Glucosamine has been used for osteoarthritis, by itself or in combination with chondroitin sulfate. Osteoarthritis is a major cause of disability among the elderly. Osteoarthritis is an age-related disease of joint cartilage, which results from structural change of the joints.
Glucosamine is an amino monosaccharide made naturally in the body from glucose and glutamine.
Glucosamine is one of the primary components of glycosaminoglycans, hyaluronic acid, and proteoglycans, all essential in the formation of cartilage.
Glucosamine supplements have been used in the treatment of osteoarthritis, back pain, joint pain, and glaucoma. Most glucosamine studies have involved people with knee osteoarthritis.
The sources of glucosamine in supplements are typically shellfish, although synthetic glucosamine is also available.
Glucosamine 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, and structures in the eyes, blood vessels, and heart valves.
Glucosamine may decrease catabolic activity by inhibiting the synthesis of proteolytic enzymes and other substances that contribute to damage of the cartilage matrix.
Glucosamine inhibits the cartilage-destructive enzymes collagenase. Glucosamine may have a protective effect on chondrocytes and may inhibit cartilage matrix degradation.
Glucosamine is well tolerated. In a three-year study using 1500 mg of glucosamine daily, no severe side effects were found.1
Glucosamine hydrochloride has been used safely in studies lasting up to 24 weeks.
The most common side effect from glucosamine intake is mild gastrointestinal discomfort.
Those with shellfish allergies should avoid glucosamine supplements derived from shellfish and should choose a vegetarian glucosamine supplement instead.
There has been concern regarding effects on insulin and blood glucose levels. However, trials conducted with healthy obese individuals with type 2 diabetes did not show an effect on hemoglobin A1C nor on blood glucose levels after taking glucosamine supplements for 3 months.
There has been concern that glucosamine might increase cholesterol levels and blood pressure. However, no adverse effects on cholesterol or blood pressure have been observed among individuals taking glucosamine supplements for up to 3 years.
From a theoretical standpoint, chondroitin does have some structural similarity to heparin and it might have weak anticoagulant activity. Glucosamine, by itself, most likely has no anticoagulant activity. There have been no reports of interactions with warfarin at recommended dosages of glucosamine or chondroitin.
Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.
Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator.
Glucosamine Unum in Die Efficacy (GUIDE) study compared glucosamine sulfate with acetaminophen or placebo in 318 patients with knee OA. Study patients were randomized to receive glucosamine sulfate soluble powder 1,500 mg once a day, acetaminophen 1,000 mg three times a day or a daily placebo for 6 months. The main efficacy measure was the 6-month change in the Lequesne Index. At 6 months, the glucosamine group achieved significantly better Lequesne Index scores compared with the placebo group (difference between glucosamine sulfate and placebo -1.2; 95% confidence interval - 2.3, -0.8; P=0.032). Those taking acetaminophen did not achieve a statistically significant benefit compared with placebo by either the Lequesne Index or WOMAC. There was no difference between the glucosamine, acetaminophen, and placebo groups in terms of safety. It should be noted
that the form of glucosamine used in this trial—glucosamine sulfate—is quite different from the form of glucosamine most often used in the United States. 8
Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study.
The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) was a multi-center, double-blind, placebo-controlled study designed to evaluate the efficacy of glucosamine, chondroitin, and the two combined in treating knee pain related to osteoarthritis. The researchers randomly assigned 1,538 patients with symptomatic knee osteoarthritis to receive 1500 mg glucosamine hydrochloride, 1200 mg chondroitin sulfate, a combination of the two, 200 mg celecoxib, or placebo every day for 24 weeks. Primary outcome measures did not show that either supplement alone or combined was efficacious. Compared to the placebo (60.1% response rate), glucosamine, chondroitin sulfate, and the combination were not significantly better (respectively, 3.9% higher, P=0.30; 5.3% higher, P=0.17; and 6.5% higher, P=0.09). However, analysis of a subgroup of patients with moderate-to-severe pain demonstrated that combination therapy (glucosamine + chondroitin) significantly decreased knee pain related to osteoarthritis compared to placebo for this group (79.2% vs. 54.3%, P=0.002). This finding, which suggests efficacy for glucosamine and chondroitin in those with moderate-to-severe symptoms, is the first one to demonstrate efficacy of the combination, and adds to the existing body of research which demonstrates efficacy of these components. These results highlight the importance of selecting the right subgroups of patients with OA who may derive benefit from glucosamine.15
Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis.
