absorption. Curcuminoids also have the
characteristics of rapid metabolism and systemic elimination.48 Never­
theless, once in the bloodstream, curcumin is stable and can even enter
the brain.49 Previous studies have shown that its bioavailability can be
enhanced by combining it with phosphatidyl choline complexes50–52 or
producing nanoparticle formulations.52–55 Therefore, it is expected that
lower doses of these complexes might be as effective as higher doses of
A.-F. Hsiao et al.
Fig. 6. Forest Plot of the effects on VAS pain A) low daily dose vs. high daily dose and B) low total dose vs. high total dose.
standard turmeric powder because the pharmacokinetics and hep­
atoprotective activities are increased.8 Other methods to improve cur­
cumin bioavailability include adding naturally occurring volatile oils
from turmeric roots or piperine,56 using heat to enhance solubility,57
inhibiting its glucuronidation,58 and using liposomal technology to
enhance absorption and reduce systemic elimination.59–61 Further
studies are needed to compare effects among different formulation types
and bio-enhancers.
Our meta-analysis has strengths because it is the first to analyse the
dose effects of curcumin on knee OA. We searched for the newest studies
until June 21, 2021 and reported the results according to the PRISMA
checklist (Appendix 4). Nonetheless, we recognized some limitations in
our study. First, we might not have included all relevant RCTs, especially
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Complementary Therapies in Medicine 63 (2021) 102775
those unpublished or not published in English or Chinese. Hence, we
could not assess publication bias objectively. Second, the number of
included RCTs was small; indeed, only 11 studies from inception to June
21, 2021were included. Therefore, we performed Hartung-Knapp ad­
justments. Third, significant publication bias for the VAS pain score was
observed in our meta-analysis, which might be due to the high variation
in intervention intensity. Fourth, a protocol was not pre-registered for
this review, which was not in alignment with the Cochrane guidance.
Finally, we only analysed curcuminoids in knee OA, and the effects of
curcuminoids for OA in other joints, such as the hip or hand, are not
clear.
A.-F. Hsiao et al. Complementary Therapies in Medicine 63 (2021) 102775

Fig. 7. Forest Plot of the incidence of AEs A) low daily dose vs. high daily dose and B) low total dose vs. high total dose.

5. Conclusions to short-term use. Thus, further high-quality RCTs of different curcu­

minoid doses with longer follow-up durations are needed.
The results of our meta-analysis suggest that curcuminoids are
effective in pain relief in knee OA and that low- and high-dose curcu­ Sources of funding
minoids have similar effects in improving pain and AEs. Curcuminoids
are also more effective in achieving pain relief than NSAIDs; therefore, Taipei Tzu chi Hospital, Buddhist Tzu chi Medical Foundation
using curcuminoids as an adjunctive treatment in knee OA is recom­ (TCRD-TPE-109-RT-6 (2/3))
mended. However, current evidence is heterogeneous and mostly refers

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A.-F. Hsiao et al. Complementary Therapies in Medicine 63 (2021) 102775

Fig. 8. Sensitivity analysis of VAS pain and AEs.

Declaration of Competing Interest References

The authors report no declarations of interest.
Acknowledgements
The authors thank Dr. Shiyou Li and Dr. Ya-Hui Wang for their
invaluable consultations regarding the data analysis.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.ctim.2021.102775.
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