Primary studies included in this systematic review

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Primary study

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Combined Treatment With Chondroitin Sulfate and Glucosamine Sulfate Shows No Superiority Over Placebo for Reduction of Joint Pain and Functional Impairment in Patients With Knee Osteoarthritis: A Six-Month Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial

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Journal Arthritis & rheumatology (Hoboken, N.J.)
Year 2017
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This article is included in 2 Systematic reviews Systematic reviews (2 references)

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Objective To assess the efficacy and safety of combination therapy with chondroitin sulfate (CS) and glucosamine sulfate (GS) compared to placebo in patients with symptomatic knee osteoarthritis (OA). Methods A multicenter, randomized, double-blind, placebo-controlled study was performed in 164 patients with Kellgren/Lawrence grade 2 or grade 3 radiographic knee OA and moderate-to-severe knee pain (mean ± SD global pain score 62.1 ± 11.3 mm on a 100-mm visual analog scale [VAS]). Patients were randomized to receive either combined treatment with CS (1,200 mg) plus GS (1,500 mg) or placebo in a single oral daily dose for 6 months. The mean change from baseline in the VAS global pain score was set as the primary end point. Secondary outcomes included the mean change in the investigator's global assessment of disease activity, total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), pain and function subscale scores on the WOMAC, responder rates based on the Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) 2004 response criteria, and rescue medication use. Adverse events were also recorded. A Data and Safety Monitoring Board was instituted to ensure patient safety and data accuracy. Results Intriguingly, in the modified intent-to-treat (mITT) population, CS/GS combination therapy was inferior to placebo in the reduction of joint pain (mean ± SD change in VAS global pain score over 6 months −11.8 ± 2.4 mm [19% reduction] in patients receiving CS plus GS versus −20.5 ± 2.4 mm [33% reduction] in patients receiving placebo; peak between-group difference in global pain score at 6 months 8.7 mm [14.2%], P < 0.03), but no between-group differences were seen in the per-protocol completers. Both placebo treatment and CS/GS combination treatment improved to a similar extent the total WOMAC score as well as the pain and function WOMAC subscale scores, both in the mITT population and in the per-protocol completers. Neither the OMERACT-OARSI responder rate nor the frequency of rescue medication use differed between the treatment groups. Severe adverse events were uncommon and equally distributed. Conclusion The results of this trial demonstrate a lack of superiority of CS/GS combination therapy over placebo in terms of reducing joint pain and functional impairment in patients with symptomatic knee OA over 6 months. Further research might fully elucidate the suitability of CS/GS combination therapy in patients with OA.

Primary study

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Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms: a multicenter randomized, double-blind, placebo-controlled study.

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Authors Lugo JP , Saiyed ZM , Lane NE
Journal Nutrition journal
Year 2016
Links Pubmed DOI PubMed Central

This article is included in 3 Systematic reviews Systematic reviews (3 references)

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<b>BACKGROUND: </b>Undenatured type II collagen (UC-II) is a nutritional supplement derived from chicken sternum cartilage. The purpose of this study was to evaluate the efficacy and tolerability of UC-II for knee osteoarthritis (OA) pain and associated symptoms compared to placebo and to glucosamine hydrochloride plus chondroitin sulfate (GC).<b>METHODS: </b>One hundred ninety one volunteers were randomized into three groups receiving a daily dose of UC-II (40 mg), GC (1500 mg G &amp; 1200 mg C), or placebo for a 180-day period. The primary endpoint was the change in total Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) from baseline through day 180 for the UC-II group versus placebo and GC. Secondary endpoints included the Lequesne Functional Index (LFI), the Visual Analog Scale (VAS) for pain and the WOMAC subscales. Modified intent-to-treat analysis were performed for all endpoints using analysis of covariance and mixed model repeated measures, while incremental area under the curve was calculated by the intent-to-treat method.<b>RESULTS: </b>At day 180, the UC-II group demonstrated a significant reduction in overall WOMAC score compared to placebo (p = 0.002) and GC (p = 0.04). Supplementation with UC-II also resulted in significant changes for all three WOMAC subscales: pain (p = 0.0003 vs. placebo; p = 0.016 vs. GC); stiffness (p = 0.004 vs. placebo; p = 0.044 vs. GC); physical function (p = 0.007 vs. placebo). Safety outcomes did not differ among the groups.<b>CONCLUSION: </b>UC-II improved knee joint symptoms in knee OA subjects and was well-tolerated. Additional studies that elucidate the mechanism for this supplement's actions are warranted.<b>Trial Registration: </b>CTRI/2013/05/003663 ; CTRI/2013/02/003348 .