A comprehensive meta-analysis on randomized placebo controlled trials was performed to assess the efficacy of glucosamine and/or chondroitin in knee osteoarthritis (OA). Analyses were based on the outcomes that are required for demonstrating the efficacy of a drug to be used in the treatment of OA: radiological evolution assessed by joint space narrowing (JSN), evaluation of pain by visual analog scale (VAS pain), joint mobility, Lequesne Index (LI), and Western Ontario MacMaster University Osteoarthritis Index (WOMAC). Results from analyses demonstrated the efficacy of glucosamine on all outcomes, including JSN and WOMAC. An outstanding finding was the structural efficacy (disease-modifying property) of glucosamine on JSN. This finding suggests that long-term (at least 3 years) glucosamine supplementation at a dose of 1500 mg/day can slow the degenerative process of the joint cartilage. Further studies are warranted to confirm the long-term effects of glucosamine. Chondroitin was found to be efficacious on the LI, VAS pain, and mobility. Further studies are also needed to confirm and evaluate the structural efficacy of chondroitin. Safety for both of these compounds was well-established. 12
The effect of glucosamine supplementation on people experiencing regular knee pain.
A small study with 46 participants tested 2000 mg glucosamine daily over a period of 12 weeks. In a placebo-controlled design, participants were randomly assigned to receive the glucosamine or a lactose placebo daily. Although clinical and functional test scores improved with time (main effects: p<0.05, p<0.01) improvements were not significantly different between the glucosamine and placebo groups. In the glucosamine group, 88% (n=21) reported some degree of improvement in their knee pain while only 17% (n=3) of participants in the placebo group reported improvements in knee pain. Data suggests that glucosamine supplementation with 2000 mg per day can provide some pain relief to people with chronic knee pain due to osteoarthritis or cartilage injury. 6
Randomised, double-blind, parallel, placebo-controlled study of oral glucosamine, methylsulfonylmethane and their combination in osteoarthritis.
A 2004 double-blind, placebo-controlled study compared the efficacy and safety of glucosamine alone, methylsulfonylmethane (MSM) alone, or the combination of the two in knee osteoarthritis. One-hundred-eighteen people with knee osteoarthritis were randomized to receive either 500 mg glucosamine, 500 mg MSM, 500 mg glucosamine plus 500 mg MSM, or a placebo three times daily for 12 weeks. Results revealed glucosamine, MSM, and their combination significantly improved signs and symptoms of osteoarthritis compared to placebo. Glucosamine significantly improved pain from baseline (1.74 +/- 0.47) to 0.65 +/- 0.71 at week 12 (p<0.0001); MSM also significantly decreased the mean pain index from baseline (1.53 +/- 0.51) to 0.74 +/- 0.65 (p<0.0001). Treatment with the combination produced in a more significant decrease in the mean pain index (1.7 +/- 0.47 to 0.36 +/- 0.33; p<0.0001). Additionally, the combination therapy (glucosamine + MSM) showed better efficacy than either agent alone in reducing pain and swelling, improving joint function, and had a more rapid onset of analgesic and anti-inflammatory activity. The authors concluded that the combination of MSM with glucosamine provided better and more rapid improvement in patients with osteoarthritis.19
Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: evidence from two 3-year studies.
Post-menopausal women are the people most frequently affected by knee osteoarthritis. A pre-planned combination of two three-year randomized, placebo-controlled, prospective, independent studies was conducted to evaluate the effects of glucosamine sulfate in 319 post-menopausal women with knee osteoarthritis. After 3 years, post-menopausal participants in the glucosamine group showed no joint space narrowing (+0.0003 vs. -0.33 mm for placebo, P<0.0001 difference between groups) and WOMAC index scores improved (-14.1% vs. 5.4% for placebo, P=0.003 compared to placebo). These studies demonstrated that glucosamine sulfate improved outcomes in knee osteoarthritis for this group of participants. 18
Glucosamine sulfate and cartilage type II collagen degradation in patients with knee osteoarthritis: randomized discontinuation trial results employing biomarkers.
