Glucosamine sulfate supplement use for arthritis and osteoarthritis, benefit and side effects, dosage, may work better in combination with chondroitin, MSM, CMO, curcumin and other nutraceuticals
October 17 2016 by Ray Sahelian, M.D.

Glucosamine supplements have become quite popular in the past few years. Many people take glucosamine and chondroitin supplements for joint health. Do these supplements work? Do they reduce symptoms of osteoarthritis? Do they cause adverse reactions? I review the latest research regarding the benefits and side effects of glucosamine sulfate and hydrochloride.
  
What is it and how does it work?
Glucosamine is made from the combination of a sugar - hence the first part of the name glucos(e) - and an amine, which is a derivative of ammonia containing nitrogen (N) and hydrogen (H) atoms. Amino sugars are key constituents of larger compounds called glycosaminoglycans and glycoproteins, which enable cells in tissues to hold together. They are necessary for the construction and maintenance of virtually all connective tissues and lubricating fluids in the body - tendons, ligaments, cartilage, bone matrix, skin, joint fluid, intestinal lining, and mucous membranes.
   Glucosamine is found largely in cartilage and plays an important role in its health and resiliency. As we age, we lose some of it and other substances in cartilage. This can lead to thinning of cartilage and the onset and progression of osteoarthritis. It is important to note that there are a number of important substances within cartilage and supplementation, by itself, should not be viewed as the complete answer. In fact, not all studies show glucosamine to be helpful by itself. Some studies show it is more likely to be effective when taken with other nutrients such as MSM and chondroitin. Glucosamine stimulates the biosynthesis (production) of some proteoglycans, restores damaged chondrocytes (cells of cartilage tissue), and has some antioxidant and anti-inflammatory abilities. The anti-inflammatory abilities of glucosamine are much less than NSAIDs and glucosamine is not known to have pain-killing abilities. Therefore, users should not expect immediate relief of their symptoms.

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Supplement Facts, dosage: Glucosamine is available as sulfate or hydrochloride in 500 mg or 1000 mg capsules (or as glucosamine sulfate potassium chloride). Take up to 2 or 3 grams a day. Glucosamine sulfate is sometimes complexed with potassium chloride to enhance stability. You will often find this nutraceutical in natural join formula products. Not enough long term research has been done to know the ideal age to start a glucosamine supplement and whether it's use for a decade or two will prevent or slow arthritis or joint problems.
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How effective are neutraceuticals in the treatment of arthritis and joint problems?
Glucosamine and chondroitin study results are inconsistent and I have listed both positive and negative outcomes: There is mixed evidence that nutraceuticals influence the natural progression of osteoarthritis. However, some of these agents seem to reduce pain and improve function.

Arthritis and Rheumatology, news release, March 11, 2014
This study, published online March 11, 2014 issue of the journal Arthritis and Rheumatology, included 200 people with mild to moderate pain in one or both knees. They were randomly selected to drink 1,500 milligrams a day of glucosamine or a placebo added to a 16-ounce bottle of diet lemonade for 24 weeks. MRI scans were used to discern cartilage damage in the patients' knees. Reductions in cartilage damage were no greater in the glucosamine group than in the placebo group, and taking glucosamine did not reduce knee pain.
   Comment: Perhaps the time period was too short, but I have a feeling glucosamine works better in combination with other nutrients for arthritis or perhaps a higher dosage is required?

Mol Med Rep. 2013 March .Evaluation of the effect of glucosamine administration on biomarkers of cartilage and bone metabolism in bicycle racers. In the present study, the effect of glucosamine administration (1.5 or 3 g/day) on cartilage and bone metabolism was investigated in bicycle racers, using cartilage‑ and bone‑specific biomarkers, including C‑terminal cross‑linked telopeptides of type II collagen (CTX‑II), C‑terminal propeptides of type II procollagen (CPII), N‑terminal telopeptides of bone‑specific type I collagen (NTx) and bone alkaline phosphatase (BAP). The results indicate that CPII (a marker of type II collagen synthesis) was not substantially changed, however, CTX‑II (a marker of type II degradation) was reduced by glucosamine administration, particularly at a dose of 3 g/day.  Observations indicate that glucosamine may exert a chondroprotective action by preventing type II collagen degradation in athletes of various sports, including soccer players and bicycle racers.

Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT;
Annals of the Rheumatic Diseases 2010.
We evaluated the efficacy and safety of glucosamine and chondroitin sulphate, alone or in combination, as well as celecoxib and placebo on painful knee osteoarthritis over 2 years. A 24-month, double-blind, placebo-controlled study, ancillary to the Glucosamine / chondroitin Arthritis Intervention Trial, enrolled 662 patients with knee OA who satisfied radiographic criteria (Kellgren / Lawrence grade 2 or 3 changes and baseline joint space width of at least 2 mm). This subset continued to receive their randomised treatment: glucosamine 500 mg three times daily, chondroitin sulphate 400 mg three times daily, the combination of glucosamine and chondroitin sulphate, celecoxib 200 mg daily, or placebo over 24 months. Compared with placebo, the odds of achieving a 20% reduction in WOMAC pain were celecoxib: 1.21, glucosamine: 1.16, combination glucosamine/CS: 0.83 and CS alone: 0.69, and were not statistically significant. Over 2 years, no treatment achieved a clinically important difference in WOMAC pain or function as compared with placebo. However, glucosamine and celecoxib showed beneficial but not significant trends. Adverse reactions were similar among treatment groups and serious adverse events were rare for all treatments.

The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: A report from the glucosamine / chondroitin arthritis intervention trial.
Arthritis Rheum. 2008.
A 24-month, double-blind, placebo-controlled study, conducted as part of the Glucosamine / Chondroitin Arthritis Intervention Trial (GAIT), enrolled 572 patients with knee osteoarthritis who satisfied radiographic criteria (Kellgren / Lawrence [K/L] grade 2 or grade 3 changes and joint space width of at least 2 mm at baseline). Patients who had been randomized to 1 of the 5 groups in the GAIT continued to receive glucosamine 500 mg 3 times daily, CS 400 mg 3 times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The minimum medial tibiofemoral joint space width was measured at baseline, 12 months, and 24 months. The primary outcome measure was the mean change in joint space width from baseline. The mean joint space width loss at 2 years in knees with osteoarthritis in the placebo group, adjusted for design and clinical factors, was 0.166 mm. No statistically significant difference in mean joint space width loss was observed in any treatment group compared with the placebo group. Treatment effects on K/L grade 2 knees, but not on K/L grade 3 knees, showed a trend toward improvement relative to the placebo group. The power of the study was diminished by the limited sample size, variance of joint space width measurement, and a smaller than expected loss in joint space width. At 2 years, no treatment achieved a predefined threshold of clinically important difference in joint space width loss as compared with placebo. However, knees with K/L grade 2 radiographic osteoarthritis appeared to have the greatest potential for modification by these treatments.
   My comments: According to the way I read this study, there was a small improvement in those who had a grade 2 level of joint space narrowing before the study started. In other words, those whose knee osteoarthritis was not very bad had some benefit from the glucosamine chondroitin joint formula supplement use. I wonder if the study had gone on a few more years the changes would have been more apparent. Also, I wonder if results would be different if all the capsules were taken at one time in the morning on an empty stomach. Many people may forget to take their pills three times a day.

Benefit of glucosamine and osteoarthritis
GS has hardly been evaluated in conditions other than osteoarthritis. Hence it is not very clear whether it is helpful in those with damage to cartilage or joints due to musculoskeletal injuries or other types of joint pain. Glucosamine appears to help rebuild cartilage in osteoarthritis patients, but it is unlikely that it would help joints where the cartilage has been surgically removed. Similarly, glucosamine has not been fully tested in autoimmune diseases involving joints such as lupus and rheumatoid arthritis. Those with artificial joints are not likely to be helped by glucosamine since they have no cartilage to rebuild. The positive effects of glucosamine in reducing joint pain are often noticed within a few weeks.
   Over the years there have been dozens of studies regarding the benefits of glucosamine for osteoarthritis. Some have shown clear benefits, whereas others did not indicate glucosamine to be helpful. There is no consensus in the medical establishment whether glucosamine is beneficial. Current drugs used for osteoarthritis, such as COX-2 inhibitors and acetaminophen, actually cause harm and side effects. At the least, glucosamine supplement use does not seem to harm the body. There is a good possibility that the benefits of glucosamine are enhanced when used together with other supplements such as chondroitin, MSM, and others.

Does glucosamine benefit those with rheumatoid arthritis?
   We doubt it would benefit patients with rheumatoid arthritis since the joint damage is due to an autoimmune reaction. However, we can't be sure until studies are completed.

