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Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms: A multicenter randomized, double-blind, placebo-controlled study

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Background Undenatured type II collagen (UC-II) is a nutritional supplement derived from chicken sternum cartilage. The purpose of this study was to evaluate the efficacy and tolerability of UC-II for knee osteoarthritis (OA) pain and associated symptoms compared to placebo and to glucosamine hydrochloride plus chondroitin sulfate (GC). Methods One hundred ninety one volunteers were randomized into three groups receiving a daily dose of UC-II (40 mg), GC (1500 mg G & 1200 mg C), or placebo for a 180-day period. The primary endpoint was the change in total Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) from baseline through day 180 for the UC-II group versus placebo and GC. Secondary endpoints included the Lequesne Functional Index (LFI), the Visual Analog Scale (VAS) for pain and the WOMAC subscales. Modified intent-to-treat analysis were performed for all endpoints using analysis of covariance and mixed model repeated measures, while incremental area under the curve was calculated by the intent-to-treat method. ResultsAt day 180, the UC-II group demonstrated a significant reduction in overall WOMAC score compared to placebo (p = 0.002) and GC (p = 0.04). Supplementation with UC-II also resulted in significant changes for all three WOMAC subscales: pain (p = 0.0003 vs. placebo; p = 0.016 vs. GC); stiffness (p = 0.004 vs. placebo; p = 0.044 vs. GC); physical function (p = 0.007 vs. placebo). Safety outcomes did not differ among the groups. ConclusionUC-II improved knee joint symptoms in knee OA subjects and was well-tolerated. Additional studies that elucidate the mechanism for this supplement’s actions are warranted. Trial registrationCTRI/2013/05/003663; CTRI/2013/02/003348.
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R E S E A R C H Open Access
Efficacy and tolerability of an undenatured
type II collagen supplement in modulating
knee osteoarthritis symptoms: a
multicenter randomized, double-blind,
placebo-controlled study
James P. Lugo
1
, Zainulabedin M. Saiyed
1
and Nancy E. Lane
2*
Abstract
Background: Undenatured type II collagen (UC-II) is a nutritional supplement derived from chicken sternum
cartilage. The purpose of this study was to evaluate the efficacy and tolerability of UC-II for knee osteoarthritis
(OA) pain and associated symptoms compared to placebo and to glucosamine hydrochloride plus chondroitin
sulfate (GC).
Methods: One hundred ninety one volunteers were randomized into three groups receiving a daily dose of
UC-II (40 mg), GC (1500 mg G & 1200 mg C), or placebo for a 180-day period. The primary endpoint was the
change in total Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) from baseline through
day 180 for the UC-II group versus placebo and GC. Secondary endpoints included the Lequesne Functional
Index (LFI), the Visual Analog Scale (VAS) for pain and the WOMAC subscales. Modified intent-to-treat analysis
were performed for all endpoints using analysis of covariance and mixed model repeated measures, while
incremental area under the curve was calculated by the intent-to-treat method.
Results: At day 180, the UC-II group demonstrated a significant reduction in overall WOMAC score
compared to placebo (p= 0.002) and GC (p= 0.04). Supplementation with UC-II also resulted in significant
changes for all three WOMAC subscales: pain (p= 0.0003 vs. placebo; p= 0.016 vs. GC); stiffness (p= 0.004
vs. placebo; p=0.044vs.GC);physicalfunction(p= 0.007 vs. placebo). Safety outcomes did not differ
among the groups.
Conclusion: UC-II improved knee joint symptoms in knee OA subjects and was well-tolerated. Additional
studies that elucidate the mechanism for this supplements actions are warranted.
Trial registration: CTRI/2013/05/003663; CTRI/2013/02/003348.
Keywords: Knee function, Osteoarthritis, T regulatory cell, Undenatured type II collagen
* Correspondence: nelane@ucdavis.edu
2
Center for Musculoskeletal Health, University of California Davis Health
System, 4625 2nd Avenue, Suite 2006, Sacramento, CA 95817, USA
Full list of author information is available at the end of the article
© 2016 Lugo et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Lugo et al. Nutrition Journal (2016) 15:14
DOI 10.1186/s12937-016-0130-8
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Introduction
Osteoarthritis, which entails the destruction of joint car-
tilage and remodeling of the adjacent bone, is the most
common form of arthritis affecting more than 25 million
Americans [1]. Current therapies for OA include various
over the counter analgesics, a number of nonsteroidal
anti-inflammatory drugs (NSAIDs), intra-articular injec-
tions of corticosteroids or hyaluronic acid, plus tramadol
and other opioid analgesics to relieve severe pain [2, 3].
While these therapies can alleviate symptoms in the near
term, their ultimate impact on the pathophysiologic pro-
gression of OA is limited [4].
Previous studies reported UC-II to be efficacious for
the treatment of arthritis [5, 6]. More recently, a statisti-
cally significant improvement in knee joint function over
placebo was also reported in a clinical study comprising
a group of healthy individuals, supplemented with
UC-II, and who developed transient knee joint pain
upon strenuous exercise [7]. These same individuals
also took longer to experience pain after 120 days of
supplementation. Based on these observations, the
current study was designed to evaluate the efficacy of
UC-II in knee OA subjects compared to placebo and
to GC, which is a widely available supplement that is
used for reducing joint pain.
Materials and methods
Investigational products
The study product UC-II® (Lot 1204004) was derived
from chicken sternum. It was manufactured under
current good manufacturing practice (cGMP) conditions
using a patented process that preserved its native struc-
ture (Chick Cart Inc., Fort Smith, AR). Both glucosamine
hydrochloride (GH) and chondroitin sulfate (CS) were
purchased through Wilke Resources (Lenexa, KS). The
Wellable group (Shishi City, Fujian) manufactured GH
under cGMP and according to United States Pharmacopeia
26 specifications. Sioux Pharm (Sioux Center, IA)
manufactured bovine-derived CS under cGMP. UC-II
and GC were encapsulated in opaque, size 00cap-
sules with sufficient amounts of excipients (microcrys-
talline cellulose and silicon dioxide) such that they
were sensory identical to placebo. InterHealth Nutra-
ceuticals provided all study materials. All American
Pharmaceutical (Billings, MT) verified the amount of
active ingredients in the study capsules. Study mate-
rials were kept in a secure cabinet with access
restricted to the site coordinator, the dispensing
pharmacist, and the principal investigator.
Study design
The objective of this randomized, double-blind, placebo-
controlled clinical study was to evaluate the ability of
UC-II to improve knee symptoms in OA subjects, as
measured by overall WOMAC score, compared to pla-
cebo and to GC. The trial was conducted at 13 centers
in southern India. Because of a limitation in synovial
fluid sampling procedures at multiple clinical sites, the
study was conducted under two separate study proto-
cols. Study protocols were approved by each centers
Institutional Ethics Committee (IEC), and listed on the
clinical trial registry of India as study protocols 003663
and 003348. Enrollment, randomization, and follow-up
visits were identical for both protocols, and were carried
out at days 1 (baseline), 7, 30, 60, 90, 120, 150 and 180
(Table 1). All investigators attended the same investiga-
tor meetings, used identical intake and data reporting
forms, and were trained and monitored by the same
group of clinical research associates.
Efficacy measurements were assessed at all visits and
included WOMAC, VAS, and LFI indices. The knee
flexion range of motion (ROM) test was performed at
each visit. Subject diaries and study product were pro-
vided at all visits, except day 180 and were collected at
all follow-up visits. Subjects were instructed to record
daily the consumption of study product, use of rescue
medication, as well as concomitant medications in the
subject dairy for the entire duration of the study. Blood
and urine were collected at screening and day 180.
Pregnancy testing was done at screening and follow-up
visits. Adverse events (AEs) were recorded using each
subjects diary inputs plus site visit questionnaires ad-
ministered by intake personnel at all study visits.
Clinical endpoints
The primary endpoint was defined as the change in total
WOMAC score from baseline through day 180 for the
UC-II group versus placebo and GC. Secondary clinical
endpoints for both protocols were similar and included
the change from baseline through day 180 versus pla-
cebo and GC for all endpoints including the following
scores: (1) mean VAS; (2) mean WOMAC subscales; (3)
LFI; and (4) knee flexion. Another endpoint included the
change from baseline to day 180 for the serum bio-
marker cartilage oligomeric matrix protein (COMP). In
protocol 003348, additional secondary endpoints in-
cluded the change in serum biomarker, C-reactive pro-
tein (CRP) plus synovial fluid biomarkers interleukin
(IL)-6, and matrix metalloproteinase (MMP)-3 from
baseline to day 180.
Study subjects
A total of 234 subjects were screened and 191 random-
ized (Fig. 1). Study inclusion criteria were 4075 years-
old male and female subjects, a body-mass index (BMI)
of 1830 kg/m
2
, moderate-to-severe OA by physical
examination (crepitus, bony enlargements, joint swelling,
etc.) in one or both knees, knee pain for at least
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3 months prior to the start of the study, an LFI score be-
tween 6 and 10 and a VAS score of 4070 mm 7 days
after withdrawal from excluded medications, plus a knee
radiograph that was graded as Kellgren and Lawrence
(K-L) radiograph score of either 2 or 3 [8]. All OA diag-
noses were confirmed by each study site investigator and
noted in the subjects case report form (CRF). In the case
of bilateral knee involvement, the index knee used for
the study was the one that presented with the most se-
vere OA symptoms at baseline. Detailed inclusionex-
clusion criteria are summarized in Table 2.
Ethics, consent and permissions
Subjects were recruited after they reviewed, understood
the study details, and then signed the IEC-approved
consent form. The study conformed to the Declaration
of Helsinki (version 1996).
