Glucosamine and Chondroitin has received a great deal of popular attention as cartilage “vitamins.”  They have been used in the veterinary industry for decades and are considered effective in animals.  A popular book in the 90’s touted these supplements as an “arthritis cure.” Unfortunately, this claim has not been substantiated in the scientific literature. 

Listed below are a number of the more important scientific articles that we have reviewed at VCC on this matter. There are 3 types of studies when evaluating the success or failure of these supplements; 1) clinical studies in which patients grade their pain and function while taking the supplements as compared to a placebo group, 2) studies which show evidence of cartilage re-growth, i.e., by X-ray or MRI, or lab-animal evidence, and 3) laboratory studies that show a positive effect on cartilage at a molecular level. 

1) While some clinical studies do show an improvement in pain and function with the use of glucosamine and chondroitin, an equal number of studies show no benefit when compared to placebo.  This ratio of success to failure in the literature generally mimics what we have found in our patients at VCC, which is to say, a subset of patients do see improvement with this supplement but this outcome is not consistent across all patient groups.
 
2) There are no reproducible studies that demonstrate cartilage re-growth as a result of taking nutritional supplements.  However, some studies have shown a delay in Xray progression of OA after 2 to 3 years of usage.

3) There are a number of well-done laboratory studies that demonstrate a potentially positive metabolic effect on cartilage.
In the paragraphs below we have attempted to simply the analysis by color-coding positive results in green and negative outcomes as blue.

What is it?
Glucosamine is naturally occurring in the body and is also a dietary supplement derived from the shells (chitin) of shellfish. It is marketed for its ability to support the structure and function of joints. The target market is people suffering from osteoarthritis. It is commonly sold as glucosamine sulfate and glucosamine hydrochloride. Glucosamine is a precursor for glycosaminoglycans, which are key elements of joint cartilage.  In theory, oral glucosamine is incorporated into the structure of cartilage and/or contribute to the modulation of cartilage production.  Therefore it may help to prevent cartilage degeneration for patients suffering from osteoarthritis.

How does it work?
The mechanism of action is yet to be clearly defined.  Glucosamine is a normal constituent of glycosaminoglycans in normal cartilage matrix and synovial fluid. Glucosamine has been shown to stimulate cultured human chondrocytes to synthesize proteoglycans, inhibit the action of catabolic enzymes, and reduce levels of IL-1 in synovial fluid. 

It has been suggested that glucosamine may make synovial fluid thick and gelatinous so that it holds more water, which aids in shock absorption and decreasing friction in the joints thereby reducing pain. Glucosamine may also help to prevent the breakdown of proteoglycans which are proteins made of chains of glycosaminoglycans. 

Largo et al (2002) studied cultured cells from arthritic knees and found that glucosamine sulfate modulated pro-inflammatory genes and their products.  They concluded that GS was a “symptom- and structure-modifying drug in the treatment of OA.”

There have been studies that show that glucosamine can get to the synovial fluid of the joint.  Meulyzer et al (2008) looked at the levels of glucosamine HCL in the joint fluid of horses after oral administration and compared these levels in normal and inflamed joints.  They found significantly higher amounts of glucosamine in the inflamed joints compared to the control group.

Dosage
Most but not all studies seem to support glucosamine sulfate over glucosamine HCL.  Both glucosamine sulfate and glucosamine hydrochloride may be taken in doses of 500mg three times daily for 90 days; or a once daily dose of 1.5g.  Patients over 200lbs may take up to 2500mg per day. The supplement is available in a capsule, tablet and powder form.  It can take up to two months for glucosamine to take full effect so it is recommended that you take it at least two to three months.  Some doctors suggest taking it indefinitely if it is helping and there are no serious adverse effects.  It seems reasonable that after 90days, you may want to titrate down the amount of drug to the least amount that controls your symptoms, such as pain.

Efficacy
R.M. Rozendaal et al (2008, OA and C) found that glucosamine sulfate is not more effective than placebo for treatment of hip osteoarthritis. They based these findings on radiographic imaging, pain, and use of pain medication.  They found that it was not effective at decreasing symptoms or at preventing the progression of the OA.

Rindone et al performed randomized double-blind study of glucosamine vs. placebo for the treatment of knee OA and found glucosamine to be no more effective than the placebo.

Wilkens et al (2010, JAMA) assessed the effect of glucosamine on patients with chronic low back pain.  A total of 250 subjects were studied for 6 months, half were the placebo group.  Taking glucosamine did not demonstrate a reduction in pain or disability.

Pavelka et al (2002) performed a double-blind study in 200 patients with mild to moderate knee arthritis.  At 3 years follow-up, patients in the placebo group demonstrated a small (.19mm) progression in joint space narrowing, while no progression of disease was seen in the glucosamine sulfate group (dose 1500mg once daily).  Symptoms of pain and function (WOMAC score) improved modestly in the placebo group and 20% in the glucosamine group. 

