1. health and fitness
2. disease
3. arthritis

WHAT IS NEW IN OSTEOARTHRITIS?
SYSADOA CLINICAL REVIEW
Josep Vergés MD, MSc, PhD.
Clinical Pharmacologist,
Medical and Scientific Director,
Bioibérica S.A., Barcelona, Spain
WHAT IS OSTEOARTHRITIS?
Definition:
It is a degenerative, inflammatory and chronic arthropathy that
affects all joint structures (Hyaline cartilage, subchondral bone
and synovial membrane).
1. Metalloproteases (MMPs)
2. Citokines: IL-1, TNF-α
3. NO and free radicals
4. PGE2
Toquero F, et al. evidencia Científica en Artrosis. Manual de Actuación. Madrid: IM&C,
2006.
1
THERAPEUTIC MEASURES
1. EDUCATION
8. REHABILITATION
2. DIET
9. DRUGS:
3. EXERCISE
- SYSTEMIC
AND/OR TÓPICAL
4. PHYSIC THERAPY
5. FOOTWEAR
6. HIDROTHERAPY
7. WALKING AIDS
(INSOLES, WALKING
STICK, ETC.)
-INTRA-ARTICULAR
10. JOINT LAVAGE
11. CHONDROCYTES
TRANSPLANT
12. SURGERY
PHARMACOLOGICAL THERAPY
¾ Symptomatic effect
per os
Analgesics and NSAIDs
i.a
Corticoids
per os
Chondroitin sulfate, glucosamine sulfate,
Diacerein
Hyaluronic acid 500-730 kDa
Fast
Slow
(SYSADOA)
i.a
¾Structure Disease Modifying Osteoarthritis Drug (S/DMOAD)
- Chondroitin sulfate
- Glucosamine sulfate
- Hyaluronic acid 500-730 kDa
- Diacerein
Lequesne M, et al. J. Rheumatol 1994; 21 (Suppl. 41):65-71
2
INTRODUCTION:
Symptomatic slow acting drugs for OA (SYSADOA) have a
slow onset of action but have additional benefits such as global
efficacy similar to NSAIDs and a carry-over effect (the effect lasts
for months even after treatment suppression).
Moreover, these drugs have a high safety profile and the ratio
cost/effectiveness is low.
The main SYSADOAs are chondroitin sulfate (CS), glucosamine
sulfate (GLU) and hyaluronic acid (HA).
They are specially indicated in elderly patients, often
polymedicated.
SYSADOAs, apart from their symptomatic effect, also have a
structure disease modifying effect slowing OA progression.
CHONDROITIN SULFATE
SULFATE
CHONDROITIN
3
1-4
CHONDROITIN SULFATE
SULFATE ACTION
ACTION MECHANISMS
MECHANISMS1-4
CHONDROITIN
STIMULATES:
STIMULATES:
proteoglycans
↑↑ proteoglycans
HA
↑↑ HA
↑
Collagen type
type II
II
↑ Collagen
INHIBITS:
INHIBITS:
cartilage degradative
degradative enzymes
enzymes
↓↓ cartilage
(collagenase,elastase,
(collagenase,elastase,
proteoglycanase, fosfolipase
fosfolipase A2,
A2,
proteoglycanase,
N-acetylglucosaminidase,
etc.)
N-acetylglucosaminidase, etc.)
MMP-3(Fig.
(Fig.I),
I),MMP-2,
MMP-2,MMP-9,
MMP-9,
↓↓MMP-3
MMP-14
MMP-14
freeradicals,
radicals,apoptosys,
apoptosys,NO
NO
↓↓free
↓
IL-1
↓ IL-1
TNF-α
↓↓TNF-α
↓
COX-2
↓ COX-2
↓
NF-kB(Fig.
(Fig.II)
II)
↓ NF-kB
EFFECT:
EFFECT:
-anti-inflammatory
-anti-inflammatory
activity
activity
-Membrane
-Membrane
stabilising action
action
stabilising
(1) Ronca F et.al. Osteoarthritis Cart 1998, 6 (Supplement A), 14-21. (2) Blanco FJ. et. al. Rev. Esp. Reumatol
2001; 28, 1: 12-17. (3) Nacher M et.al. Ann Rheum Dis 2004 (suppl.) 371: FRI0422. (4) Verges J. Ann Rheum
Dis (suppl.) 2004: 372, FRI0428.