Efficacy of a progressive walking program and glucosamine sulphate supplementation on osteoarthritic symptoms of the hip and knee: a feasibility trial.
Arthritis Res Ther, 2010.
Recent research has found that a progressive walking program that includes a glucosamine sulphate supplement can reduce the symptoms of osteoarthritis. The study included 36 participants aged 42 to 73 years with mild to moderate hip or knee osteoarthritis. The participants were provided with 1500 mg of glucosamine sulphate per day for six weeks and then began a 12 week progressive walking program, while continuing to take the glucosamine. The subjects were randomly assigned to walk either three or five days per week and given a pedometer to monitor step counts. Both groups were gradually increased to 3,000 steps per day during the first six weeks and then up to 6,000 steps per day for the following six weeks. Both groups achieved significant improvement in their symptoms. It appears that osteoarthritis sufferers can benefit from a combination of glucosamine sulphate and walking give or take 3,000 steps per day for exercise, in bouts of at least 1,500 steps each, on at least three days per week.

Glucosamine sulfate or hydrochloride?
This nutrient is available as sulfate and hydrochloride (hcl ). A review of the scientific literature indicates the sulfate form has been tested more often since a company in Europe funded the studies. However, the hydrochloride form has been used by doctors for many years and it seems to work well, too, and it is cheaper.

Glucosamine liquid
Various supplement companies now make this nutrient available in liquid form. Glucosamine liquid may be appropriate for those who are not able to swallow capsules. We have not seen any research comparing liquid glucosamine to the pills. We doubt it offers any advantages except to those who have difficulty swallowing pills.

Glucosamine and allergies - where does it come from?
Those who are allergic to sulfates may take glucosamine hydrochloride and not sulfate, and they should avoid chondroitin sulfate. Glucosamine is derived from shrimp, oyster and crab shells and chondroitin is derived from cartilage of cows, pigs, and sharks. There is no synthetically made glucosamine on the market.

Glucosamine allergy for those allergic to shrimp
Do shrimp-allergic individuals tolerate shrimp-derived glucosamine?
Clin Exp Allergy. 2006.
There is concern that shrimp allergic individuals may react to glucosamine containing products as shrimp shells are a major source of glucosamine used for human consumption. The purpose of this study was to determine whether shrimp allergic individuals can tolerate therapeutic doses of glucosamine. Subjects with a history of shrimp allergy were recruited. Fifteen subjects with positive skin tests to shrimp and an ImmunoCAP class level of two or greater were selected for a double-blind placebo-controlled food challenge using glucosamine chondroitin tablets containing 1,500 mg of synthetically produced (control) or shrimp-derived glucosamine. No allergies were noticed. This study demonstrates that glucosamine supplements from specific manufacturers do not contain clinically relevant levels of shrimp allergen and therefore appear to pose no threat to shrimp-allergic individuals.

Combining glucosamine supplement with drugs
Glucosamine supplements may be taken together with acetaminophen or NSAIDs such as ibuprofen and naproxen. After a few weeks, hopefully the dose of the drugs can be reduced or they can be eliminated. I am not aware of adverse nutrient-medication interactions. It appears that glucosamine, chondroitin and other arthritis herbs are safer than the pain medicines.

Glucosamine side effects - long term safety
Based on our current understanding, glucosamine has few side effects, and can be taken for extended periods, months and years. Thus far, after being on the market for quite a number of years, there have been only rare reports in the medical literature of any significant glucosamine side effects. It is possible glucosamine is harmful in those who have chronic or severe liver disease and take it for prolonged periods.

World J Gastroenterol. 2013. Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease. A questionnaire was given to 151 consecutive patients with chronic liver disease of different etiology (mean age 59 years) attended in an outpatient clinic with the aim of evaluating the frequency of consumption of these drugs and determine whether their use coincided with a worsening in liver function test results. Twenty-three patients (15%) recognized having taken products containing glucosamine or chondroitin sulfate previously or at the time of the questionnaire. Review of the clinical records and liver function tests identified 2 patients presenting an elevation in aminotransferase values temporarily associated with glucosamine treatment; one of the cases simultaneously presented a skin rash attributed to the drug. Review of these two patients and the cases described in the literature suggest toxicity of glucosamine and chondroitin sulfate. The clinical spectrum is variable, and the mechanism of toxicity is not clear but may involve reactions of hypersensitivity. The consumption of products containing glucosamine and/or chondroitin sulfate is frequent among patients with chronic liver diseases and should be taken into account on the appearance of alterations in liver function tests not explained by the underlying disease.

Int J Clin Pharmacol Ther. 2013. Drug-induced acute liver injury mimicking autoimmune hepatitis after intake of dietary supplements containing glucosamine and chondroitin sulfate. We here present a case of a male patient with biopsy-proven acute and severe autoimmune hepatitis subsequent to intake of a preparation containing glucosamine and chondroitine sulfate.

