![Change in WOMAC scores at 30 days. a) Undenatured (Native) Collagen vs Placebo [31] b) Boswellia Extract (Aflapin) vs Placebo [37] WOMAC Western Ontario and McMaster Universities Osteoarthritis Index, U(N)C II Undenatured (Native) Collagen.](https://www.researchgate.net/profile/Varsha-Narayanan/publication/331671743/figure/fig3/AS:735475270705156@1552362377878/Change-in-WOMAC-scores-at-30-days-a-Undenatured-Native-Collagen-vs-Placebo-31-b_Q320.jpg)
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Review Article
Volume 3 Issue 4 - February 2019
DOI: 10.19080/NTAB.2019.03.555618
Nov Tech Arthritis Bone Res
Copyright © All rights are reserved by Varsha Narayanan
Osteoarthritis Management - Review of T Cell
Immunomodulation with Undenatured (Native)
Rakesh Mahajan12 and Varsha Narayanan3*
1Director of Orthopaedics, Institute for Bone, Joint Replacement, Orthopaedics Spine & Sports Medicine, BLK Super speciality Hospital, New Delhi
2Consultant Orthopaedic Surgeon, Rathod Orthopaedic Hospital, Borivali, Mumbai
3Chief - Medical Affairs, Integrace Health (Bone Health and Pain Management), Mumbai
Submission: February 08, 2019; Published: February 25, 2019
Varsha Narayanan, Integrace Health, Raheja Platinum, Marol, Mumbai 400059
Introduction
Osteoarthritis (OA) has traditionally been a degenerative
disease caused by long term and repeated wear and tear of the
cartilage of weight bearing joints leading to loss of cartilage
followed by exposure and damage to underling bone surfaces
[1]. The joint hyaline cartilage is made up of Chondrocytes which
synthesize and maintain the main components of cartilage:
Type II Collagen and Extracellular Matrix (ECM) Proteoglycans
containing Glycosaminoglycans (GAGs) like Chondroitin sulphate
and Hyaluronic acid [2]. Chondrocytes also produce lubricating
and destruction of cartilage leads to decreased number of
chondrocytes and thereby also a decrease in synthesis of Collagen
type II and GAGs. Therefore, in Osteoarthritis, an overall imbalance
Inammatory Pathways in Osteoarthritis
-
tion in the joint as a result of T cell mediated immune response
plays an important role in ongoing cartilage destruction as well
as symptoms of pain, swelling and loss of mobility. Studies have
shown increased number of CD4 cells in the serum and synovial
Response to autologous chondrocytes of
peripheral T cells isolated from OA patients is greater than that
of peripheral T cells isolated from controls, and this response is
partially blocked by antibodies against human leukocyte antigen
(HLA) classes I and II, CD4, and CD8 [5]. -
id of OA patients expressed class II HLA (an indicator of activated
T cells) and the percentages of CD4+ and CD8+ cells in the syno-
Nov Tech Arthritis Bone Res 3(4): NTAB.MS.ID.555618 (2019) 001
Abstract
involving multiple pathways. T cell mediated immune response to joint cartilage collagen is now one of the recognized pathways causing
thereafter to prostaglandins and leukotrienes by the Cyclo-oxygenase 2 (COX2) and Lipo-oxygenase 5 (5LOX) enzymes respectively, is also well
known.
to elaborate on the pharmacotherapeutic approaches involving modulating T cell immune response to cartilage and inhibiting the LOX pathways
by Undenatured (Native) Collagen Type II and Boswellia extract respectively.
Keywords: Osteoarthritis; Cartilage; Undenatured (Native) Collagen Type II; Boswellia; T Cell; COX; LOX; Leukotrienes; Matrix Metalloproteinase;
Cytokines
How to cite this article: Rakesh M, Niranjan R R, Varsha N. Multimodal Anti-Inammatory Approach to Osteoarthritis Management - Review of T Cell
Immunomodulation with Undenatured (Native) Collagen Type II and LOX Inhibition with Boswellia. Nov Tech Arthritis Bone Res. 2019; 3(4): 555618.
DOI: 10.19080/NTAB.2019.03.555618.
002
Novel Techniques in Arthritis and Bone Research
in RA patients [6]. Synovial aggregates from OA patients express
CD80, an inducible costimulatory ligand involved in T-cell activa-
tion suggesting that synovial aggregates in OA patients are areas
of antigen recognition and T-cell activation [7].
