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© 2016 EDIZIONI MINERVA MEDICA

Online version at http://www.minervamedica.it European Journal of Physical and Rehabilitation Medicine 2016 June;52(3):321-30
ORIGINAL ARTICLE
The efficacy and safety of a combination

of glucosamine hydrochloride, chondroitin
sulfate and bio-curcumin with exercise in the
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treatment of knee osteoarthritis: a randomized,
double-blind, placebo-controlled study
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Silvia STERZI 1, Laura GIORDANI 2, Michelangelo MORRONE 1 *, Emanuela LENA 2, Giovanni MAGRONE 1,
Claudia SCARPINI 2, Stefano MILIGHETTI 1, Leonardo PELLICCIARI 1, Marco BRAVI 1, Ilaria PANNI 3,
Concetta LJOKA 2, Federica BRESSI 1, Calogero FOTI 2
1Department IG E
of Physical and Rehabilitation Medicine, Campus Bio-Medico University, Rome, Italy; 2Department of Physical and
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Rehabilitation Medicine, Tor Vergata University, Rome, Italy; 3Fidia Farmaceutici S.p.A., Abano Terme, Italy
*Corresponding author: Michelangelo Morrone, Department of Physical and Rehabilitation Medicine, Campus Bio-Medico University, Via Álvaro del Por-
tillo 5, 00128, Rome, Italy. E-mail: [email protected]
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ABSTRACT
BACKGROUND: Knee osteoarthritis (OA) conservative treatment aims to delay cartilage degeneration; chondroprotective agents are a valid
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approach in this sense. A commercially available dietary supplement, CartiJoint Forte, containing glucosamine hydrochloride (GH), chondroitin
sulfate (CS) and Bio-Curcumin BCM-95®, was used in this trial.
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AIM: The aim of this study was to assess efficacy and safety of CartiJoint Forte combined with physical therapy in treating subjects with knee
OA.
DESIGN: A multicenter, prospective, randomized, double blind, placebo-controlled clinical trial.
SETTING: Outpatients referred to the Rehabilitation Departments of two University Hospitals.
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POPULATION: Fifty-three patients were randomly assigned to an experimental group (N=26) or a control group (N.=27). Experimental subjects
received two tablets of CartiJoint Forte each day for 8 weeks, while those in the control group were provided with a placebo. Three subjects
dropped out during the course of the study.
METHODS: The two groups both received 20 sessions of physical therapy during the course of the trial. Primary outcome was pain intensity,
measured both at motion and at rest, using the Visual Analogue Scale (VAS). A secondary outcome was an assessment of knee function by West-
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ern Ontario and McMaster Universities Arthritis Index and Lequesne Index, knee ROM, and two inflammation markers (C-reactive protein and
erythrocyte sedimentation rate). Each assessment was carried out at baseline (T0), at 8 weeks (T1) and at 12 weeks (T2).
RESULTS: VAS at rest was found to be reduced between T0 and T1, as well as between T0 and T2 (F=13.712; P=0.0001), with no differences
between groups (F=1.724; P=0.191). VAS at motion revealed a significant “group × time-check” interaction (F=2.491; P=0.032), with increasing
effect of time on VAS reduction (F=17.748; P=0.0001). This was most pronounced in the experimental group at 8 weeks (F=3.437; P=0.045).
The Lequesne Index showed reductions at T1 and T2 compared to T0 (F=9.535; P=0.0001), along with group effect, since the experimental
group presented a lower score at T2 (F=7.091; P=0.009). No significant changes were found in the knee ROM and inflammation markers.
CONCLUSION: CartiJoint Forte, added to physical therapy, may ameliorate pain and help to improve algofunctional score in knee OA patients.
CLINICAL REHABILITATION IMPACT: Treatment of knee OA with curcuminoids plus glycosaminoglycans, added to physical therapy, im-
proves VAS at motion and Lequesne Index scores.
or other proprietary information of the Publisher.
(Cite this article as: Sterzi S, Giordani L, Morrone M, Lena E, Magrone G, Scarpini C, et al. The efficacy and safety of a combination of glucosamine
hydrochloride, chondroitin sulfate and bio-curcumin with exercise in the treatment of knee osteoarthritis: a randomized, double-blind, placebo-
controlled study. Eur J Phys Rehabil Med 2016;52:321-30)
Key words: Dietary supplements - Knee osteoarthritis - Physical therapy modalities - Pain management.
Vol. 52 - No. 3 European Journal of Physical and Rehabilitation Medicine 321

not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, log
STERZI CHONDROPROTECTIVE AGENT SUPPLEMENTATION IN KNEE OA
O steoarthritis (OA) is a medical condition charac-