Timing of ingestion
It's difficult to say when the best time or frequency, whether with or without food, but a good option is to take glucosamine before meals. All 1,500 mg a day can be taken at one time or split in two or three divided doses throughout the day. 

Pregnancy and glucosamine supplement use
It is best pregnant women not take it until more is known about this interaction. Fortunately, most pregnant women are not at an age where they would have osteoarthritis.

Diabetes and high blood sugar
Glucosamine supplements do not seem to have a significant effect on blood sugar or have a negative impact in patients with diabetes. The usual dose, one or two grams a day, is minimal as a sugar source compared to the amounts of carbohydrates found in the foods we consume. Studies do indicate that glucosamine is safe for patients with diabetes.
   In a study published in Archives of Internal Medicine, 38 elderly patients with type two diabetes were divided into two groups. The first diabetes group took 1500 mg of glucosamine supplement a day combined with 1200 mg of chondroitin sulfate. The other group took placebo pills. Two-thirds of the dose was taken in the morning and one-third in the evening. The study lasted for 90 days. Blood studies were done to evaluate blood sugar levels, and also levels of hemoglobin A1c, a specific blood marker than can tell us average blood sugar levels over long periods of time. There was no statistically significant rise in hemoglobin A1c levels in those who were supplemented.
   Patients with diabetes are often at risk from toxic effects from many of the current treatments for osteoarthritis, such as the NSAIDs ibuprofen and naprosyn. These medicines cause stomach ulcers and kidney damage if used for prolonged periods. Glucosamine sulfate provides a safe and natural alternative.

The effect of glucosamine chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial.
Arch Intern Med. 2004 
The present study was undertaken to determine whether glucosamine supplementation altered hemoglobin A1c concentrations in patients with well-controlled diabetes mellitus. Patients were typically elderly patients being treated with 1 or 2 drugs for blood sugar control. In daily doses for 90 days, patients received either placebo or a combination of 1500 mg of glucosamine hydrochloride with 1200 mg of chondroitin sulfate (Cosamin DS; Nutramax Laboratories Inc, Edgewood, Md). There were 4 withdrawals from the glucosamine hydrochloride treated group. Three were related to comorbidities (myocardial infarction, congestive heart failure, and atrial fibrillation) and 1 to a possible side effect (excessive flatus). No other patient reported any side effects of glucosamine therapy, and no patient had any change in their diabetes management. Mean hemoglobin A1c concentrations were not significantly different between groups prior to glucosamine therapy. Posttreatment hemoglobin A1c concentrations were not significantly different between groups. This study demonstrates that oral glucosamine supplementation does not result in clinically significant alterations in glucose metabolism in patients with type 2 diabetes mellitus.

Effect of glucosamine supplementation on fasting and non-fasting plasma glucose and serum insulin concentrations in healthy individuals.
Osteoarthritis Cartilage. 2004.
Healthy adults ingested 1500 mg of glucosamine sulfate or placebo (double blind) each day for 12 weeks. Three-hour oral glucose tolerance tests were performed using 75 g of dextrose. These occurred before the start of supplementation, at 6 weeks, and at the completion of supplementation (12 weeks). There were no significant differences between fasted levels of serum insulin or blood glucose. Glucosamine sulfate supplementation did not alter serum insulin or plasma glucose during the oral glucose tolerance tests. The data suggests that glucosamine supplementation, with normal recommended dosages, does not cause glucose intolerance in healthy adults.

Glucosamine sulfate and cholesterol levels
Apparently it does not seem to influence blood levels of cholesterol.

The effect of glucosamine sulfate on the blood levels of cholesterol or triglycerides
Ugeskr Laeger. 2007.
A study performed with parallel groups of 66 patients over 40 years of age with joint pain of long duration receiving either recommend dosage (1500 mg per day) of glucosamine sulfate or placebo. No significant differences between the treatment group and the placebo group with respect to cholesterol and triglycerides were observed.

Glucosamine and chondroitin
If glucosamine itself is not helpful in relieving arthritic symptoms, it may be combined with chondroitin and other nutrients. Alternatively, they can be started together with several other nutrients such as MSM and CMO.

Would a glucosamine chondroitin supplement offer benefits that go beyond a glucosamine supplement by itself?
   Based on my evaluation of studies, I believe that the addition of chondroitin to a glucosamine supplement regimen does provide additional benefits.

