1. 1 GLUCOSAMINE AND CHONDROITIN SULFATE REDUCE RISK OF OSTEOARTHRITIS Luke R. Bucci, PhD Vice President, Research Weider Nutrition Group Salt Lake City, UT Human tracheal cartilage – Bailey’s Textbook of Histology 1948, p.108

2. 2 This presentation will: Review the need for reducing risk of osteoarthritis (OA) List the proposed Health Claims Review roles of Glucosamine and Chondroitin Sulfate in reducing OA risk Explain credible evidence supporting claims

3. 3 OSTEOARTHRITIS IMPACT “Arthritis is the leading cause of disability in the United States.” $86B

4. 4 GLUCOSAMINE & CHONDROITIN REDUCE RISK OF OA - PROPOSED HEALTH CLAIMS 1.Glucosamine may reduce the risk of osteoarthritis (OA). 2.Chondroitin sulfate may reduce the risk of OA. 3.Glucosamine may reduce the risk of joint degeneration. 4.Chondroitin sulfate may reduce the risk of joint degeneration. 5.Glucosamine may reduce the risk of cartilage deterioration. 6.Chondroitin sulfate may reduce the risk of cartilage deterioration.

5. 5 ILLUSTRATIONS: JOINT CARTILAGE (Visual references for Glucosamine and Chondroitin Sulfate Roles)

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9. 9 Lifespan of aggrecan PG in adult human cartilage is 600-1000 days

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12. 12 HUMAN SUPPLEMENTATION STUDIES WITH GLUCOSAMINE AND CHONDROITIN SULFATE: APPLICABILITY TO RISK REDUCTION

13. 13 SUPPLEMENTATION TRIALS IN OA: APPLICABILITY TO RISK REDUCTION Cartilage tissue turnover is constant and ongoing, but normally at a slow rate (half-life of aggrecan and collagen is 1-2 years) Normal “wear and tear” produces degraded fragments constantly (free radicals, shear stress) Cartilage responds to molecular pieces of most exposed macromolecular constituents (hyaluronan, chondroitin) to monitor structural integrity via CD36, CD44 receptors

14. 14 SUPPLEMENTATION TRIALS IN OA: APPLICABILITY TO RISK REDUCTION Joint tissues can only maintain themselves and resist degradation only by biosynthesis of more matrix The only way joint tissues can make more matrix is to utilize Glucosamine and manufacture more Chondroitin Biosynthesis of Chondroitin is essential to maintenance and thus, prevention of joint deterioration

15. 15 SUPPLEMENTATION TRIALS IN OA: APPLICABILITY TO RISK REDUCTION “The integrity of this matrix is critical for the unique biochemical properties of hyaline cartilage and depends on a maintenance of the quantity and quality of the matrix components. Such maintenance must be the result of a balance between synthetic and degradative processes within the tissue. Thus, any loss of, e.g., proteoglycan from the cartilage matrix due to physiologic or pathologic processes must be balanced by de novo synthesis of proteoglycans by the chondrocytes.” Lohmander LS, Kimura JH. Biosynthesis of cartilage proteoglycan. In Articular Cartilage Biochemistry, Kuettner K, et al, Eds., Raven Press, New York, 1986, p. 93.

16. 16 SUPPLEMENTATION TRIALS IN OA: APPLICABILITY TO RISK REDUCTION Same biochemical, regulatory, cellular, biosynthetic, anabolic, catabolic, metabolic mechanisms are operative in cartilage whether condition is perfect health or OA Maintenance of cartilage consists of the same processes and events that occur during normal wear and tear, during normal aging and in diagnosed OA

17. 17 SUPPLEMENTATION TRIALS IN OA: APPLICABILITY TO RISK REDUCTION There is an unbroken continuum of events in cartilage from health to degenerative disease Therefore, there is no agreed-upon threshold or marker that clearly defines the onset of OA

18. 18 SUPPLEMENTATION TRIALS IN OA: APPLICABILITY TO RISK REDUCTION Considerable overlap for biomarkers and appearance of cartilage exists between healthy controls and OA subjects Same type and extent of imbalance between matrix component synthesis and degradation can be seen in “healthy” and “osteoarthritic” subjects

19. 19 SUPPLEMENTATION TRIALS IN OA: APPLICABILITY TO RISK REDUCTION OA diagnosis based on clinical signs (pain, stiffness) and X-ray evidence of structural changes in joints (Kellgren-Lawrence staging) Staging is arbitrary and subjective Human studies with OA subjects have examined a portion of the continuum of joint health Pre-diagnostic joint damage must exist in greater incidence than diagnosed OA (i.e., damage does not start the day before diagnosis)