Randomization & blinding
Block randomization, consisting of nine individuals
per block, was executed in a 1:1:1 ratio using random
numbers generated by an independent statistician
(SPSS version 16.0). Knowledge of the randomization
code was limited to the statistician plus one QA
monitor unrelated with the study. Each investigator
was given opaque, sealed envelopes denoting single
patient identity numbers, randomization codes, and
supplementation regimen to be opened in case of an
emergency. The code was broken after the clinical
database was locked.
Table 1 Protocol Schedule and Activities
Procedures common to both protocols Screening
(Visit 1)
Study period
Day 1 (Baseline
Visit 2)
Days 7, 30, 60, 90, 120, 150
(Visits 3, 4, 5, 6, 7, 8)
Day 180
(Visit 9)
Signed Informed Consent X
Inclusion/Exclusion Reviewed X X X
Medical/Surgical/Medication History X
Physical Examination X
Vital Signs X X X X
Height
a
, Weight, BMI X X
Clinical Assessment for Knee Pain & Swelling X X X X
Knee Flexion Range of Motion X X X
X-ray examination X
WOMAC Score X X X X
VAS Scale X X X X
LFI Score X X X X
Clinical Laboratory Tests (hematology, chemistry, urinalysis) X X
Urine Pregnancy Test (if applicable) X X X
Serum biomarker analysis-COMP X X
Randomization Number Assigned X
Investigational Product Administration X
Dispense Subject Diary X X
Collect/Review Subject Diary XX
Provide Directions for Concomitant Medication and
Rescue Medication Use
XX X
Dispense New Investigational Product X X
Review Product Accountability XX
Assess use of Concomitant Medications X X X
Adverse Events Assessed X X X
Procedures Confined to Protocol 003348
Synovial fluid biomarkerMMP-3 and IL-6 X X
Serum biomarker analysisCRP X X
a
Height was measured only at Visit 1
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Dosing regimen
Subjects ingested two blue pills in the morning with
breakfast and two white capsules before bedtime. For
the UC-II cohort, the two morning capsules were pla-
cebo, while the evening capsules contained 20 mg each
of UC-II totaling 40 mg, which is identical to previously
used clinical dose levels [5, 7]. This dose delivered
1.2 mg of undenatured type II collagen as determined by a
newly developed and validated extraction-ELISA protocol
(AIBiotech, Richmond, VA & Chondrex, Redmond, WA).
For the GC group, the morning and evening doses
delivered 750 mg of GH plus 600 mg of CS each to-
taling a daily dose of 1,500 mg of GH plus 1,200 mg
of CS. The placebo group ingested identical numbers
of blue and white capsules containing excipients only.
Study bottles were labeled according to ICH-GCP and
applicable local regulatory guidelines.
Prior and concomitant therapies
Prior medications were documented at the screening
visit by the study investigator. At each visit, study
personnel reviewed subject diaries and questioned each
participant on the use of any concomitant medications
including those on the prohibited list. Prohibited medi-
cations included ibuprofen, aspirin, other NSAIDS, or
any other pain relievers (OTC or prescription), plus any
dietary supplements (excluding vitamins) that could sup-
port joint health. All concomitant medications used dur-
ing the study was documented in the subjects medical
record by the study investigator then transcribed into
their CRF by study personnel.
Rescue medications
Acetaminophen was allowed at a dose of 500 mg
twice daily. Participants were instructed to not take
this medication within 48 h of an evaluation visit.
Usage levels and timing was entered at each visit into
the subjects medical record by the study investigator.
Study personnel transcribed this information into the
subjectsCRF.
Compliance and safety
Subjects were instructed to bring their bottles to each
visit. Remaining capsules were counted and recorded in
the subjects CRF and accountability log. As a secondary
measure of compliance, subjects completed a diary
indicating daily dosing of the study products. Safety as-
sessments were performed at all visits by the site investi-
gator and staff (see Table 9).
Study evaluations
WOMAC scores were determined using the WOMAC
VA3.1 questionnaire containing 24 items grouped into
three categories: pain, stiffness, and physical function
(score range 02400). Each respective WOMAC sub-
scale mean scores was determined by dividing the sub-
scale score by the number of questions (5, pain; 2,
stiffness; 17, physical function) it contained. The mean
VAS score was determined using a VAS questionnaire
containing 7 pain-related questions (score range 0700),
and then dividing the overall score by seven. LFI score
was determined using an LFI questionnaire that assessed
pain, walking distance, and activities of daily living,
Fig. 1 Enrollment and randomization flow chart
Lugo et al. Nutrition Journal (2016) 15:14 Page 4 of 15
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(score range 024). Knee flexion was measured using
goniometry with the subject lying in the prone position
and the leg to be tested positioned along the edge of the
table [9].
Synovial fluid biomarkers
Synovial fluid (~0.5 mL) was aspirated from the knee
joint using an appropriate sized needle (1824 gauge,
depending on joint size). Harvested fluid was stored
frozen until tested. IL-6 and MMP-3 levels were deter-
mined using the corresponding Duoset ELISA kits (R&D
Systems, Minneapolis, MN).
Serum biomarkers
COMP levels (Quantikine ELISA, R&D Systems) were
determined in both study protocols. CRP levels (Latex
COBAS INTEGRA, Roche Diagnostics GmbH, Mannheim)
were assessed in protocol 003348. Serum was stored frozen
until analyzed. Interassay and intrassay coefficients of vari-
ation for COMP and CRP were <5 %.
Statistics
We verified, using 2-way analysis of variance (ANOVA),
that the results of the two protocols could be combined
into a single analysis by demonstrating there was no
group by study interaction and that the magnitude of
the efficacy observed under the two protocols was
similar.
A modified intent-to-treat (mITT) analysis was used
to assess the efficacy and safety outcomes that was
defined apriori. This included all subjects who were
randomized, consumed study product, and had at
least one completed post-baseline visit. An analysis of
covariance (ANCOVA), that included supplementation
as a fixed factor and the corresponding baseline value
of the variable being tested as a covariate, was used
for assessing the overall statistical significance of the
primary and secondary endpoints. Following
ANCOVA, the Tukey-Kramer multiple comparison
test was used for determining pairwise statistical sig-
nificance and calculating 95 % confidence intervals.
Also, a mixed model repeated measures (MMRM)
analysis of the primary endpoint was performed to ac-
count for the multiple assessments obtained during
this study. In addition, the method of trapezoids was
used to calculate incremental area under the curve (iAUC)
for all study groups. For iAUC estimation, missing values
were imputed using the expectation-maximization algo-
rithm in SAS. Rescue medication usage between groups
was compared using logistic regression followed by pair-
wise comparisons using the Tukey-Kramer test. In
addition, a stratified analysis of the primary endpoint was
performed according to baseline serum COMP levels
above and below the median value for this biomarker.
Table 2 Inclusion-exclusion criteria
Inclusion
Ambulatory, 4075 years of age, with a BMI of 18 to 30 kg/m
2
Females of childbearing age must agree to use a medically approved
form of birth control and have a negative urine pregnancy test result
throughout the study
Female subjects of limited to no childbearing potential must be
amenorrheic for at least 1 year or have had a hysterectomy, a
bilateral oophorectomy, or both
Unilateral or bilateral OA of the knee for greater than 3 months plus a
Kellgren and Lawrence radiographic grade of 2 or 3
VAS score during knee movement between 4070 mm after 7 day
withdrawal of excluded medications
LFI score between 610 points after 7 day withdrawal of excluded
medications
Clinical laboratory results that are within normal range or considered
not clinically significant by the Principal Investigator
Be willing to participate in all scheduled visits, tests, and other trial
procedures according to the clinical protocol
Be willing to refrain from taking ibuprofen, aspirin or other NSAIDS, or
any other pain reliever (OTC or prescription) during the entire trial
other than acetaminophen (paracetamol) as rescue medication
Provide a signed and dated informed consent indicating that the
subject has been informed of all pertinent aspects and possible risks
associated with participation in the trial
Exclusion
History of hypersensitivity to the rescue medication or any of the
products used in the study
History of hypersensitivity to eggs, chicken or fowl, or shellfish
History of inflammatory arthropathy, severe RA, OA (VAS score greater
than 70), or Systemic Lupus Erythematosus
Hyperuricemia (>440 μmol/L), past history of gout, or both
Anticipation of surgery within the next 4 months
Recent injury in the target knee (past 4 months)
History of use for corticosteroid, indomethacin, glucosamine &
chondroitin within 3 months of Visit 2; intra-articular treatments,
including injections of corticosteroid or hyaluronic acid; consumption
of Omega 3 fatty acids dietary supplements within 6 months preceding
the treatment period (a 2-week washout period is allowed for subjects
taking omega 3 fatty acid supplements)
History of congestive heart failure
Anticipated problems with product consumption
Evidence or history of clinically significant hematological, renal,
endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic,
neurologic diseases, or malignancies within the last 5 years
High alcohol intake (>2 standard drinks per day) or use of recreational
drugs (e.g., cocaine, methamphetamine, marijuana, etc.)
Females who are pregnant or lactating or planning to become
pregnant
History of any mental illness that might impair the ability of subjects
to provide a written informed consent
Consumed acetaminophen (paracetamol), ibuprofen, aspirin or other
NSAIDS, or any other pain reliever (OTC or prescription), or any natural
health product, (excluding vitamins) within 7 days of first visit
Participation in any clinical trials within 30 days prior to first visit
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Differences were considered significant if the resultant p-
value was 0.05. An independent statistician performed
the analyses and other calculations using SAS version 9.3
(Cary, NC).