T cell mediated immune response is postulated to be as a re-
sult of glycosylation alterations in joint cartilage collagen, and this
like IL1, IL6, and TNF alpha, which activate matrix metalloprotein-
ase (MMP) and cause further destruction of cartilage [8-9]. Conse-
-
induce T regulatory differentiation and suppress MMPs [10-11].
Cartilage destruction leads to release of phospholipids converted
to arachidonic acid by phospholipases which are then converted
by Cyclo-oxygenase (COX2) and Lipo-oxygenase (5LOX) to prosta-
of prostaglandins (PGE2) in causing pain, swelling and increase
in temperature are well studied and therefore NSAIDs (COX in-
hibitors) are the most recognized drugs in OA management [12].
However, the LOX pathway also plays an important role in the in-
them to Leukotrienes (LTs). Leukotrienes (like LTB4 and cysteinyl
LTB4 enhances the production of interleukin (IL)-1 and Tumour
necrosis factor (TNF)- which activate MMP mediated cartilage
destruction. LTs also activate Interstitial Cell Adhesion Molecules
(ICAMs) which act as potent chemotactic agents stimulating mi-
gration and activation of T cells and macrophages, leading to
phagocytic activity and release of Reactive Oxygen Species (ROS),
which further mediate cartilage destruction [14-16]. These prop-
erties of LTB4, similar to PG E2, also play a role in stimulating bone
resorption in OA [17]. Therefore, cartilage destruction and loss in
and this should be taken into consideration during therapeutic
Figure 1: Inammatory pathways for cartilage loss in OA.
MMP: Matrix Metalloproteinase, LT: Leukotrienes, ICAM: Interstitial Cell Adhesion Molecule, NSAIDs: Non-steroidal Anti-inammatory drug,
TNF: Tumor Necrosis Factor, IL: Interleukin
erapeutic Approaches in OA
Current non-surgical treatment options in OA consist of
-
caused by PGE2. NSAIDs though effective, have long term limita-
co-use of proton pump inhibitors (PPIs) also associated with long
term safety concerns. NSAIDs also do not address the aetiology of
continued T cell immune mediated or LOX mediated cartilage de-
struction. Inhibiting only COX pathways with NSAIDs can increase
Leukotriene synthesis through diverting arachidonate through the
LOX5 pathway.18 Drugs like Corticosteroids act by Phospholipase
inhibition which may address both prostaglandin and leukotriene
synthesis however they are generalized immune-suppressants as
response against cartilage collagen II in OA [19-20].
Corticosteroids are also associated with systemic side effects
IL1[21]. Hydrolysed collagen supplements and SYSADOAs- Sys-
temic slow acting drugs in Osteoarthritis (GAGs and their pre-
cursors like Chondroitin sulphate, Glucosamine sulphate and Hy-
aluronic acid) act by providing building blocks for regenerating
cartilage. These agents do not present any patient tolerance or
side effect issues but rely on the body’s ability to assimilate these
supplements to regenerate lost cartilage [22]. This proves not only
to be a slow approach but also far less effective as these agents
do not act upon arresting the ongoing immune mediated and in-
How to cite this article: Rakesh M, Niranjan R R, Varsha N. Multimodal Anti-Inammatory Approach to Osteoarthritis Management - Review of T Cell
Immunomodulation with Undenatured (Native) Collagen Type II and LOX Inhibition with Boswellia. Nov Tech Arthritis Bone Res. 2019; 3(4): 555618.
DOI: 10.19080/NTAB.2019.03.555618.
003
Novel Techniques in Arthritis and Bone Research
to address both symptom relief as well as control ongoing carti-
lage destruction in a multiprong manner in OA patients so that the
body can then regenerate and rebuild cartilage more effectively.
Undenatured (Native) Collagen Type II
The joint cartilage is made up predominantly of type II colla-
gen synthesized by chondrocytes. Collagen is a complex protein
present only in animals and humans, with a triple helical struc-
ture. Our body cannot absorb intact collagen therefore collagen
supplements are made up of heat denatured and acid hydrolysed
collagen with the prospect of absorption by the body and further
assimilation into the triple helical collagen type II by the joint car-
tilage chondrocytes [24]. However, the absorption and assimila-
tion of hydrolysed collagen would be an uphill task against on-go-
Undenatured (Native) Collagen Type II -U(N)C II is non-hydro-
lysed collagen with intact structure, active epitopes and antigenic-
ity while hydrolysed collagen loses its native structure and anti-
genicity [25-26]. Undenatured type II collagen is extracted from
chicken sternum using little or no heat unlike the high heat used
in hydrolysed collagen, and very limited processing just enough
to concentrate the collagen and make it soluble [27]. The manu-
facturing process ensures that the collagen remains biologically
active in its most native, triple helix form with antigenic sites (epi-
topes) intact for immunomodulation. ELISA studies with simulat-
-
tenance of triple helical form of Undenatured Type II Collagen.
