Two health claim petitions were submitted to FDA. One petition was
submitted on behalf of Weider Nutrition International, Inc. (petitioner
A) and the other was submitted on behalf of Rotta Pharmaceutical, Inc.
(petitioner B). The claims concerned the relationships between the
consumption of: (1) glucosamine and/or chondroitin sulfate and reduction
in the risk of: osteoarthritis; joint degeneration; and cartilage
deterioration (petitioner A), and; (2) crystalline glucosamine sulfate
and a reduced risk of osteoarthritis (petitioner B). The following is a
brief synopsis of the scientific data provided in the petitions, and the
conclusions reached by the petitioners. This synopsis is of the
petitions alone and does not include any FDA conclusions. The petitions
can be found in the appendix of the briefing book.

**I. Synopsis of Petitions** (Note: Letters "A" and "B" preceding
reference numbers correspond to the citations from petitioner A (Weider
Nutrition International, Inc.) and petitioner B (Rotta Pharmaceutical,
Inc.), respectively.)

**A. Substance**

Glucosamine is a glycoprotein derived from marine exoskeletons or
produced synthetically. It is sold as the sulfate sodium chloride
(sulfate) salt, hydrochloride (HCL) salt and N-acetyl-glucosamine. It is
an endogenous substance that is required for the synthesis of
glycoproteins, glycolipids, and glycosaminoglycans (also known as
mucopolysaccharides). These carbohydrate- containing compounds are found
in tendons, ligaments, cartilage, synovial fluid, mucous membranes,
structures in the eye, blood vessels, and heart valves.

Chondroitin sulfate belongs to a class of very large molecules called
glucosaminoglycans (GAGs), which are made up of glucuronic acid and
galactosamine. Chondroitin is manufactured from natural sources, such as
shark and bovine cartilage. Pure chondroitin is a relatively large
molecule, weighing about 16,900 daltons. The species or tissue of
origin, and the extraction method used, can affect the size of the
molecule.

**B. In vitro mechanistic data**

Studies in human and animal primary cell cultures, established cell
culture models, and tissue/organ cultures have reported various
biochemical effects following exposure to glucosamine sulfate,
glucosamine hydrochloride (HCl), and chondroitin sulfate. Preliminary
research suggests that glucosamine affects cytokine-mediated pathways
regulating inflammation and cartilage degradation and immune responses.
Glucosamine seems to inhibit interleukin 1-beta (IL-1β), thereby
reducing inflammation and cartilage degradation (A113/B8, A132, A133,
A134, A135, A136, A137, A138/B10, A139). Glucosamine reportedly
stimulated proteoglycan synthesis, which may also be through inhibition
of IL-1β (A14, A113B8, A132, A133, A138/B10, A140/B9, A142, A143, A144,
A148, A149). In addition, glucosamine reportedly possesses
immunomodulatory activity (A150, A151) and has been reported to be a
substrate for and stimulate new chondroitin sulfate synthesis (A113/B8,
A147).

Chondroitin sulfate has been reported to stimulate production of
proteoglycans (A142, A153, A155, A156, A157) and prevent cartilage
degradation (A153, A159, A165, A166, A172), possibly via inhibition of
IL-1β (A153, A158). Reports also suggest a role for chondroitin sulfate
in prevention of inflammation (A137, A160, A161) and immunomodulation
(A131, A165, A166, A167, A168, A169, A170).

**C. Animal models of OA**

Dietary glucosamine sulfate has been reported to reduce kaolin- and
adjuvant-induced tibio-tarsal arthritis in rats (A141) and
glucosamine-HCL, with and without chondroitin sulfate, was reported to
reduce cartilage degredation in a rabbit model of OA (A219). Consumption
of glucosamine-HCl has been reported to enhance the rate of new
articular cartilage proteoglycan synthesis in mice (A144). Diets
supplemented with chondroitin sulfates have been reported to prevent
articular cartilage degredation induced by chymopapin in rabbits (A162),
Freund's adjuvant in mice (A163) and in a rabbit surgical instability
model of OA (A219).

**D. Human clinical studies**

**1. Mitigation of Symptoms**

Relief of OA symptoms has been reported in OA patients taking
glucosamine hydrochloride, glucosamine sulfate, chondroitin sulfate, and
combination products of glucosamine plus chondroitin sulfate. The
majority of the studies are on glucosamine sulfate relieving the
symptoms of knee OA. Studies lasting from a few weeks to three years
have reported that oral glucosamine sulfate/hydrochloride, chondroitin
sulfate and their combination products can significantly improve
symptoms of pain and functionality indices in patients with
osteoarthritis (A111/B36, A173, A176/B25, A178/B32, A179/B26, A180/B16,
A181/B15, A182/B31, A185/B34, A186/B29, A192, A193, A196, A197, A205
A206, A207, A208, A211, A212, A213, A218, A220/B48, A221/B47, A227,
A228/B28, B27). Relief of OA symptoms by glucosamine and chondroitin
sulfate has been compared with the non-steroidal anti-inflammatory drugs
(NSAIDs) ibuprofen (A184/BB33, A185/B34, A186/B29, A187/B46), diclofenac
sulfate (A208) and naproxen (A215).

