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WHAT IS NEW IN OSTEOARTHRITIS? SYSADOA CLINICAL REVIEW

Josep Vergés MD, MSc, PhD.

Clinical Pharmacologist,

Medical and Scientific Director,

Bioibérica S.A., Barcelona, Spain

Definition:Definition:It is a degenerative, inflammatory and chronic arthropathy that affects all joint structures (Hyaline cartilage, subchondral bone and synovial membrane).

WHAT IS OSTEOARTHRITIS?WHAT IS OSTEOARTHRITIS?

1. Metalloproteases (MMPs) 2. Citokines: IL-1, TNF-α3. NO and free radicals 4. PGE2

Toquero F, et al. evidencia Científica en Artrosis. Manual de Actuación. Madrid: IM&C,

2006.

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1. EDUCATION

2. DIET

3. EXERCISE

4. PHYSIC THERAPY

5. FOOTWEAR

6. HIDROTHERAPY

7. WALKING AIDS (INSOLES, WALKING STICK, ETC.)

THERAPEUTIC MEASURES

8. REHABILITATION

9. DRUGS:

- SYSTEMIC AND/OR TÓPICAL

-INTRA-ARTICULAR

10. JOINT LAVAGE

11. CHONDROCYTES TRANSPLANT

12. SURGERY

PHARMACOLOGICAL THERAPYPHARMACOLOGICAL THERAPY

Symptomatic effectSymptomatic effect

Structure Disease Modifying OsteoarthritisStructure Disease Modifying Osteoarthritis Drug Drug (S/DMOAD)(S/DMOAD)

per os Analgesics and NSAIDs

Corticoidsi.a

per os Chondroitin sulfate, glucosamine sulfate,Diacerein

i.a Hyaluronic acid 500-730 kDa

Slow(SYSADOA)

Fast

- Chondroitin sulfate - Glucosamine sulfate - Hyaluronic acid 500-730 kDa - Diacerein

Lequesne M, et al. J. Rheumatol 1994; 21 (Suppl. 41):65-71

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Symptomatic slow acting drugs for OA (SYSADOA) have a slow onset of action but have additional benefits such as globalefficacy 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), glucosaminesulfate (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.

INTRODUCTION:INTRODUCTION:

CHONDROITIN SULFATECHONDROITIN SULFATE

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STIMULATES:↑ proteoglycans↑ HA↑ Collagen type II

STIMULATES:↑ proteoglycans↑ HA↑ Collagen type II

EFFECT:-anti-inflammatory activity-Membrane stabilising action

EFFECT:-anti-inflammatory activity-Membrane stabilising action

INHIBITS:↓ cartilage degradative enzymes (collagenase,elastase, proteoglycanase, fosfolipase A2, N-acetylglucosaminidase, etc.) ↓ MMP-3 (Fig. I), MMP-2, MMP-9, MMP-14↓ free radicals, apoptosys, NO↓ IL-1↓ TNF-α↓ COX-2↓ NF-kB (Fig. II)

INHIBITS:↓ cartilage degradative enzymes (collagenase,elastase, proteoglycanase, fosfolipase A2, N-acetylglucosaminidase, etc.) ↓ MMP-3 (Fig. I), MMP-2, MMP-9, MMP-14↓ free radicals, apoptosys, NO↓ IL-1↓ TNF-α↓ COX-2↓ NF-kB (Fig. II)

CHONDROITIN SULFATE ACTION MECHANISMS1-4CHONDROITIN SULFATE ACTION MECHANISMS1-4

(1) Ronca F et.al. Osteoarthritis Cart 1998, 6 (Supplement A), 14-21. (2) Blanco FJ. et. al. Rev. Esp. Reumatol2001; 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.

p38 MAPKs

H2O2O2

•−

IL-1βTNF-α

RNAm

↑ NOS2↑ MMPs↑ COX2↑ PLA2↑ cytokines

NF-κB(p65/p50)

activation

translocationp65 p50

CD44

CS CS

FN-f

chondrocyte

CS

OA?

PGHAGAG

↓ IL-1β, TNF-α, MMPs, PLA2, COX2, PGE2, ON, apoptosys…

integrin α5β1

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In a rat model, CS reduced synovitis and articular cartilage destruction associated to chronic inflammation.