CD44
CS
IL-1β
TNF-α
inte
grin
α
5 β1
↑ NOS2
PG ↑ MMPs
HA ↑ COX2
GAG ↑ PLA2
p38 MAPKs
↑ cytokines
RNAm
H2O2
O2•−
t
va
ion
CS
?
ti
ac
-f
FN
NF-κB
↓ IL-1β, TNF-α,
MMPs, PLA2,
COX2, PGE2,
ON, apoptosys…
OA
CS
on
ati p65 p50
loc
s
n
tra
(p65/p50)
chondrocyte
4
Omata T, et al. Effects of Chondroitin sulfate-C on Articular
Cartilage Destruction in Murine collagen-induced arthritis.
Arzneim-Forsch / Drug Res 2000, 50 (1),148-153.
ƒ In a rat model, CS reduced synovitis and
articular cartilage destruction associated to
chronic inflammation.
ƒ The results show that oral CS prevented
articular cartilage destruction and reduced
severity of poli-arthritis induced in rats.
CLINICAL EVIDENCE
EVIDENCE
CLINICAL
ƒ 9 randomized, controlled, clinical trials have been
conducted in Europe with Condrosan® /
Condrosulf®, comparing its effect against placebo
(PBO) and sodium diclofenac (SD) (150 mg) in 1163
patients with knee and hand osteoarthritis (OA)5-13.
ƒ The results from these clinical trials conclude that CS is
as effective as SD and around 50% more effective
than PBO in the reduction of OA symptoms5,14,15.
Besides, its efficacy lasts for at least 3 months after
treatment suppression.
(5) Morreale, et al. J. Rheumatol. 1996, 23: 1385-1391. (6) Kissling R. et al. Osteoarthritis Cart 1997, 5
(Supplement A), 9: 70. (7) Bucsi L, et.al. Osteoarthritis Cart 1998, 6 (supplement A):31-36. (8). Pavelka K, et al.
Litera Rheumatologica 1998, 24:21-30. (9). Uebelhart D, et.al. Osteoarthritis Cart 1998, 6, (Supplement A), 39-46.
(10). Uebelhart D, et al. Osteoarthritis Cart 2004, 12:269-276. (11) Michel B, et al. Osteoarthritis Cart 2001, 9
(supplement B), LA2. (12) Verbruggen G, et al. Osteoarthritis Cart (1998) 6, (Supplement A), 37-38. (13)
Vebruggen G. et al. Clinical Rheumatology 2002, 21: 231-241. (14) Leeb F, et al. J. Rheumatol. 2000; 27: 1: 205
211. (15) du Souich P, Vergés J. Clin. Pharm. Ther. 2001; 70: 5-9.
5
S/DMOAD
S/DMOAD
ƒ CS may act as a structure disease
modifying OA drug (S/DMOAD), that is, it
may slow down disease progression16.
ƒ 3 clinical trials in knee OA have evidenced
a stabilization of joint space with CS
treatment as opposed to a narrowing of
joint space with PBO9-11.
ƒ 2 clinical trials in hand OA concluded that
disease progression was lower in CStreated patients and less patients from
this group developed erosive OA12-13.
(9). Uebelhart D, et.al. Osteoarthritis Cart 1998, 6, (Supplement A), 39-46. (10). Uebelhart D, et al. Osteoarthritis
Cart 2004, 12:269-276. (11) Michel B, et al. Arthritis Rheum 2005, 52 (3): 779-786. (12) Verbruggen G, et al.
Osteoarthritis Cart (1998) 6, (Supplement A), 37-38. (13) Vebruggen G. et al. Clinical Rheumatology 2002, 21: 231241. (16). Jordan KM, et al.Ann Rheum Dis 2003; 62:1145-1155
SAFETY PROFILE
PROFILE
SAFETY
ƒ
The tolerance of the product is very well documented;
equivalent to PBO and much higher than that of
SD14.