Results
Demographics and baseline characteristics
Two hundred and thirty-four subjects were screened and
191 subjects who met the eligibility criteria were random-
ized to placebo (n=62), GC (n= 66), or UC-II (n=63)
(Fig. 1). Per mITT criteria, 5 subjects were excluded from
all analyses because they failed to present at any post-
randomization visits resulting in an absence of clinical
data. Table 3 summarizes the demographics of the
remaining 186 subjects that were eligible for efficacy and
safety analyses. Baseline subject characteristics, OA sever-
ity, serum CRP, COMP, IL-6 and other characteristics
were similar among the three groups.
Subject dropouts
One hundred and sixty four subjects completed the
study: 53, placebo; 57, GC; and 54, UC-II. The 27 drop-
outs, which included the five subjects mentioned previ-
ously, were allocated across the three cohorts as follows:
9, placebo; 9, GC; and 9, UC-II. The final dropout rate
was 14 %. Subjectsdropout reasons are summarized in
Fig. 1. No subject withdrew from the trial due to an ad-
verse event attributable to any study product.
Study product compliance
Compliance with daily dosing of study capsules exceeded
90 % for all cohorts (data not shown).
Total WOMAC score
The UC-II supplemented group had statistically signifi-
cant changes in the total WOMAC score compared to
placebo (551 vs. 414; 95 % CI 232 to 42; p= 0.002)
and GC (551 vs. 454; 95 % CI 190 to 3; p= 0.04) at
day180(Fig.2a,Table4).WhenthetotalWOMAC
results were analyzed, using MMRM, to account for
treatment by time interactions, there remained a sta-
tistically significant difference between the UC-II and
the placebo groups (514 vs. 397; 95 % CI 210 to 24;
p= 0.0097; Table 4). An iAUC analysis also yielded
statistically significant differences between the UC-II
group versus placebo (2042 vs. -1479; 95 % CI
1012 to 113; p= 0.0098; Table 4). No significant
changes were observed between the GC and placebo
Table 3 Demographic and baseline characteristics of the trial subjects
Characteristics Placebo (n= 58) GC (n= 65) UC-II (n= 63)
Sex ((n) male + (n) female) 28M + 30F 28M + 37F 33M + 30F
Age (years) 53.1 ± 1.02 52.6 ± 1.02 53.5 ± 0.99
Height (cm) 162 ± 1.00 161 ± 1.12 161 ± 0.89
Body weight (kg) 64.5 ± 1.20 66.0 ± 1.13 65.5 ± 1.12
Body mass index (kg/m
2
) 24.7 ± 0.40 25.5 ± 0.40 25.2 ± 0.37
Kellgren Lawrence radiographic score
Grade 2 (n) 39 45 42
Grade 3 (n) 19 20 21
Lequesne's Functional Index 7.74 ± 0.12 8.02 ± 0.12 7.90 ± 0.13
Visual analog score (mm) 58.2 ± 0.97 59.1 ± 0.97 58.4 ± 0.99
Total WOMAC score 1382 ± 34.8 1396 ± 31.8 1398 ± 27.9
Mean WOMAC pain 56.9 ± 1.36 57.5 ± 1.33 58.1 ± 1.03
Mean WOMAC physical function 57.9 ± 1.51 58.5 ± 1.37 58.3 ± 1.24
Mean WOMAC stiffness 56.3 ± 1.63 57.3 ± 1.52 58.1 ± 1.32
Knee flexion ROM (°) 114 ± 1.62 114 ± 1.36 114 ± 1.57
Serum CRP (mg/L)
a
5.29 ± 1.47 8.15 ± 1.79 3.35 ± 0.58
Serum COMP (ng/mL)
b
325.2 ± 30.5 381.2 ± 44.1 334.6 ± 36.5
Synovial IL-6 (ng/mL)
c
13.3 ± 4.73 13.9 ± 5.57 15.3 ± 6.04
Synovial MMP-3 (μg/mL)
d
4.03 ± 1.20 2.54 ± 0.78 4.86 ± 1.74
Values presented as Mean ± SE
a
Number of subjects used for analyses: 27, placebo; 29, GC; 29, UC-II
b
Number of subjects used for analyses, 54, placebo; 58, GC; 55, UC-II
c
Number of subjects used for analyses, 23, placebo; 24, GC; 21, UC-II
d
Number of subjects used for analyses, 25, placebo; 27, GC; 23, UC-II
Lugo et al. Nutrition Journal (2016) 15:14 Page 6 of 15
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cohorts regardless of the type of analytical model
used.
Total WOMAC score based on baseline COMP levels
We found that subjects supplemented with UC-II, and
presented with baseline COMP levels 285 ng/mL
(median), had a greater reduction in the total WOMAC
score than both placebo and GC groups with similar
COMP levels under all modeling conditions (Table 5).
For study participants with baseline COMP levels
<285 ng/mL, no significant differences between the study
groups were noted. Interestingly, we did observe a smaller
placebo effect among individuals with baseline COMP
levels 285 ng/mL as compared to those with <285 ng/mL
(28 % vs 32 %). Despite this, UC-II efficacy, as defined by a
reduction in overall WOMAC score, was higher in subjects
with COMP levels 285 ng/mL versus subjects with COMP
levels < 285 ng/mL (43 % vs 36 %).
WOMAC mean subscorespain, stiffness and physical
function
At day 180, we observed significant reductions in all
three WOMAC subscales for UC-II group compared
to placebo (Table 6): pain (24.0 vs. 17.0; 95 % CI
11.1 to 2.8; p= 0.0003), stiffness (23.8 vs. 17.8;
95 % CI 10.4 to 1.6; p= 0.004), and physical func-
tion (22.5 vs. 17.3; 95 % CI 9.3 to 1.3; p=0.007).
The UC-II cohort also had significant reductions in
WOMAC pain (24.0 vs. 19.2; 95 % CI 8.9 to 0.7;
p= 0.016) and stiffness (23.8 vs. 19.4; 95 % CI 8.7
to 0.1; p= 0.044) at day 180 compared to GC.
Mean VAS score
The UC-II supplemented group had a significant
decrease in mean VAS score at day 180 (Fig. 2b)
versus both placebo (22.6 vs. 17.0; 95 % CI 9.5 to 1.8;
p= 0.002) and GC (22.6 vs. 18.4; 95 % CI 8.0 to 0.4;
p= 0.025). In contrast, the GC group was not signifi-
cant compared to placebo at any time.
LFI score
A significant reduction was observed in the LFI score for
the UC-II group at day 180 versus placebo (2.9 vs. 2.1;
95 % CI 1.4 to 0.2; p= 0.009; Fig. 2c). UC-II supplemen-
tation also has a greater improvement in LFI score versus
GC (2.9 vs. 2.2; 95 % CI 1.4 to 0.2; p= 0.008). No sig-
nificant change was observed between the GC and pla-
cebo cohorts. Improvement in the total LFI score for the
UC-II group was attributed to a significant reduction in
the LFI subscale for daily activities at day 180 (p=0.004
vs. placebo; p= 0.013 vs. GC, data not shown).
Knee flexion
No significant differences were observed between the
study groups (data not shown).
Serum biomarkers
A significant increase in the final CRP levels versus base-
line occurred in all three cohorts (p= 0.001). However, no
statistical difference between the three cohorts (Table 7;
p> 0.05) was noted. The scientific reason behind this in-
crease is not well understood. A significant decrease in
serum COMP levels was seen in all groups versus baseline
(p= 0.04) with no significant changes between groups.
Synovial fluid biomarkers
Similar non-significant decreases in IL-6 and MMP-3
levels were noted for all cohorts (Table 7).
Rescue medication usage
The number of subjects that used rescue medication was
significantly lower in the UC-II group compared to
Fig. 2 Total WOMAC score (a), Mean VAS (b), Total LFI (c) in the UC-II, GC and placebo groups over the 180-day study period. Values are
presented as mean ± SE. *Significant difference between the UC-II (n= 54) and the placebo (n= 53) group, p< 0.05. Significant difference
between the UC-II (n= 54) and the GC group (n= 57), p< 0.05
Lugo et al. Nutrition Journal (2016) 15:14 Page 7 of 15
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Table 4 Change in total WOMAC score from baseline
Analytical
method
Type of
analysis
Time point
(Days)
Placebo
(n= 53)
GC
(n= 57)
UC-II
(n= 54)
pvalue (95 % CI)
Overall
a
GC vs PBO UC-II vs PBO
b
UC-II vs GC
ANCOVA mITT 180 414 ± 28.5 454 ± 27.5 551 ± 28.2 0.002 0.56 (134 to 53) 0.002 (232 to 42) 0.04
c
(190 to 3)
MMRM mITT 180 397 ± 28.6 452 ± 27.6 514 ± 28.3 0.014 0.33 (148 to 37) 0.0097 (210 to 24) 0.25 (153 to 30)
(n= 58) (n= 65) (n= 63)
iAUC ITT 1 to 180 1479 ± 137 1751 ± 130 2042 ± 132 0.014 0.33 (718 to 174) 0.0098 (1012 to 113) 0.26 (727 to 146)
Values presented as Mean ± SE
Abbreviations:PBO placebo
a
Overall p value was obtained by comparing the mean changes among the three groups using ANCOVA
b
Significant difference between the UC-II and the placebo groups using Tukey-Kramer test
c
Significant difference between the UC-II and the GC groups using Tukey-Kramer test
Lugo et al. Nutrition Journal (2016) 15:14 Page 8 of 15
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Table 5 Stratified analysis for change in total WOMAC score based on baseline COMP levels
COMP
(ng/mL)
Analytical
method
Type of
analysis
Time point
(Days)
Placebo
(n= 27)
GC
(n=28)
UC-II
(n= 27)
pvalue (95 % CI)
Overall
a
GC vs PBO UC-II vs PBO UC-II vs GC
285 ANCOVA mITT 180 368 ± 41.7 396 ± 40.9 574 ± 41.6 0.002 0.88 (168 to 112) 0.002
b
(347 to 65) 0.009
c
(317 to 38)
MMRM mITT 180 351 ± 44.1 398 ± 41.1 540 ± 44.2 0.006 0.71 (188 to 94) 0.006
b
(330 to 48) 0.048
c
(282 to 1)
iAUC
d
ITT 1 to 180 1351 ± 212 1582 ± 204 2384 ± 207 0.003 0.72 (934 to 473) 0.002
b
(1741 to 325) 0.02
c
(1498 to 107)
(n= 26) (n=29) (n= 26)
<285 ANCOVA mITT 180 463 ± 38.8 508 ± 36.6 526 ± 38.7 0.48 0.67 (173 to 82) 0.49 (195 to 68) 0.94 (145 to 109)
MMRM mITT 180 442 ± 38.2 493 ± 37.3 521 ± 38.1 0.34 0.60 (178 to 76) 0.32 (208 to 50) 0.86 (155 to 100)
iAUC
e
ITT 1 to 180 1626 ± 185 1908 ± 178 1902 ± 185 0.49 0.52 (896 to 333) 0.55 (902 to 350) 0.99 (607 to 618)
Values presented as Mean ± SE
a
Overall p value was obtained by comparing the mean changes among the three groups using ANCOVA
b
Significant difference between the UC-II and the placebo groups using Tukey-Kramer test
c
Significant difference between the UC-II and the GC groups using Tukey-Kramer test
d
Number of subjects used for analyses, 27, placebo; 29, GC; 28, UC-II
e
Number of subjects used for analyses, 27, placebo; 29, GC; 27, UC-II
Lugo et al. Nutrition Journal (2016) 15:14 Page 9 of 15
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placebo (Table 8; p= 0.001). Sixty individuals used
rescue medications, at least once, during the study.