Glucosamine and chondroitin slow bone loss in osteoarthritis
In experiments with bone tissue samples from patients with knee arthritis, chondroitin and glucosamine affect osteoblasts in a manner that slows arthritis related bone loss. Bone remodeling is a continuous process in which existing bone is broken down and replaced with new bone tissue. Osteoarthritis occurs when the cartilage cushioning the joints begins to break down; but there is also a breakdown in the bone underneath the cartilage. This bone loss is related to an imbalance in the activity of the cells that break down bone (osteoclasts) and cells that build bone (osteoblasts). When osteoblast cells taken from patients undergoing knee-joint replacement for severe knee arthritis are exposed to chondroitin, glucosamine or a combination of the two affected osteoblast activity in a way that may inhibit bone breakdown. Arthritis Research & Therapy, 2007.

Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis.
Drugs Aging. 2007.
This review evaluates published studies of the effect of glucosamine and chondroitin sulfate preparations on the progression of knee or hip osteoarthritis. Despite multiple double-blind, controlled clinical trials of the use of glucosamine and chondroitin sulfate in osteoarthritis, controversy regarding the efficacy of these agents with respect to symptomatic improvement remains. Several potential confounders, including placebo response, use of prescription medicines versus over-the-counter pills or food supplements, or use of glucosamine sulfate versus glucosamine hydrochloride, may have relevance when attempting to interpret the seemingly contradictory results of different clinical trials. On the basis of the results of recent trials and meta-analyses, we can conclude that glucosamine sulfate (but not glucosamine hydrochloride) and chondroitin sulfate have small-to-moderate symptomatic efficacy in osteoarthritis, although this is still debated.

Glucosamine and MSM work better together for arthritis
It seems there's another nutrient that could be helpful in combination with glucosamine. This nutrient is known as MSM -- which stands for Methylsulfonylmethane. In the June 2004 issue of the journal Clinical Drug Investigations, scientists report that although the individual supplements did improve pain and swelling in arthritic joints, the combined therapy was more effective than the single nutrients in reducing symptoms and improving the function of joints. In a clinical trial conducted at Nizam's Institute of Medical Sciences in Hyderabad, India, 118 patients with mild to moderate osteoarthritis were treated three times daily with either 500 milligrams of glucosamine, 500 milligrams of MSM, a combination of both, or an inactive placebo. After 12 weeks of treatment, the average pain score had fallen from 1.74 to 0.65 in the glucosamine only group. In MSM only participants, it fell from 1.53 to 0.74. However, in the combination group, it fell from 1.7 to 0.36.
   Comments: It would seem reasonable for those with arthritis to take this combination. The dose of glucosamine has been established to be 500 mg 3 times a day. We still don't know enough about MSM to determine whether lesser amounts than 500 mg three times a day would still be effective.

Can glucosamine pills be absorbed from the stomach and end up in cartilage?
Yes. After oral administration of glucosamine sulfate, 90% is absorbed. (Sulfate means that the glucosamine is attached to a sulfur and oxygen atoms.)
   In a study done in Italy, two healthy male volunteers were given 250 mg of oral glucosamine sulfate, tagged with radioactive carbon 14 as a tracer, in the morning on an empty stomach. The radioactive glucosamine sulfate was found an hour later in blood and then later in other tissues. The researchers state, "Glucosamine sulfate very rapidly diffuses in most tissues and organs and that it has a special tropism (attraction) for articular tissue (cartilage) and for bone." These volunteers were also given glucosamine sulfate intravenously (IV) and intramuscularly (IM). The amount of glucosamine sulfate in blood after oral administration was only a quarter of the amount available by IV and IM. Therefore oral administration is effective, but not as good as IV or IM. When oral glucosamine sulfate is absorbed, it first goes to the liver where a large portion gets broken down into smaller molecules such as carbon dioxide, urea and water.

Availability
Most often glucosamine is sold as sulfate or hydrochloride. Very frequently glucosamine and chondroitin are combined together. Lately, more products are being sold with glucosamine, chondrotin, and MSM. Furthermore, more recently, these last three nutrients have been combined with other herbs and nutrients that play a role in joint health including CMO, curcumin, boswellia, and others.
   Glucosamine supplements are also sold as a liquid or powder. You will also find glucosamine formulas for dogs.

Would a glucosamine tablet absorb better than a capsule?
   I doubt there would be much of a clinical difference.

Does every patient with osteoarthritis benefit from glucosamine and chondroitin?
   No. Based on my clinical experience, the results of published studies, and discussions with doctors who use glucosamine supplements, I would estimate that about a third of patients notice a moderate to significant improvement while another third notice slight improvement. Other patients are disappointed. The reasons why some individuals do not respond adequately are not known. We should keep in mind that the biochemistry of cartilage tissue is complicated and many factors besides glucosamine and chondroitin are involved in the process of cartilage formation. It is possible that additional nutrients and herbs taken along may benefit those who do not respond to glucosamine and chondroitin alone.

