REVIEW ARTICLE

The Effects of Curcuma Longa on the Osteoarthritis: A

Systematic Review of Placebo-Controlled Clinical
Studies
Luiz Henrique Alvarenga Martines1; Gabrielle Gomides Marconato2;
Gabriela Garcia Fracaro2; Lucas Fornari Laurindo2; Adriano Cressoni
Araújo1,2; Claudio José Rubira3; Jefferson Aparecido Dias1,4; Sandra M.
Barbalho1,2,5*; Elen Landgraf Guiguer1,2,5
1 Postgraduate Program in Structural and Functional Interactions in
Rehabilitation-University of Marília (UNIMAR) - Marília – SP, Brazil
2 Department of Biochemistry and Pharmacology, School of Medicine –

UNIMAR
3 Hospital Beneficente UNIMAR – São Paulo, Brazil
4 Postgraduate Program in Law - UNIMAR - Marília SP, Brazil
OPEN ACCESS 5School of Food and Technology of Marilia (FATEC) – São Paulo, Brazil.

Published: June 30, 2022 * [email protected]

Citation: Alvarenga Martines ABSTRACT
LH, Gomides Marconato G, et Osteoarthritis (OA) is a joint disorder characterized by chronic,
al., 2022. The Effects of degenerative, and irreversible inflammation leading to pain and disability.
Curcuma Longa on the The standard drugs are ineffective for many patients and are usually
Osteoarthritis: A Systematic associated with numerous side effects such as gastrointestinal complaints.
Review of Placebo-Controlled Curcuma longa and its bioactive compounds have been considered for OA.
Clinical Studies, Medical The objective of this study was to perform a systematic review of the effects
Research Archives, [online] of Curcuma longa and its derivatives on OA. Pubmed, Cochrane, and
10(6). Embase were searched, and PRISMA guidelines were followed to build this
https://doi.org/10.18103/mra. review. Only Randomized Clinical Trials (RCTs) that performed placebo-
v10i6.2888 comparison were included. Most included studies showed that Curcuma
longa or formulations prepared with curcuminoids can benefit the OA scores
Copyright: © 2022 European such as Visual Analog Scale, Knee injury and Osteoarthritis Outcome Score,
Society of Medicine. This is an Western Ontario and McMaster Universities Osteoarthritis Index; and
open- access article distributed Lequesne's pain functional index. The use of Curcuma longa extracts or
under the terms of the Creative curcuminoids can benefit patients with OA. Nevertheless, the available RCTs
Commons Attribution License, show treatment time, doses, and formulations heterogeneity. Thus, the
which permits unrestricted use, standardization of RCTs can guide researchers and physicians on the
distribution, and reproduction in dosages and formulations that are most effective in addressing this
any medium, provided the condition, which is very prevalent in the world's populations.
original author and source are
credited. Keywords: Curcuma longa; curcuminoids; curcumin; arthritis; Osteoarthritis
DOI
https://doi.org/10.18103/mra.
v10i6.2888

ISSN: 2375-1924

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 The Effects of Curcuma Longa on the Osteoarthritis

1. INTRODUCTION and chondroblasts there is also an increase in

Osteoarthritis (OA) is a joint disorder enzymes that degrade cartilage, such as
characterized by chronic, degenerative, disintegrins and metalloproteinases (collagenase
progressive, and irreversible inflammation. It can be and gelatinase). These enzymes are associated with
caused naturally by aging (primary or idiopathic the release of inflammatory cytokines such as Tumor
Osteoarthritis) or due to trauma, infections, or Necrosis Factor-α (TNF-α), Interleukin 1-β (IL-1β), IL-
malformations that result in joint degeneration. Its 6, and IL-17. The resulting loss of the cartilage leads
symptoms are usually characterized by pain, to persistent friction followed by deformation of the
functional weakness, and primary disability in more bones related to the usual symptoms. Moreover,
advanced stages. These conditions impose a osteophyte formation, bone remodeling, and
substantial burden on individuals, the health system, alterations in the synovium and joint capsule are
and society since it is not effectively treatable 1-6. observed. The degenerative process may affect
In the early stages of degeneration, any joints, but the knees, fingers, neck, lower back,
chondrocytes are stimulated in an attempt to repair and hips are most common 2,7-9. Figure 1 shows the
tissue, with a consequent increase in the production risk factors for developing the OA.
of proteoglycans and collagen. Besides the
migration of beneficial cells such as chondrocytes

Figure 1. Risk factors related to the development of Osteoarthritis.