Twenty-eight of these users were from the placebo
group, 21 and 11 were from the GC and UC-II cohorts,
respectively.
Safety assessments
No clinical or statistically significant changes were
reported for any of the hematologic, blood biochem-
istry or vital signs results (Table 9). No significant
changes were noted for the urinalyses results (data
not shown).
A total of 45 AEs were reported during the 180-day
study period: 9, placebo; 28, GC; and 8, UC-II (Table 10).
The majority (62 %) of these occurred in the GC group.
Fifteen of 45 events were classified as possibly related to
supplementation, 14 of which belonged to the GC group
and 1 to placebo. The 14 possible events linked to GC
supplementation were primarily gastrointestinal in na-
ture. The eight AEs noted for the UC-II cohort were
deemed not related to supplementation. One individual
in the GC group was removed from the study due to a
respiratory tract infection (cough & fever). This infection
was classified as an SAE. The event was investigated by
Table 6 Reduction in mean WOMAC subscores in placebo, GC and UC-II groups over 180 days
Parameter reduction Day Placebo (n= 53) GC (n= 57) UC-II (n= 54) pvalue
Overall
a
GC vs PBO UC-II vs PBO
b
UC-II vs GC
c
WOMAC pain 7 3.21 ± 0.58 4.57 ± 0.54 3.88 ± 0.55 - - - -
30 6.61 ± 1.04 7.89 ± 1.00 9.18 ± 1.01 - - - -
60 8.17 ± 1.10 10.1 ± 1.07 12.7 ± 1.09 0.0149 - 0.011 -
90 11.2 ± 1.17 12.7 ± 1.14 16.4 ± 1.16 0.0063 - 0.0059 -
120 12.9 ± 1.28 15.6 ± 1.22 19.9 ± 1.26 0.0005 - 0.0004 0.040
150 15.0 ± 1.21 17.5 ± 1.16 21.5 ± 1.20 0.0007 - 0.0006 0.047
180 17.0 ± 1.25 19.2 ± 1.20 24.0 ± 1.23 0.0003 - 0.0003 0.016
WOMAC stiffness 7 3.47 ± 0.64 4.22 ± 0.61 4.24 ± 0.62 - - - -
30 6.81 ± 1.10 8.76 ± 1.05 9.28 ± 1.07 - - - -
60 9.36 ± 1.28 11.5 ± 1.25 13.1 ± 1.27 - - - -
90 11.3 ± 1.36 13.8 ± 1.32 17.0 ± 1.35 0.0158 - 0.010 -
120 13.6 ± 1.40 15.0 ± 1.34 20.0 ± 1.39 0.0035 - 0.0039 0.029
150 15.5 ± 1.32 17.7 ± 1.26 21.3 ± 1.31 0.0079 - 0.0058 -
180 17.8 ± 1.31 19.4 ± 1.27 23.8 ± 1.30 0.0043 - 0.004 0.044
WOMAC physical function 7 3.17 ± 0.56 4.14 ± 0.53 3.91 ± 0.53 - - - -
30 6.30 ± 1.00 7.80 ± 0.96 9.26 ± 0.98 - - - -
60 7.75 ± 1.08 9.50 ± 1.05 11.9 ± 1.07 0.0278 - 0.020 -
90 10.4 ± 1.17 12.1 ± 1.14 15.1 ± 1.16 0.0182 - 0.0136 -
120 12.7 ± 1.20 14.5 ± 1.15 17.9 ± 1.19 0.0083 - 0.0064 -
150 14.8 ± 1.19 16.9 ± 1.14 20.0 ± 1.18 0.0078 - 0.006 -
180 17.3 ± 1.21 18.8 ± 1.16 22.5 ± 1.20 0.0068 - 0.007 -
Values presented as Mean ± SE
a
Overall p value was obtained by comparing the mean changes among the three groups using ANCOVA
b
Significant difference between the UC-II and the placebo groups using Tukey-Kramer test
c
Significant difference between the UC-II and the GC groups using Tukey-Kramer test. -denotes a non-significant statistical outcome
Table 7 Change from baseline to day 180 in serum and synovial fluid biomarkers
Matrix Parameter reduction Day Placebo (n) GC (n) UC-II (n)
Serum COMP (ng/mL) 180 51.2 ± 31.3 (53) 56.5 ± 36.0 (56) 69.6 ± 40.8 (53)
CRP (mg/L) 180 15.1 ± 6.33 (26) 9.09 ± 5.36 (28) 13.0 ± 4.64 (28)
Synovial IL-6 (ng/mL) 180 9.54 ± 4.83 (23) 9.72 ± 5.28 (24) 11.8 ± 5.37 (21)
MMP-3 (μg/mL) 180 2.24 ± 1.26 (25) 0.93 ± 0.79 (27) 2.67 ± 1.85 (23)
Values presented as Mean ±SE. Statistical analysis was performed on log transformed and baseline adjusted values. No significant differences were observed
between the study groups (p> 0.05)
Lugo et al. Nutrition Journal (2016) 15:14 Page 10 of 15
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the attending physician and center staff and judged as
not related to GC consumption.
Discussion
We assessed the ability of UC-II to improve joint symp-
toms in moderate-to-severe knee OA subjects. The re-
sults presented herein demonstrate that individuals
consuming UC-II presented with better clinical out-
comes versus those supplemented with placebo or GC.
Analysis of the WOMAC subscales showed that reduc-
tions in all three WOMAC subscales contributed to the
improvement in the overall WOMAC score observed in
subjects supplemented with UC-II. In contrast, GC sup-
plementation failed to induce a statistically significant
improvement in the WOMAC, VAS or LFI scores versus
placebo. These results confirm previous findings by
Crowley et al. [5], which reported greater reduction in
knee OA symptoms after 90 days of UC-II supplementa-
tion than what was observed with GC.
An interesting finding that emerged from this study is
that stratification, according to baseline COMP levels,
appears to have selected for individuals that responded
better to UC-II supplementation. A greater reduction in
knee OA symptom scores was observed among individ-
uals with baseline serum COMP levels 285 ng/mL and
supplemented with UC-II. This improvement was of suf-
ficient magnitude that statistically significant outcomes
for UC-II were observed versus both placebo and GC
supplementation under all the statistical analyses we
employed (ANCOVA, MMRM and iAUC). COMP, a car-
tilage turnover marker, is released into serum by chon-
drocytes and synovial cells [1012]. Levels of this
biomarker have been shown in several studies to have
modest correlation with OA severity. However, serum
COMP levels in groups of OA subjects overlap with
levels observed in healthy populations, and this has lim-
ited the use of COMP as a prognostic marker for OA
progression [1214]. While the biologic or clinical
significance to these findings remains to be understood,
we find this preliminary observation an interesting one
suitable for further investigation and confirmation.
The etiology behind UC-IIs impact on OA symptoms
is not known. However, undenatured type II collagen
has been shown to protect animals against the onset of
joint damage in both OA and RA experimentally in-
duced arthritis models [1518]. This protection is hy-
pothesized to occur via the induction and migration of
T regulatory cell (Tregs) to the area of inflammation and
damage [19, 20]. The proposed role of Tregs may also
have relevance to the moderation of OA symptoms, as
in vitro studies have found that Tregs produce anti-
inflammatory cytokines that stimulate chondrocytes to
synthesize cartilage matrix components [2123]. Add-
itional studies that elucidate the precise mechanism
through which UC-II mediates a reduction in knee OA
symptoms are required.
The in vivo effects mentioned above may only be initi-
ated by ingesting undenatured type II collagen as dena-
tured (e.g., hydrolyzed) type II collagen fails to protect
animals against the onset of arthritis [15]. This latter ob-
servation could explain why van Vijven and coworkers
[24] concluded that there was insufficient evidence to sup-
port collagen for the treatment of OA as they combined
data from all published clinical studies regardless whether
native or denatured collagen was used in the trial.