Primary study

Unclassified

Glucosamine and chondroitin for knee osteoarthritis: a double-blind randomised placebo-controlled clinical trial evaluating single and combination regimens.

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Journal Annals of the rheumatic diseases
Year 2015
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This article is included in 11 Systematic reviews Systematic reviews (11 references)

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<b>OBJECTIVE: </b>To determine if the dietary supplements, glucosamine and/or chondroitin, result in reduced joint space narrowing (JSN) and pain among people with symptomatic knee osteoarthritis. <b>METHODS: </b>A double-blind randomised placebo-controlled clinical trial with 2-year follow-up. 605 participants, aged 45-75 years, reporting chronic knee pain and with evidence of medial tibio-femoral compartment narrowing (but retaining &gt;2 mm medial joint space width) were randomised to once daily: glucosamine sulfate 1500 mg (n=152), chondroitin sulfate 800 mg (n=151), both dietary supplements (n=151) or matching placebo capsules (n=151). JSN (mm) over 2 years was measured from digitised knee radiographs. Maximum knee pain (0-10) was self-reported in a participant diary for 7 days every 2 months over 1 year. <b>RESULTS: </b>After adjusting for factors associated with structural disease progression (gender, body mass index (BMI), baseline structural disease severity and Heberden's nodes), allocation to the dietary supplement combination (glucosamine-chondroitin) resulted in a statistically significant (p=0.046) reduction of 2-year JSN compared to placebo: mean difference 0.10 mm (95% CI 0.002 mm to 0.20 mm); no significant structural effect for the single treatment allocations was detected. All four allocation groups demonstrated reduced knee pain over the first year, but no significant between-group differences (p=0.93) were detected. 34 (6%) participants reported possibly-related adverse medical events over the 2-year follow-up period. <b>CONCLUSIONS: </b>Allocation to the glucosamine-chondroitin combination resulted in a statistically significant reduction in JSN at 2 years. While all allocation groups demonstrated reduced knee pain over the study period, none of the treatment allocation groups demonstrated significant symptomatic benefit above placebo. <b>Trial Registration Clinicaltrialsgov Identifier: </b>NCT00513422; http://www.clinicaltrials.gov.

Primary study

Unclassified

Effect of Oral Glucosamine on Joint Structure in Individuals With Chronic Knee Pain: A Randomized, Placebo-Controlled Clinical Trial.

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Journal Arthritis & rheumatology (Hoboken, N.J.)
Year 2014
Links Pubmed DOI PubMed Central

This article is included in 3 Systematic reviews Systematic reviews (3 references) 1 Broad synthesis Broad syntheses (1 reference)

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OBJECTIVE: To determine the short-term efficacy of oral glucosamine supplementation by evaluating structural lesions in the knee joints, as assessed using 3T magnetic resonance imaging (MRI). METHODS: This study was designed as a randomized, double-blind, placebo-controlled trial. Recruitment was performed via mass mailings and an arthritis registry in southwestern Pennsylvania. In total, 201 participants with mild-to-moderate pain in one or both knees, as defined by a Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score ≥25 and ≤100, were enrolled. Of these subjects, 69.2% had a Kellgren/Lawrence grade ≥2 in at least 1 knee. Participants received 24 weeks of treatment with 1,500 mg glucosamine hydrochloride in beverage form or a placebo beverage. The primary outcome was decreased worsening of cartilage damage on 3T MRI of both knees, assessed according to a validated scoring system, the Whole-Organ MRI Score (WORMS). Secondary outcomes included change in bone marrow lesion (BML) scores in all knees and change in excretion of urinary C-terminal crosslinking telopeptide of type II collagen (CTX-II). RESULTS: The adjusted odds ratio (OR) for the likelihood of decreased cartilage damage over 24 weeks in any WORMS-scored subregion of the knee in the glucosamine treatment group compared to the control group was 0.938 (95% confidence interval [95% CI] 0.528, 1.666). Compared to subjects treated with glucosamine, control subjects showed more improvement in BMLs (adjusted OR 0.537, 95% CI 0.291, 0.990) but no difference in worsening BMLs (adjusted OR 0.691, 95% CI 0.410, 1.166) over 24 weeks. There was no indication that treatment with glucosamine decreased the excretion of urinary CTX-II (β = -0.10, 95% CI -0.21, 0.002). CONCLUSION: The results of this short-term study provide no evidence of structural benefits (i.e., improvements in MRI morphologic features or urinary CTX-II excretion) from glucosamine supplementation in individuals with chronic knee pain.