ƒ
It is not metabolized
cytochrome P450.
by
enzymes
from
It can not present drug interactions at this level
ƒ Pharmacosurveillance data from Europe, where no
serious adverse events have been reported for more
than 10 years, support the safety of the product.
(14) Leeb F, et al. J. Rheumatol. 2000; 27: 1: 205 211.
6
EULAR RECOMMENDATIONS 200318
Evidence based medicine
(18). Jordan KM, et al.Ann Rheum Dis 2003; 62:1145-1155.
EULAR RECOMMENDATIONS 200316
Evidence based medicine
(16). Jordan KM, et al.Ann Rheum Dis 2003; 62:1145-1155.
7
CS ADVANTAGES
ADVANTAGES
CS
¾Clinical efficacy on symptom
reduction and improvement of
functional capacity.
¾Persistent clinical effect after
treatment suppression (evidenced for
at least 3 months).
¾Greater safety than conventional
therapy (analgesics, NSAIDs). It does
not cause drug interactions.
CONCLUSION
CONCLUSION
CS –– effective
effective
CS
SYSADOA
SYSADOA
Positive impact
impact on
on
Positive
disease
progression
disease progression
No adverse
adverse
No
effects
effects
Pharmacoeconomic
Pharmacoeconomic
advantages
advantages
No drug
drug
No
interactions
interactions
IDEAL
IDEAL
PRODUCT
PRODUCT
FOR OA
OA
FOR
TREATMENT
TREATMENT
month carry
carry -33 month
over effect
effect
over
8
CLINICAL BIOEQUIVALENCE
BIOEQUIVALENCE II
CLINICAL
ƒ The clinical trials mentioned before have been conducted with
one specific CS formulation, which is approved as a
drug in several European countries.
ƒ This CS, which is manufactured by BIOIBERICA, meets the
highest quality standards, as for the origin and
pureness of the raw material, manufacturing process
(GMP, GLPs), safety requirements (viral inactivation), etc.
ƒ It has also been approved as a reference standard by the
US Pharmacopeia for being the highest quality product in
the market.
ƒ For these reasons, this CS was the one chosen by the NIH
for its Glucosamine/Chondroitin Arthritis Intervention Trial
(GAIT)17.
(17). Jamie G. Barnhill et al. Chondroitin Product Selection for the Glucosamine/Chondroitin
Arthritis Intervention Trial. J Am Pharm Assoc. 2006;46:14–24.
CLINICAL BIOEQUIVALENCE
BIOEQUIVALENCE II
II
CLINICAL
ƒ A study analysing the contents of
glucosamine and CS of several US
products, concluded that the
amounts found were
significantly different from
label claim in some products,
with deviations from 0 to 115%18.
ƒ It also evidenced that
characteristics such as: molecular
weight, flexibility of structure,
sulfation and method of
manufacture may influence
oral absorption.
ƒ Among all products compared, the
one from Bioibérica evidenced
the highest permeability rate.
ƒ Different parameters have been
established to determine CS
bioequivalence21.
Raw
material
Permeability
coefficient
(x 10-6) (n=3)
(cm/sec)
A1
B
C
D
E
F
10.1 (± 0.6)
8.73 (± 9.07)
7.94 (± 7.35)
0.00 (± 0.00)
3.63 (± 2.07)
1.03 (± 1.78)
1mol
Wt = 16,900 dalton (95% Bioiberica)
(18) Adebowale A, et al. JAMA 2000, 3 (1): 37-44.
(21) Vergés J, Castañeda-Hernández G. Proc.
West. Pharmacol. Soc. 2004, 47: 50-53 (2004).
9
Clegg DO, et al. Glucosamine, chondroitin sulfate, and the two in combination for
painful knee osteoarthritis. N Engl J Med. 2006 Feb 23;354(8):795-808.