20. 20 SUPPLEMENTATION TRIALS IN OA: APPLICABILITY TO RISK REDUCTION Normal aging shows loss of Chondroitin in cartilage and hyaluronan in synovial fluid Normal aging shows decrease in length of Chondroitin and proteoglycans synthesized routinely for upkeep Normal aging shows decrease of chondroitin, water and size in cartilage

21. 21 SUPPLEMENTATION TRIALS IN OA: APPLICABILITY TO RISK REDUCTION OA results from an imbalance of normal anabolic and catabolic activities in cartilage OA = deficiency of normal regulation of cartilage maintenance

22. 22 SUPPLEMENTATION TRIALS IN OA: APPLICABILITY TO RISK REDUCTION Both Glucosamine and Chondroitin Sulfate help regulate (normalize) cartilage maintenance Maintenance of normal balance of anabolic & catabolic actions = return towards health, reducing risk of OA

23. 23 GLUCOSAMINE

24. 24 GLUCOSAMINE FACTS RELEVANT TO RISK REDUCTION Availability of Glucosamine is the key, rate-limiting step for synthesis of connective tissue macromolecules Preformed Glucosamine is preferred 300% over glucose for GAG synthesis

25. 25 GLUCOSAMINE – TYPES OF PUBLISHED EVIDENCE Type of SubstantiationNumber of Publications Consensus Statement 4 supportive 1 nonsupportive Independent expert opinions (reviews) 43 supportive 14 nonsupportive Meta-Analyses 14 supportive 0 nonsupportive Large, Well-Designed Human Clinical Trials 12 (18) supportive 2 (3) nonsupportive Smaller, Well-Designed Human Clinical Trials 13 (13) supportive 4 (5) nonsupportive Uncontrolled Human Clinical Trials 29 supportive 4 nonsupportive Animal Intervention Studies 20 supportive 3 (4) nonsupportive In Vitro Studies 45 supportive 9 nonsupportive Total 180 (186) supportive 33 (36) nonsupportive

26. 26 BIOMARKERS AFFECTED BY GLUCOSAMINE Biosynthesis of HA, GAGs, collagen –aminosugar unit precursor –preferred substrate - 300% better than glucose Biosynthesis of HA, GAGs, collagen –enhanced production, gene expression –regulatory Biological Response Modifier

27. 27 BIOMARKERS AFFECTED BY GLUCOSAMINE Inhibition of cartilage breakdown –Prevention of joint space loss in knee OA (humans) –Correlation of keratan sulfate with radiologic image (humans) –Prevention of joint degeneration in healthy animals induced to become osteoarthritic –In vitro cartilage cultures – direct addition Inhibition of degradative enzymes –In vitro: Matrix metalloproteinase expression Collagenase

28. 28 BIOMARKERS AFFECTED BY GLUCOSAMINE Antiinflammatory effects –Animal models of acute inflammation –Counteracts IL1-beta proteoglycan loss via NF K B –Decreases levels and/or expression of inflammatory cytokines, COX2, PGE 2, PLA 2 –Synergy with NSAIDs

29. 29 BIOMARKERS AFFECTED BY GLUCOSAMINE Downregulates inducible nitric oxide Antioxidant protective effects Immune modulation –Reduces T-cell activation & reactivity –Reduces neutrophil chemotaxis, outputs

30. 30 CHONDROITIN SULFATE

31. 31 CHONDROITIN – TYPES OF PUBLISHED EVIDENCE Type of Substantiation# Consensus Statement 4 supportive 0 nonsupportive Independent expert opinions (reviews) 103 supportive 10 nonsupportive Meta-Analyses 8 supportive 0 nonsupportive Large, Well-Designed Human Clinical Trials 18 (27) supportive 0 nonsupportive Smaller, Well-Designed Human Clinical Trials 14 (15) supportive 1 nonsupportive Uncontrolled Human Clinical Trials 35+ supportive 3 nonsupportive Animal Intervention Studies 13 supportive 3 (4) nonsupportive In Vitro Studies 51 supportive 3 nonsupportive Total 246 (256) supportive 20 (21) nonsupportive

32. 32 BIOMARKERS AFFECTED BY CHONDROITIN Biosynthesis of HA, GAGs proteoglycans, collagen in joints –aminosugar unit precursor –enhance production (regulatory) –upregulation of gene expression

33. 33 BIOMARKERS AFFECTED BY CHONDROITIN Inhibition of cartilage breakdown –Prevention of new lesions in finger OA –Prevention of joint space loss in knee OA –Decrease in biomarkers of cartilage loss: cartilage oligomeric protein, keratan sulfate, urine pyridinoline/creatinine ratio, urine deoxypyridinoline/creatine ratio in humans –Prevention of joint degeneration in healthy animals induced to become osteoarthritic –In vitro cartilage cultures – direct addition (sizes)