Can I find glucosamine in foods?
No food sources of glucosamine are known that would provide this nutrient in the dosages required for arthritic relief. Hence, the best source of glucosamine is through taking supplements.

Is glucosamine toxic?
We know that NSAIDs can cause stomach ulcers and bleeding. A 1991 study published in the journal Drug Research showed glucosamine to be safe. When daily oral doses of up to 2700 mg/kg were given in the rat and 2100 mg/kg in the dog for one year and six months, respectively, no anatomical lesions were found in the gastrointestinal system or other organs. The dose given to the dogs would be equivalent to 150,000 mg in a 70 kg human. Most of the recommended dosages for patients with arthritis are about 500 mg three times a day. However, Italian researchers have found that the LD50 (the lethal dose at which half of the animals die) of glucosamine sulfate is 8000 mg/kg. In humans this would be equivalent to ingesting over 500,000 mg at one time or 1,000 pills each containing 500 mg.

Glucosamine sulfate versus acetaminophen
Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator.
Arthritis Rheum. 2007.
To assess the effects of the prescription formulation of glucosamine sulfate (1,500 mg administered once daily) on the symptoms of knee osteoarthritis during a 6-month treatment course. Three hundred eighteen patients were enrolled in this randomized, placebo-controlled, double-blind trial in which acetaminophen, the currently preferred medication for symptomatic treatment of osteoarthritis, was used as a side comparator. Patients were randomly assigned to receive oral glucosamine sulfate 1,500 mg once daily, acetaminophen 3 gm/day, or placebo. There were more responders to the nutrient (39%) and acetaminophen (33%) than to placebo (21%). Safety was good, and was comparable among groups.

Will supplements help if I have a knee replacement?
Glucosamine and chondroitin help regrow cartilage. However, if you have no cartilage left, these nutrients will not do any good to artificial knees. They may help, though, with your other joints. The best option is to prevent the joint from getting to a stage of destruction by using nutrients that help keep cartilage tissue healthy.

Glucosamine and osteoarthritis research - some studies show benefit, others don't
Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.
N Engl J Med. 2006.
Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled glucosamine / chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis. We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60 percent), the rate of response to glucosamine was 3.9 percentage points higher, the rate of response to chondroitin sulfate was 5.3 percentage points higher, and the rate of response to combined treatment was 6.5 percentage points higher. The rate of response in the celecoxib control group was 10 percentage points higher than that in the placebo control group. For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo. Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. The combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain.

Initial results of two highly anticipated clinical trials involving the use of glucosamine and / or chondroitin by individuals experiencing pain from osteoarthritis were announced Sept, 2005 in abstract form, and demonstrate strong support for use of both by osteoarthritis patients to relieve pain. Both studies, which were presented at a conference of the American College of Rheumatology, add further support to the growing scientific literature demonstrating the benefits of glucosamine and chondroitin for joint health. The multi-centered Glucosamine / chondroitin Arthritis Intervention Trial (GAIT) conducted by NIH involved nearly 1,500 osteoarthritis patients who were supplemented with 1,500 mg/day glucosamine hydrochloride and/or 1,200 mg/day chondroitin sulfate vs. 200 mg/day of the common prescription pain medication celecoxib (Celebrex) or placebo for 24 weeks. Preliminary results indicate that both celecoxib and glucosamine - chondroitin combination significantly reduced knee pain compared to placebo, and that all treatments were well tolerated by the study subjects. These findings were mirrored by the preliminary results of another multi-centered clinical study, the European-sponsored Glucosamine Unum in Die Efficacy (GUIDE) Trial, which compared the effect of glucosamine sulfate (1,500 mg/day) vs. acetaminophen (3,000 mg/day) or placebo over 24 weeks on various pain and mobility indices of osteoarthritis. Researchers reported that glucosamine sulfate was more effective than acetaminophen, and concluded that "glucosamine sulfate…might be the preferred symptomatic medication in knee osteoarthritis," and "There were no differences among groups in safety."

Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis.
Arthritis Rheum. 2004.
To assess the efficacy of glucosamine sulfate in knee osteoarthritis. A 6-month, randomized, double-blind, placebo-controlled glucosamine discontinuation trial was conducted in 137 current users of glucosamine with knee osteoarthritis who had experienced at least moderate improvement in knee pain after starting glucosamine. Study medication dosage was equivalent to the dosage of glucosamine taken prior to the study (maximum 1,500 mg/day). Follow up continued for 6 months or until disease flare, whichever occurred first. Disease flare was seen in 28 (42%) of 66 placebo patients and 32 (45%) of 71 glucosamine patients. At final study visit, acetaminophen was used in 27% and 21% of placebo and glucosamine patients, respectively, nonsteroidal antiinflammatory drugs were used in 29% and 30%, and both were used in 20% and 21%. No differences were found in severity of disease flare or other secondary outcomes between placebo and glucosamine patients. In patients with knee osteoarthritis with at least moderate subjective improvement with prior glucosamine use, this study provides no evidence of symptomatic benefit from continued use of glucosamine sulfate.

Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: evidence from two 3-year studies.
Menopause. 2004.
This study consisted of a preplanned combination of two three-year, randomized, placebo-controlled, prospective, independent studies evaluating the effect of glucosamine sulfate on symptoms and structure modification in osteoarthritis and post-hoc analysis of the results obtained in postmenopausal women with knee osteoarthritis. After 3 years, postmenopausal participants in the glucosamine sulfate group showed no joint space narrowing, whereas participants in the placebo group experienced a narrowing of -0.33 mm. Percent changes after 3 years in the WOMAC index showed an improvement in the glucosamine sulfate group and a trend for worsening in the placebo group. This analysis, focusing on a large cohort of postmenopausal women, demonstrated for the first time that a pharmacological intervention with glucosamine for osteoarthritis has a disease-modifying effect in this particular population, the most frequently affected by knee osteoarthritis.

NAG - N acetyl glucosamine supplement
N-Acetyl glucosamine, or N Acetyl D glucosamine is a form of glucosamine and a precursor to hyaluronic acid. There is early research testing n acetyl glucosamine as a potential helpful treatment for the symptoms arising from ulcerative colitis and Crohn's disease. Much less research has been done with n acetyl glucosamine than with glucosamine supplements.

Emails - newer ones are added at the bottom
Q. I have begun taking glucosamine sulfate and found it to be very rewarding toward back pain. I have spinal stenosis and with all the cut-backs on pain medication, it was hard to get my doctor to prescribe something for the pain I endured for over 3 months. I tried glucosamine sulfate and received great benefits. My question is: Do I continue to take this as an ongoing medication or do I take it only when symptoms are present?
   A. As a rule, glucosamine is slow acting and needs to be taken for a prolonged periods to be effective. Although it is possible to take breaks for a while and then return to using glucosamine again.

Q. This sounds like a joke but it's not. Perhaps a month or two after I began to take a glucosamine and chondroitin supplement to protect against knee pain, I began to notice that my penis, which had always assumed a straight position in the erect state, was developing a noticeable bend. (If I had said I was taking the supplement for joint pain, then you really would have been inclined to toss this one out.) Over the next month or two, the bend became more pronounced and I was on the verge of consulting a urologist to look into the possibility of Peyronie's Disease, a condition that apparently afflicts our ex-president Clinton and can I understand, interfere with sex if it progresses too far. The only change in my daily routine I could think of during this time was the addition of the glucosamine and chondroitin to my usual vitamins and mineral regimen. I dropped the supplement and over the next couple of months the bend in the penis gradually disappeared. Perhaps it was a coincidence (although I don't think so).
   A. This is the first time I have heard of glucosamine and chondroitin involved in this after several years of looking into these combinations. I don't know what to say. I think it's possible but just as likely it could have been a coincidence. Were there other ingredients in the formula or just glucosamine and chondroitin? There's so little we know about the long term effects of supplements and herbs that I keep any side effects as a possibility. I guess a good way to find out for sure is to retake it and see what happens, since it appears to be reversible on stopping... but i can see one's reluctance in this trial when it comes to such an important member of the body :)

Have you had anyone using either glucosamine alone or in combination with chondroitin report that their total cholesterol increased? I have a friend who discontinued taking the combination for that reason. I don't know how long she had been taking it.
   It is unlikely that glucosamine and chondroitin have much of an influence on cholesterol levels. Dietary changes are much more likely to have led to the changes. 

Q. I am a retired pathologist. My wife and I have been taking the standard dose of glucosamine and chondroitin for 5 months ( age 78 years). Both of us have noted that our fingernails seem to grow  faster and be stronger than before. Our son (age 50) has noted the same, and he is a guitar player who uses his nails as a pick.  I have not found this effect in a cursory exam of the net and thought you might be interested.
   A. This is the first we have heard of their influence on nail growth.