Therefore, the mechanism of action of Undenatured (Native)
Collagen Type II is not related to its absorption or assimilation as
it acts in the small intestine itself through a process called oral
-
matory damage of type II collagen in the joint cartilage [25]. Pay-
er’s patches (also called (GALT- Gut-associated lymphoid tissue)
are GI lymph nodes rich in T cells. Dendritic cells (DCs) in GALT
take up the Undenatured (Native) Collagen Type II in its glyco-
sylated form, and repeated low dose administration of the same
with its intact antigenic sites stimulates T regulatory cell and sup-
presses T helper cell stimulation [28].
Figure 2: Mechanism of Oral Tolerance of Undenatured Type II collagen.
U(N)C II: Undenatured (Native) Collagen Type II, DC: Dendritic Cell, Th: T helper, Tc: T cytotoxic (killer), T reg: T regulatory, OA: Osteoarthritis,
IL: Interleukin, TNF: Tumor Necrosis Factor, TGF: Transforming Growth Factor, MMP: Matrix Metalloproteinase.
T helper cells (Th) develop ‘tolerance’ thereby attenuating the
immune response against cartilage collagen. The immune balance
thereby shifts towards T regulatory cells (Treg) and increased
-
presses the cartilage collagen degrading MMP enzymes [29].
Therefore, endogenous collagen synthesis can be more effective in
suppressed. Understanding the difference between undenatured
(native) and hydrolysed collagen supplements attains crucial im-
How to cite this article: Rakesh M, Niranjan R R, Varsha N. Multimodal Anti-Inammatory Approach to Osteoarthritis Management - Review of T Cell
Immunomodulation with Undenatured (Native) Collagen Type II and LOX Inhibition with Boswellia. Nov Tech Arthritis Bone Res. 2019; 3(4): 555618.
DOI: 10.19080/NTAB.2019.03.555618.
004
Novel Techniques in Arthritis and Bone Research
-
sponse against cartilage collagen type II, while hydrolysed colla-
gen needs to be supplemented in large doses (often along with
GAGs and its precursors (like Chondroitin sulphate, Glucosamine
sulphate etc) as it intends to supply building blocks for chondro-
cytes to assimilate and rebuild cartilage [24].
The distinction lies clearly in Undenatured (Native) Collagen
Type II reducing cartilage destruction while hydrolysed collagen
intending to help regenerate cartilage. However, our body is al-
same is limited and falls short in view of senescence and increased
ongoing cartilage destruction.
Type II - U(N)C II (40mg) in Osteoarthritis has been demonstrat-
combination of Glucosamine and Chondroitin sulphate (G+C:
-
-
line at 90 days which was not observed in G+C treatment group
(N=26/group). Treatment with U(N)C II reduced the Western
Ontario and McMaster Universities Osteoarthritis Index (WOM-
-
tional Index (LFI) score by 33%, 40%, 20% as compared to 14%,
15.4% and 6% in G+C treated group after 90 days suggesting a
-
A higher number of subjects (23%)
on G+C demonstrated adverse events possibly related to product
as compared to 11.4% of subjects on U(N)C II (P<0.05). For U(N)
C II the possible adverse events related to products were inter-
mittent constipation and headaches while for G+C it was bloating,
stomach pain, rash, swelling around the eyes and scars, hives and
headache.