The available therapies for OA remain a The major are curcumin, demethoxycurcumin, and
challenge. The traditional therapeutic approach bisdemethoxycurcumin. Several studies have shown
uses analgesics, corticosteroids, and nonsteroidal that curcumin exhibits remarkable antioxidant and
anti-inflammatory drugs. However, in addition to anti-inflammatory actions due to inhibiting pro-
the costs, the use of these drugs is associated with inflammatory pathways such as cyclooxygenase-2
numerous side effects such as gastrointestinal (COX-2), prostaglandins, leukotrienes, and the
conditions, tiredness, hyperglycemia, problems with release of pro-inflammatory biomarkers such as
immunity, swelling, agitation, and insomnia, mainly TNF-α, IL-1β, IL 6, and IL-8. By inhibiting the
if they are prescribed for long periods. Long-term signaling pathways mediated by Nuclear Factor
use of these drugs leads to renal and Kappa β (NFkβ) and Inhibitor of nuclear factor
cardiovascular adverse events 10-12. There is a need kappa-B kinase subunit beta (IKK), there is a
for new therapeutic approaches that help treat OA reduction in the processes associated with pain and
for these reasons. Therefore, studies have shown other symptoms reported by patients with OA. In
that plants with anti-inflammatory potential can this sense, Curcuma longa can benefit the patient
improve patients' symptoms and may reduce the use with OA since it is related to reducing the
of medications that promote many adverse effects inflammatory process that is characteristic in these
13-15.
patients31.
Curcuma longa and derivatives are the For these reasons, the objective of this study
most studied for the treatment of OA. The main is to perform a systematic review of the effects of
bioactive compounds of this plant are curcuminoids. Curcuma longa and curcuminoids on OA.

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 The Effects of Curcuma Longa on the Osteoarthritis

2- LITERATURE SEARCH 3- RESULTS OF THE LITERATURE SEARCH

2.1 Focused question According to the inclusion and exclusion
The focused question used for this review criteria (Figure 2), we selected fourteen RCT that
was: Which are the effects of Curcuma longa on are found in Table 1 18-31. The studies were
Osteoarthritis? performed mainly in India (six studies) and other
2.2 Language countries around the world: Thailand (two studies),
Only studies in English were selected. Iran (two studies), Belgium (one study), Japan (one
2.3 Databases study), Italy (one study), Armenia (one study), Spain
For this study, we searched the PubMed, (one study), and Tasmania-Australia (one study). All
EMBASE, and COCHRANE databases. The these RCTs used Curcuma longa or its extracts or
descriptors used were Curcuma longa or curcumin formulations orally in 1,167 patients (about 70%
and Osteoarthritis. These mesh terms helped were women).
identify trials that reported using Curcuma longa or Most studies evaluated OA scores such as
turmeric or curcumin or curcuminoids and knee VAS (Visual Analog Scale), KOOS (Knee injury and
osteoarthritis. The PRISMA (Preferred Reporting Osteoarthritis Outcome Score), WOMAC (Western
Items for a Systematic Review and Meta-Analysis) Ontario and McMaster Universities Osteoarthritis
guidelines were followed to perform this review 16 Index), LPFI (Lequesne's pain functional index), and
(Figure 1). PGADA (Patient Global Assessment of Disease
2.4 Study selection Activity). These studies showed that the use of
In this study, we included trials that Curcuma longa extracts and formulations with
reported the effects of Curcuma longa or its curcuminoids can improve the above-mentioned
derivatives in the therapeutic approach of OA. The scores and can reduce biomarkers of inflammation
inclusion criteria were Double-blind, Randomized such as IL-4, IL-6, TNF-α, C reactive protein, and
Clinical Trials (RCTs), and placebo-controlled oxidative markers such as malonaldehyde. The
studies. We only included studies that were full reduction of oxidative stress and inflammation
texts. Only studies that used a placebo were contributes to the improvement of OA scores.
included. Except for Rahimina et al 23, who did not
The exclusion criteria included in vitro find differences between the placebo and the
studies, animal studies, clinical trials associated with treated group for C Reactive Protein, IL-4, IL-6, and
different herb formulations, reviews, studies not in Prostaglandin E2, all the included trials indicated
English, poster presentations, case reports, and that the Curcuma longa could bring benefits for the
editorials. Reviews were consulted to help in the patient with OA. As already mentioned, Curcuma
discussion section but were not included in the longa reduces pain and improves physical function
systematization of the data. and stiffness (at different scores such as VAS,
2.5 Data extraction KOOS, LPFI, WOMAC, and PGADA).
The selected period for the search was The trials that compared the plant with
January 2012 to May 2021. The included studies ibuprofen28,69 or diclofenac 18,25,32 showed that
are shown in Table 1. Curcuma longa exhibits similar effects compared to
2.6 Quality Assessment these drugs, without the side effects regularly
The possible risk of bias (regarding the reported by patients that are treated with these
selection of the study, detection, and reporting drugs.
biases of each clinical trial) was evaluated using the The most common adverse events observed
Cochrane Handbook for Systematic Reviews of in the trials were nausea, dyspepsia, and diarrhea,
Interventions to perform this quality assessment 17. but Curcuma longa extracts or formulations are
considered well-tolerated and safe.