Primary study

Unclassified

Equivalence of a single dose (1200 mg) compared to a three-time a day dose (400 mg) of chondroitin 4&amp;6 sulfate in patients with knee osteoarthritis. Results of a randomized double blind placebo controlled study.

Journal Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society
Year 2013
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This article is included in 5 Systematic reviews Systematic reviews (5 references) 1 Broad synthesis Broad syntheses (1 reference)

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<b>OBJECTIVE: </b>Evaluation of the efficacy and safety of a single oral dose of a 1200 mg sachet of chondroitin 4&amp;6 sulfate (CS 1200) vs three daily capsules of chondroitin 4&amp;6 sulfate 400 mg (CS 3*400) (equivalence study) and vs placebo (superiority study) during 3 months, in patients with knee osteoarthritis (OA).<b>DESIGN: </b>Comparative, double-blind, randomized, multicenter study, including 353 patients of both genders over 45 years with knee OA. Minimum inclusion criteria were a Lequesne index (LI) ≥ 7 and pain ≥ 40 mm on a visual analogue scale (VAS). LI and VAS were assessed at baseline and after 1-3 months. Equivalence between CS was tested using the per-protocol procedure and superiority of CS vs placebo was tested using an intent-to-treat procedure.<b>RESULTS: </b>After 3 months of follow-up, no significant difference was demonstrated between the oral daily single dose of CS 1200 formulation and the three daily capsules of CS 400. Patients treated with CS 1200 or CS 3*400 were significantly improved compared to placebo after 3 months of follow-up in terms of LI (&lt;0.001) and VAS (P &lt; 0.01). No significant difference in terms of security and tolerability was observed between the three groups.<b>CONCLUSION: </b>This study suggests that a daily administration of an oral sachet of 1200 mg of chondroitin 4&amp;6 sulfate allows a significant clinical improvement compared to a placebo, and a similar improvement when compared to a regimen of three daily capsules of 400 mg of the same active ingredient.

Primary study

Unclassified

Chondroitin sulphate reduces both cartilage volume loss and bone marrow lesions in knee osteoarthritis patients starting as early as 6 months after initiation of therapy: a randomised, double-blind, placebo-controlled pilot study using MRI.

Journal Annals of the rheumatic diseases
Year 2011
Links Pubmed DOI PubMed Central

This article is included in 5 Systematic reviews Systematic reviews (5 references) 1 Broad synthesis Broad syntheses (1 reference)

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<b>OBJECTIVE: </b>To determine the effect of chondroitin sulphate (CS) treatment on cartilage volume loss, subchondral bone marrow lesions (BML), synovitis and disease symptoms in patients with knee osteoarthritis (OA).<b>METHODS: </b>In this pilot multicentre, randomised, double-blind, controlled trial in primary knee OA, 69 patients with clinical signs of synovitis were randomised to receive CS 800 mg or placebo once daily for 6 months followed by an open-label phase of 6 months in which patients in both groups received CS 800 mg once daily. Cartilage volume and BML were assessed by MRI at baseline and at 6 and 12 months; synovial membrane thickness was assessed at baseline and at 6 months.<b>RESULTS: </b>The CS group showed significantly less cartilage volume loss than the placebo group as early as 6 months for the global knee (p=0.030), lateral compartment (p=0.015) and tibial plateaus (p=0.002), with significance persisting at 12 months. Significantly lower BML scores were found for the CS group at 12 months in the lateral compartment (p=0.035) and the lateral femoral condyle (p=0.044). Disease symptoms were similar between the two groups.<b>CONCLUSION: </b>CS treatment significantly reduced the cartilage volume loss in knee OA starting at 6 months of treatment, and BML at 12 months. These findings suggest a joint structure protective effect of CS and provide new in vivo information on its mode of action in knee OA.