The results show that oral CS prevented articular cartilage destruction and reduced severity of poli-arthritis induced in rats.

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.

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.

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.

CLINICAL EVIDENCECLINICAL EVIDENCE

(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.

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CS may act as a structure disease modifying OA drug (S/DMOAD), that is, it may slow down disease progression16.

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.

2 clinical trials in hand OA concluded that disease progression was lower in CS-treated patients and less patients from this group developed erosive OA12-13.

S/DMOADS/DMOAD

(9). Uebelhart D, et.al. Osteoarthritis Cart 1998, 6, (Supplement A), 39-46. (10). Uebelhart D, et al. OsteoarthritisCart 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: 231-241. (16). Jordan KM, et al.Ann Rheum Dis 2003; 62:1145-1155

The tolerance of the product is very well documented; equivalent to PBO and much higher than that of SD14.

It is not metabolized by enzymes from cytochrome P450.

SAFETY PROFILESAFETY PROFILE

(14) Leeb F, et al. J. Rheumatol. 2000; 27: 1: 205 211.

It can not present drug interactions at this level

Pharmacosurveillance data from Europe, where no serious adverse events have been reported for more than 10 years, support the safety of the product.

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EULAR RECOMMENDATIONS 200318

Evidence based medicine

(18). Jordan KM, et al.Ann Rheum Dis 2003; 62:1145-1155.

(16). Jordan KM, et al.Ann Rheum Dis 2003; 62:1145-1155.

EULAR RECOMMENDATIONS 200316

Evidence based medicine

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Clinical efficacy on symptom reduction and improvement of functional capacity.

Persistent clinical effect after treatment suppression (evidenced for at least 3 months).

Greater safety than conventional therapy (analgesics, NSAIDs). It does not cause drug interactions.

CS ADVANTAGESCS ADVANTAGES

CONCLUSION CONCLUSION CS – effective

SYSADOA CS – effective

SYSADOA

No drug interactionsNo drug

interactions

3 month carry -over effect

3 month carry -over effect

Pharmacoeconomic advantages

Pharmacoeconomic advantages

No adverse effects

No adverse effects

Positive impact on disease progressionPositive impact on

disease progression

IDEAL PRODUCT FOR OA

TREATMENT

IDEAL PRODUCT FOR OA

TREATMENT

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The clinical trials mentioned before have been conducted with one specific CS formulation, which is approved as a drug in several European countries. 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. It has also been approved as a reference standard by the US Pharmacopeia for being the highest quality product in the market. For these reasons, this CS was the one chosen by the NIHfor its Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)17.

CLINICAL BIOEQUIVALENCE ICLINICAL BIOEQUIVALENCE I

(17). Jamie G. Barnhill et al. Chondroitin Product Selection for the Glucosamine/ChondroitinArthritis Intervention Trial. J Am Pharm Assoc. 2006;46:14–24.

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.It also evidenced that characteristics such as: molecular weight, flexibility of structure, sulfation and method of manufacture may influence oral absorption. Among all products compared, the one from Bioibérica evidenced the highest permeability rate.Different parameters have been established to determine CSbioequivalence21.

10.1 (± 0.6)8.73 (± 9.07)7.94 (± 7.35)0.00 (± 0.00)3.63 (± 2.07)1.03 (± 1.78)

A1

BCDEF

Permeability coefficient

(x 10-6) (n=3) (cm/sec)

Rawmaterial

1mol Wt = 16,900 dalton (95% Bioiberica)

CLINICAL BIOEQUIVALENCE IICLINICAL BIOEQUIVALENCE II

(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).

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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.

The Glucosamine / Chondroitin Arthritis Intervention Trial (GAIT)

SYMPTOMATIC PART RESULTS

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WOMAC PAIN SCORE

All randomized patients

Placebo 60.1% Celecoxib 70.1%**

Glucosamine 64.0% Chondroitin

sulfate 65.4%

G + CS 66.6%+ ** p= 0.008 CE vs P

+p= 0.09 G+CS vs P

•35% placebo was expected

•Patients with mild pain; “floor effect”

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

WOMAC pain 301-400 mm

Placebo 54.3% Celecoxib 69.4%¶

Glucosamine 65.7% Chondroitin

sulfate 61.4%

G + CS 79.2%# ¶p = 0.06 CE vs P

#p= 0.002 G+CS vs P

HIGHLY SIGNIFICATIVE WHILE CELECOXIB DOESN’T ACHIEVE SIGNIFICANCE

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.