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 The Effects of Curcuma Longa on the Osteoarthritis

Figure 2. Flow diagram showing the study selection (PRISMA guidelines).

4. SOME ASPECTS OF CURCUMA LONGA around 3%. They are nontoxic polyphenolic
Curcuma longa, also named turmeric, is a compounds that can exhibit immunosuppressant
perennial rhizomatous plant belonging to the actions 39,40. They can downregulate the expression
Zingiberaceae family. Curcuma is one of the largest of cyclooxygenase-2, lipoxygenase-5, inducible
genera in this family. It is found in tropical and nitric oxide synthase, and several other pro-
subtropical regions from South China to India, inflammatory mediators, such as TNF-α, IL-1β, IL-6,
Papua New Guinea, northern Australia, and South and IL-8. Moreover, curcuminoids can inhibit the
America 33. It has been considered to treat several phosphorylation and elimination of the Nuclear
illnesses since ancient times in India and China. It can Factor of Kappa light polypeptide gene enhancer
be cosidered antibacterial, antioxidant, anti- in B-cells inhibitor, alpha (IκBα). They may activate
inflammatory, antidiabetic, anticarcinogenic, the γ receptor mechanism started by the
antiobesity, and hepatoprotective agent, besides peroxisome proliferator, decreasing the
being used as a spice, food flavors, and cosmetics inflammation scenario stimulated by NFκB
34-38.
pathways. The antioxidant effects are associated
The compounds present in Curcuma longa
with the upregulation of antioxidant enzymes such
are mainly flavonoids, terpenoids, anthocyanin,
as superoxide dismutase and catalase 41-43. Figure
tannins, and organic acids. Curcuminoids are among
3 summarizes some results of Curcuma longa and its
the main bioactive components. Curcumin accounts
curcuminoids.
for almost 77% of the total; bisdemethoxycurcumin
represents about 17), and demethoxycurcumin is

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 The Effects of Curcuma Longa on the Osteoarthritis

Figure 3. The anti-inflammatory and antioxidants of Curcuma longa and its bioactive compounds. COX:
cyclooxygenase-2; IKK: I Kappa Beta Kinase; IL: Interleukin; NFκβ: Nuclear Factor kappa beta; RNS:
Reactive Nitrogen Species; ROS: Reactive Oxygen Species; TNF-α: Tumor Necrosis Factor-alpha.

Curcuma longa and curcumin have shown 5. PHYSIOPATHOLOGY OF OSTEOARTHRITIS:

that they are safe for human consumption, mainly if AN OVERVIEW OF THE GENERAL ASPECTS
they are administrated by oral delivery. They are The pathophysiology of Osteoarthritis is
considered non-mutagenic, non-genotoxic, and complex, not fully understood, and involves
generally recognized as safe (GRAS). Clinical numerous inflammatory and oxidative events that
investigations have shown that the oral safe dose is we would not be able to explore here fully. Below
6 g daily for 4–7weeks. Nevertheless, minor are just a few points from these events.
adverse effects an occur (dyspepsia, nausea, Below are just a few points from these
diarrhea) 38,44,45 events (Figure 4).

Figure 4. Osteoarthritis is associated with the up-regulation in the expression of pro-inflammatory

biomarkers leading to injury, pain and physical limitation. COX: cyclooxygenase-2; IL: Interleukin; MMP:
metalloproteinase; PGE-2: Prostaglandin E-2; RNS: Reactive Nitrogen Species; ROS: Reactive Oxygen
Species; TNF-α: Tumor Necrosis Factor-alpha.

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 The Effects of Curcuma Longa on the Osteoarthritis

OA process can start due to impairment in mechanisms. Mechano-protection is based on a