Publication Thread

STOPP (STudy on osteoarthritis progression prevention)

This thread includes 4 references

Primary study

Unclassified

The efficacy and tolerability of glucosamine sulfate in the treatment of knee osteoarthritis: a randomized, double-blind, placebo-controlled trial.

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Journal Current therapeutic research, clinical and experimental
Year 2009
Links Pubmed DOI PubMed Central

This article is included in 6 Systematic reviews Systematic reviews (6 references) 1 Broad synthesis Broad syntheses (1 reference)

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BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis and is often associated with disability and impaired quality of life. OBJECTIVE: The aim of the study was to assess the efficacy and tolerability of glucosamine sulfate (GS) in the treatment of knee OA. METHODS: Consecutive outpatients affected by primary monolateral or bilateral knee OA were enrolled in this double-blind, double-dummy, prospective, randomized, placebo-controlled trial. One group received GS 1500 mg QD for 12 weeks, and the other group received placebo QD for 12 weeks. The treatment period was followed by a 12-week treatment-free observation phase. Each patient was examined at baseline and at weeks 4, 8, 12, 16, 20, and 24. The primary efficacy criteria were pain at rest and during movement, assessed on a visual analog scale (VAS) of 0 to 100 mm. The secondary criteria included the Western Ontario and McMaster Universities (WOMAC) index for total pain score (W-TPS), total stiffness score (W-TSS), and total physical function score (W-TPFS). VAS, W-TPS, W-TSS, and W-TPFS were evaluated at baseline and at weeks 4, 8, 12, 16, 20, and 24. Analgesic drug consumption (ie, acetaminophen or NSAIDs) was also assessed. RESULTS: Patient demographics were similar in the GS and placebo groups. Of 60 randomized patients (30 per group), 56 completed the study (28 treated with GS and 28 who received placebo). Statistically significant improvements in symptomatic knee OA were observed, as measured by differences in resting pain at weeks 8, 12, and 16 (all, P &lt; 0.05 vs placebo) and in pain during movement at weeks 12 and 16 (both, P &lt; 0.05). W-TPS was lower with GS than placebo at weeks 8, 12, and 16 (all, P &lt; 0.01), and at week 20 (P &lt; 0.05). W-TSS was also lower with GS than placebo at weeks 8, 12, 16, and 20 (all, P &lt; 0.05). W-TPFS was lower with GS than placebo at weeks 8 (P &lt; 0.05), 12 (P &lt; 0.01), 16 (P &lt; 0.05), and 20 (P &lt; 0.05). Drug consumption was lower in the GS group than the placebo group at weeks 8, 12, 16, and 20 (all, P &lt; 0.05). The incidence of adverse events was 36.7% with GS and 40.0% with placebo. CONCLUSIONS: GS 1500 mg QD PO for 12 weeks was associated with statistically significant reductions in pain and improvements in functioning, with decreased analgesic consumption, compared with baseline and placebo in these patients with knee OA. A carryover effect was detected after treatment ended.

Primary study

Unclassified

Effect of glucosamine sulfate on hip osteoarthritis: a randomized trial.