We failed to observe any changes in knee ROM and dis-
tance walked regardless of supplementation. Improve-
ments in these clinical outcomes are likely to be based not
just on a symptomatic reduction in pain but also on phys-
ical improvements in the knee joints overall functionality.
Until we undertake trials of longer duration, it remains an
open question as to whether a slow acting supplement like
UC-II can impact the biomechanical status of the OA
knee sufficiently to improve knee ROM.
In the current study, GC supplementation did not sig-
nificantly improve the signs and symptoms associated
with knee OA. The scientific literature supporting the
efficacy of GC is mixed, but there are various published
studies which suggest that GC may moderate OA symp-
toms [2527]. The GAIT study found that GC, and each
component of GC individually, failed to impact OA
symptoms as measured by the WOMAC pain scale;
however, the placebo effect in that study was nearly
60 % which resulted in an underpowered study to deter-
mine differences between the treatments [28]. In con-
trast, a significant difference in knee pain was observed
in the GC subgroup with moderate-to-severe knee pain
compared to the placebo treated group [28]. To confirm
the observation that GC may be more efficacious in sub-
jects with moderate-to-severe knee OA pain, Hochberg
and coworkers [29] performed a study in which OA sub-
jects with moderate-to-severe knee pain, were randomized
Table 8 Number of subjects reporting use of rescue medication
Day Placebo GC UC-II
7 11/58 12/65 3/63
30 18/58 7/63 4/61
60 12/58 9/61 6/59
90 12/56 8/59 3/57
120 13/54 13/59 7/55
150 10/54 12/59 3/55
180 11/53 7/57 4/54
Entire study period 28/58 21/65 11/63
a
The table summarizes the number of unique individuals reporting the use of
rescue medication. Data presented as number of subjects using rescue
medication / total number of subjects observed.
a
statistically significant versus
the placebo (p= 0.001) based on pairwise Tukey-Kramer multiple comparison
test. The overall group effect p-value was 0.002 using logistic regression
Lugo et al. Nutrition Journal (2016) 15:14 Page 11 of 15
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Table 9 Safety parameter assessment at baseline and day 180 in placebo, GC and UC-II groups
Parameter (Units) Baseline Day 180
Normal
range
Placebo
(n= 58)
GC
(n= 65)
UC-II
(n= 63)
pvalue GC
vs PBO
pvalue UC-II
vs PBO
pvalue UC-II
vs GC
Placebo
(n= 53)
GC
(n= 56)
UC-II
(n= 53)
pvalue GC
vs PBO
pvalue UC-II
vs PBO
pvalue UC-II
vs GC
Hematology
Hemoglobin (gm/dL) 12.117.2 12.1 ± 0.22 11.9 ± 0.21 12.1 ± 0.20 0.7613 0.9948 0.8095 12.7 ± 0.24 12.4 ± 0.20 12.7 ± 0.18 0.4454 0.9727 0.5851
ESR (mm/h) 029 21.1 ± 1.77 23.9 ± 2.18 17.5 ± 1.56 0.7629 0.1034 0.0144 15.1 ± 1.24 17.0 ± 1.91 13.6 ± 1.28 0.9424 0.5364 0.3387
RBC (million/mm
3
) 4.76.1 4.29 ± 0.08 4.21 ± 0.08 4.33 ± 0.09 0.7747 0.9388 0.5498 4.32 ± 0.08 4.25 ± 0.08 4.37 ± 0.08 0.7935 0.8946 0.5129
WBC (/mm
3
) 4500-10,000 7979 ± 234 8248 ± 222 7795 ± 249 0.7020 0.8483 0.3523 7984 ± 204 7981 ± 209 7769 ± 204 1.0000 0.7706 0.7639
Platelet count
(x100000/mm
3
)
1.5-4.5 2.77 ± 0.08 2.84 ± 0.08 2.78 ± 0.08 0.7837 0.9946 0.8319 2.77 ± 0.07 2.84 ± 0.07 2.77 ± 0.09 0.8304 0.9993 0.8113
Liver Function
Albumin (gm/dL) 3.55.5 3.98 ± 0.06 4.02 ± 0.06 3.94 ± 0.06 0.8957 0.9089 0.6503 4.00 ± 0.05 4.03 ± 0.05 3.96 ± 0.04 0.8931 0.8902 0.6292
ALP (IU/L) 44147 117 ± 5.74 118 ± 5.84 115 ± 5.57 0.9871 0.9838 0.9404 123 ± 5.72 116 ± 5.49 115 ± 5.59 0.5622 0.4847 0.9890
SGOT (U/L) 1034 25.2 ± 0.93 24.0 ± 0.97 24.4 ± 0.60 0.5778 0.7796 0.9421 24.6 ± 0.73 23.9 ± 0.81 23.9 ± 0.65 0.7711 0.7930 0.9995
SGPT (U/L) 535 25.9 ± 1.23 25.0 ± 1.40 24.1 ± 0.95 0.5977 0.6004 1.0000 24.5 ± 0.94 24.3 ± 1.00 23.3 ± 0.99 0.9688 0.7119 0.8427
Total bilirubin (mg/dL) 0.31.9 0.78 ± 0.08 0.69 ± 0.03 0.72 ± 0.03 0.5376 0.9424 0.7343 0.72 ± 0.03 0.67 ± 0.03 0.78 ± 0.04 0.4243 0.6098 0.0718
Cardiac Function
Systolic BP (mm Hg) <120 125 ± 1.28 127 ± 1.35 127 ± 1.21 0.5980 0.7320 0.9752 127 ± 1.18 125 ± 1.33 128 ± 1.22 0.7263 0.8949 0.4409
Diastolic BP (mm Hg) < 80 81.2 ± 1.19 80.2 ± 0.83 81.7 ± 1.02 0.7544 0.9283 0.5094 80.2 ± 1.03 80.5 ± 1.07 78.9 ± 0.96 0.9877 0.6233 0.5180
Pulserate(beats/min) 60100 80.0 ± 0.92 79.6 ± 0.98 80.3 ± 0.99 0.9149 0.9719 0.7956 80.0 ± 0.89 78.2 ± 0.82 79.2 ± 1.03 0.3201 0.8018 0.6989
Renal Function
Creatinine (mg/dL) 0.61.3 1.00 ± 0.03 1.01 ± 0.04 0.96 ± 0.03 0.9995 0.5767 0.5778 0.96 ± 0.03 0.95 ± 0.02 0.96 ± 0.02 0.9904 0.9846 0.9508
BUN (mg/dL) 624 18.1 ± 1.08 18.0 ± 1.11 18.0 ± 1.15 0.9929 0.9878 0.9992 18.6 ± 1.11 17.8 ± 1.09 17.9 ± 1.02 0.7602 0.7953 0.9985
Results are presented as Mean ± SE. Normal ranges were obtained from Medline
a
and the Mayo Clinic
b
. Data was analyzed using ANCOVA followed by Tukeys multiple comparisons test (p> 0.05)
Abbreviations:
ESR erythrocyte sedimentation rate; RBC red blood cell; WBC white blood cell; ALP alkaline phosphatase; SGOT serum glutamic oxaloacetic transaminase; SGPT serum glutamic pyruvic transaminase; BP blood pressure;
BUN blood urea nitrogen
a
ADAM, Inc.: http://www.nlm.nih.gov/medlineplus/encyclopedia.html (accessed October 2015)
b
Mayo Foundation for Medical Education and Research: Mayo Clinic. www.mayoclinic.org (accessed October 2015)
Lugo et al. Nutrition Journal (2016) 15:14 Page 12 of 15
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
to GC or celecoxib for a period of 6 months. The results
showed that GC treatment reduced WOMAC measured
knee pain by 50 %, comparable to the results obtained
with celecoxib [28]. It is worth noting that results such as
these are not consistent across a number of studies for
reasons yet to be determined [2527].
In recent years, interest has focused on developing
various biomarkers for monitoring OA progression and
drug development [12, 30]. We therefore assessed sev-
eral biomarkers of inflammation (CRP, IL-6 and MMP-
3) plus cartilage breakdown (COMP) and found no
significant change for any of these biomarkers in this
clinical trial. Since OA appears to impact the biology of
several key components of the knee (e.g., synoviocytes,
chondrocytes, etc.), the ability to achieve a significant
change in any one biomarker could prove challenging
for a slow acting supplement like UC-II. Also, multiple
factors including ethnicity, physical activity, gender
differences, and diurnal variation influence these bio-
markers resulting in large variability in their levels
[3135]. Therefore, any change in these markers would
have to occur as a result of a highly significant impact on
the underlying pathophysiology of OA, given that the cor-
relation between these biomarkers and OA pathophysi-
ology are weak [12]. Such effects might be expected to
occur more readily with a targeted agent [4, 36].
Conclusion
This study found that UC-II, a nutritional ingredient
containing undenatured type II collagen, significantly
improved knee function in OA subjects by day 180,
compared to placebo and to GC, and was well-tolerated.
Based on the data presented herein, we believe that add-
itional research is warranted both to confirm and to de-
fine these findings more extensively.
Abbreviations
AEs: adverse events; ANCOVA: analysis of covariance; ANOVA: analysis of
variance; cGMP: current good manufacturing practice; CI: confidence interval;
COMP: cartilage oligomeric matrix protein; CRF: case report form; CRP: C-reactive
protein; GC: glucosamine hydrochloride plus chondroitin sulfate;
iAUC: incremental area under the curve; IEC: Institutional Ethics Committee;
IL-6: interleukin-6; ITT: intent-to-treat; K-L: Kellgren and Lawrence; LFI: Lequesne
functional index; mITT: modified intent-to-treat; MMP-3: matrix metalloproteinase-
3; MMRM: mixed model repeated measures; NSAIDs: nonsteroidal anti-
inflammatory drugs; OA: osteoarthritis; PBO: placebo; ROM: range of motion;
Tregs: T regulatory cell; UC-II: undenatured type II collagen; VAS: visual analog
scale; WOMAC: Western Ontario McMaster Universities Osteoarthritis Index.