**2. Joint Degeneration and Cartilage Deterioration**

Radiographic evidence suggests that glucosamine sulfate and chondroitin
sulfate may slow joint degeneration in patients with osteoarthritis. OA
patients taking glucosamine sulfate for up to three years had
significantly less knee joint degeneration, less joint space narrowing,
and significant symptom improvement when compared with placebo
(A180/B16, A181/B15). Progression of knee joint space narrowing was
reportedly prevented in OA patients taking chondroitin sulfate for one
to three years when compared with placebo (A194, A207) or baseline
(A193, A205, A206).

Compared with placebo, consumption of chondroitin sulfate for three
years did not prevent development of OA in finger joints that were
non-affected at the start of the study, but a significant decrease in
the number of patients with new "erosive" OA finger joints was
reportedly observed (A198). In a separate two year study, chondroitin
sulfate plus naproxen did not prevent development of OA in finger joints
that were non-affected at the start of the study, but compared with
naproxen alone, a significant decrease in the number of joints with new
erosions was reportedly observed (A215).

Investigators have reported biochemical evidence from OA patients that
chondroitin sulfate may protect against cartilage and bone degradation.
Compared with placebo, one year treatment of OA patients with
chondroitin sulfate was reported to decrease markers of bone metabolism
(serum osteocalcin, urine pyridinoline/deoxypyridinoline) and cartilage
metabolism (serum keratin sulfate, cartilage oligometric matrix
protein[^1] (COMP)) (A193, A205). Compared with pre-treatment levels,
short term treatment (5-10 days) with chondroitin sulfate elevated
synovial fluid proteoglycan and hyaluronic acid levels and decreased
collagenolytic activity, phospholipase A2 and N-acetylglucosaminidase
(A119/B49, A131).

**II. Petitioners\' Conclusions (see Appendix for copies of the
petitions)**

**A. Petitioner A (Weider Nutrition International, Inc.)**

The following conclusions are found on page 23 of petitioner\'s Exhibit
1 (scientific summary) submitted by petitioner A.

1.  Maintaining the structural and functional integrity of the
    proteoglycan component of the extracellular matrix of articular
    cartilage is required for preservation of healthy joint architecture
    and biomechanics.

2.  Imbalanced metabolism favoring catabolism within the extracellular
    matrix of articular cartilage produces degenerative changes in the
    proteoglycan composition of the matrix.

3.  Compromise of the structural and functional integrity of the
    proteoglycan component of the extracellular matrix of articular
    cartilage results in net loss of articular cartilage tissue,
    inferior biomechanical competence and structural defgormation of
    jopint architecture.

4.  Net degredation of the extracellular matrix of articular cartilage,
    accompanied by the production of spontaneous repair matrix with
    abnormal proteoglycan composition, results in asymptomatic
    subclinical osteoarthritic change.

5.  The progression of degenerative asymptomatic osteoarthritic change
    to osteoarthritis is not inevitable.

6.  The progression of degenerative osteoarthritic change is required in
    order for abnormalities in articular cartilage composition and
    structure to progress to osteoarthritis.

7.  Osteoarthritic change in the absence of joint pain represents a
    modifiable risk factor for later development of osteoarthritis.

8.  Dietary supplementation with D-glucosamine, glucosamine-HCL,
    glucosamine sulfate or chondroitin sulfate contributes to the
    preservation of articular cartilage, inhibits the initiation of
    osteoarthritic change in articular cartilage and inhibits the
    progression of osteoarthritic change to symptomatic osteoarthritis.

9.  Dietary supplementation with D-glucosamine, glucosamine-HCL,
    glucosamine sulfate or chondroitin sulfate is an effective modifier
    of osteoarthritic change and reduces the risk for osteoarthritis.

**B. Petitioner B (Rotta Pharmaceutical, Inc.).**

The following conclusions are found on pages 5 and 45 of the petition.

> "The scientific evidence in this Petition convincingly establishes
> that crystalline glucosamine sulfate, when given to individuals
> diagnosed with osteoarthritis, can prevent further joint degradation,
> can reverse the symptoms by minimizing the inflammation and restoring
> articular cartilage, can reduce joint pain and can result in increased
> joint function. Given the physiological mechanism of action of
> crystalline glucosamine sulfate and other factors, there also are
> sufficient data demonstrating the ability of crystalline glucosamine
> sulfate to be effective in reducing the risk of developing
> osteoarthritis." (page 5)
>
> "The preventative effects of crystalline glucosamine sulfate in this
> patient population with "mild osteoarthritis," a patient population
> very similar to the "healthy population," combined with the well-known
> mechanism of action for crystalline glucosamine sulfate support the
> ability of crystalline glucosamine sulfate to be effective in
> preventing the onset of osteoarthritis." (page 45)

[^1]: Not clearly identified as serum or urine COMP levels.