terized by loss of joint cartilage; this leads to pain
and a loss of function primarily in the knees and hips.
OA itself, while the main focus of physiotherapy is to
decrease pain; in effect, it acts on the symptoms, rather
than the causes, of chondropathy.7 In a recent study,
It has been estimated that OA will represent the sixth 622 patients with knee OA were treated with CS once
leading cause of disability worldwide by 2020.1 The a day over a period of two years; the patients reported
2010 Global Burden of Disease Study 2 showed that the a rapid and enduring improvement in pain symptoms
overall prevalence of symptomatic knee OA was 3.8% which was underlined by a significant reduction in the
higher in females than in males (means 4.8% and 2.8%, consumption of non-steroidal anti-inflammatory drugs
respectively). In terms of age, its prevalence reaches a during the study.8 Recently, the effectiveness of another
peak at around 50 years of age. The same study clas- substance, curcumin, was identified as being able to re-
sified knee and hip OA as the 11th highest contributor duce symptoms of rheumatoid arthritis. CartiJoint Forte,
to global disability, accounting for 2.2% of years lived a dietary supplement, has recently become available. It
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with disability. The following are the main known risk contains CS, glucosamine hydrochloride (GH) and Bio-
factors for developing knee OA: obesity, traumatic knee Curcumin BCM-95®, a Curcuma longa extract in high
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injury, misalignment, female gender, increasing age (es- bioavailability titrated to 95% from curcuminoids, all
pecially between 50 and 75 years), occupational joint substances known to have antioxidant properties.9 It
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loading, and hand OA.1, 3 Overweight or obese people functions in maintaining joint function by promoting
have a 2.96 fold higher risk for the onset of knee OA cartilage tropism.
than those with a normal Body Mass Index (BMI).4 The The purpose of this study was to assess the efficacy
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most common symptom is pain, which is increased by
mechanical stress, such as kneeling or lifting activi-
of CartiJoint Forte, combined with physical therapy,
as a treatment for subjects with knee OA. Given the
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ties, and reduced by rest. Moreover, knee OA pain is proven validity of physical treatment for knee OA, it
also frequently associated with limited joint functional- was hypothesized that its association with oral supple-
ity and morning stiffness; these are partially recovered mentation with CS, GH and curcumin would result in
after movement. Treatment of knee OA includes both decreased pain, better functionality and improved mo-
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non-pharmacological measures, such as weight loss and bility compared to exercise alone.
physical therapy, and pharmacological measures. These
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include treatment with analgesic/anti-inflammatory Materials and methods

drugs as well as symptomatic slow-acting drugs to treat
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OA; treatment is mainly focused on symptom relief and A randomized, placebo-controlled study was per-
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joint function preservation.5 However, the main goal of formed by the Physical and Rehabilitation Medicine
OA therapy should be to delay cartilage degeneration Departments of the Campus Bio-Medico University and
and possibly to regenerate the cartilage structure. Tor Vergata University, Rome, Italy.
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Treatment with chondroprotectives is a valid ap- Subjects were selected if they satisfied a variety of
proach in this sense. Chondroprotectives include glu- inclusion and exclusion criteria. They were required to
cosamine sulfate (GS), chondroitin sulfate (CS) and be a minimum of 50 years old, have primary knee OA of
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hyaluronic acid, important basic natural components of the medial or lateral femorotibial compartment, meet the
cartilage and synovial fluid. They are produced natu- American College of Rheumatology classification crite-
rally by the body but these can be supplemented in the ria,10 have disease severity Grade II or III on the Kell-
diet. In cases of articular cartilage damage, or less se- gren and Lawrence 11 classification (radiographic exam-
rious joint pathologies of traumatic origin, it has been ination) and have suffered knee pain for a minimum of
observed that the combination of GS and CS can sig- one month confirmed by a Visual Analogue Scale (VAS)
nificantly reduce painful symptoms and improve joint score greater than 40 mm on a 100-mm scale.
function. This is achieved by improving cartilage me- Subjects were excluded if they had: a history or pres-
tabolism and acting as a protective action so preventing ence of rheumatic disease resulting in secondary OA,
any worsening of the disease.6 This treatment has been a history of traumatic knee lesions or actual injuries,
shown to play a preventive role in the progression of previous knee surgery, a known or suspected allergy to
322 European Journal of Physical and Rehabilitation Medicine June 2016

CHONDROPROTECTIVE AGENT SUPPLEMENTATION IN KNEE OA STERZI
components in the investigational product or had taken femoris muscles (flexing the hip against a progressive
oral, parenteral or intra-articular corticosteroids or infil- resistance starting with a one kilo weight on the thigh).
trative therapies in the previous three months. Further Throughout the whole study, the experimental group
exclusions were made on general medical conditions, received two tablets of CartiJoint Forte per day, while the
such as pregnancy, metabolic or oncological diseases, control group received two placebo tablets per day. In or-
as well any condition that might confound the subse- der to ensure the double-blind masking, the physiatrists
quent clinical evaluation of the outcomes. who administered the tablets, were different from those
Enrolled subjects were randomly assigned to one of who assessed the outcome measures. Both the physio-
two groups (experimental or control) using a random- therapists and the subjects were blinded as to whether in-
ization chart based on a stratification sequence for both dividual patients had been assigned to the experimental
age (under 65 vs. over 65 years) and gender (64% fe- or control group in the trial. Compliance with study treat-
male proportion, to represent the greater prevalence of ment was checked by providing the patients with a diary
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knee OA in the female population 1). The method used where they self-reported missing doses and by counting
was as follows: integer numbers, starting at 1, were as- unused tablets at the end of the study period. The same
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signed to subjects according to the stratification speci- diary also registered daily usage and doses of any rescue
fication above, i.e. age and gender. Random numbers analgesia (restricted to paracetamol in 500-mg tablets).
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were generated by computer with each of them being
successively paired with the integer numbers previously Outcome assessment
assigned. The random numbers were sorted in decreas-
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ing order. The subjects associated with the first half of
the ordered random numbers, via their linked integer
After recruitment, individuals who met the eligibility
criteria underwent an initial evaluation involving clini-
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labels, were assigned to the experimental group. The cal and demographic information. The primary outcome
remainder formed the control group. for the trial was pain intensity measured by two VAS
The study was approved by the Ethics Committee of scores from 0 mm (no pain) to 100 mm (worst pain imag-
the Campus Bio-Medico University (Prot.: 63/12 PAR inable); one registered pain during normal daily living
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ComEt CBM). Prior to conducting the study-related and the other pain when at rest. The secondary outcomes
procedures, each subject read and signed an informed were measured using a number of instruments: knee
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consent form, as required in the World Medical Asso- function assessed by the Western Ontario and McMaster
ciation Declaration of Helsinki.12 Universities Index for Osteoarthritis (WOMAC)13, the
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Lequesne Index,14 flexion and extension ROM, as well