In the second study 191 volunteers were randomized into
three groups receiving a daily dose of U(N)C II (40 mg), G+C (1500
mg G+1200 mg C), or placebo. At day 180, the U(N)C II group
compared to placebo and G+C: U(N)C II compared to placebo (
-551 vs. -414; 95 % CI -232 to -42; p = 0.002) and compared to
G+C ( -551 vs. -454; 95 % CI -190 to -3; p = 0.04). Supplementa-
stiffness WOMAC subscales versus G+C and placebo: pain (24 vs
19.2 vs 17 ; p = 0.016 vs. G+C; p = 0.0003 vs. placebo;); stiffness
(23.8 vs 19.4 vs 17.8; p=0.044 vs. G+C ; p = 0.004 vs. placebo); and
17.3; p = 0.007 vs. placebo).
in mean VAS score at day 180 versus both G+C and placebo (22.6
vs 18.4 vs 17.0; p = 0.025 vs G+C; p = 0.002vs placebo). A signif-
icant reduction was also observed in the LFI score for the U(N)
C II group at day 180 versus G+C and placebo (2.9 vs 2.2 vs 2.1;
was observed between the G+C and placebo for both VAS and LFI
scores. Safety outcomes did not differ among the groups. U(N)C
II improved knee joint symptoms in knee OA subjects and was
well-tolerated [31]. 15 product related adverse events were seen,
14 of which belonged to the GC group (gastro-intestinal) and 1 to
placebo while no AEs noted for the U(N)C II cohort were deemed
to be product related.
Another study in 39 patients was performed to evaluate the
effect of adding Undenatured (Native) Collagen Type II to Acet-
aminophen (Paracetamol) 1500mg/day [32]. After 3 months of
treatment, the patients of the combination group showed sig-
(p=0.003), WOMAC total (p=0.004), WOMAC physical function-
ing (p=0.016) scores and subscales of SF36 bodily pain score
-
ceiving only Acetaminophen. Comparisons between the groups
of the combination group (50% reduction) as compared to the
Acetaminophen monotherapy group (p=0.002). A study done in
non-arthritic healthy volunteers who had knee pain on physical
-
tive) Collagen Type II versus placebo in increasing degree of knee
extension and time to pain onset on physical activity [29].
Boswellia
Boswellia serrata is a tree from India also called Indian frank-
incense, Salai or Indian Olibanum. Boswellic Acids (BAs) with the
characteristic pentacyclic triterpene ring, present in the gum resin
of B. serrata
for leukotriene production, without affecting other LOX and COX
activities. 3-O-acetyl-11-keto--Boswellic acid (AKBA) possess-
es the most potent inhibitory activity on 5LOX [33].
preparation that contains B. serrata extract selectively enriched
with AKBA and B. serrata non-volatile oil and has shown supe-
-
ti-osteoarthritic agent, with better oral bioavailability compared
to B. serrata extracts (BEs) commercially available in the market
[34-35]. Inhibition of 5LOX and Leukotriene formation reduce the
leading to decreased cartilage destruction by MMPs, increased
and overall tilting the balance in favour of cartilage regeneration
over cartilage loss.
-
ious clinical studies (Table 1). A double-blind, randomized, study
in 75 OA patients with Boswellia (BE-30 containing 30% AKBA)
100mg, 250mg) and placebo once daily showed clinically sig-
How to cite this article: Rakesh M, Niranjan R R, Varsha N. Multimodal Anti-Inammatory Approach to Osteoarthritis Management - Review of T Cell
Immunomodulation with Undenatured (Native) Collagen Type II and LOX Inhibition with Boswellia. Nov Tech Arthritis Bone Res. 2019; 3(4): 555618.
DOI: 10.19080/NTAB.2019.03.555618.
005
Novel Techniques in Arthritis and Bone Research
placebo with both Boswellia dosage groups at 90 days, with the
250-mg dose showing improvements in pain score and functional
ability in 7 days after the start of treatment [36]. Both doses of BE-
showed a rise in placebo group.
Another double blind randomized study with Boswellia
B. serrata extract selectively
enriched with 20% AKBA and B.
in 60 patients with mild or moderate unilateral or bilateral OA of
-
ments with 37.6%, 32.0%, 40.1%, 41.3% and 38.8% reductions
in VAS, LFI, WOMAC pain, WOMAC stiffness and WOMAC function
scores respectively over the placebo group. Improvement with Al-
laboratory parameters were seen [37].