cartilage healing, aging, loss of cartilage function, stable joint, healthy thick cartilage, and strong
and environmental and genetic factors. Typically, it muscle that support the joint and intact gait reflexes.
is observed an accelerated cartilage degradation Imbalance in these variables is associated with a
is enforced by an augment of matrix pro-inflammatory environment named
metalloproteinases (MMPs) and metalloproteinase mechanoflammation. It involves the stimulation of
thrombospondin motifs (ADAMTS) (in homeostasis, the TGF-β-activated kinase 1 (TAK1), which is
there is a balance of components of extracellular closely related to the up-regulation of mitogen-
matrix (ECM) and cartilage degrading enzymes). activated protein kinases such as p38 and c-Jun N-
Alarmins are also increased in OA. These molecules terminal kinase, and NFκB signaling. TNF-α, and IL-
represent the Damage-associated Molecular 1β also stimulate TAK1 and Toll-Like Receptor (TLR)
Patterns (DAMPs) produced as standard cellular ligation. TAK1 stimulation leads to relevant
components from degraded ECM, which bind to pathways associated with the control of aggrecan
other cells' membranes or intracellular receptors, degradation. Besides, it also stimulated nerve
triggering the inflammatory responses. DAMPs can growth factor stimulation, a key mediator of pain
attach to the Toll-like receptor family, in OA 52-54.
complementing the inflammatory activation and The NFκB signaling is related to the pro-
contributing to OA pathogenesis. Moreover, ECM
inflammatory environment since it releases several
neo-synthesis is reduced in chondrocytes.
Furthermore, the characteristic inflammatory cytokines. The stimulation by TNF-α and IL-1β leads
process in the joint to the activation of I Kappa Beta Kinase (IKK),
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC resulting in the phosphorylation of IKB-α. Their
degradation products act in the nucleus leading to
7887204/ - cit0021results in an imbalance release
the activation of numerous genes responsible for
of pro-inflammatory cytokines such as TNF-α, IL-1β, producing multiple inflammatory and pro-apoptotic
and IL-6, which have an essential role in the factors 8,55,56.
progression of OA, besides the presence of IL-8 and Parallel to the destruction of cartilage for the
IL-18. The release of cytokines is observed in reasons mentioned above, a disrupted bone
synovial fibroblasts, macrophages, and resorption process is observed, and
chondrocytes. Chondrocytes can undergo apoptosis osteoclastogenesis occurs. The receptor activator
due to extrinsic factors or mitochondria-associated NFκLigand (RANKL) is released by osteoblast and
signaling pathways related to oxidative stress and
shows an affinity for RANK leading to
lysosomal dysfunction. Other inflammatory markers
phosphorylation pathways resulting in the activation
such as cyclooxygenase -2, released by synovial
monocytes, and prostaglandins-2 are also involved of NFκB. The osteoprotegerin also can bind to
in the pathophysiology of OA 9,46-48. RANK, competing with RANKL and leading to
The inflammatory stimulus is also related to apoptosis of mature osteoclasts. 57-59.
the release of ADAMTS4 and ADAMTS5 that are Besides inflammation and mechanical load,
aggrecanases and slip aggrecan. After aggrecans oxidative stress also has a pivotal role in the
degradation, the MMP-3 plays a role in the degradation of joint tissues, including articular
synergism of proteoglycans degradation. MMPs cartilage, synovial membrane, subchondral bone,
are related primarily to the degradation of type II and meniscus, essential to the maintenance of the
collagen and play an essential role in cartilage functionality of joints. Oxidative stress is
destruction. MMP-1, MMP-3, MMP-9, and MMP-13 characterized mainly by reactive oxygen species,
are closely linked to this process, and the MMP-13 such as superoxide anion radicals, nitric oxide, and
is not found in healthy cartilage. The inflammatory peroxynitrite. The repetitive vicious cycle of
inflammation and disrupted anabolic-catabolic
scenario and the presence of IL-1β and TNF-α also
switch lead to overproduction of reactive species in
stimulate the release of MMP. The synoviocytes can
cartilage, misbalancing the intracellular redox
also synthesize inflammatory cytokines biomarkers,
status crucial to regulating mitochondria function
which amplify the inflammation and cartilaginous
chondrocyte hypertrophy, oxidative damages to
destruction 2,49-51.
proteins, lipids, and DNA). For these reasons,
Mechanical load is a critical risk factor for the
oxidative stress results in modifications in the
development of OA. This risk comes from an
proteins of the cartilaginous matrix found in the
excessive mechanical strain over a normal joint due
endoplasmic reticulum and Golgi compartment of
to obesity or occupational risk. It comes from a joint
chondrocytes, reducing their synthesis. Moreover,
that has waisted its mechano-protective

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 The Effects of Curcuma Longa on the Osteoarthritis

the excessive free radicals production orchestrates 5). Besides that, some authors postulate that special
the degradation of the extracellular matrix via attention should be paid to Curcuma longa since it
hydrolysis of matrix components and stimulation of possess other bioactive compounds such as phenolic
the expression of MMPs that leads to hypertrophic compounds (curcumin, demethoxycurcumin, and
cartilage matrix 60-63. bisdemethoxycurcumin), essential oils (such as ar-
curcumene, curcumol, cineole, linalool,
6. OSTEOARTHRITIS, CURCUMA LONGA, AND caryophyllenezingiberen, turmerone, and α-
CURCUMINOIDS terpinene), and other components such as
Several dietary supplements have been campesterol, β-sitosterol, fatty acids, cholesterol,
evaluated for OA treatment, but undoubtedly and several elements such as magnesium, potassium,
curcumin is the most relevant. The benefits of OA calcium, sodium, iron, zinc). Due to the presence of
are due to the anti-inflammatory actions of curcumin this plethora of compounds that may act in
resulting from the inhibition of inflammatory signals synergism, Curcuma longa can exhibit multi-target
such as leukotrienes, prostaglandins, and COX-2. and multi-signal pathways in the therapeutic
Moreover, curcumin can suppress the release of approach to pain and inflammation that are
TNF-α, IL-1, IL-6, and nitric oxide synthase (Figure characteristic of OA 64-68.