Table 10 Summary of analysis of adverse events in all subjects
Study group
Placebo
(n= 58)
GC
(n= 65)
UCII
(n= 63)
Severity
Mild 7 21 5
Moderate 2 7 3
Severe 0 0 0
Relationship to Test Article
Not related 8 14 8
Possible 1 13 0
Definite 0 1 0
Body System and AEs
Gastrointestinal
Acidity 2 3 2
Acute peptic disorder 1 0 1
Diarrhea 1 1 0
Epigastric burning 0 1 0
Febrile Enteritis 0 1 0
Heart burn 0 1 0
Vomiting 0 1 0
Nausea 0 1 0
Pain
Arthralgia 0 1 0
Body pain 0 1 0
Low back pain 1 1 0
Neck Pain 0 1 1
Headache 2 4 0
Myalgia 0 1 0
Dermatology
Itching 0 2 0
Xerotic skin 0 0 1
Pulmonary/Upper Respiratory
Lower respiratory tract
infection
00 2
Upper respiratory tract
infection
01 0
Cough 0 2 0
Genitourinary
Burning micturition 1 0 0
Burning sensation 0 0 1
Cardiovascular
Palpitation 0 2 0
Constitutional Symptoms
Fever 1 2 0
Insomnia 0 1 0
9288
Table 10 Summary of analysis of adverse events in all subjects
(Continued)
Total Number of Adverse
Events Experienced During
Study
Total Number of Subjects
Experiencing Adverse
Events: n (%)
7/58 (12 %) 20/65 (31 %) 8/63 (13 %)
Lugo et al. Nutrition Journal (2016) 15:14 Page 13 of 15
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Competing interests
JPL and ZMS are employees of InterHealth Nutraceuticals. NEL provided
consulting services to InterHealth. This study was sponsored by InterHealth
Nutraceuticals, Inc. Benicia, CA. The study was run and managed
independently by Laila Pharmaceuticals Pvt. Ltd., India. Data collection was
done by the clinical study staff at each respective site. Data analyses was
performed by an independent statistician.
Authorscontributions
JPL and ZMS contributed in the conception and design of the study, data
interpretation and manuscript preparation. NEL participated in data
interpretation, manuscript drafting and revisions. All authors read and
approved the final version of the manuscript.
Acknowledgements
We gratefully acknowledge the support of Janet M. Peerson, M.S., University
of California, Davis, for carrying out the statistical analyses shown herein and
for helpful discussions. We acknowledge the support of the Laila Pharma
Clinical team and the study investigators including Dr. Sundar Subramanian
from V. S. Hospital, Tamilnadu; Dr. Meenakshi Sundaram from Vinayaka
Mission Hospital, Tamilnadu; Dr. Balaji Thiruvadi and Dr. GM Bharat Kumar
from Gram Clinical Research Karpagam Hospital, Tamilnadu; Dr. Saji Thomas
from Little Flower Hospital and Research Center, Kerala; Dr. K. Balakondiah
from Bollineni Superspeciality Hospital, Andhra Pradesh; Dr. Siva Prasad from
Apollo Hospitals, Andhra Pradesh; Dr. K Rajapandian from Apollo Speciality
Hospitals, Tamilnadu; Dr. K. Vasu from Pujitha Hospital, Andhra Pradesh; Dr.
MAVV Prasad from Vijaya Super Speciality Hospitals, Andhra Pradesh; Dr. P.
Ashok Kumar from King George Hospital, Andhra Pradesh; Dr. P. Pavan
Kumar from R. K. Hospital, Andhra Pradesh; Dr. G Satish Reddy from Prime
Hospital, Andhra Pradesh. We thank Jonathan Hull, Ph.D. and Weiman Xu,
Ph.D. for assisting with data assembly and manuscript preparation.
Author details
1
InterHealth Nutraceuticals, Benicia, CA, USA.
2
Center for Musculoskeletal
Health, University of California Davis Health System, 4625 2nd Avenue, Suite
2006, Sacramento, CA 95817, USA.
Received: 7 November 2015 Accepted: 20 January 2016
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... таблицу). Механизм действия разных видов коллагена (неденатурированного и денатурированного) обусловливает их клиническое применение: НК-II назначается в основном при заболеваниях ОДА [16,17], в частности ОА; основная область применения ГлК-II -косметология, при инволюционных процессах в коже [18,19], назначается также и при заболеваниях ОДА [20, 21]. ...
... В большинство ЛП наряду с коллагеном включен комплекс лекарственных трав (босвеллия, куркумин и др.) или других хорошо изученных SYSADOA (ХС, ГС, гиалуроновая кислота). В сравнительном многоцентровом рандомизированном исследовании [17] с участием 191 пациента в возрасте от 40 до 75 лет с ОА коленных суставов (крепитация, наросты на костях, припухлость суставов и т. д.) наблюдались три группы: первая группа получала НК-II (40 мг/с), вторая -глюкозамина гидрохлорид (1500 мг) + ХС (1200 мг), третья -плацебо. Курс лечения составил 180 дней. ...
... В группе НК-II в сравнении с группой плацебо получено статистически значимое снижение показателей по шкале WOMAC, включая существенное достоверное уменьшение баллов по подшкалам WOMAC «боль», «скованность» и «физическая функция». Показатели безопасности в группах не различались [17]. ...
Article
Collagens play an important structural role and contribute to the mechanical properties, organization and shape of tissues. In musculoskeletal system diseases (MSD), the amount of type II collagen in the cartilage extracellular matrix significantly decreases. Degradation and reduction of type II collagen are associated with osteoarthritis (OA). At present, SYSADOA (Symptomatic Slow Acting Drugs for Osteoarthritis) are widely used in the treatment of OA for oral and parenteral use. Besides, increased attention has been paid to the new treatment methods for OA based on a new promising type II collagen molecule: undenatured (UC-II) and hydrolyzed (HC-II) collagen. UC-II is a native collagen (fibrillar protein with a molecular weight of 300 kDa), whereas HC-II is a polypeptide (molecular weight of 2–9 kDa). The article describes the molecular mechanisms of action of UC-II and HC-II, and identifies the main differences between them. The diverse mechanism of action of the described collagen types determines their clinical use: UC-II is prescribed mainly in MSD, in particular OA, and HC-II is mainly used in cosmetology, as well as in MSD. The article also presents the study results demonstrating the safety and efficacy of drugs and dietary supplements containing UC-II and HC-II in relieving pain syndrome during OA. KEYWORDS: undenatured type II collagen native collagen, hydrolyzed collagen, collagen peptides, SYSADOA, pain syndrome, osteoarthritis. FOR CITATION: Shavlovskaya O.A., Bokova I.A., Romanov I.D., Shavlovsky N.I. Efficacy of undenatured and hydrolyzed type II collagen in the treatment of pain syndrome. Russian Medical Inquiry. 2022;6(10):571–575 (in Russ.). DOI: 10.32364/2587-6821-2022-6-10-571-575.
... Although adjuvant methods for OA treatment can significantly relieve the pain of OA, they have disadvantages such as low potency, low tolerability, and a large dosage. The consumption of various forms of collagen, such as undenatured or native type II (TII) collagen, has also been studied for their potential benefits during OA management in pre-clinical and clinical studies, demonstrating positive results with substantially lower therapeutic doses [14][15][16][17]. The aim of the study was primarily to determine the effect of TII collagen (Native CT-II ® ) derived from the chicken sternum on osteoarthritis specific measures as compared to the placebo as well as glucosamine hydrochloride + chondroitin sulfate (G + C) and at the same time assess the safety of the product. ...
... The products that have been clinically proven to be effective in OA management include a combination of glucosamine and chondroitin sulfate [12,[29][30][31], Boswellia, curcumin, pycnogenol, methylsulfonylmethane, and undenatured type II collagen [32]. Out of these products, undenatured type II collagen is one of the few products that provides a significant effect at a relatively low dose [14,15]. The treatment duration for the OA trials varies between 4 weeks and 3 years. ...
Article
Full-text available
Purpose: Knee osteoarthritis (OA) is the most common form of clinical arthritis in middle-aged and older individuals. Undenatured or native type II (TII) collagen derived from the chicken sternum has a good therapeutic effect on relieving severe pain of OA. Hence, the present study aimed to investigate the efficacy and safety of TII collagen (Native CT-II®) in individuals with knee OA. Methods: We conducted a 12-week randomised, double-blind, placebo-controlled, parallel-group study on 101 participants aged 40-65 years with knee OA. The participants were randomised to receive either TII collagen, glucosamine hydrochloride + chondroitin sulfate (G + C) or a placebo. The primary outcome was an improvement in the joint health of the participants assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) compared to G + C and placebo. Results: Compared with the placebo group (n = 27), the TII collagen group (n = 29) and G + C group (n = 29) significantly improved the overall joint health measured by the change in WOMAC total score (week 12: TII collagen = -32.47 ± 19.51 and G + C = -33.74 ± 24.64 vs. placebo = -13.84 ± 17.61; p < 0.05) and relieved knee joint pain (week 12: TII collagen = -5.69 ± 3.66 and G + C = -6.03 ± 4.72 vs. placebo = -2.71 ± 3.95; p < 0.05). The statistically significant effect was observed as early as 4 weeks after the investigational product administration. Additionally, the TII collagen was more effective in improving the quality of life than the G + C. Conclusion: TII collagen not only has a significantly better effect and high safety profile for OA but also improves the quality of life of patients. Level of evidence: Level 1 - Randomized Controlled Trial. Trial registration: ClinicalTrials.gov Identifier: NCT04470336 ; First submitted date: July 08, 2020; First posted date: July 14, 2020.