SYMPTOMATIC PART RESULTS
The Glucosamine / Chondroitin
Arthritis Intervention Trial (GAIT)
10
WOMAC PAIN SCORE
Placebo
Celecoxib
Glucosamine
Chondroitin
sulfate
G + CS
All randomized
patients
60.1%
70.1%**
64.0%
65.4%
•35% placebo was
expected
•Patients with mild pain;
“floor effect”
66.6%+
** p= 0.008 CE vs P
+p= 0.09 G+CS vs P
Clegg DO, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee
osteoarthritis. N Engl J Med. 2006 Feb 23;354(8):795-808.
COMBINATION
Placebo
Celecoxib
Glucosamine
Chondroitin
sulfate
G + CS
WOMAC pain 301400 mm
54.3%
69.4%¶
65.7%
61.4%
HIGHLY SIGNIFICATIVE
WHILE CELECOXIB
DOESN’T ACHIEVE
SIGNIFICANCE
79.2% #
¶p = 0.06 CE vs P
#p= 0.002 G+CS vs P
Clegg DO, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee
osteoarthritis. N Engl J Med. 2006 Feb 23;354(8):795-808.
11
CS GRADE II
Outcome
K
CS
PBO
L N = 318 N = 313
Valor p
KL2v3
CS v PBO
Clegg DO, et al. Chondroitin sulfate
may have differential effects on OA
symptoms related to degree of
radiographic involvement.
Osteoarthritis Cart 2005, 13 (Suppl.
A), P.145: S 76.
WOMAC subscales changes
Pain
2
-101.5
-90.3
0.0042
0.0907
TREND
Stiffness
3
2
-59.5
-40.7
-80.4
-37
0.0049
0.0271
SIGNIFICANCE
Function
3
2
-18.1
-289.6
-35.7
-218.6
0.0617
0.0100
SIGNIFICANCE
-160.3
-239.2
Outcome
3
K
L
CS
N=
318
Percentage of patients
follow-up
Swelling
2 10.6
3 15.0
PBO
P value
N = K L 2 v CS v
313
3
PBO
with swelling at end of
16.7
24.2
0.0126
SIGNIFICANCE
JOINT EFFUSION
CS reduces joint effusion very significantly at 6
months of treatment.
Clegg DO, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee
osteoarthritis. N Engl J Med. 2006 Feb 23;354(8):795-808.
12
CONCLUSIONS GAIT-NIH
•
Patients with mild pain (low WOMAC) are difficult to value
because the placebo effect is very high. More patients should
be needed in order to achieve a lower placebo effect.
•
Positive facts:
1. CS works good in patients with K&L grade II.
2. CS works good in patients with joint effusion.
3. Combination (CS plus GLU) has excellent results in
patients with moderate-to-severe pain with an efficacy
10% higher than COX-2.
CONCLUSIONS GAIT-NIH
THIS IS ANOTHER CLINICAL TRIAL THAT
BRINGS NEW FACTS ABOUT EFFICACY AND
SAFETY OF CS AND GLU.
IN ADDITION THERE ARE SUB-GROUPS OF
RESPONDING PATIENTS.
13
GLUCOSAMINE SULFATE
SULFATE
GLUCOSAMINE
GLUCOSAMINE SULFATE
SULFATE ACTION
ACTION
GLUCOSAMINE
MECHANISMS
MECHANISMS
STIMULATES:
STIMULATES:
-↑ proteoglycans
proteoglycans
-↑
EFFECT:
EFFECT:
Anti-inflammatory
-- Anti-inflammatory
activity
activity
Membrane
-- Membrane
stabilising activity
activity
stabilising
INHIBITS:
INHIBITS:
cartilage degradative
degradative
↓↓ cartilage
enzymes (collagenase,
(collagenase,
enzymes
aggrecanase,
aggrecanase,
phospholipase A2,
A2, etc.)
etc.)
phospholipase
MMP-3, MMP-2,
MMP-2, MMP-9
MMP-9
↓↓ MMP-3,
↓
free
radicals
↓ free radicals
PGE2
↓↓ PGE2
↓
IL-1
↓ IL-1
NF-kB
↓↓ NF-kB
14
Reginster J.Y. et al. Long-term effects of glucosamine
sulphate on osteoarthritis progression: a randomised,
placebo-controlled clinical trial. The Lancet 2001, 357
(9252): 251-256.