Figure 5. Curcumin can inhibit inflammation and oxidative stress due to the downregulation in the expression
of pro-inflammatory cytokines, COX-2, PGE-2 and decrease of the production of free radicals. COX:
cyclooxygenase-2; IKBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha;
IKK: I kappa beta Kinase; IL: Interleukin; NFκβ: Nuclear Factor kappa beta; PGE-2: Prostaglandin E-2.

Ross et al 69 performed a Randomized, study with 144 patients with knee OA (37 men and
double-blind, controlled multicenter clinical trial 107 women and age range of 41-64years),
with 367 patients over 50 years possessing OA evaluated the effects of BCM-95® (bioavailable
(rating of knee pain ≥ 5 by the American turmeric extract / 1000mg /day) or paracetamol
Rheumatism Association). The subjects received 1.2g for 6 weeks and found that the treated group
daily of ibuprofen or 1.5g daily of curcumin extract showed significant improvements in WOMAC total
(containing 75%-85% curcuminoid; 250 mg of score (pain, stiffness, and function scores), as well as
curcuminoids/capsule). After one month, patients TNF-α and C reactive when comparing to
presented improvement in WOMAC scores in both paracetamol group. This RCT was not included in
groups at weeks 0, 2, and 4 showing that curcumin our review since it did not meet the inclusion criteria
extract can play a role similar to ibuprofen. (not controlled by placebo).
In India, SINGHAL et al. 64, in a Another randomized trial 70 investigated
Randomized, non-inferiority, controlled clinical the effects of BCM-95® with diclofenac or

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 The Effects of Curcuma Longa on the Osteoarthritis

diclofenac alone for 28 days in patients with OA. It in participants with initial scores of 0.15 or less.
showed that both treatments resulted in However, this study also included a small sample.
improvement in KOOS subscales (pain and quality Rahiminia et al 23 evaluated the effects of pure
of life) when compared to diclofenac. Fewer curcumin and placebo in patients with mild to
patients needed rescue analgesics in the moderate OA and found benefits in treating OA
curcuminoid plus diclofenac group compared to the symptoms. However, this study also included a small
diclofenac group. The side effects were significantly sample.
less in the first group compared to the diclofenac Using a formulation containing Curcumin
group. BCM95® in patients included in the trial performed
Several other RCTs have been performed by Sterzi et al 24 showed improvements in pain
to investigate the effects of Curcuma longa or during daily life activities and reduced LPFI.
curcuminoids in the therapeutic approach of OA, as However, the sample size is a limitation of this study.
we show in Table 1. The evaluation of the included The study performed by Srivastava et al 25 showed
studies shows heterogeneity in some aspects, such as improvements in OA scores and oxidative status in
the time of the treatment (the follow-up varied from patients with OA that used Curcuma longa extract.
three days to four months), formulations, and the This study does not seem to have any bias since the
doses (from 180mg to 1500mg/day of curcumin). number of patients, age, allocation, and follow-up
Regarding administration, all the included RCTs are adequate.
used Curcuma longa or curcumin orally. Panahi et al 20 investigated the effects of
Concerning the trials included in Table 1, curcuminoids on the systemic oxidative stress in
the possible risk of bias is shown in Table 2. patients with knee OA and suggest that the
PINSORNSAK et al 18 performed the first trial antioxidant actions observed in these patients are
regarding the use of curcumin on OA. This related to the reported relief of OA symptoms.
interesting study investigated the effects of curcumin However, as shown in Table 2, many biases are
as an adjuvant treatment of diclofenac in primary associated with this trial. Moreover, the authors
OA. The authors evaluated KOOS in 5 different included a small sample of patients ≤ 80 years.
categories (pain, symptom, function in daily living, Oxidative stress measured by antioxidant enzymes
role in sport and recreation, and knee associated and malonaldehyde production is susceptible to
quality of life) and found that curcumin associated numerous physical exercise and diet factors, which
with diclofenac presented a tendency to improve can be very different in patients of very different
function in daily living and pain (although without ages.
significance). In conclusion, the authors found that Haroyan et al 26 investigated the effects of
the association of curcumin and diclofenac is better two formulations (CuraMed® that possess only
than diclofenac alone in the therapeutic approach curcuminoids and Curamin® that possess
of OA. curcuminoids and boswellic acid). WOMAC and
The study of Madhu et al 19 included many physical performance tests showed that both
more women than men (as observed in almost all the formulations are superior to placebo but still
included RCTs). This interesting study showed that superior in the Curamin® group. This study was
the formulation NR-INF02 could bring benefits since performed with a larger sample compared to the
it was observed a significant reduction in the VAS, other RCT reducing the risk of bias in interpreting
WOMAC, and CGIC compared to placebo, even in the results. The RCT performed by Panda et al 27
a short time (21 and 42 days). Moreover, patients showed the effects of Curene® (a formulation of
could reduce the rescue medications along with the Curcuma longa extract containing naturally derived
trial. In another RCT, the authors evaluated the curcuminoids) in patients with uni or bilateral OA
effects of curcuminoids in patients with knee OA and and found that this formulation can significantly
showed improvements in VAS, Lequesne's pain reduce stiffness, and pain, and can improve
functional index (LPFI), and WOMAC compared physical functioning. The short sample and the
with placebo. Nevertheless, this study included a heterogenicity in the included patients' age are the
small sample of patients with mild to moderate OA. main biases found in this RCT.
Moreover, the authors included patients ≤ 80 years, Gupte et al 28 investigated the use of solid
which leads to the inclusion of patients with a large lipid curcumin particles in patients with knee OA and
age range 71. The study of Nakagawa et al 22 found it is effective in relieving symptoms. However,
evaluated the effects of Theracurcumin in knee OA this pilot study shows many biases, such as the
(Kellegren–Lawrence grade II or III) and found that absence of blind randomization, small sample and
this compound can reduce pain VAS scores except missing sample calculation. Henrotin et al 29 studied