34. 34 BIOMARKERS AFFECTED BY CHONDROITIN Inhibition of degradative enzymes –Human synovial fluid –In vitro: Aggrecanase Elastase Hyaluronidase Lysosomal enzymes (mixtures) – pH Cathepsin B release Matrix metalloproteinases

35. 35 BIOMARKERS AFFECTED BY CHONDROITIN Tensegrity (mechanostructural) Immune modulation –Block complement, receptors –Slow neutrophil chemotaxis –Inhibit lysosomal content release –Protect other cytokines or regulatory molecules –Enhance cytokine secretion by macrophages

36. 36 BIOMARKERS AFFECTED BY CHONDROITIN Downregulates inducible nitric oxide Antioxidant protective effects Antiinflammatory effects –Animal models of acute inflammation –Counteracts IL-1β-induced loss of proteoglycans –Decreases levels and/or expression of inflammatory cytokines

37. 37 SUMMARY OF EVIDENCE

38. 38 ORAL BIOAVAILABILITY OF GLUCOSAMINE AND CHONDROITIN Glucosamine in all its forms is readily absorbed almost entirely, and some is incorporated into joint tissues. Chondroitin is absorbed into the blood stream to 7-70% of an oral dose. Chondroitin is absorbed as intact chains and a spectrum of fragments down to monomers. Some chondroitin fragments are partially desulfated. Absorption and uptake into joint tissues has been confirmed for both Glucosamine and Chondroitin.

39. 39 ECONOMIC IMPACT OF CHONDROITIN 11000 subjects taking Chondroitin resulted in decreased NSAID use (63-85%) “The cost related to CS 4&6 treatment was compensated for by the reduction in physiotherapy costs and by fewer co- prescriptions for gastroprotective drugs.” –Henry-Launois B. Evaluation of the use and financial impact of Chondrosulf 400 in current medical practice. Litera Rheumatol 1999; 24:49-51. –Conrozier T. Les chondroitines sulfates (CS 4&6): schema d’utilisation et impact economique. [Chondroitin sulfate (CS 4&6): practical applications and economic impact.] Presse Med 1998 Nov21; 27(36):1866-1868. Chondroitin use has beneficial economic impact

40. 40 HUMAN STUDIES OF OA: APPLICABILITY TO PREVENTION Both Glucosamine and Chondroitin prevented loss of cartilage over time Earlier stages of OA showed larger effects, indicating prevention of progression over treatment of symptoms Effects were long-lasting after cessation of administration

41. 41 BIOMARKER SUMMARY Both Glucosamine and Chondroitin affect many biomarkers known to cause, promote or exacerbate joint degeneration Biomarker effects illustrate overlapping and unique properties of each nutrient Biomarkers correlated with signs and symptoms of joint degeneration

42. 42 ANIMAL MODELS OF OA: APPLICABILITY TO PREVENTION Multiple methods of rapid induction of joint degeneration all produce same end result Glucosamine and Chondroitin administered before or during the induction of joint degeneration lessen the end result = prevention Relatively large intakes reflect relatively rapid onset of degeneration and extreme response of tissues Mechanisms of induction & biological response remain same whether onset is rapid or gradual

43. 43 IN VITRO STUDIES: APPLICABILITY TO PREVENTION In vitro studies have found multiple potential mechanisms of action for Glucosamine and Chondroitin These mechanisms exist and are operative in vivo Concentration dependency indicates effects at low doses seen in vivo.

44. 44 CONCLUSIONS

45. 45 GLUCOSAMINE & CHONDROITIN REDUCE RISK OF OA Data from all types of publications is extensive, reproducible and consistent for benefits supporting prevention of joint degeneration Time course of human findings fits the mechanisms of improving regulation of anabolic/catabolic ratio of joint tissues

46. 46 GLUCOSAMINE & CHONDROITIN REDUCE RISK OF OA Glucosamine supplementation has been shown to prevent progression of joint deterioration in human studies Chondroitin supplementation has been shown to prevent progression of joint deterioration in human studies Animal studies have shown prevention of progression of joint deterioration when given before stress

47. 47 GLUCOSAMINE & CHONDROITIN REDUCE RISK OF OA Glucosamine and Chondroitin have the ability to prevent joint deterioration and joint degeneration by all lines of evidence, and thus, reduce the risk of osteoarthritis (which is the progression of joint deterioration and degeneration)

48. 48 THANK YOU