... В экспериментальных исследованиях показано, что НК-II увеличивал долю регуляторных Т-клеток типа CD4+/CD25+ [57], снижал уровни провоспалительных цитокинов (ИЛ1β, ИЛ6, ФНОα, СРБ) в сыворотке крови и уровни MMP3, NF-κB в коленном суставе [58], ингибировал продукцию ПГE2 (на 20%) и экспрессию генов, кодирующих провоспалительные ИЛ1β, ИЛ6, ФНОα, COX2, MCP1, NF-κB, MMP3, RANKL [59]. В клинических исследованиях показана перспективность адъювантной терапии боли при ОА с использованием НК-II [60], подтверждены эффективность и безопасность НК-II при долговременном приеме [61]. Метаанализ рандомизированных плацебоконт- ролируемых исследований подтвердил эффективность приема НК-II при ОА: подтверждено статистически значимое снижение суммарного балла по шкале WOMAC (-8; 95% ДИ от -13 до -3; p=0,002), в том числе по подшкале «скованность» (-0,41; 95% ДИ от -0,74 до -0,08; p=0,01). ...
... KNEE osteoarthritis is a common degenerative musculoskeletal disorder characterized by pain that increase with use and decrease with rest [1]. ...
... Further studies that explain the mechanism for this supplement's actions are garranted.(Lugo, J. P., Saiyed,…,2015) The second case, The randomized study both double-blind and placebo (PLA)-managed was proceeded in vigorous subjects with ArJD who have never had osteoarthritis. Ninety-six n = 96 patients who approximately age 20-55 years old and informed joint ailment as acting Formula One leg stepping down examination were earned either PLA n = 48 or 40 mg of undenatured collagen n = 48 every day will gain supplements for 24 weeks. ...
Article
Undenatured type II collagen (UC-II) is supplementary which is from chicken sternum cartilage. (Lugo, J. P., Saiyed,…,2015) UC-II has undenatured type II collagen componentand. The safety and capability of UC-II in adjusting joint discomfort in Osteoarthritis and Rheumatoid arthritis support by previous preclinical and clinical studies. (Lugo, J. P., Saiyed,…,2013) Osteoarthritis (OA) is atrophy joint disease affecting the quality of life of the elderly population. A lot of evidence that nutraceuticals from natural herbs may play essential part in inflammation and joint catastrophe in OA. Moreover, various studies these supplements have been found to be proficient in OA. None of these supplements have reported side effects. However, questions connected to their capability and safety for OA prevention and treatment is quality trials are needed to give absolute answers. (Vaishya, R., Agarwal,…,2018)
... В последние годы накапливаются данные о новых молекулах, применяемых в лечении ОА. Перспективным направлением терапии ОА в настоящее время считаются фармацевтические композиции, в состав которых включен коллаген II типа -основной структурный компонент межклеточного матрикса хряща, количество которого уменьшается на фоне заболевания [20,21]. Для профилактики и лечения ОА применяется как денатурированный (или гидролизованный) коллагеновый пептид II типа, расщепленный до полипептидов, так и неденатурированный (нативный) коллаген II типа (НК-II; undenatured type II collagen, UC-II). ...
Article
The article presents new views on the treatment of pain syndromes in musculoskeletal diseases, in particular in osteoarthritis (OA) of various localizations (gonarthrosis, coxarthrosis). New recommendations (2019–2020) of international societies for the study of symptomatic delayedacting drugs (SYSADOA) and their use in the treatment of OA are presented. We present the opinions of experts from different communities: the American College of Rheumatology (ACR, 2019), the European Alliance of Associations for Rheumatology (EULAR, 2019), the European Society for the Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO, 2020) – on the prescription of SYSADOA, which include chondroitin sulfate (CS), glucosamine sulfate (GS), avocado and soy unsaponifiable compounds, diacerein, hyaluronic acid for intraarticular administration. New domestic clinical guidelines (2020–2021) for the treatment of OA are presented. The changes that have taken place in the terminology of pain and in the classification of pain syndromes, reflected in the new International Classification of Diseases of the 11th revision (ICD-11), are analyzed. New approaches to the stratification of OA, taking into account endo- and phenotyping, as well as new aspects in pain therapy associated with the molecular genetic mechanisms of SYSADOA are shown. According to the EULAR recommendations, there is indisputable evidence of the efficacy and safety of pharmaceutical CS, which is reflected in a meta-analysis (2019), a randomized placebo-controlled trial (2019), approved by the Russian Ministry of Health, and confirmed in Chondroguard’s meta-analysis of clinical trials (2020). New approaches in the treatment of pain syndromes provide for parenteral administration of CS and GS according to an intermittent scheme. The search and development of new molecules comparable in efficacy to SYSADOA in the treatment of pain in OA and low back pain have led to the emergence in clinical practice of biologically active compositions, including undenatured type II collagen, the effectiveness of which is associated with a neuroimmune mechanism of action.
... Развитие некоторых заболеваний суставов, сопровождающихся воспалением и эрозивными изменениями суставного хряща, связано с иммунным ответом на эндогенный коллаген II типа. Для лечения ОА в последние годы применяется неденатурированный (нативный) коллаген II типа (НК-II) и ГлК, расщепленный на низкомолекулярные пептидные фрагменты [8]. Неденатурированный коллаген характеризуется высокой (300 кДа), а ГлК -низкой (от 2 до 9 кДа) молекулярной массой [9]. ...
Article
Standardized extracts of undenatured type II collagen (UC-II) are used as alternative approaches to the treatment of osteoarthritis (OA). The effect of UC-II extracts is associated with the modulation of the mechanisms of innate and acquired immunity, a decrease in the activity of proinflammatory cytokines and prostaglandins. Epitopes of native collagen in the structure of UC-II contribute to a decrease in the activity of autoimmune reactions that stimulate cartilage degradation. Interacting with discoidin receptors, UC-II accelerates the reconstruction of cartilage connective tissue and inhibits the pro-inflammatory effects of endogenous collagens. Experimental and clinical studies confirm the effectiveness of the use of standardized substances UC-II for acceleration of cartilage regeneration and reduce pain in OA and subclinical joint dysfunction.
Article
The dominant collagen of the cartilaginous matrix in adults is type II collagen. The amount of type II collagen in the intercellular matrix of cartilage is significantly reduced against the background of musculoskeletal system diseases. The basis of articular cartilage is hyaline cartilage tissue consisting of chondrocytes with tissue-specific antigens that induce the production of antibodies in patients with osteoarthritis (OA). Today, new approaches are being considered in the treatment of OA with the use of udenatured type II collagen (UC-II). Such molecular mechanisms of action of UC-II as the formation of a systemic response through oral tolerance are discussed, since the induction of tolerance is the immune pathway, by default, in the intestine. A number of experimental, preclinical (on volunteers) and clinical studies have shown the effectiveness and safety of the use of UC-II in OA. Standardized extracts of UC-II exhibit anti-inflammatory, immunoregulatory, chondroprotective effects, contributing to the reduction of pain symptoms of OA. Against the background of taking UC-II with induced OA, there is a statistically significant decrease in the level of proinflammatory cytokines, such as interleukin (IL-1β, IL-6), tumor necrosis factor alpha (TNF), C-reactive protein (CRP) in serum and the level of max proteinases (MMP-3), nucleated factor «kappa-bi» (NF-κB) in the knee joint. UC-II significantly inhibits the production of prostaglandin E2 (by 20%) and the expression of genes encoding proinflammatory proteins. In experimental models and in OA patients, a decrease in the severity of pain syndrome, an increase in endurance, mobility and an improvement in the functional state of the joints were noted. Clinically, no changes in the structure of the muscle fiber were detected with increased physical exertion. With OA on the background of UC-II (10-40 mg/s), there was a statistically significant decrease in joint pain according to WOMAC. A promising direction of OA therapy is the combination of UC-II with chondroitin sulfate and glucosamine sulfate.
Research
Full-text available
Orally administered collagen in its many different forms is recognised as a highly biocompatible, safe form of supplementation, which has the potential to act on the body as an anti-inflammatory and antioxidant, and through structural remodelling and reduced lipotoxicity. The aim of this systematic review was to determine diseases where collagen has been indicated; assess safety, bioavailability and efficacy; and to provide therapeutic recommendations. It was concluded that collagen supplementation is strongly indicated for its positive therapeutic effect on pain management of osteoarthritis, balancing blood sugars in type II diabetes, wound healing, skin ageing, and post-exercise body composition and strength. Promising results were also seen for the use of collagen supplementation in osteoporosis, hypertension, rheumatoid arthritis, tendinopathy, cellulite, atopic dermatitis, sarcopenia and brittle nail syndrome. Although therapeutic recommendations were indicated in most of these diseases, owing in the large part to the use of these supplements as part of dual therapy or the uncertainty over translatability of branded products it was concluded that more studies are required to make definitive recommendations. There was a lack of clinical evidence to support the use of collagen for weight loss in obesity, gut health and in fibromyalgia.