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Therapy prescriptions as inflammation assessment using C-reactive protein

(CRP) and erythrocyte sedimentation rate (ESR) mea-
Subjects in both the experimental and control groups surements. The WOMAC total score, designed to mea-
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received two cycles of 10 one-hour physical therapy sure severity of knee OA, is calculated from responses
sessions, three times a week, each session being con- to a self-administered questionnaire. It comprises three
ducted under the supervision of experienced physio- subscales: WOMAC pain (assessed by means of five
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therapists. During the first cycle, all the subjects per- questions), WOMAC stiffness (two questions), and
formed a range of exercises. These included active and WOMAC physical function (17 questions). Each ques-
active-assisted mobilizations to recover the range of tion has a score that ranges from 0 to 10; higher scores
motion (ROM) of the hip, knee and ankle, stretching represent greater pain, more stiffness, and worse knee
exercises of the quadriceps, hamstring, gastrocnemius function. The maximum WOMAC score is 240. The
and adductor muscles and exercises for strengthening Lequesne Index contains eleven items, 5 related to pain,
the vastus medialis oblique muscle, first in supine posi- 2 related to the maximum distance walked and four re-
tion and subsequently in sitting posture. lated to daily activities. The maximum Lequesne Index
During the second cycle, subjects performed isomet- score is 24, again with higher scores representing worse
ric closed kinetic chain exercises (squat and semi-squat) conditions. A questionnaire on lifestyle and eating behav-
and strengthening of adductors, abductors and rectus ior was administrated in order to evaluate any possible

changes during the trial. Finally, as a secondary objec- to determine the appropriate sample size for each arm
tive, safety of the treatments was assessed by monitoring of the trial (treatment/control). A decrease in the per-
adverse events, both treatment-emergent and other, and ception of pain of 20% due to the treatment with nu-
by clinical evaluation. All measurements were recorded traceutical supplement, with 26 patients in each group,
by physiatrists at baseline (T0), after 8 weeks (T1) and represented an 85% power.
at the end of treatment after 12 weeks (T2), while CRP
and ESR tests were performed at T0 and T2 checkpoints. Statistical analysis
All assessors were blinded to the subjects’ assignments
to the experimental or control groups. The main statistical measures were descriptive statis-
tics such as the mean and standard deviation (SD) or the
Sample size calculation median with minimum and maximum values. In some in-
stances relative frequencies with percentages were used
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The primary outcome variable, the VAS score, was to describe the behavior of parameters under consider-
assumed to have a Gaussian distribution and was based ation. Where required, normality of distributions was
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on an ordinal centesimal scale (0-100). Choosing an a- assessed using the Kolmogorov-Smirnov test. Where
priori risk of alpha error equal to 0.05, it was possible variables followed a normal distribution, one-way/two-
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ENROLLMENT Assessed for eligibility (n=80)
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• Inconvenience/refusal (n=10)
• Did not meet criteria (n=15)
• Excluded due to abnormal blood
chemistry (n=2)
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ALLOCATION Randomized (n=53)

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Experimental group (n=26) Control group (n=27)

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Lost to follow-up (n=3) FOLLOW-UP

• Change of address (n=2) AFTER 8 Lost to follow-up (n=0)
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• Inconvenience (n=1) WEEKS (T1)
FOLLOW-UP
Lost to follow-up (n=0) AFTER 12 Lost to follow-up (n=0)
WEEKS (T2)
Analysed (n=23) Analysed (n=27)

ANALYSIS
Excluded (n=0)) Excluded (n=0))
Figure 1.—Flow chart showing the number of subjects randomized and studied in each group.