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 The Effects of Curcuma Longa on the Osteoarthritis

the effects of bio-optimized Curcuma longa extract prepared with this plant or its bioactive compounds
in two different doses in patients with knee OA and can effectively relief OA symptoms even in short-
found that both doses effectively reduce PGADA term studies, as shown by the RCT performed by
and inflammatory biomarkers of AO, showing Calderón-Dias et al 30. These findings are not in
significant reduction of pain reported by patients. accordance with those from Zeng et al 66 that
The main biases of this study are the small sample suggested that the use of Curcuma longa extracts or
size and the inclusion of patients that were non- curcumin must last at least three months to achieve
responders to the standard drugs used to treat OA; therapeutic effects. Moreover, our results show that
thus, they are not sensitive to anti-inflammatory the therapeutic approach with Curcuma longa
treatments. extracts or formulations with its bioactive
Wang et al 31 showed that Curcuma longa constituents can produce effects equivalent to
extracts CL is better than placebo for treating knee standard drugs considered to the therapeutic
pain in OA patients. However, the extract did not approach of OA, however, with much less critical
modify cartilage composition or knee effusion– side effects.
synovitis. The main bias of this trial is the small
sample and the short duration which may be related 7. BIOAVAILABILITY AND ADVERSE EFFECTS OF
to the non-detection of changes in the cartilage. CURCUMA LONGA
Calderón et al 30 performed an exciting Curcuma longa has been used orally for
trial evaluating the acute effects of Curcuma longa numerous conditions, but curcumin suffers poor
extracts and insoluble curcuminoids or placebo in absorption and fast metabolism. Due to these
participants with knee joint pain. They found that reasons, many researchers have used the
after three days and one week, there was reduced combination with other substances such as piperine.
pain if walking on a flat surface, sitting, going up, This association leads to the increased concentration
or downstairs in both groups, but only the treated of curcumin in the blood, the elimination is
group showed a reduction in pain during the night, prolonged, the clearance rate is reduced, and the
in bed, and an upright posture standing position. bioavailability is improved 72-74.
Moreover, the group treated with the formulation Curcuma longa is generally considered well
showed decreased C-reactive protein levels, tolerated, even in high doses. However,
indicating analgesic actions. This was the first RCT gastrointestinal symptoms can be observed, such as
investigating the acute effect of Curcuma longa bloating, nausea, and diarrhea. Allergic reactions
formulation. have also been reported 75,76.
The interpretation of our results shows that
the use of Curcuma longa extracts or formulations

Table 1. Randomized Clinical Trials showing the effects of curcumin in Osteoarthritis.

Reference Type of the study Intervention Outcomes Adverse
and local events
Pinsornsak Double-blind Patients (n=44) used All patients had NR
et al. 18 prospective diclofenac (75 mg/d) with improvement in pain (Vas
randomized control placebo and 44 used and KOOS scores
trial with 88 patients diclofenac (75 mg/d) with decreased more in the
with OA; 15 men curcumin (1g/d)/3m. VAS for curcumin group.
and 73 women (≥ pain and KOOS were
45 y). evaluated every month for 3
Thailand m.
Madhu et Randomized, single- Patients received a placebo VAS, WOMAC, and CGIC Dyspepsia
al 19 blind, placebo- (400 mg 2xd) or NR-INF-02 had significant
controlled, (500 mg 2xd) or GS (750 mg improvement at each
comparative study 2xd) alone or a combination clinical visit compared to
with 120 subjects of NR-INF-02 and GS/ 42 d. placebo. NR-INF-02
(37men and 83 promoted a significant
women; ≥40y) with reduction with the rescue
knee OA. medication and clinical
India improvement compared to
the placebo

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 The Effects of Curcuma Longa on the Osteoarthritis