-
placebo) in 60 subjects with OA. Both groups showed clinically
scores versus placebo [34]. In comparison to placebo, the im-
provements in in VAS, LFI, WOMAC pain, WOMAC stiffness and
of 47.3% (P<0.0001), 35.8% (P=0.0004), 61.7% (P<0.0001),
60.1% (P=0.0001) and 49.4% (P=0.0001) as compared to 31.6%
(P=0.006), 18.35% (P=0.060), 30.3% (P=0.009), 42.2% (p=0.006)
and 21.25% (P=0.078) respectively.
and functional ability as early as 7 days of treatment with better
group exhibited 8.09% (P=0.002), 8.68% (P=0.031) and 8.35%
(p=0.015) reductions in VAS, WOMAC pain and WOMAC func-
group exhibited 12.8% (P=0.0004), 9.17% (P=0.003), 11.78%
(P=0.012), 18.48% (P=0.012) and 10.24% (p=0.005) reductions
in VAS, LFI WOMAC pain, WOMAC stiffness and WOMAC function
level by 65.04% and 38.83%
-
inhibited MMP enzymes better than BE-30 by 41.36% [33].
Conclusion
Cartilage destruction in Osteoarthritis involves multiple
Prostaglandins, 5LOX action producing Leukotrienes and T cell
activation in response to altered Collagen II glycosylation in hyaline
like IL1, TNF alpha and ICAM, increases the action of MMP
enzymes which degrade cartilage, and leads to recruiting more
therapeutic approach seems rational with agents which can
act on the COX pathway, Undenatured (Native) Collagen Type II
response and activates T regulatory cells, which reduces cartilage
damage. Boswellia acts by inhibiting the LOX pathway and
Therefore, using these agents together can be an effective way of
reducing cartilage damage, and increasing cartilage regeneration.
Initiating treatment with combination therapies like U(N)C II
with BE for early symptomatic relief and rapid reduction in
tolerance with U(N)C II alone can also be a possible approach.
More studies with combination of these agents will add further
value to this therapeutic approach.
Figure 3: Change in WOMAC scores at 30 days.
a) Undenatured (Native) Collagen vs Placebo [31] b) Boswellia Extract (Aapin) vs Placebo [37]
WOMAC Western Ontario and McMaster Universities Osteoarthritis Index, U(N)C II Undenatured (Native) Collagen.
How to cite this article: Rakesh M, Niranjan R R, Varsha N. Multimodal Anti-Inammatory Approach to Osteoarthritis Management - Review of T Cell
Immunomodulation with Undenatured (Native) Collagen Type II and LOX Inhibition with Boswellia. Nov Tech Arthritis Bone Res. 2019; 3(4): 555618.
DOI: 10.19080/NTAB.2019.03.555618.
006
Novel Techniques in Arthritis and Bone Research
Table 1: Summary of clinical studies with Undenatured (Native) Collagen II and Boswellia.
Study Product Study Design Patients Duration Main Results
1[30]
Undenatured
(Native)
Collagen Type II
U(N)CII 40mg/day
Glucosamine(G)
Chondroitin(C)
G (1.5g) +C
(1.2g)/day
RCT
Double blind
2 centers
(Canada) N=52
OA knee
(>3 months
duration)
Age-40-75
years
90 days
U(N)C II vs G+C: Improvement from baseline
•WOMAC:33%** vs 14%
•VAS:40%** vs 15.4%
•LFI:20%* vs 6%
Product related ADRs: 11.4% vs 23%
2[31]
Undenatured
(Native)
Collagen Type II
U(N)CII 40mg/day
G (1.5g) +C
(1.2g)/day
Placebo (P)
RCT
Double blind
13 centers
(South India)
N=191
OA knee
(moderate
to severe
>3 months
duration)
Age-40-75
years
180 days
Spacing should be as below:
U(N)C II vs G+C vs P: Improvement at 180
days- Total WOMAC: 551** vs. 454* vs 414
U(N)C II* vs G+C; U(N)C II** vs P; G+C vs P (NS)
U(N)C II vs G+C; U(N)C II vs P: Improvements
from baseline-
WOMAC pain: 24* vs 19.2; 24** vs 17
WOMAC stiffness: 23.8* vs 19.4; 23.8** vs 17.8
WOMAC physical function: 22.5 vs 18.8; 22.5**
vs 17.3
VAS: 22.6* vs 18.4; 22.6** vs 17.0
LFI: 2.9** vs 2.2; 2.9** vs 2.1
Product related ADRs: (U(N)C II vs G+C vs P):
0 vs 14 vs 1
3[32]
Undenatured
(Native)
Collagen Type II
U(N)C II 10mg/
day + 1500mg/day
Acetaminophen(AP)
1500mg/day
Acetaminophen
(AP)
RCT
Double blind
Single Centre
(Turkey) N=39
OA knee
Age: 40-75
years 90 days
U(N)C II +AP vs AP alone: Improvements from
baseline–
•Total WOMAC: 9.5** vs -2
•WOMAC pain: 3**vs -2
•WOMAC stiffness: 0.5* vs 0
•WOMAC physical function: 6** vs -2
•VAS (walking): 3** vs 0
•SF36 bodily pain score 10** vs 0
4[29]
Undenatured
(Native)
Collagen Type II
U(N)C II 40mg/day
Placebo (P)
RCT
Double blind
Single Centre
(USA) N=55
Healthy
volunteers
with joint
discomfort
on
physical
activity
120 days
Knee extension: baseline vs day 120
•U(N)C II: 73.2 vs 81** degrees
•P: 71 vs 74 degrees (U(N)C II ** vs P day 120).