way ANOVA or ANOVA for repeated measures were em- Results

ployed. The Kellgren-Lawrence grades had a non-normal Sample characteristics
distribution, so the non-parametric Kruskal-Wallis test
was employed. χ2 or Fisher’s exact test (if cells sizes were Fifty-three patients, previously diagnosed with OA,
below 5) were employed to testing dichotomous or cat- were enrolled onto the trial between January 2013 and
egorical variables. Given the small sample size, when a July 2013; 26 were assigned to the experimental group
statistically significant result was found, in order to check and 27 to the control group. After enrolment, three sub-
the robustness of the finding, the relative observed power jects from the experimental group dropped out from the
(with alpha error = 0.05) was also computed. For all statis- study (Figure 1); hence the experimental group size was
tical analyses the level of significance was set at P<0.05. reduced to 23 participants, representing an 83% power.
The statistical software package, SPSS Statistics Demographic and clinical characteristics were similar
v.15.0 for Windows (IBM Corp., Chicago, IL, USA) for both groups at the baseline assessment (P>0.05)
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was used to process data and perform tests and analyses. (Table I). Compliance with the treatment required in the
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Table I.—Clinical and demographic characteristics of the sample at the baseline.
Sample CartiJoint group Control group
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Variables P value
(N.=50) (N.=23) (N.=27)
Gender
Male 17 (34.0%) 9 (39.1%) 8 (29.6%) 0.480
Female 33 (66.0%) 14 (60.9%) 19 (70.4%)
Age (years)
Weight (kg)
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77.7±15.7
71.3±8.8
78.4±14.5
71.0±8.1
77.1±16.9
0.991
0.959
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Height (cm) 162.9±9.0 164.4±9.6 161.7±8.5 0.402
BMI (kg/m2) 34.5±7.0 34.8±6.4 34.3±7.5 0.959
Education level
Elementary 11 (22.0%) 4 (17.4%) 7 (25.9%) 0.814
Middle school 17 (34.0%) 9 (39.1%) 8 (29.6%)
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High school 19 (38.0%) 9 (39.1%) 10 (37.0%)

University degree 3 (6.0%) 1 (4.3%) 2 (7.4%)
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Job
Housewife 10 (20.0%) 6 (26.1%) 4 (14.8%) 0.418*
Employee 3 (6.0%) 2 (8.7%) 1 (3.7%)
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Retired 34 (68.0%) 15 (65.2%) 19 (70.4%)

Craftsman 2 (4.0%) 0 (0.0%) 2 (7.4%)
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Other 1 (2.0%) 0 (0.0%) 1 (3.7%)

Smoking habit
No 44 (88.0%) 18 (78.3%) 26 (96.3%) 0.082*
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Yes 6 (12.0%) 5 (21.7%) 1 (3.7%)

Alcohol habit
No 28 (56.0%) 13 (56.5%) 15 (55.6%) 0.945
Yes 22 (44.0%) 10 (43.5%) 12 (44.4%)
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Knee pain
Right 20 (40.0%) 8 (34.8%) 12 (44.4%) 0.487
Left 30 (60.0%) 15 (65.2%) 15 (55.6%)
Duration of disease (years) 7.0±6.7 6.8±7.6 7.2±6.0 0.837
Number of previous treatments 8 (16.0%) 4 (17.4%) 4 (14.8%) 0.578
Kellgren and Lawrence Grade 2.0 (2-4) 2.0 (2-4) 2.0 (2;4) 0.181**
VAS at rest 41.5±23.7 37.0±25.8 45.3±21.5 0.531
VAS on moving 63.8±17.9 65.7±21.1 62,2±14,8 0.499
Mean Global WOMAC Score 40.3±11.6 37.4±11.0 42.9±11.6 0.091
Lequesne Index 12.1±3.2 11.4±3.4 12.7±3.0 0.150

Use of walking aids 4 (8.0%) 2 (8.7%) 2 (7.4%) 0.867
Data are expressed as absolute number (%), mean ± SD, or median (range) (for non-normally distributed variables).
*Fisher’s Exact Test; **Kruskal-Wallis test.
BMI: Body Mass Index; VAS: Visual Analogue Scale; WOMAC: Western Ontario and McMaster Universities Arthritis Index.

Table II.—Differences of mean change of primary outcome measures within and between groups at T0, T1 and T2.
CartiJoint group (N.=23) Control group (N.=27) P value Observed power
Variables
T0 T1 T2 T0 T1 T2 Group Check Group Group Check Group
× check × check
VAS at rest 37.0±25.8 24.2±29.9* 14.6±17.3§ 45.3±21.5 22.7±20.8* 22.6±18.5§ 0.191 0.0001 0.458 – – –
VAS at motion 65.7±21.1 37.5±20.2*† 38.1±25.6§ 62.2±14.8 51.9±21.1* 45.5±17.6§ 0.045 0.0001 0.032 0.653 1.000 0.793
Data are expressed as mean ± SD. VAS: Visual Analogue Scale.
*P<0.05 (T1 vs. T0); §P<0.05 (T2 vs. T0); †P<0.05 (CartiJoint vs. control group).
Table III.—Differences of mean change of secondary outcome measures within and between groups at T0, T1 and T2.
CartiJoint group (N.=23) Control group (N.=27) P value Observed power
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Variables Group Group ×
T0 T1 T2 T0 T1 T2 Group Check × check Group Check check
WOMAC total score 37.4±11.0 26.5±13.3* 23.0±16.9§ 42.9±11.6 28.7±13.7* 26.5±15.4§ 0.099 0.0001 0.833 – 1.000 –
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Lequesne Index 11.4±3.4 8.7±4.3* 7.9±3.5§ † 12.7±3.0 10.2±3.5* 10.1±3.6§ 0.009 0.0001 0.824 0.887 0.994 –
Knee extension ROM 4.7±5.1 3.8±5.6 4.1±5.5 7.7±5.6 5.2±5.5 4.7±5.8 0.067 0.194 0.557 – – –
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Knee flexion ROM 106.1±10.7 110.5±10.8 110.4±8.4 105.6±16.6 109.7±12.3 109.5±9.6 0.693 0.133 0.996 – – –
CRP test 3.1±3.2 N/A 4.2±4.4 4.6±4.7 N/A 4.2±4.2 0.369 0.374 0.995 – – –
ESR test 33.9±20.5 N/A 36.5±25.3 40.8±27.9 N/A 40.7±25.4 0.096 0.815 0.776 – – –
Data are expressed as absolute count plus percentage (between brackets) or mean ± SD.
WOMAC: Western Ontario and McMaster Universities Index for Osteoarthritis; ROM: range of motion; N/A: not assessed; CPR: C-reactive protein; ESR: erythrocyte
sedimentation rate.
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*P<0.05 (T1 vs. T0); §P<0.05 (T2 vs. T0); †P<0.05 (CartiJoint vs. control group).
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study was excellent; the number of patients reporting both groups. There was however a substantial inter-
over 90% drug/placebo intake during the study period groups difference, especially at the T1 check (F=3.437;
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ranged from 89% to 97%, with no significant difference P=0.045). Indeed, after 8 weeks of treatment, knee pain
between the groups. at motion for the experimental group appeared to be sig-
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nificantly reduced compared to the control group.