Lee et al (2009, Rheum Int.) did a meta-analysis if 6 studies involving 1,502 cases.  Glucosamine sulfate did not show a significant effect versus controls on X-ray joint space narrowing over the first year of treatment.  However, after 3 years of treatment, glucosamine sulfate revealed a small to moderate effect on joint space narrowing.  The authors concluded that glucosamine might delay radiological progression of OA of the knee after daily administration for 2 to 3 years. A prescription form of the drug (Rotta Pharmaceuticals, 1500mg) was used.

The GAIT study (2006, NEJM). 

Glucosamine is not approved by the FDA in the United States and is therefore a supplement. Supplement manufacturers are not required to prove the safety and efficacy of their product as long as they don’t market it as a treatment for a condition.  Glucosamine is considered safe for use as long as one doesn’t take more than the recommended dose. 

Side Effects
Some mild side effects include diarrhea, upset stomach, headache, and rash.
In Europe glucosamine sulfate is approved by the FDA as a medical drug for the treatment of osteoarthritis. On a scale of zero to one hundred, with one hundred being toxic; the task force of the European League Against Rheumatism rated glucosamine sulfate a five.  It is felt to be a relatively safe medication.

What is it?
Chondroitin Sulfate is also naturally found in the joints of the body. It is a major component of the matrix of connective tissue. In cartilage, high levels of chondroitin can create increased osmotic pressure that expands the matrix and places the collagen network under tension. Additionally. Chondroitin sulfate may help prevent proteolytic enzymes from breaking down cartilage. It can be taken in the form of a supplement and is often derived from animal cartilage, in particular that from cows. It is often used in conjunction with glucosamine sulfate.

Dosage
The typical dose of chondroitin sulfate used to treat osteoarthritis is 200-400 mg 2-3 times daily or a once daily dose of 1,000-1,200 mg. It may take 8 to 12 weeks to reach the full effects of chondroitin. At this point a maintenance dose of approximately 2/3 the starting dose is recommended.

Side Effects
Side effects of the supplement seen occasionally are nausea, stomach pains, diarrhea, constipation, and rare reports of hair loss, irregular heartbeat and leg swelling. It is felt to be a relatively safe medication.

Efficacy
Uebelhart et al (2004) performed a randomized, double blind, placebo controlled study evaluating the effectiveness of chondroitin in treating knee OA.  They found chondroitin to be more effective than placebo.  After one year radiographical images of patients’ knees in the placebo group showed the OA had progressed while the OA in patients in the chondroitin group did not.

Lee et al (2009, Rheum Int.) did a meta-analysis if 4 studies involving 1,502 cases. Chondroitin sulfate did not show a significant effect versus controls on X-ray joint space narrowing over the first year of treatment.  However, after 2 years of treatment, chondroitin revealed a small but significant protective effect on joint space narrowing.  The authors concluded that chondroitin might delay radiological progression of OA of the knee after daily administration for 2 to 3 years.  A prescription form of the drug (Rotta Pharmaceuticals, 800mg) was used.

Gabay et al (2011, Arthritis and Rheumatism) performed a randomized, double blind study of 163 patients with symptomatic hand OA taking chondroitin sulfate, 800mg once daily for 6 months.  Decrease in hand pain and morning stiffness was significantly more pronounced in the chondroitin sulfate group over the placebo group, Hand function improved significantly in the chondroitin group as well.  There was no difference in grip strength between the 2 groups.

The GAIT study (2006, NEJM).  See below

Glucosamine and chondroitin sulfate are commonly taken in combination. They may be more effective when taken in combination than when taken separately.

McAlindon et al (JAMA, 200) performed a Meta-analysis of the 37 clinical studies performed from 1966 to 1999, of which 15 met their criteria.  They concluded, “Trials of glucosamine and chondroitin preparations for OA symptoms demonstrate moderate to large effects, but quality issues and likely publication bias suggest that these effects are exaggerated”.  Nevertheless, some degree of efficacy appears probable for these preparations.

The GAIT study (2006, NEJM).

Clegg et al performed perhaps the most important study of GS and CS, known as the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT). The authors studied 1583 patients with knee arthritis assigned to 5 groups; 1) glucosamine 1500mg daily, 2) chondroitin sulfate 1200mg daily, 3) both drugs combined, 4) 200mg of Celebrex daily, or 5) placebo.  Treatment period was 24 weeks.  Glucosamine and chondroitin alone or in combination did not reduce pain effectively in the overall group as compared to placebo.  Celebrex faired slightly better (10% improvement in symptoms).
Of note, however was an improvement in a subset of patients with “moderate to severe“ knee pain when taking the combined GS plus CS therapy. They found 79.2% of patients improved in the combo group vs. 54.3% in the placebo group (P=.002).  Improvement was seen in both WOMAC pain score as well as the HAQ pain score.

Because of lack of consistency, the authors were cautious to suggest that these results supported the use of the drug, and felt more study needed to be performed before such a conclusion could be reached.