• Patients
treated
with
glucosamine
presented
symptomatic improvement around 20-25%, compared to
placebo (Figs. I y II).
Fig. II. WOMAC function
Fig. I. WOMAC pain
* p = 0.047; ** p = 0.020
10
40
0
0
P
B
O
S
G
P
EA V
-10
-20
-30
-40
-50
B
O
S
G
-40
-80
PBO
-120
SG
-160
*
PBO
SG
**
-200
• Joint space narrowing after 3 years was significantly lower
for the glucosamine group compared to placebo.
™ Pavelka K. et al. Glucosamine sulfate as an osteoarthritits
disease-modifying agent:
a
confirmatory,
long-term,
randomized, placebo-controlled, independent study. Ann
Rheum Dis 2001; 60 (Suppl. 1): 57.
Table 1. Joint space measurement, Lequesne Index and WOMAC
scale at baseline and end of the study for both groups.
Joint space width (mm) at baseline
Joint space narrowing after 3 years (mm)
Lequesne index (baseline)
After 3 years
WOMAC index (baseline)
After 3 years
PBO
(N = 101)
SG
(N = 101)
3.59
- 0.19
8.9
-0.8
30.5
-4.9
3.97
+ 0.02** ♦
9.0
-1.7**
30.7
-8.0*
15
HYALURONIC ACID
ACID
HYALURONIC
HYALURONIC ACID ACTION MECHANISMS
STIMULATES
↑ HA
↑ GAGs
↑ TIMPs
EFFECT
- Anti-inflammatory
activity
- Improves synovial
fluid viscosupplementation
INHIBITS
↓ PGE2
↓ NO
↓ apoptosys
↓ free radicals
↓ leukocytes
proliferation, migration
and fagocytosis
↓counteracts some IL-1
effects
↓ Stromelysin (MMP-3)
16
™Altman R, Moskowitz R. Intraarticular sodium
hyaluronate (Hyalgan®) in the treatment of patients
with osteoarthritis of the knee: a randomized clinical
trial. The Journal of Rheumatology 1998; 25:11. (Impact
Factor 2.9)
Fig. 1. Mean pain that was experienced during a 50
foot walk
60
VAS pain (mm)
50
HA
Naproxen
40
30
20
10
0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
time (w eeks)
Reference study used to achieve Hyalgan® (HA)
approbation in the United States of America by the
FDA (Food and Drug Administration)
This large, controlled randomized clinical trial confirms that 5
weekly injections of Hyalgan® (HA) in patients with OA
of the knee are generally well tolerated, provide
sustained relief of pain and improved patient function,
and were at least as effective with fewer adverse
reactions as continuous treatment with naproxen for 26
weeks.
These results are not only due to temporary viscoelastic restoration and
give new evidences that HA is a useful tool to treat OA, with a
possible structure modifying activity.
17
HYALURONIC ACID ORALLY
HYAL-JOINT ™
ƒFood supplement
ƒComposition:
ƒHyaluronic acid (60%)
ƒHydrolyzed collagen
ƒOther glycosaminoglicans
ƒClinical trial: “A Randomized Double Blind Placebo Clinical Trial
Evaluating the Efficacy and Safety of Hyal-Joint™ Compared to Placebo for the
Improved of Quality of Life in Adults with Osteoarthritis of the Knee”.
- Significant improvement in the WOMAC-ADL and reduction in SF-Bodily Pain.
- Significantly lowers levels of Prostaglandin E2 (PGE2) in fibroblasts cells
cultured under conditions similar to those of inflammation.
Research center: Miami Research Associates
Principal investigator: Eric Sheldon, MD, FACR, Medical Director, Rheumatology
CONCLUSION
According to the reviewed literature we can
state that SYSADOAs are a good alternative
to NSAIDs and analgesics due to their high
efficacy and safety profile. Among them, CS
seems the most interesting product. CS
works at the three structures of the joint
(cartilage, subchondral bone and
synovium).
18
THANK YOU FOR
YOUR
ATTENTION
19