Primary outcome
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Secondary outcomes
As a primary outcome, we assessed the effect of Car-
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tiJoint Forte, supplemented with a physical training pro- In order to assess the effect of nutraceutical supplemen-
gram, on knee pain, by means of VAS scores recorded tation on functional status, and, consequently on daily life
under two different conditions (Table II). For the VAS performance, a series of parameters were investigated us-
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at rest, we found no interaction ‘group x time-check’ ing some widely used evaluation tools (Table III). First,
(F=0.785; P=0.458). However, a within-groups statisti- the WOMAC Index was been measured. As described
cally significant reduction between T1 vs. T0 and T2 above, higher scores are associated with worse functional
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vs. T0 (F=13.712; P=0.0001) emerged, although no dif- status (including joint pain and stiffness). An analysis of
ferences were found in the comparison between groups variance test of the WOMAC score showed a statistically
(F=1.724; P=0.191). Neither group showed a similar significant reduction, independent of groups (F=2.751;
reduction of rest pain at times T1 and T2 compared to P=0.099), between check 1 vs. check 0 and check 2 vs.
that recorded at baseline (T0), providing no evidence of check 0 (F=17.463; P=0.0001). No relevant differences
changes between half-treatment evaluation and at end of were found between T2 and T1, in either group.
the treatment. In relation to the VAS on moving scores, Similarly, with the Lequesne Index, an ANOVA test
a test using repeated measures ANOVA revealed a sig- showed a statistically significant decrease observed be-
nificant “group × time-check” interaction (F=2.491; tween check 1 and check 0, and between check 2 and
P=0.032), which underpins an increasing effect of time check 0 (F=9.535; P=0.0001), but without any signifi-
on VAS score reduction (F=17.748; P=0.0001) for cant change from T1 to T2.

Table IV.—Differences in caloric intake, weight and BMI at the baseline (T0) and final (T2) assessment.
CartiJoint group (N.=23) Control group (N.=27)
Variables P value (between groups)
T0 T2 T0 T2
Kcal/die 2087.1±317.7 2065.3±345.7 2107.4±344.0 2109±325.9 0.880
Weight (kg) 78.4±14.5 79.1±14.6 77.1±16.9 77.0±16.6 0.907
BMI (kg/m2) 34.8±6.4 34.0±9.7 34.3±7.5 34.2±7.4 0.880
Data are expressed as mean ± SD. BMI: Body Mass Index.
However, a group effect was identified; the experi- due to their benefits on joint structure among patients
mental group showed a lower score at the T2 check with mild to moderate disease.16 Apart from their ef-
compared to the placebo group (F=7.091; P=0.009). ficacy, both glucosamine and chondroitin are safe medi-
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Assessment of knee ROM did not show any intra or cations with no difference in their adverse effects com-
inter-groups differences either with flexion (F=0.004; pared to a placebo.17
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P=0.996) or extension (F=0.588; P=0.557). Finally, Bio-molecular studies have shown that the combi-
neither ESR and CRP tests revealed any significant nation of glucosamine and chondroitin suppresses IL-
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changes after therapy; between groups “group × time- 1-induced gene expression of iNOS, COX-2, mPGEs
check” interaction ANOVA results were CRP (F=0.000; and NF-kB in cartilage explants.18 This leads to reduced
P=0.995) and ERS (F=0.082; P=0.776). production of NO and PGE2, two mediators responsible
for cell death of chondrocytes and inflammatory reac-
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Questionnaire on lifestyle and eating behaviors tions.19 In comparison to glucosamine and chondroitin,
hyaluronic acid has a minor anti-inflammatory and anti-
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No statistically significant differences for calorie in- apoptotic effect.20 In previous randomized controlled
take, weight or BMI, before and after treatment, were studies the effectiveness of the association of glucos-
found in either group (Table IV). amine and chondroitin in knee OA was evaluated, and
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this combination proved more effective than a placebo

Adverse effects (AE) in attenuating pain and joint rigidity.21 This benefit was
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evident in patients with mild-to-moderate disease but

