Glucosamine & Chondroitin: Additional Information

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Studies on Chondroitin Sulfate

1. Bucsi L and Poor G. Efficacy and tolerability of oral chondroitin sulfate as a symptomatic slow-acting drug for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis. Osteoarthritis and Cartilage 1998; 6 (Supplement A):31-36.
   
   
2. Daniel O Clegg, Domenic J Reda, Crystal L Harris, Marguerite A Klein, et al. Glucosamine, Chondroitin Sulfate, and the Two in Combination for Painful Knee Osteoarthritis. New England Journal of Medicine 2006; 354:795-808.
   

   Abstract: Background: 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. Methods: 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. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. Results: 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 (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups. Conclusions: Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890).

   
   
3. Mazieres B, et al. Chondroitin sulfate in osteoarthritis of the knee: a prospective, double blind, placebo controlled multicenter clinical study. J Rheum 2001 28:173-181.
   
   
4. Morreale P, et al. Comparison of the antiinflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. J Rheumatol 1996 23: 1385-1391.
   
   
5. Uebelhart D, Malaise M, Marcolongo R, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage 2004 Apr 12(4):269-76.

Studies on Glucosamine

1. Bruyere O, Pavelka K, Rovati LC, et al. Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: evidence from two 3-year studies. Menopause 2004 11(2):138-43.
   
   
2. Christgau S, Henrotin Y, Tanko LB, et al. Osteoarthritic patients with high cartilage turnover show increased responsiveness to the cartilage protecting effects of glucosamine sulphate. Clin Exp Rheumatol 2004 22(1):36-42.
   
   
3. Cibere J, Kopec JA, Thorne A, et al. Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis. Arthritis Rheum. 2004 51(5):738-45.
   
   
4. Daniel O Clegg, Domenic J Reda, Crystal L Harris, Marguerite A Klein, et al. Glucosamine, Chondroitin Sulfate, and the Two in Combination for Painful Knee Osteoarthritis. New England Journal of Medicine 2006; 354:795-808.
   
   Abstract: Background: 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. Methods: 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. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. Results: 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 (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups. Conclusions: Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890).
   
   
5. Herrero-Beaumont G et al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: A randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator. Arthritis & Rheumatism 2007; 56(2): 555-567.
   

   Abstract: Objective: To assess the effects of the prescription formulation of glucosamine sulfate (1,500 mg administered once daily) on the symptoms of knee osteoarthritis (OA) during a 6-month treatment course. Methods: 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 OA, was used as a side comparator. Patients were randomly assigned to receive oral glucosamine sulfate 1,500 mg once daily (n = 106), acetaminophen 3 gm/day (n = 108), or placebo (n = 104). The primary efficacy outcome measure was the change in the Lequesne index after 6 months. Secondary parameters included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and response according to the Osteoarthritis Research Society International criteria. These outcome measures were assessed using an intent-to-treat analysis. Results: At baseline, the study patients had moderately severe OA symptoms (mean Lequesne index 11 points). Glucosamine sulfate was more effective than placebo in improving the Lequesne score, with a final decrease of 3.1 points, versus 1.9 with placebo (difference between glucosamine sulfate and placebo -1.2 [95% confidence interval -2.3, -0.8]) (P = 0.032). The 2.7-point decrease with acetaminophen was not significantly different from that with placebo (difference -0.8 [95% confidence interval -1.9, 0.3]) (P = 0.18). Similar results were observed for the WOMAC. There were more responders to glucosamine sulfate (39.6%) and acetaminophen (33.3%) than to placebo (21.2%) (P = 0.004 and P = 0.047, respectively, versus placebo). Safety was good, and was comparable among groups. Conclusion: The findings of this study indicate that glucosamine sulfate at the oral once-daily dosage of 1,500 mg is more effective than placebo in treating knee OA symptoms. Although acetaminophen also had a higher responder rate compared with placebo, it failed to show significant effects on the algofunctional indexes.

6. Pavelka K, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis. Arch Intern Med 2002; 162:2113-2123.
   
   Abstract: Background: Conventional symptomatic treatments for osteoarthritis do not favorably affect disease progression. The aim of this randomized, placebo-controlled trial was to determine whether long-term (3-year) treatment with glucosamine sulfate can modify the progression of joint structure and symptom changes in knee osteoarthritis, as previously suggested. Methods: Two hundred two patients with knee osteoarthritis (using American College of Rheumatology criteria) were randomized to receive oral glucosamine sulfate, 1500 mg once a day, or placebo. Changes in radiographic minimum joint space width were measured in the medial compartment of the tibiofemoral joint, and symptoms were assessed using the algo-functional indexes of Lequesne and WOMAC (Western Ontario and McMaster Universities). Results: Osteoarthritis was of mild to moderate severity at enrollment, with average joint space widths of slightly less than 4 mm and a Lequesne index score of less than 9 points. Progressive joint space narrowing with placebo use was -0.19 mm (95% confidence interval, -0.29 to -0.09 mm) after 3 years. Conversely, there was no average change with glucosamine sulfate use (0.04 mm; 95% confidence interval, -0.06 to 0.14 mm), with a significant difference between groups (P = .001). Fewer patients treated with glucosamine sulfate experienced predefined severe narrowings (>0.5 mm): 5% vs 14% (P = .05). Symptoms improved modestly with placebo use but as much as 20% to 25% with glucosamine sulfate use, with significant final differences on the Lequesne index and the WOMAC total index and pain, function, and stiffness subscales. Safety was good and without differences between groups. Conclusion: Long-term treatment with glucosamine sulfate retarded the progression of knee osteoarthritis, possibly determining disease modification.
   