Panahi et al Randomized double- Patients received The use of curcuminoids Mild

21 blind placebo- curcuminoids (1.5g/d in 3 significantly reduced gastrointestinal
controlled trial; 53 divided doses) or placebo WOMAC, VAS, and LPFI symptoms.
subjects; 80 y, 9 men /6 w. WOMAC, VAS, and compared to placebo. In
and 44 women. LPFI scores were the WOMAC subscales, it
India evaluated/6w. was observed significant
improvements in physical
function and pain. It was
not observed significant
differences in VAS,
WOMAC, and LPFI
between the two groups at
baseline.
Nakagawa Randomized, Patients received a placebo After 8 w, VAS scores No major side
et al 22 double-blind, or Theracurmin (180 significantly decreased in effects were
placebo-controlled mg/d)/8w. The symptoms the Theracurmin group. observed.
prospective study; were evaluated at 0, 2, 4, 6, Theracurmin also reduced
41 subjects with knee and 2m. the celecoxib dependence
OA (Kellgren– (more than the placebo
Lawrence grade II or group).
III and), ≥ 40 y, 9
men and 32 women.
Japan
Rahimnia et Randomized double- Subjects received pure hs-CRP, IL-4, and IL-6 were NR
al 23 blind placebo- curcuminoids (1.5g/d; n=19) significantly reduced in
control parallel- or placebo (n=21) /6w both groups
group clinical trial; (curcuminoids were
40 patients with associated with piperine
mild-to-moderate (15 mg/day).
degree knee OA.
Iran
Sterzi et al Multicenter, Participants (n=26) received No significant difference NR
24 prospective, CartiJoint Forte (chondroitin was seen in VAS between
randomized, double- (400mg), glucosamine the groups. There were
blind, placebo- hydrochloride (500mg) / 2 reductions on the Lequesne
controlled clinical tablets, and bio-curcumin Index at 8 and 12w
trial; 53 subjects ≥ BCM-95 (50mg)/d/2m, or compared to 0w, along
50y, 17 men, 33 placebo. All patients with the treated group. No
women. performed 20 sessions of significant modifications
Italy physical therapy along the were observed in
trial. inflammation biomarkers
and in the knee ROM.
Srivastava Randomized, Patients received CL extract Significant improvement Dyspepsia and
et al 25 double-blind, (500 mg) or placebo plus the was observed in EVA and nausea.
placebo-controlled standard treatment WOMAC in the patients
trial; 160 subjects ≥ (diclofenac 50 mg/day) / treated with CL. The levels
50 y, 57 men and 4m. of inflammation and
103 women, with oxidative biomarkers (IL-
knee OA. 1β, ROS, and MDA) were
India significantly improved.

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 The Effects of Curcuma Longa on the Osteoarthritis

Panahi et al Randomized double- Patients received SOD, GSH, and MDA in NR

20 blind placebo- curcuminoids 1.5g/day serum were similar
controlled parallel- (n=19); or placebo between the groups at
group trial; 40 (n=21)/6w. Curcuminoid baseline. The Curcuminoid
subjects presenting capsule contained piperine 5 group presented
degenerative mg/4m. significant a significant
primary knee OA reduction in MDA and
with mild to elevation in SOD and GSH,
moderate severity attenuating the systemic
and bilateral OA; < oxidative stress in the
80 years. patients and contributing
Iran to the relieving OA
symptoms.
Haroyan et Comparative, The subjects received Curamin® and CuraMed No adverse
al 26 randomized, double- Curamin (350mg led to improved WOMAC effects related
blind, placebo- curcuminoids + and 150 mg and physical performance to the
controlled study; Boswellic acid), CuraMed tests compared to placebo. treatment.
201 participants, (333mg curcuminoids) or Curamed was superior to
40–77y, 187 women placebo (500 mg), 3xd /3m. placebo tests of physical
and 14 men with performance. Curcumin
degenerative and boswellic acid are
hypertrophic knee more effective (due to the
OA. synergic effect promoted
Armenia by the acid).
Panda et al Randomized, Subjects were divided to Significant improvements in Not relevant
27 double-blind, receive 500 mg 1xd of WOMAC score (also side effects
placebo-controlled, Curene® (bioavailable subscale scores) and VAS were reported.
parallel-group formulation of CL) or scores were observed in
study; 50 placebo/ 3m. the treated group
participants, 40-75y compared to the placebo.
presenting unilateral
or bilateral knee
OA.
India
Gupte et al Randomized pilot Patients received SLCP (80 Both groups showed No serious
28 clinical study; 42 mg) 2xd/90d. The control significant improvement in adverse events
patients ≥65 y, 8 group received Ibuprofen WOMAC and VAS scores were reported.
men and 34 women. (400 mg) 1xd and placebo suggesting comparable
India (dextrin) in the/ 3m. effects of SLCP and
ibuprofen in alleviating
symptoms.
Henrotin et Double-blind, Participants were allocated BCL groups promoted a Abdominal
al 29 multicenter in three groups with a ratio of more significant reduction discomfort and
randomized 1:1:1: (a) placebo 2 × 3 of PGADA compared to diarrhea.
placebo-controlled caps/d, (b) BCL (46.67mg of placebo. The global KOOS
three-arm trial; 141 CL extract) low dosage significantly decreased
patients, 113 women (2 × 2 caps/day) plus over time in all groups.
and 28 men, 45- placebo, and (c) BCL high
80 y with knee OA. dosage 2 × 3 caps/day/
Belgium 3m.