No adverse events were reported during the study. was not demonstrated in those with severe conditions.22
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Curcumin offers considerable potential as an aid in

Discussion preventing, or at least delaying, the onset of OA. Cur-
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cumin and its derivatives are part of the curcuminoids

In developed countries there is an increasing interest family, being derived from Curcuma longa L. or tur-
in using natural remedies, particularly those of botani- meric. Curcumin is recognized as being able to suppress
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cal origin, for the treatment of chronic OA pain. This gene expression of matrix metalloproteinases,23 which
randomized placebo-controlled study was performed are destructive enzymes that can dissolve cartilage
to evaluate, for the first time, if an integrated approach structure.24 Moreover, it can block inflammatory signal-
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based on oral intake of Bio-Curcumin with GH and CS, ing molecules (multiple cytokine IL-1β), that aggravate
accompanied by a physical exercise program, could re- painful joint inflammation.25 Laboratory studies show
duce pain symptoms and improve knee function in pa- that curcumin slows cartilage IL-1β induced degenera-
tients with primary knee OA. In the literature, several tion by restoring normal production of proteins of the
combinations of pharmacological and non-pharmaco- cartilage.26, 27 Hence, it might be a beneficial addition to
logical approaches for treating knee OA may be found. the conventional drug regimen in OA treatment.
However, treatment is traditionally based on each in- In the present study, a significant improvement was
dividual patient’s assessment, taking into account their found VAS scores at motion for each study group at
needs and preferences.15 In the pharmacological part of both 8 and 12 weeks; further, the experimental group
the knee OA treatment, glucosamine and chondroitin showed a more consistent reduction in pain after eight
represent a non-negligible time, since the beginning, weeks of treatment, probably due to the effect of the

nutraceutical supplementation demonstrating its full ef- Provenza et al.32 observed that combined GS and CS,
fect. At the end of the study period, no between-groups once or three times daily, provided appropriate analgesia
differences were observed, likely due to a plateau effect in knee OA, independent of dose level and whether in
for the CartiJoint Forte. Similarly, with respect to the capsule or sachet formulation. The findings stated above
algofunctional Lequesne Index, this study revealed an seem to contradict those of the study by Messier et al.,33
improvement at the end of the study for both groups; on a sample of 89 older adults suffering from knee OA.
however, treated patients had better scores compared to They found no difference in VAS score and WOMAC
the controls. WOMAC global scores exhibited an ame- function for a one-year treatment using 1500/1200 mg/d
liorating trend across all study time-points, without any GH/CS accompanied by up to 6 months of physical ther-
discrepancy between groups. apy compared to placebo plus exercise. The long-lasting
The results from this trial are in line with those found treatment period could account for these results; indeed,
in the literature. In a recent randomized, double-blind, a meta-analysis suggests that glycosaminoglycans have
® A
placebo-controlled study, Nakagawa et al.28 reported a short-term effect on pain relief.34 However, another re-
a trial with 50 knee OA patients, with Kellgren-Law- view supports its structural and symptomatic efficacy.35
T C
rence grade II or III, where a significant reduction in A recent meta-analysis by Wu et al.36 examined 19 ran-
pain was observed after an 8 week administration of a domized clinical trials involving an overall sample size
H DI
surface-controlled water-dispersible form of curcumin. of 3159 knee/hip OA patients; in comparing the efficacy
The authors also observed a more pronounced lower- of different preparations of glucosamine (sulfate and
ing of celecoxib dependence in the group of patients hydrochloride) for pain reduction and physical function
IG E
treated with curcumin than in the placebo group. Pa-
nahi et al.29 conducted a pilot randomized double-blind
against placebo, it concluded no efficacy for glucosamine
in reducing pain and only a mild effect in improving
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placebo-controlled parallel-group clinical trial among physical function, as evaluated by the Lequesne Index.
19 patients with mild to moderate knee OA. They were Our study did not identify differences between and
assigned either 1500 mg/day curcuminoids or a placebo within groups with respect to ROM assessment, proba-
for 6 weeks. By analyzing changes in WOMAC, VAS bly due to the fact that at the baseline assessment subjects
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and Lequesne Index scores, they concluded that cur- showed an almost full knee ROM. Finally, when com-
cuminoids represent an effective and safe alternative paring ESR and CRP test values before and after treat-
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treatment for OA. The results from our trial are sub- ment, no differences were found in either group; these
stantially consistent with these findings, although less results may be due to the older average age of our sample
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pronounced. This may be the result of the beneficial and so may be influenced by possible comorbidities.
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effect of physical therapy, which was provided to both Several studies suggest that pain relief and improve-
experimental and control subjects. ment of joint function in patients with knee OA may be
Kuptniratsaikul et al.,30 in a multicenter research attributable to weight loss.37, 38 In our study no differ-
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study on 367 primary knee OA patients, compared the ence in BMI was found between the baseline and final
efficacy and safety of Curcuma domestica extracts to assessments; therefore, this finding could confirm the
ibuprofen. They concluded that Curcuma domestica validity of the results of our study.
M
extracts are as effective as ibuprofen in the treatment Throughout the study, no adverse side effects were
of knee OA; they noted a similar side effect profile in observed that could be attributed to the intake of Bio-
both groups but with fewer gastrointestinal AE reports Curcumin with GH, CS. This finding confirms numer-
for the Curcuma domestica extracts group. By contrast, ous literature reports of the good safety profile of bio-
Pinsorsnak et al.,31 in a double-blind placebo-controlled curcumin, GH and CS although it diverges from the
parallel-groups trial, found no significant difference in Kuptniratsaikul et al.30 study of 185 patients suffering
VAS scores after 3 months of treatment with diclofenac from knee OA that found a 29.7% occurrence of adverse
75 mg/d plus curcumin 1000 mg/d in a cohort of 37 events in a treatment with Curcuma domestica extracts.
over-50 year old patients with mild to moderate knee The majority of the side effects were related to the
OA, compared to diclofenac plus placebo in 36 age- gastro-enteric tract, for example dyspepsia, abdominal
matched knee OA subjects. pain/distension and nausea. A possible explanation for