What is it?
S-Adenosyl Methionine (aka SAM, SAMe, and SAM-e) is pronounced as “SAMMY” and is another naturally occurring nutritional supplement used for the treatment of osteoarthritis.  SAM-e is made up of ATP and L-methionine and is commonly produced in the liver.  SAM-e is needed for cell repair and cell growth.  It is unclear how SAM-e assists with pain control but they know it plays a role in three major pathways: transmethylation, transsulferation and aminopropylation.

Efficacy
In a review of the literature by Soeken et al. they found that SAM-e is just as effective as traditional NSAIDs at decreasing OA pain and increasing function. Two studies comparing SAM-e to placebo however, found no significant change in pain level; however one study did find increase in level of function compared to placebo.

Dosage
The typical dose of SAM-e for the treatment of osteoarthritis pain is 600-1200mg per day often taken in doses of 200 or 400mg three times daily.

Side Effects
Side effects include but are not limited to: headache, anxiety, diarrhea, dyspepsia, insomnia, allergy, and rash.

Brand Name vs. Generic
Nutritional supplements are not FDA approved.  They are covered under the Dietary Health and Education Act of 1994, which classifies dietary supplements as a subcategory of food, allowing manufacturers to market products without submitting proof of safety or efficacy to the FDA.
It may matter what brand of glucosamine you buy. Buying generic glucosamine or any supplement for that matter is not recommended.  There is no way of being able to tell what you are actually taking. You should only buy glucosamine and other supplements reputable, well known companies. Some recommended labels are Kirkland, Puritan’s Pride and Cosamin.

One way of identifying a reputable source of any of the above supplements is to look for the USP logo. The United States Pharmacopeial Convention (USP) has a supplement verification program that tests the quality of supplements. If a supplement has this logo then it means: that it contains the actual amounts of each substance as listed on the label, it doesn’t contain harmful amounts of contaminants, the body is able to break down the substance, and it is made in accordance with FDA good manufacturing practices (GMPs.)            
                                                                                   

Although the scientific evidence is patchy, we feel it is reasonable that patients with arthritis consider a trial course of glucosamine and chondroitin in combination.  The medication carries a low risk as described above.  Some patients do respond favorably to the medication (though a portion of this response may be the result of the placebo effect).

In efforts to be scientific, we suggest that you answer a few questions from the KOOS Self Pain and Function Scoring System (short versi0on) prior to taking arthritis medication and then re-evaluate yourself with the same questions at 6 and 12 months.  This may help to determine its effectiveness by tracking your function.

The full version of the KOOS questionnaire is rather lengthy, 41 questions (www.koos.nu/).  The short version is as follows:

KOOS-Physical Function Short Form
(KOOS-PS)
Today’s date:_______/________/______

INSTRUCTIONS: This survey asks for your view about your knee. This information will help us keep track of how well you are able to perform different activities. Answer every question by ticking the appropriate box, only one box for each question. If you are unsure about how to answer a question, please give the best answer you can so that you answer all the questions.
The following questions concern your level of function in performing usual daily activities and higher-level activities. For each of the following activities, please indicate the degree of difficulty you have experienced in the last week due to your knee problem.

1. Rising from bed
None  Mild    Moderate  Severe   Extreme  

2. Putting on socks/stockings
None  Mild    Moderate  Severe   Extreme  

3. Rising from sitting
None  Mild    Moderate  Severe   Extreme  

4. Bending to floor
None  Mild    Moderate  Severe   Extreme  

5. Twisting/pivoting on your injured knee
None  Mild    Moderate  Severe   Extreme  

6. Kneeling
None  Mild    Moderate  Severe   Extreme  

7. Squatting
None  Mild    Moderate  Severe   Extreme  

REFERENCES

• R.M. Rozendaal et al. Effect of Glucosamine Sulfate on Hip Osteoarthritis. A Randomized Trial. American College of Physicians. 2008 February; 148(4):268-277.
• Rindone JP, Hiller D, Collacott E, Nordhaugen N, Arriola G. Randomized, Controlled Trial of Glucosamine for Treating Osteoarthritis of the Knee. West J Med. 2000 February; 172(2):91-94.
• Uebelhart D et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind multicenter study versus placebo. Osteoarthritis and Cartilage. 2004 April; 12(4): 269-276.
• Clegg et al.  Glucosamine, Chondroitin Sulfate, and the Two in Combination for Painful Knee Osteoarthritis. N Engl J Med. 2006 February; 354:795-808.
• Soeken KL, Lee W, Bausell RB, Agelli M, Berman BM. Safety and Efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. The Journal of Family Practice. 2002 May; 51(5); 425-430.

Product Review:
Joint Health Supplements with Glucosamine, Chondroitin, and/or MSM: https://www.consumerlab.com/reviews/Joint_Supplements
Accessed September 27, 2011.

U.S.Pharmacopia (USP) dietary supplement verification program:

http://www.usp.org/USPVerified/dietarySupplements/
Accessed September 27, 2011.