Time to pain onset: baseline vs day 120:
•U(N)C II: 1.4 vs 2.8 minutes*
•Placebo: 1.1 vs 1.7 minutes
(U(N)C II* vs P day 120)
AEs: (U(N)C II vs P): 4 vs 4
5[36]
BE-30(BE+30%
AKBA)
=100mg, 250mg
daily
Placebo (P)
RCT
Double blind
Single Centre
(South India)
N=75
OA knee
Age: 40-80
years 90 days
E-30: (100mg) vs BE-30 (250mg) vs P:
Improvements from baseline-
•WOMAC pain: 22.9*** vs 21.9*** vs 6.3
•WOMAC stiffness: 17.7*** vs 18.5*** vs 8.7
•WOMAC physical function: 17.2*** vs 21.3***
vs 7.2
•VAS: 35.7*** vs 41.4*** vs 15.1*
•LFI: 4*** vs 5***vs 2.6*
•MMP (ng/ml): 256.5*** vs 429.4*** vs -26.4
Product related ADRs: 18 vs 27 vs 30
How to cite this article: Rakesh M, Niranjan R R, Varsha N. Multimodal Anti-Inammatory Approach to Osteoarthritis Management - Review of T Cell
Immunomodulation with Undenatured (Native) Collagen Type II and LOX Inhibition with Boswellia. Nov Tech Arthritis Bone Res. 2019; 3(4): 555618.
DOI: 10.19080/NTAB.2019.03.555618.
007
Novel Techniques in Arthritis and Bone Research
6[37]
(BE+ 20% AKBA +
B. serrata non-
volatile oil)
100mg daily
Placebo (P)
RCT
Double blind
Single Centre
(South India)
N=60
OA knee
(>3 months
duration)
Age-40-80
years
30 days
A vs P: Improvements from baseline-
•WOMAC pain: 23.6*** vs 5.6
•WOMAC stiffness: 18.8*** vs 3.4
•WOMAC physical function: 18.6*** vs 3.8
•VAS: 23.5*** vs 8.3*** (A*** vs P)
•LFI: 4.4*** vs 0.1
Product related ADRs: 1 vs 1
7[34]
day
BE-30 100mg/day
Placebo (P)
RCT
Double blind
Single Centre
(South India)
N=60
medial tibio-
femoral OA
Knee
(>3months
duration)
Age-40 years
or more
90 days
A vs BE-30: vs P:
Improvements from baseline-
•WOMAC pain: 31.1*** vs 20.8*** vs 8.4**
•WOMAC stiffness: 27.7*** vs 22.7*** vs 9.9**
•WOMAC physical function: 25.8*** vs 17.9***
vs 10**
•VAS: 27.5*** vs 22*** vs 9.4**
•LFI: 5*** vs 3.5*** vs 1.4*
Product related ADRs: 1 vs 0 vs 1
*p ≤ 0.05, ** p ≤ 0.01, ***≤ 0.0001, NS not signicant. WOMAC Western Ontario and McMaster Universities Osteoarthritis Index, VAS Visual
Analog Scale, LFI Lequesne’s Functional Index, RCT Randomized clinical trial, N Number of patients, U(N)C II Undenatured (Native) Collagen
Type II, G+C Glucosamine + Chondroitin, P placebo, AP Acetaminophen, AE Adverse event, ADR Adverse Drug Reaction, BE Boswellia Extract,
AKBA 3-O-acetyl-11-keto-β-boswellic acid, A Aapin, MMP Matrix MetalloProteinases
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DOI: 10.19080/NTAB.2019.03.555618