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 The Effects of Curcuma Longa on the Osteoarthritis

Wang et al Randomized, Participants received 1g of CL led to improvement in Adverse events

31 double-blind, CL (extract with 80% wt/wt VAS (but did not modify were similar in
placebo-controlled aqueous-based, with effusion–synovitis volume) both groups
trial; 70 participant, turmerosaccharides + 20% and WOMAC knee pain. (allergy and
31 men, 39 women, wt/wt curcuminoids) or /3m. gastrointestinal
> 40 y with knee symptoms).
pain.
Tasmania –
Australia.
Calderón et Randomized, pilot Participants received B- After 3 d and 1 w, both NR
al 30 clinical trial, 68 Turmactive (500 mg of treatments decreased pain
subjects (29 men, 39 turmeric extract + 19.5 mg of during walking, going up
women, 18-65y with curcuminoid complex) or or downstairs, and sitting
mild-to-moderate- placebo/ 1w. or lying, but only turmeric
intensity knee joint decreased pain at night in
pain, scored 6 to10 bed. B-Turmactive also
of 20 points in the reduced C reactive protein
WOMAC score pain at 1 week, indicating an
subscale). analgesic effect due to
Spain decreased inflammatory
biomarkers.
OA: Osteoarthritis; VAS: Visual Analog Scale; KOOS: Knee injury and Osteoarthritis Outcome Score; NR-INF-02:
Bioactive Turmerosaccharides from Curcuma longa Extract; WOMAC: Western Ontario and McMaster Universities
Osteoarthritis Index; AE: Adverse events; LPFI: Lequesne's pain functional index; IL-4: interleukins 4; IL-6: interleukins
6; TNF- α: tumor necrosis factor-α; hs- CRP: high-sensitivity C-reactive protein; CL: Curcuma longa; MDA:
malondialdehyde; SOD: superoxide dismutase; GSH: glutathione; MDA: malondialdehyde; KOOS: Knee Injury and
Osteoarthritis Outcome Score; SLCP: solid lipid curcumin particles; BCL: Bio-optimized Curcuma longa extracts;
PGADA: Patient Global Assessment of Disease Activity; AE: adverse events; y: year; m: month; w: week.

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 The Effects of Curcuma Longa on the Osteoarthritis

Table 2. Descriptive table of the biases of the included randomized clinical trials.

Intention
Question Appropriate Allocation Double- Losses Prognostics or Outcomes Sample
Study to treat
focus randomization blinding blind (<20%) demographic calculation
analysis
Characteristics
Pinsornsak
Yes Yes Yes Yes ? Yes Yes ? ?
et al. 18
Madhu et
Yes Yes Yes Yes Yes Yes Yes Yes Yes
al 19
Panahi et
Yes Yes ? Yes No Yes Yes NR No
al 21
Nakagawa
Yes Yes Yes Yes Yes Yes Yes NR No
et al 22
Rahimnia
Yes Yes Yes Yes No Yes Yes NR No
et al 23
Sterzi et al Yes Yes Yes Yes Yes Yes Yes Yes
24 No
Srivastava Yes Yes Yes Yes Yes Yes Yes Yes Yes
et al25
Panahi et
Yes Yes ? Yes No No Yes NR No
al 20
Haroyan et
Yes Yes Yes Yes
al 26 Yes Yes Yes Yes Yes
Panda et Yes Yes Yes Yes Yes Yes Yes Yes Yes
al 27
Gupte et
Yes No No No Yes Yes Yes No No
al 28
Henrotin et Yes Yes Yes Yes Yes Yes Yes Yes
Yes
al 29
Wang et Yes Yes Yes Yes Yes Yes Yes Yes Yes
al 31
Calderón Yes Yes Yes Yes Yes Yes Yes Yes Yes
et al 30
NR: Not reported.

8. CONCLUSION and formulations that are most effective in addressing

The use of Curcuma longa extracts or this condition, which is very prevalent in the world's
curcuminoids can benefit patients with OA. populations.
Nevertheless, the available clinical trials show relevant
heterogeneity since the treatment time is different and CONFLICT OF INTEREST
the administered doses and the type of formulation The authors declare no conflict of interest.
used. Thus, the standardization of clinical trials can
guide researchers and physicians as to the dosages

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 The Effects of Curcuma Longa on the Osteoarthritis

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