Q. Just wanted to comment on one of the emails quoted on your glucosamine supplement page (the one from the retired pathologist who noticed his nails growing faster). I've been taking glucosamine sulfate and chondroitin for the last 2 years, to relieve bursitis of the wrists. I consider myself 90% recovered, which is wonderful, but I've also discovered an unexpected side effect. My fingernails, which have always been very thin and brittle, and would flake off at the edges before they had a chance to grow, are now much thicker and stopped flaking completely. I noticed this effect after taking the supplement for about 2 months. I'm a 33 y/o female and for the first time in my life I can wear long nails!! It's very exciting for me. Just thought you might like to know.
   A. Interesting, this is the second report we have had regarding the influence of glucosamine and chondroitin on nail growth.

Q. I am a 37 year old male who has been active all my life. Last year I started having major middle back pains that even wiped me out when I washed dishes in my home. Mowing the yard really did me in. I was an avid runner, worked out 4 to 5 times a week, have 2 jobs. One at a desk, the other waiting tables in an Italian restaurant. I have consistently taken Bayer aspirin to relieve the pain yet I knew it didn't repair the problem. Recently, in a health food store I saw a glucosamine chondroitin product and thought I would give it a try. Never having taken any vitamins or supplements, I purchased the Joint Power Rx joint formula. I have been on it for 3 weeks now. On Sunday, I mowed the yard, dug a one foot deep and 15 foot long drainage trench, cleared about a 4x20 area of weeds with a hoe, and later that evening, I went to the gym and waited tables for 4 hours. I know I was pushing it. Seriously when I got back home I cried because I felt I had a lot of my physical strength back.

Q. I think your glucosamine site is very informative and I found it very useful however, I have taken glucosamine for a while and thought I knew a bit about it. I thought that 1500mg glucosamine sulfate daily is best for most people. The 500 mg glucosamine product suggests 500mg to 1500mg (3 x 500mg daily) but your Joint Power Rx product says 6000 mg (2 x 1500mg twice daily) or 9000mg (3 x 1500mg twice daily) for the first month. There is a big difference between the lowest recommendation of 500mg glucosamine sulfate daily and the highest of 9000mg glucosamine daily on your two products. Are you able to tell me which one is correct or which is optimal for most people. Also the 500mg glucosamine says "as glucosamine sulfate potassium chloride" which presumably means that it only provides around 375mg of actual glucosamine sulfate? since the Joint Power Rx does not say this am I to assume this is 1500 mg of actual glucosamine sulfate? Finally, the Joint Power Rx looks like a comprehensive formula, but with such a lot of ingredients and a high dose I am wondering what size the capsule is as I have difficulty swallowing larger ones.
   A. Joint Power Rx has 1,500 mg of glucosamine sulfate per 4 capsules. This product has many other herbs and extracts and we have great feedback, users are satisfied. Scientists still don't know how often to take glucosamine for best results, once, twice, or three times a day.

Q. Quest - a vitamin company in Canada makes a shellfish free glucosamine product. I have allergies and I take this product every day now for over 2 years.
   A. Thanks for letting us know. In June 2003, Cargill Acidulants began producing Regenasure glucosamine. Cargill Acidulants claims Regenasure glucosamine is the only commercially available glucosamine product not derived from shellfish. It wasn't clear from their website the source of their glucosamine hydrochloride.

Q. I have purchased 3 containers of 60 CMO tablets, reference a book by Dr L Sands (Arthritis beaten today) in the book he states that sea cucumber extract and time release glucosamine sulphate is also required can you help.
   A. There are many herbs or nutrients, besides CMO, that could potentially help someone with joint health, many of them are found in Joint Power Rx including sea cucumber and glucosamine. We have not seen any studies that compare time release glucosamine sulfate to that of regular form, and for the time being we think this is a marketing tactic.

I wish there were a web site where I and others could post, under disease categories, what has worked for them. I think it would be of great benefit to readers. For example Glucosamine 750 mg and MSM 1500 have given total relief from osteoarthritis chronic pain in a knee that was operated on 40 years ago to repair torn medial collateral and anterior cruciate ligaments. Of course there could be confounding with the other supplements I take.

I have started to see a bit about using glycosaminoglycans as a health supplement. I don't see any comments on your web site is this a subject you could give your expertise to?
   Glycosaminoglycan is a loose term that applies to long unbranched polysaccharides with repeating disaccharide units. The repeating unit often is made of an amino sugar (N-acetylglucose amine or N-acetylgalactose amine) along with a uronic sugar. The term glycosaminoglycans is not specific enough as it relates to being sold as a supplement since the molecules and composition can be of varying lengths and compositions.