this discrepancy lies in the different rescue medications 2. Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, et al.
The global burden of hip and knee osteoarthritis: estimates from the
administered for the relief of severe pain; the patients global burden of disease 2010 study. Ann Rheum Dis 2014;73:1323-
in the above-mentioned study took tramadol while only 30.
3. Allen KD, Golightly M. Epidemiology of osteoarthritis: state of the
acetaminophen was permitted in the present study. evidence. Curr Opin Rheumatol 2015;27:276-83.
Some limitations to the current study need to be not- 4. Apold H, Meyer HE, Nordsletten L, Furnes O, Baste V, Flugsrud
GB. Risk factors for knee replacement due to primary osteoarthritis,
ed. It lacks a follow up evaluation, for example to check a population based, prospective cohort study of 315,495 individuals.
for possible long-lasting effects of the treatment beyond BCM Musculoskelet Disord 2014;15:217.
the 3-month duration of the trial, perhaps at 6 and/or 12 5. McAlidon TE, Bannuru RR, Sullivan MC, Arden NK, Berenmaum
F, Bierma-Zeinstra SM, et al. OARSI guidelines for the non-sur-
months. gical management of knee osteoarthritis. Osteoarthritis Cartilage
This was the time frame suggested for glycosami- 2014;22:363-88.
6. Clegg DO, Reda DJ, Harris CL, Klein MA, O’Dell JR, Hooper MM,
noglycans.39 Indeed, recently it has been shown that et al. Glucosamine, chondroitin sulfate, and the two in combination
some components of glycosaminoglycans (also known for painful knee osteoarthritis. N Engl J Med 2006;354:795-808.
® A
7. Henrotin Y, Marty M, Mobasheri A. What is the current status of
as Symptomatic Slow Acting Disease Drugs for Os- chondroitin sulfate and glucosamine for the treatment of knee oste-
teoarthritis), when prescribed over a long time period, oarthritis? Maturitas 2014;78:184-7.
T C
8. Kahan A, Uebelhart D, De Vathaire F, Delmas PD, Reginster JY.
present disease modifying potential as measured by Long term effects of chondroitin 4 and 6 sulfate on knee osteoar-
joint space narrowing on X-ray or nuclear magnetic thritis. The study on osteoarthritis progression and prevention, a
H DI
two-year, randomized, double blind placebo controlled trail. Arthritis
resonance imaging.40 This suggests another limitation Rheum 2009:60:524-33.
of the present study; although the enrolled patients were 9. Chainani-Wu N, safety and anti-inflammatory activity of curcumin: a
evaluated using an X-ray examination of their knees at component of turmeric (Curcuma longa). J Altern Complement Med
2003;9:161-8.
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the baseline, there was no further radiographic exami-
nation during the study. Hence, it has not been possible
10. Altman R, Asch E, Bloch D, Bole G, Borestein D, Brandt K, et al.
Development of criteria for the classification and reporting of oste-
oarthritis. Classification of osteoarthritis of the knee. Diagnostic and
R M
to objectively quantify the disease-modifying potential Therapeutic Criteria Committee of the American Rheumatism Asso-
of the nutraceutical treatment on knee OA. ciation. Arthritis Rheum 1986;29:1039-49.
11. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthro-
sis. Ann Rheum Dis 1957;16:494-502.
12. World Medical Association. World Medical Association Declaration
Conclusions
P A
of Helsinki: ethical principles for medical research involving human

subjects. JAMA 2013;310:2191-4.
Our preliminary results show that treatment with Bio- 13. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW.
O V
Validation study of WOMAC: a health status instrument for measur-

Curcumin BCM-95® with GH and CS, accompanied by ing clinically important patient relevant outcomes to antirheumatic
physical therapy, may improve pain symptoms during drug therapy in patients with osteoarthritis of the hip or knee. J Rheu-
C ER
the activities of daily living and reduce algofunctional matol 1988;15:1833-40.