The efficacy of glucosamine sulfate in knee osteoarthritis was assessed in a trial with 137 current glucosamine users who experienced moderate improvement in knee pain after starting glucosamine. The study was a six-month randomized, double-blind, placebo-controlled glucosamine discontinuation trial. Primary outcome was proportion of disease flares in both glucosamine and placebo groups. Disease flare was seen in 42% (28 of 66) of placebo participants and 45% (32 of 71) of glucosamine participants. The data from this study provides no evidence of symptomatic benefit from continued use of glucosamine sulfate. 17
Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study.
A three-year randomized, double-blind, placebo-controlled trial was conducted to evaluate the effects of 1500 mg glucosamine sulfate versus placebo in delaying the progression of osteoarthritis (OA) of the knee. Two-hundred-two patients were included in the study with mild to moderately severe knee OA for 10 years or longer. There was no significant difference between groups of the patients who did not complete the three-year treatment course. After each year, participants receiving glucosamine sulfate did not experience joint space narrowing (loss in joint space width) as compared to the placebo group (p < 0.001). According to the Lequesne index and WOMAC (Western Ontario and McMaster Universities) index, symptoms of joint pain and limitation of function significantly improved in the glucosamine sulfate group compared with the placebo group throughout the three-year period. This study demonstrated long-term safety of glucosamine sulfate and revealed long-term administration of glucosamine sulfate can slow progression of osteoarthritis of the knee. 13
Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial
A randomized, double blind, placebo-controlled study was conducted with 212 patients randomly assigned to 1500 mg glucosamine or a placebo daily for three years. During the study, patients consuming the placebo had a progressive joint-space narrowing (mean 0.31 mm (95% CI -0.48 to -0.13)), while patients consuming glucosamine did not have significant joint-space loss (-0.06 mm (-0.22 to 0.09)). Incidence of side effects such as GI discomfort was similar in both groups. Results of this study indicated that glucosamine may be a good choice for people osteoarthritis. 1
Total joint replacement after glucosamine sulphate treatment in knee osteoarthritis: results of a mean 8-year observation of patients from two previous 3-year, randomised, placebo-controlled trials.
Participants from prior three-year, randomized, placebo-controlled trials were followed after the discontinuation of the trials for a mean of eight years. Total knee replacements occured in 14.5% of the participants who consumed placebo and in only 6.3% of those who had consumed glucosamine (P=0.024, chi-square test). The relative risk for knee replacement was 0.43 for the glucosamine group (95% confidence interval (CI): 0.20-0.92). These results suggest that glucosamine supplementation for at least 12 months to 3 years may reduce the risk for total joint replacement for this group of knee osteoarthritis patients.
Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee.
Glucosamine was compared with ibuprofen to determine the effect on symptoms of osteoarthritis of the knee. Almost two-hundred people with knee osteoarthritis were given either 1500 mg glucosamine sulfate or 1200 mg ibuprofen daily for four weeks; participants were evaluated weekly during the trial. Ibuprofen demonstrated greater benefit during the first week of the trial (48% responders vs. 28% for glucosamine after the 1st treatment week; P=0.06, Fisher's Exact test). No difference between groups were noted for the remainder of the trial. The success rate for ibuprofen was 52% and 48% in the glucosamine group (P=0.67). Results revealed both treatments improved the symptoms of osteoarthritis. Although ibuprofen showed a slightly faster effect, there was no difference in effectiveness between treatments. Glucosamine sulfate was significantly better tolerated than ibuprofen, with fewer adverse effects (6% in glucosamine vs. 35% in ibuprofen group P<0.001). 7
The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial.
