GLUCOSAMINE AND CHONDROITIN SULFATE REDUCE RISK OF OSTEOARTHRITIS

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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 Baileys Textbook of
Histology 1948, p.108
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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

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OSTEOARTHRITIS IMPACT
Arthritis is the leading cause of disability in
the United States.
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GLUCOSAMINE CHONDROITIN REDUCE RISK OF OA -
PROPOSED HEALTH CLAIMS

• Glucosamine may reduce the risk of osteoarthritis
  (OA).
• Chondroitin sulfate may reduce the risk of OA.
• Glucosamine may reduce the risk of joint
  degeneration.
• Chondroitin sulfate may reduce the risk of joint
  degeneration.
• Glucosamine may reduce the risk of cartilage
  deterioration.
• Chondroitin sulfate may reduce the risk of
  cartilage deterioration.

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ILLUSTRATIONSJOINT CARTILAGE(Visual
references for Glucosamine and Chondroitin
Sulfate Roles)
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Lifespan of aggrecan PG in adult human cartilage
is 600-1000 days
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HUMAN SUPPLEMENTATION STUDIES WITH GLUCOSAMINE
AND CHONDROITIN SULFATEAPPLICABILITY TO RISK
REDUCTION
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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

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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

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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.
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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

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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

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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

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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)

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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

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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

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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

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GLUCOSAMINE
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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

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GLUCOSAMINE TYPES OF PUBLISHED EVIDENCE
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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

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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

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BIOMARKERS AFFECTED BY GLUCOSAMINE

• Antiinflammatory effects
• Animal models of acute inflammation
• Counteracts IL1-beta proteoglycan loss via NFKB
• Decreases levels and/or expression of
  inflammatory cytokines, COX2, PGE2, PLA2
• Synergy with NSAIDs

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BIOMARKERS AFFECTED BY GLUCOSAMINE

• Downregulates inducible nitric oxide
• Antioxidant protective effects
• Immune modulation
• Reduces T-cell activation reactivity
• Reduces neutrophil chemotaxis, outputs

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CHONDROITIN SULFATE
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CHONDROITIN TYPES OF PUBLISHED EVIDENCE
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BIOMARKERS AFFECTED BY CHONDROITIN

• Biosynthesis of HA, GAGs proteoglycans, collagen
  in joints
• aminosugar unit precursor
• enhance production (regulatory)
• upregulation of gene expression

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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)

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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

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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

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BIOMARKERS AFFECTED BY CHONDROITIN

• Downregulates inducible nitric oxide
• Antioxidant protective effects
• Antiinflammatory effects
• Animal models of acute inflammation
• Counteracts IL-1ß-induced loss of proteoglycans
• Decreases levels and/or expression of
  inflammatory cytokines

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SUMMARY OF EVIDENCE
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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.

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ECONOMIC IMPACT OF CHONDROITIN

• 11000 subjects taking Chondroitin resulted in
  decreased NSAID use (63-85)
• The cost related to CS 46 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
  2449-51.
• Conrozier T. Les chondroitines sulfates (CS 46)
  schema dutilisation et impact economique.
  Chondroitin sulfate (CS 46) practical
  applications and economic impact. Presse Med
  1998 Nov21 27(36)1866-1868.
• Chondroitin use has beneficial economic impact

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HUMAN STUDIES OF OAAPPLICABILITY 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

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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

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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

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IN VITRO STUDIESAPPLICABILITY 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.

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CONCLUSIONS
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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

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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

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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)

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