Article
A promising direction of osteoarthritis (OA) therapy is currently being considered pharmaceutical compositions of Symptomatic Slow Acting Drugs for Osteoarthritis (SYSADOA), which include type II collagen. A clinical observational study was conducted. Objective: To Identify the effect of physical activity complex effects with dietary supplements Cartilox (composition: hydrolyzed type II collagen, hyaluronic acid, boswellia, curcumin, piperine) on the severity of pain syndrome in OA knee and hip joint patients, low back pain (LBP); assessment of the need for the appointment of NSAIDs against the background of taking Cartilox. Material and methods: The study included 60 patients aged 35-65 years, with a confirmed diagnosis of knee and hip OA I-II st., LBP with a slight degree of severity of pain syndrome - 4-5 points on a numerical rating scale (NRS). Patients with comorbid diseases: arterial hypertension (AH), type 2 diabetes mellitus (DM-2), hypothyroidism, diseases of the gastrointestinal tract (gastrointestinal tract). By randomization, the patients were divided into two groups: Main group (n=30; 54.36±8.57 years) received a complex effect of non-drug therapy (physical therapy complex) with dietary supplements Cartilox 1 sachet per day during or immediately after meals for 1 month, in combination with non-medical therapy (physical therapy complex). And Control group (n=30; 53.03±16.18 years) used only non-medical therapy (physical therapy complex). In both groups, topical NSAIDs were used «on demand». The patients included in the study had imaging data of the spine and joints. Clinical and neurological examination was used: day 0 (Visit 1), Day 14 (Visit 2), Day 30 (Visit 3) of therapy. The dynamics of the condition was assessed: 10-point NRS of pain assessment (at rest, while walking, palpation), functional status of Oswestry Disability Index (ODI), blood pressure (BP) was measured, the dynamics of biochemical parameters (before and after 30 days) of blood glucose, liver enzymes (AST, ALT), weight indicators, registration of adverse events (AEs). A sub-objective assessment (1 to 5 balls) was given to the patient and the physician. Results: Against the background of taking Cartilox, a statistically significant decrease in the severity of pain syndrome was noted, an improvement on ODI (to a greater extent in the Main group vs the Control group). In no case has a registered AEs. Changes in the level of biochemical blood parameters (glucose, liver enzymes) and blood pressure levels were not observed. The topical NSAIDs use was observed only in the Control group. Conclusion: The complex effect of physical exertion with dietary supplements Cartilox can be recommended for patients with unexpressed pain syndrome (4-5 points on the NRS) with LBP and knee and hip OA (I-II st.). The absence of changes in the level of biochemical parameters of blood and blood pressure makes it possible to recommend Cartilox to patients with OA and comorbid diseases.
Article
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Background: Osteoarthritis, a common joint disorder, is one of the leading causes of disability. Chondroitin has emerged as a new treatment. Previous meta-analyses have shown contradictory results on the efficacy of chondroitin. This, in addition to the publication of more trials, necessitates a systematic review. Objectives: To evaluate the benefit and harm of oral chondroitin for treating osteoarthritis compared with placebo or a comparator oral medication including, but not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, opioids, and glucosamine or other "herbal" medications. Search methods: We searched seven databases up to November 2013, including the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, CINAHL, EMBASE, Science Citation Index (Web of Science) and Current Controlled Trials. We searched the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) websites for adverse effects. Trial registers were not searched. Selection criteria: All randomized or quasi-randomized clinical trials lasting longer than two weeks, studying adults with osteoarthritis in any joint, and comparing chondroitin with placebo, an active control such as NSAIDs, or other "herbal" supplements such as glucosamine. Data collection and analysis: Two review authors independently performed all title assessments, data extractions, and risk of bias assessments. Main results: Forty-three randomized controlled trials including 4,962 participants treated with chondroitin and 4,148 participants given placebo or another control were included. The majority of trials were in knee OA, with few in hip and hand OA. Trial duration varied from 1 month to 3 years. Participants treated with chondroitin achieved statistically significantly and clinically meaningful better pain scores (0-100) in studies less than 6 months than those given placebo with an absolute risk difference of 10% lower (95% confidence interval (CI), 15% to 6% lower; number needed to treat (NNT) = 5 (95% CI, 3 to 8; n = 8 trials) (level of evidence, low; risk of bias, high); but there was high heterogeneity between the trials (T² = 0.07; I² = 70%, which was not easily explained by differences in risk of bias or study sample size). In studies longer than 6 months, the absolute risk difference for pain was 9% lower (95% CI 18% lower to 0%); n = 6 trials; T² = 0.18; I² = 83% ), again with low level of evidence. For the Western Ontario and McMaster Universities Osteoarthritis Index Minimal Clinically Important Improvement (WOMAC MCII Pain subscale) outcome, a reduction in knee pain by 20% was achieved by 53/100 in the chondroitin group versus 47/100 in the placebo group, an absolute risk difference of 6% (95% CI 1% to 11%), (RR 1.12, 95% CI 1.01 to 1.24; T² = 0.00; I² = 0%) (n = 2 trials, 1253 participants; level of evidence, high; risk of bias, low). Differences in Lequesne's index (composite of pain,function and disability) statistically significantly favoured chondroitin as compared with placebo in studies under six months, with an absolute risk difference of 8% lower (95% CI 12% to 5% lower; T²= 0.78; n = 7 trials) (level of evidence, moderate; risk of bias, unclear), also clinically meaningful. Loss of minimum joint space width in the chondroitin group was statistically significantly less than in the placebo group, with a relative risk difference of 4.7% less (95% CI 1.6% to 7.8% less; n = 2 trials) (level of evidence, high; risk of bias, low). Chondroitin was associated with statistically significantly lower odds of serious adverse events compared with placebo with Peto odds ratio of 0.40 (95% CI 0.19 to 0.82; n = 6 trials) (level of evidence, moderate). Chondroitin did not result in statistically significant numbers of adverse events or withdrawals due to adverse events compared with placebo or another drug. Adverse events were reported in a limited fashion, with some studies providing data and others not. Comparisons of chondroitin taken alone or in combination with glucosamine or another supplement showed a statistically significant reduction in pain (0-100) when compared with placebo or an active control, with an absolute risk difference of 10% lower (95% CI 14% to 5% lower); NNT = 4 (95% CI 3 to 6); T² = 0.33; I² = 91%; n = 17 trials) (level of evidence, low). For physical function, chondroitin in combination with glucosamine or another supplement showed no statistically significant difference from placebo or an active control, with an absolute risk difference of 1% lower (95% CI 6% lower to 3% higher with T² = 0.04; n = 5 trials) (level of evidence, moderate). Differences in Lequesne's index statistically significantly favoured chondroitin as compared with placebo, with an absolute risk difference of 8% lower (95% CI, 12% to 4% lower; T² = 0.12; n = 10 trials) (level of evidence, moderate). Chondroitin in combination with glucosamine did not result in statistically significant differences in the numbers of adverse events, withdrawals due to adverse events, or in the numbers of serious adverse events compared with placebo or with an active control. The beneficial effects of chondroitin in pain and Lequesne's index persisted when evidence was limited to studies with adequate blinding or studies that used appropriate intention to treat (ITT) analyses. These beneficial effects were uncertain when we limited data to studies with appropriate allocation concealment or a large study sample (> 200) or to studies without pharmaceutical funding. Authors' conclusions: A review of randomized trials of mostly low quality reveals that chondroitin (alone or in combination with glucosamine) was better than placebo in improving pain in participants with osteoarthritis in short-term studies. The benefit was small to moderate with an 8 point greater improvement in pain (range 0 to 100) and a 2 point greater improvement in Lequesne's index (range 0 to 24), both likely clinically meaningful. These differences persisted in some sensitivity analyses and not others. Chondroitin had a lower risk of serious adverse events compared with control. More high-quality studies are needed to explore the role of chondroitin in the treatment of osteoarthritis. The combination of some efficacy and low risk associated with chondroitin may explain its popularity among patients as an over-the-counter supplement. © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Article
Context Glucosamine and chondroitin preparations are widely touted in the lay press as remedies for osteoarthritis (OA), but uncertainty about their efficacy exists among the medical community.Objective To evaluate benefit of glucosamine and chondroitin preparations for OA symptoms using meta-analysis combined with systematic quality assessment of clinical trials of these preparations in knee and/or hip OA.Data Sources We searched for human clinical trials in MEDLINE (1966 to June 1999) and the Cochrane Controlled Trials Register using the terms osteoarthritis, osteoarthrosis, degenerative arthritis, glucosamine, chondroitin, and glycosaminoglycans. We also manually searched review articles, manuscripts, and supplements from rheumatology and OA journals and sought unpublished data by contacting content experts, study authors, and manufacturers of glucosamine or chondroitin.Study Selection Studies were included if they were published or unpublished double-blind, randomized, placebo-controlled trials of 4 or more weeks' duration that tested glucosamine or chondroitin for knee or hip OA and reported extractable data on the effect of treatment on symptoms. Fifteen of 37 studies were included in the analysis.Data Extraction Reviewers performed data extraction and scored each trial using a quality assessment instrument. We computed an effect size from the intergroup difference in mean outcome values at trial end, divided by the SD of the outcome value in the placebo group (0.2, small effect; 0.5, moderate; 0.8, large), and applied a correction factor to reduce bias. We tested for trial heterogeneity and publication bias and stratified for trial quality and size. We pooled effect sizes using a random effects model.Data Synthesis Quality scores ranged from 12.3% to 55.4% of the maximum, with a mean (SD) of 35.5% (12%). Only 1 study described adequate allocation concealment and 2 reported an intent-to-treat analysis. Most were supported or performed by a manufacturer. Funnel plots showed significant asymmetry (P≤.01) compatible with publication bias. Tests for heterogeneity were nonsignificant after removing 1 outlier trial. The aggregated effect sizes were 0.44 (95% confidence interval [CI], 0.24-0.64) for glucosamine and 0.78 (95% CI, 0.60-0.95) for chondroitin, but they were diminished when only high-quality or large trials were considered. The effect sizes were relatively consistent for pain and functional outcomes.Conclusions Trials of glucosamine and chondroitin preparations for OA symptoms demonstrate moderate to large effects, but quality issues and likely publication bias suggest that these effects are exaggerated. Nevertheless, some degree of efficacy appears probable for these preparations.