In a double-blind, placebo-controlled, multi-center trial, glucosamine, chondroitin, and celecoxib were evaluated for attenuation of knee osteoarthritis. A total of 572 people with knee osteoarthritis participated in the twenty-four month trial. For inclusion in the trial, subjects must have Kellgren/Lawrence (K/L) grade 2 or grade 3 changes and joint space width of at least 2 mm at baseline. Participants were randomized to receive 1500 mg glucosamine, 1200 mg chondroitin, both, 200 mg celecoxib, or a placebo daily for the duration of the trial. At the end of the trial, the mean joint space width loss for the placebo group was 0.166 mm. No group demonstrated joint space width loss that was statistically different from the placebo group. However, participants with K/L grade 2 but not grade 3 showed a trend toward improvement compared to placebo. These results suggest that people with K/L grade 2 changes have potential to benefit from glucosamine, chondroitin, or celecoxib. More studies are needed to investigate this finding. 5
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.
A study was conducted to determine the effect of glucosamine hydrochloride supplementation on hemoglobin A1C (HbA1C) concentrations in 38 elderly patients with stable, well-controlled type 2 diabetes mellitus over a 90-day period. Participants must have been consistently taking an oral anti-hyperglycemic agent or under strict diet control, and have a stable HbA1C level for at least two consecutive measurements separated by at least 90 days. Twenty-six patients were randomized to 1500 mg glucosamine daily and 12 to placebo. At baseline, both groups had similar HbA1C levels and the HbA1C mean values did not significantly change during the study. There was no significant difference in the glycemic control between the glucosamine and placebo group (p=0.20). In the glucosamine group, mean HbA1C increased from 6.45% to 6.5%; in the placebo group the mean HbA1C decreased from 6.25% to 6.09%. This study suggests that oral glucosamine hydrochloride supplementation at the recommended dose (1500 mg/day) does not adversely effect glycemic control in patients with type 2 diabetes.14
Effect of glucosamine supplementation on fasting and non-fasting plasma glucose and serum insulin concentrations in healthy individuals.
To evaluate the effects of glucosamine on glucose tolerance, 1500 mg of glucosamine sulfate was given to nineteen healthy adults for twelve weeks. Supplementation with glucosamine sulfate did not alter serum insulin or plasma glucose during the oral glucose tolerance test, administered at baseline, six weeks, and twelve weeks. Glycated hemoglobin measurements showed no significant change over time. The authors concluded that the recommended doses of glucosamine supplementation do not cause glucose intolerance in healthy adults. These findings are not conclusive until further studies are done using alternative types of testing and larger study groups.20
Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy
A recent review was conducted evaluating the safety and effects on glucose metabolism of glucosamine from clinical trial data with 3,036 human subjects. Altered glucose metabolism has been associated with parenteral administration of large doses of glucosamine in animals, and with high concentrations in in vitro studies. In some in vitro studies which demonstrated effects of glucosamine on glucose metabolism, concentrations are 100-200 times higher than tissue levels expected from oral glucosamine administration. This review noted that in some trials, fasting plasma glucose values decreased slightly after oral glucosamine was given for approximately 66 weeks. In addition, there were no adverse effects of oral glucosamine administration on blood, urine or fecal parameters. Side effects were significantly less common with glucosamine than placebo or non-steroidal anti-inflammatory drugs (NSAIDs). In comparison to NSAIDs, no serious or fatal side effects have been reported for glucosamine. The results from the review indicate that glucosamine is safe under current conditions of use and does not affect glucose metabolism. 16
Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects.
A randomized, placebo-controlled, double-blind, crossover trial investigated the impact of glucosamine supplements on insulin resistance and endothelial dysfunction in lean and obese subjects. Twenty lean and twenty obese but otherwise healthy participants were recruited for the trial. Participants were randomly assigned to receive 1500 mg glucosamine or a placebo daily for six weeks followed by a one week washout period and then a six week crossover period. Obese subjects had insulin resistance and endothelial dysfunction when compared to lean subjects (hyperinsulinemic-isoglycemic glucose clamp [median 25th-75th percentile]=4.3 [2.9-5.3] vs. 7.3 [5.7-11.3], P<0.0001; insulin-stimulated changes in brachial artery blood flow [% over basal]=12 [-6 to 84] vs. 39 [2-108], P<0.04). Glucosamine supplements had no significant affect on insulin resistance or endothelial dysfunction in either group. These results support the hypothesis that glucosamine supplements to not contribute to insulin resistance or endothelial dysfunction. 11
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