14. Lequesne MG. The algofunctional indices for hip and knee osteoar-
Lequesne Index values in mild to moderate knee OA
Y
thritis. J Reumatol 1997;24:779-81.

patients. 15. Rabini A, Piazzini DB, Tancredi G, Foti C, Milano G, Ronconi G,
et al. Deep heating therapy via microwave diathermy relieves pain
Although the validity of the findings in the trial is and improves physical function in patients with knee osteoarthritis:
IN
limited by the sample size, the results provide prelimi- a double-blind randomized clinical trial. Eur J Phys Rehabil Med
2012;48:549-59.
nary evidence of the usefulness of CartiJoint Forte in 16. Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Rob-
knee OA management. Further research along a number inson V, et al. Glucosamine therapy for treating osteoarthritis. Co-
chrane Database Syst Rev 2005:CD002946.
of paths is warranted. Possible extensions include using
M
17. Fransen M, Agaliotis M, Nairn L, Votrubec M, Bridgett L, Su S, et

a longer follow-up period in order to assess the opti- al. Glucosamine and chondroitin for knee osteoarthritis: a double-
blind randomised placebo-controlled clinical trial evaluating single
mal duration of treatment as well as expansion to other and combination regimens. Ann Rheum Dis 2015;74:851-8.
populations, for example, to determine if it could be a 18. Mattiello-Sverzut AC, Petersen SG, Kjaer M, Mackey AL. Morpho-
therapeutic treatment for sufferers of hip OA. logical adaptation of muscle collagen and receptor of advanced gly-
cation end product (RAGE) in osteoarthritis patients with 12 weeks
of resistance training: influence of anti-inflammatory or glucosamine
treatment. Rheumatol Int 2013;33:2215-24.
19. Yasuda T. Comparison of hyaluronan effects among normal, osteoar-
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Conflicts of interest.—I. Panni is a clinical project manager at Fidia Farmaceutici S.p.A., which owns the rights to CartiJoint (trademark application no.
008952087).
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Acknowledgements.—The authors wish to thank Sandra Miccinilli, Marco Del Duca, Manuela Mori and Antonella Migliorino for their help in collecting
and organizing the data, as well as Roberto P. Sorge and Maria C. Buè for their contribution to the data analysis and presentation. Fidia Farmaceutici S.p.A.
provided Nutraceutical supplies to the study on a non-profit study basis.
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Article first published online: March 3, 2016. - Manuscript accepted: March 1, 2016. - Manuscript revised: January 8, 2016. - Manuscript received: January
12, 2015.
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© 2016 EDIZIONI MINERVA MEDICA

The efficacy and safety of a combination

Vol. 52 - No. 3 European Journal of Physical and Rehabilitation Medicine 321

STERZI CHONDROPROTECTIVE AGENT SUPPLEMENTATION IN KNEE OA

O steoarthritis (OA) is a medical condition charac-

include treatment with analgesic/anti-inflammatory Materials and methods

322 European Journal of Physical and Rehabilitation Medicine June 2016

CHONDROPROTECTIVE AGENT SUPPLEMENTATION IN KNEE OA STERZI

Lequesne Index,14 flexion and extension ROM, as well

Therapy prescriptions as inflammation assessment using C-reactive protein

Vol. 52 - No. 3 European Journal of Physical and Rehabilitation Medicine 323

STERZI CHONDROPROTECTIVE AGENT SUPPLEMENTATION IN KNEE OA

ALLOCATION Randomized (n=53)

Experimental group (n=26) Control group (n=27)

Lost to follow-up (n=3) FOLLOW-UP

• Inconvenience (n=1) WEEKS (T1)

Analysed (n=23) Analysed (n=27)

324 European Journal of Physical and Rehabilitation Medicine June 2016

CHONDROPROTECTIVE AGENT SUPPLEMENTATION IN KNEE OA STERZI

way ANOVA or ANOVA for repeated measures were em- Results

High school 19 (38.0%) 9 (39.1%) 10 (37.0%)

Retired 34 (68.0%) 15 (65.2%) 19 (70.4%)

Other 1 (2.0%) 0 (0.0%) 1 (3.7%)

Yes 6 (12.0%) 5 (21.7%) 1 (3.7%)

Lequesne Index 12.1±3.2 11.4±3.4 12.7±3.0 0.150

Vol. 52 - No. 3 European Journal of Physical and Rehabilitation Medicine 325

STERZI CHONDROPROTECTIVE AGENT SUPPLEMENTATION IN KNEE OA

nificantly reduced compared to the control group.

326 European Journal of Physical and Rehabilitation Medicine June 2016

CHONDROPROTECTIVE AGENT SUPPLEMENTATION IN KNEE OA STERZI

this combination proved more effective than a placebo

evident in patients with mild-to-moderate disease but

Curcumin offers considerable potential as an aid in

cumin and its derivatives are part of the curcuminoids

Vol. 52 - No. 3 European Journal of Physical and Rehabilitation Medicine 327

STERZI CHONDROPROTECTIVE AGENT SUPPLEMENTATION IN KNEE OA

328 European Journal of Physical and Rehabilitation Medicine June 2016

CHONDROPROTECTIVE AGENT SUPPLEMENTATION IN KNEE OA STERZI

of Helsinki: ethical principles for medical research involving human

Validation study of WOMAC: a health status instrument for measur-

the activities of daily living and reduce algofunctional matol 1988;15:1833-40.

thritis. J Reumatol 1997;24:779-81.

17. Fransen M, Agaliotis M, Nairn L, Votrubec M, Bridgett L, Su S, et

thritis, and rheumatoid arthritis cartilages stimulated with fibronectin

Vol. 52 - No. 3 European Journal of Physical and Rehabilitation Medicine 329

STERZI CHONDROPROTECTIVE AGENT SUPPLEMENTATION IN KNEE OA

330 European Journal of Physical and Rehabilitation Medicine June 2016

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