Glucosamine and OsteoarthritisKatarina Brown, Zach DeLanoit, Sharon Huang

Background

● Osteoarthritis affects over 20 million Americans and expected to double over the next two decades

● Difficult to diagnose and treat

● Glucosamine is one of the most widely used supplements in osteoarthritis (sulfate salt, hydrochloride salt, N-acetyl-glucosamine)

● May come as a combination with chondroitin, hyaluronan, cetyl myristoleate, methylsulfonylmethane

● Global glucosamine market valued at $2 billion in 2008

Clegg DO, et al. Glucosami3;354(8):795-808. PubMed PMID: 16495392.

(http://www.nutraingredients-usa.com/Markets/Why-US-glucosamine-sales-are-slow)ne, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006 Feb 2

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Hypothesis

Does glucosamine work by placebo effect?

● Is orally administered glucosamine therapeutically active in the management of osteoarthritis?

● Are manufactures misleading consumers about glucosamine?● How is arthritis relief measured?● Do industry and medicine influence patient habits?

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Glucosamine Products•Daily dose: 1500 mg

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ADME •Bioavailability: low (26% in humans with oral dosing)1

•Absorption: low absorption from small intestine (minor site for GLUT2)2,3

•Distribution: must localize in joints after first pass metabolism4

•Metabolism and Elimination: extensive by first pass effect into CO2, H2O, and urea5

Barclay et al., 1998Physicians Desk Reference, 2001

3. Freeze and Elbein, 20094. Mroz and Silbert, 2004

Coates et al., 2005

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Glycosaminoglycan Biosynthesis• Hyaluronan: forms cartilage; involved in protein interaction influencing

angiogenesis, cell motility, adhesion, wound healing, and cancer6

• Chondroitin sulfate: binds water for form interstitial fluid between cells6

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Structure of Glucosamine

6. Ashry et al., 2007

Safety•Rates of AE similar compared to placebo, fewer compared to

NSAIDs•AE: constipation, diarrhea, dyspepsia, nausea, vomiting,

headache, insomnia, somnolence

•DDI are possible but studies inconclusive: anticoagulants, chemotherapy agents, pain medication, diabetes medications7,8

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Market●  Global glucosamine demand:

25,582 tons in 2013 [1]

○ Expected to reach: ■ 63,789 tons by 2020 → CAGR of

14% from 2014 to 2020 [1]; 1,246 million USD

●U.S. = largest regional market for glucosamine [2]

● Accounting for more than 30% of global demand in 2013 [2]

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1. Grand View Research Inc. | Oct 08, 2014. "Global glucosamine market to hit $1.2 billion by 2020." New Hope Network. N.p., 02 Aug. 2016. Web.2. Research, Grand View. "Glucosamine Market Worth Will Grow To $1,246.4 Million From 2014 To 2020: New Report By Grand View Research, Inc." GlobeNewswire News Room. N.p., 19 Nov. 2014.

Glucosamine Products

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Rexall Sundown Class Action Settlement● “Plaintiffs allege certain statements made on labeling of

certain products are false, deceptive and misleading”

● Rexall Sundown denies any wrongdoing or liability

● Labeling changes○ Will not make the same statements on any products

moving forward

●Statements shift toward joint space narrowing

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Rexall Glucosamine Settlement. N.p., n.d. Web.

Joint Space Narrowing

● Difficulty is assessment and diagnosis of osteoarthritis

● Knee pain and disability also influenced by psychosocial status and muscle strength

● Lack of association between joint space narrowing and osteoarthritis progression

Szebenyi B, Hollander AP, Dieppe P, Quilty B, Duddy J, Clarke S, Kirwan JR. Associations between pain, function, and radiographic features in osteoarthritis of the knee. Arthritis Rheum. 2006 Jan;54(1):230-5. PubMed PMID: 16385522Poinier, MD, Anne C., and Stanford M. Shoor, MD. "X-Ray of Osteoarthritis of the Knee." WebMDwww.webmd.com/osteoarthritis/x-ray-of-osteoarthritis-of-the-knee. 11

Influence of Practitioners

● Questionnaire sent to rheumatologists

● Published in 2010 (GAIT Trial 2006)

● 2007 Osteoarthritis Research Society International guidelines list glucosamine as non-pharmacological treatment

● Products available widely, especially in pharmacies

● Many practitioners would still recommend

Manek NJ, Crowson CS, Ottenberg AL, Curlin FA, Kaptchuk TJ, Tilburt JC. What rheumatologists in the United States think of complementary and alternative medicine: results of a national survey. BMC Complementary and Alternative Medicine. 2010;10:5. doi:10.1186/1472-6882-10-5. 12

GAIT Trial● Largest trial evaluating glucosamine to

date

● Double-blinded randomized multi-center trial

● Comparators: glucosamine, chondroitin, glucosamine and chondroitin, celecoxib, and placebo

● Primary outcome: 20% decrease in knee pain by week 24

● No statistically significant difference in pain reduction between any agent

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. PubMed PMID: 16495392.

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Conclusion

● Does glucosamine work by placebo effect?○ Bioavailability of glucosamine is low, and it is not a precursor to cartilage synthesis○ Progression and treatment of osteoarthritis are difficult to measure○ Placebo has been shown to have an effect in treating osteoarthritis, but it may be due to false

marketing by industry and a reluctance to disparage glucosamine in medicine○ Glucosamine market is large and expected to continue to grow

● Glucosamine’s role in treating osteoarthritis may be a placebo effect.

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