   
7. Reginster JY, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001; 357: 251-256.
   

   Abstract: Background: Treatment of osteoarthritis is usually limited to short-term symptom control. We assessed the effects of the specific drug glucosamine sulphate on the long-term progression of osteoarthritis joint structure changes and symptoms. Methods: We did a randomised, double-blind placebo controlled trial, in which 212 patients with knee osteoarthritis were randomly assigned 1500 mg sulphate oral glucosamine or placebo once daily for 3 years. Weightbearing, anteroposterior radiographs of each knee in full extension were taken at enrolment and after 1 and 3 years. Mean joint-space width of the medial compartment of the tibiofemoral joint was assessed by digital image analysis, whereas minimum joint-space width--ie, at the narrowest point--was measured by visual inspection with a magnifying lens. Symptoms were scored by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index. Findings: The 106 patients on placebo had a progressive joint-space narrowing, with a mean joint-space loss after 3 years of 20.31 mm (95% CI 20.48 to 20.13). There was no significant joint-space loss in the 106 patients on glucosamine sulphate: 20.06 mm (20.22 to 0.09). Similar results were reported with minimum joint-space narrowing. As assessed by WOMAC scores, symptoms worsened slightly in patients on placebo compared with the improvement observed after treatment with glucosamine sulphate. There were no differences in safety or reasons for early withdrawal between the treatment and placebo groups. Interpretation: The long-term combined structure-modifying and symptom-modifying effects of gluosamine sulphate suggest that it could be a disease modifying agent in osteoarthritis.
   

8. P.R. Usha and M.U.R. Naidu. Randomised, Double-blind, Parallel, Placebo-Controlled Study of Oral Glucosamine, Methylsulfonylmethane and their Combination in Osteoarthritis. Clin Drug Invest 2004 24(6):353-363.
   
   Abstract: Objective: Glucosamine, classified as a slow-acting drug in osteoarthritis (SADOA), is an efficacious chondroprotective agent. Methylsulfonylmethane (MSM), the isoxidised form of dimethyl-sulfoxide (DSMO), is an effective natural analgesic and anti-inflammatory agent. The aim of this study was to compare the efficacy and safety of oral glucosamine (Glu), methylsulfonylmethane (MSM), their combination and placebo in osteoarthritis of the knee. Patients and design: A total of 118 patients of either sex with mild to moderate osteoarthritis were included in the study and randomised to receive either Glu 500mg, MSM 500mg, Glu and MSM or placebo capsules three times daily for 12 weeks. Patients were evaluated at 0 (before drug administration), 2, 4, 8 and 12 weeks post-treatment for efficacy and safety. The efficacy parameters studied were the pain index, the swelling index, visual analogue scale pain intensity, 15m walking time, the Lequesne index, and consumption of rescue medicine. Results: Glu, MSM and their combination significantly improved signs and symptoms of osteoarthritis compared with placebo. There was a statistically significant decrease in mean (± SD) pain index from 1.74 ± 0.47 at baseline to 0.65 ± 0.71 at week 12 with Glu (p < 0.001). MSM significantly decreased the mean pain index from 1.53 ± 0.51 to 0.74 ± 0.65, and combination treatment resulted in a more significant decrease in the mean pain index (1.7 ± 0.47 to 0.36 ± 0.33; p < 0.001). After 12 weeks, the mean swelling index significantly decreased with Glu and MSM, while the decrease in swelling index with combination therapy was greater (1.43 ± 0.63 to 0.14 ± 0.35; p < 0.05) after 12 weeks. The combination produced a statistically significant decrease in the Lequesne index. All treatments were well tolerated. Conclusion: Glu, MSM and their combination produced an analgesic and anti-inflammatory effect in osteoarthritis. Combination...
   
   
9. C. Valvason, E. Musacchio, A. Pozzuoli, R. Ramonda, R. Aldegheri and L. Punzi. Influence of glucosamine sulphate on oxidative stress in human osteoarthritic chondrocytes: effects on HO-1, p22^Phox and iNOS expression. Rheumatology 2008; 47:31-35.
   
   Abstract: Objective: Reactive oxygen species (ROS) are major determinants in the alteration of articular cartilage. Among protective cellular mechanisms, the inducible isoform of haem oxygenase (HO-1) plays a particularly relevant role. On the other hand, the enzymatic activity of the Nicotinamide adenine dinucleotide phosphate (NADPH) system could contribute to the generation of ROS. Glucosamine sulphate (GS) is one of the drugs used in the treatment of osteoarthritis; however, its mechanism of action is still largely unknown. The aim of the present study was to investigate the effects of GS on primary human chondrocytes in vitro, in particular with regard to HO-1, p22Phox (a subunit of NADPH complex) and inducible nitric oxide synthase (iNOS) expression. Methods: Primary human chondrocytes were treated with different concentrations of GS; gene expression of HO-1, p22Phox and iNOS was assessed by the reverse transcriptase-polymerase chain reaction method. In a separate set of experiments, the cells were stimulated with human recombinant interleukin (IL)-1
   and simultaneously treated with GS. Moreover, HO-1 protein and total nitrite production were evaluated. Results: HO-1 gene expression was up-regulated (þ40% with respect to the controls, P<0.001) by 10 mmol/l GS at 24 h, while p22Phox gene expression was down-regulated by 10 mmol/l GS with a maximum inhibitory effect observed after 48 h treatment. IL-1
   stimulation induced expression of iNOS reverted by 1 and 10 mmol/l GS. Moreover, HO-1 gene expression was down-regulated by IL-1
   and 10 mmol/l GS restored baseline values. These data were confirmed by evaluating HO-1 protein level and nitrite production. Conclusions: The influence of GS on oxidative stress observed in this study discloses a possible new mechanism of action and seems to be in keeping with a potential protective effect on chondrocyte population.