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Journal Annals of internal medicine
Year 2008
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This article is included in 10 Systematic reviews Systematic reviews (10 references) 2 Broad syntheses Broad syntheses (2 references)

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<b>BACKGROUND: </b>The effectiveness of glucosamine sulfate as a symptom and disease modifier for osteoarthritis is still under debate.<b>OBJECTIVE: </b>To assess whether glucosamine sulfate has an effect on the symptoms and structural progression of hip osteoarthritis during 2 years of treatment.<b>DESIGN: </b>Randomized, controlled trial.<b>SETTING: </b>Primary care in the Netherlands.<b>PATIENTS: </b>222 patients with hip osteoarthritis who were recruited by their general practitioner. Patients were eligible if they met the American College of Rheumatology clinical criteria for hip osteoarthritis.<b>Intervention: </b>2 years of treatment with 1500 mg of oral glucosamine sulfate or placebo once daily.<b>Measurements: </b>Primary outcome measures were Western Ontario and McMaster Universities (WOMAC) pain and function subscales over 24 months and joint space narrowing after 24 months. The main secondary outcome measures were WOMAC pain, function, and stiffness after 3, 12, and 24 months.<b>RESULTS: </b>At baseline, both groups were similar in demographic and clinical variables. Overall, WOMAC pain did not differ (mean difference [glucosamine sulfate minus placebo], -1.54 [95% CI, -5.43 to 2.36]), nor did WOMAC function (mean difference, -2.01 [CI, -5.38 to 1.36]). Joint space narrowing also did not differ after 24 months (mean difference, -0.029 [CI, -0.122 to 0.064]). Only 1 of the sensitivity analyses, based on extreme assumptions regarding missing assessments due to total hip replacement, provided results consistent with a glucosamine effect.<b>Limitations: </b>Twenty patients had total hip replacement during the trial. Half of the patients had a Kellgren and Lawrence score of 1.<b>CONCLUSION: </b>Glucosamine sulfate was no better than placebo in reducing symptoms and progression of hip osteoarthritis. International Standard Randomised Controlled Trial Number: ISRCTN54513166.

Primary study

Unclassified

Effect of chondroitin sulphate in symptomatic knee osteoarthritis: a multicentre, randomised, double-blind, placebo-controlled study.

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Journal Annals of the rheumatic diseases
Year 2007
Links Pubmed DOI PubMed Central

This article is included in 6 Systematic reviews Systematic reviews (6 references) 2 Broad syntheses Broad syntheses (2 references)

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OBJECTIVE: To evaluate the efficacy and tolerability of chondroitin sulphate (chondroitin sulphate) in knee osteoarthritis. PATIENTS AND METHODS: A 24-week, randomised placebo-controlled trial of chondroitin sulphate (1 g/day) in patients with symptomatic knee osteoarthritis as measured on a visual analogue scale. Pain on daily activities and Lequesne's Index were the primary efficacy criteria. Secondary outcomes included the rate of responders according to the outcome measures in rheumatoid arthritis clinical trials of the Osteoarthritis Research Society International (OMERACT-OARSI) criteria, quality of life, patient's/physician's global assessments and carry-over effect after treatment. Biochemical markers of bone (CTX-I), cartilage (CTX-II) and synovium (hyaluronic acid) metabolism were also measured. Safety was assessed by recording adverse events (AEs). Statistical analysis was performed on the inter-group differences in the intention-to-treat population. RESULTS: 307 patients were included in the study. 28 (9%) patients discontinued the study because of lack of efficacy or AEs. At the end of treatment, the decrease in pain was -26.2 (24.9) and -19.9 (23.5) mm and improved function was -2.4 (3.4) (-25%) and -1.7 (3.3) (-17%) in the chondroitin sulphate and placebo groups, respectively (p = 0.029 and 0.109). The OMERACT-OARSI responder rate was 68% in the chondroitin sulphate and 56% in the placebo group (p = 0.03). The investigator's assessments and short form 12 (SF-12) physical component reported improvement more frequently in the chondroitin sulphate than in the placebo group (p = 0.044 and 0.021, respectively). No significant difference was observed between treatment groups for changes in biomarkers over 24 weeks. However, there was a significant difference between non-responders and responders according to the OARSI criteria for 24-week changes of CTX-I (p = 0.018) and CTX-II (p = 0.014). Tolerance was considered to be satisfactory. CONCLUSION: This study failed to show an efficacy of chondroitin sulphate on the two primary criteria considered together, although chondroitin sulphate was slightly more effective than placebo on pain, OMERACT-OARSI response rate, investigator's assessment and quality of life.