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CS GRADE IIValor p Outcome K

L CS

N = 318 PBO

N = 313K L 2 v 3 CS v PBO

WOMAC subscales changes

2 -101.5 -90.3 0.0042 0.0907 Pain

3 -59.5 -80.4 2 -40.7 -37 0.0049 0.0271 Stiffness

3 -18.1 -35.7 2 -289.6 -218.6 0.0617

0.0100

Function

3 -160.3 -239.2 P value Outcome K

L CS

N = 318

PBO N = 313

K L 2 v 3

CS v PBO

Percentage of patients with swelling at end of follow-up

2 10.6 16.7 Swelling 3 15.0 24.2

0.0126

TREND

SIGNIFICANCE

SIGNIFICANCE

SIGNIFICANCE

Clegg DO, et al. Chondroitin sulfatemay have differential effects on OA symptoms related to degree of radiographic involvement. Osteoarthritis Cart 2005, 13 (Suppl. A), P.145: S 76.

JOINT EFFUSION

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.

CS reduces joint effusion very significantly at 6 months of treatment.

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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.

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GLUCOSAMINE SULFATEGLUCOSAMINE SULFATEGLUCOSAMINE SULFATE

EFFECT:- Anti-inflammatory activity- Membrane stabilising activity

EFFECT:- Anti-inflammatory activity- Membrane stabilising activity

INHIBITS:↓ cartilage degradative enzymes (collagenase,aggrecanase, phospholipase A2, etc.) ↓ MMP-3, MMP-2, MMP-9↓ free radicals↓ PGE2↓ IL-1↓ NF-kB

INHIBITS:↓ cartilage degradative enzymes (collagenase,aggrecanase, phospholipase A2, etc.) ↓ MMP-3, MMP-2, MMP-9↓ free radicals↓ PGE2↓ IL-1↓ NF-kB

STIMULATES:-↑ proteoglycansSTIMULATES:-↑ proteoglycans

GLUCOSAMINE SULFATE ACTION MECHANISMS

GLUCOSAMINE SULFATE ACTION MECHANISMS

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Reginster J.Y. et al. Long-term effects of glucosaminesulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. The Lancet 2001, 357 (9252): 251-256.

• Patients treated with glucosamine presentedsymptomatic improvement around 20-25%, compared toplacebo (Figs. I y II).

Fig. I. WOMAC pain

-50

-40

-30-20

-10

0

10

P B O S G

EAV

PBOSG

*

Fig. II. WOMAC function

-200

-160

-120

-80

-40

0

40

P B O S G

PBO

SG

**

* p = 0.047; ** p = 0.020

• Joint space narrowing after 3 years was significantly lower for the glucosamine group compared to placebo.

Pavelka K. et al. Glucosamine sulfate as an osteoarthrititsdisease-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.

PBO (N = 101)

SG (N = 101)

Joint space width (mm) at baseline 3.59 3.97 Joint space narrowing after 3 years (mm) - 0.19 + 0.02** ♦ Lequesne index (baseline) After 3 years

8.9 -0.8

9.0 -1.7**

WOMAC index (baseline) After 3 years

30.5 -4.9

30.7 -8.0*

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HYALURONIC ACIDHYALURONIC ACIDHYALURONIC ACID

HYALURONIC ACID ACTION MECHANISMS

EFFECT- Anti-inflammatory activity- Improves synovialfluid visco-supplementation

INHIBITS

↓ PGE2↓ NO↓ apoptosys↓ free radicals ↓ leukocytesproliferation, migration and fagocytosis↓counteracts some IL-1 effects↓ Stromelysin (MMP-3)

STIMULATES↑ HA↑ GAGs↑ TIMPs

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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

0

10

20

30

40

50

60

0 2 4 6 8 10 12 14 16 18 20 22 24 26

time (w eeks)

VAS

pain

(mm

)

HANaproxen

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.

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HYALURONIC ACID ORALLY HYAL-JOINT ™

Food supplement

Composition:Hyaluronic acid (60%)

Hydrolyzed collagen

Other glycosaminoglicans

Clinical 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 AssociatesPrincipal 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).

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