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
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Clinical Question
In patients with symptomatic osteoarthritis of the knee, is the combined treatment of glucosamine and chondroitin safe and effective in reducing joint pain, based on the VAS global pain score, as compared to the placebo?
Bottom Line
Chondroitin Sulfate (CS) and Glucosamine (GS) used in combination therapy is not more efficacious in reducing pain when compared to placebo in patients with symptomatic knee osteoarthritis over a 6 month period.
Major Points
Chondroitin sulfate and Glucosamine are supplements used to reduce the pain and loss of function associated with osteoarthritis (OA). Chondroitin and Glucosamine are both found naturally in the cartilage of joints. These supplements are synthesized in the laboratory or harvested from animals. However, their efficacy is often under criticism because most studies show little to no improvement in symptoms compared to placebo. The objective of this study was to assess the efficacy and safety of chondroitin sulfate and glucosamine used in combination therapy compared to placebo in treating patients with symptomatic knee OA. The primary endpoint of the study was a mean reduction, from baseline, in the VAS global pain score. Secondary endpoints included a mean change in the investigator’s global assessment of disease activity, total WOMAC pain and function subscale scores, responder rates based on the Outcome Measures in Rheumatology (OMERACT)- Osteoarthritis Research Society international (OARSI) 2004 response criteria, and rescue medication use. The study design existed as a multicenter, double-blind, placebo controlled, randomized clinical trial that included 164 patients. These patients experienced moderate-to-severe knee pain (mean +/- SD global pain score 62.1 +/- 11.3 mm on a 100-mm visual analog scale [VAS]) and Kellgren/Lawrence grade 2 or grade 3 radiographic knee OA. Randomized patients received either a combination treatment of chondroitin sulfate (CS) 1,200 mg plus glucosamine sulfate (GS) 1,500 mg or a placebo in a single, oral daily dose for 6 months. The combination therapy of CS/GS was inferior to the placebo in mean reduction of pain as per VAS global pain score. Combination treatment of CS/GS was not more efficacious in reducing joint pain associated with symptomatic osteoarthritis. In fact, the results indicate that the placebo resulted in better pain reduction and the study was stopped early for this reason. In practice, consider alternative lines of therapy that have strong evidence for reducing joint pain associated with osteoarthritis.
Guidelines
Osteoarthritis Research Society International guidelines (2014, adapted)
Guidelines for non-surgical management of knee osteoarthritis recommend weight loss, muscle strengthening, and analgesic/antiinflammatory drugs. Nonsteroidal antiinflammatory drugs (NSAIDs), paracetamol, and opioids are the most frequently prescribed medications in daily clinical practice, although long-term use of these drugs is associated with a high incidence of side effects. There is much controversy surrounding the use of slow acting drugs in OA such as, CS and GS.
Design
Study Design
- Multicenter, randomized, double-blind, placebo-controlled study
- N= 158
- Chondroitin sulfate plus glucosamine sulfate (n=80)
- Placebo (n=78)
- Setting: 9 rheumatology referral centers and 1 orthopedic surgery referral center in Spain
- Follow up: 4, 12, and 24 weeks following the baseline visit
- Analysis: Modified intention-to-treat
- Primary outcome: Assess the efficacy of chondroitin sulfate plus glucosamine sulfate (CS/GS) therapy compared to placebo after 6 months of treatment in patients with painful knee OA using the self-reported global pain score 0-100 mm Visual analogue scale (VAS).
- VAS global pain scale is a scale consisting of a 100 mm line fixed by 2 verbal descriptors for symptoms. “No pain” indicated score of zero and “worst imaginable pain” indicated score of 100. Patients were asked each visit “how much pain did you experience in your knee during the previous week?”
Population
Inclusion Criteria
- Primary symptomatic knee OA classified as having grade 2 or grade 3 knee OA by the Kellgren/Lawrence scale
- Moderate-to-severe knee pain with a self-reported global pain score of 40-80 mm on 100 mm visual analog scale
Exclusion Criteria
- Obesity (BMI ≥35 kg/m2)
- Concurrent arthritic conditions
- Coexisting disease that could preclude successful completion of the study
Baseline Characteristics
- Demographics: Women 85%, age 65 +/- 8, BMI (kg/m2 ) 28.5 +/- 3.4
- Duration of knee OA: 6.3 +/- 5 years
- Global Pain Score (0-100 mm VAS): 62.2 +/- 11.0
- Investigator’s global assessment of disease activity (0-100 mm VAS): 57.2 +/- 11.8
- Western Ontario and McMaster Universities Index (WOMAC) score
- An assessment of pain, stiffness, and and physical function in patients with knee or hip osteoarthritis consisting of 24 items that are divided into the 3 subscales.
- Total 52.7 +/- 11.9
Interventions
- Patients were randomized to a group using block randomization:
- Single oral daily dose of chondroitin sulfate 1200 mg (CS) plus crystalline glucosamine sulfate 1500 mg (GS)
- Placebo (conveniently masked)
- Global pain score 0-100 mm VAS to assess pain at every visit
- WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) scores, pain, and function scores were assessed at every visit
- Only acetaminophen allowed as rescue medication (maximum dosage of 3 gm/day) except for 48 hrs prior to clinical evaluation
Outcomes
Comparisons are intensive therapy vs. standard therapy.
Primary Outcomes
The primary endpoint of the study was a mean reduction, from baseline, in the VAS global pain score. The outcome showed a greater reduction in pain of the placebo group compared to the treatment group.
- Placebo vs CS/GS
- -20.5 +/- 2.4 vs -11.8 +/- 2.4; [p=0.029]
Secondary Outcomes
- Annual rate of death from any cause
- 1.41% vs. 1.14% (HR 1.22; 95% CI 1.01-1.46; P=0.04)
- Placebo vs CS/GS
- -20.7 +/- 2.1 vs -15.1 +/- 2.1; [p=0.039]
Adverse Events
Severe adverse events were uncommon and equally distributed. Although a high incidence of adverse events was observed, only a small number of dropouts were reported from both groups. The majority of adverse events were due to abdominal symptoms such as diarrhea, upper abdominal pain, and constipation. Placebo vs CS/GS
- At least one AE: 50% vs 58.75%
- At least one SAE: 2.56% vs 2.50%
- AE leading to treatment discontinuation: 3.84% vs 11.25%
Criticisms
- The possibility of uneven quality of the products tested could have altered the results. However, the quality of both CS and GS were approved by the Spanish Medicines Agency, which strengthened results.
- There was a loss to follow up due to lack of efficacy (N=12, Figure 1), which could have affected the results. This could be attributed to patients wanting immediate relief from pain.
- The long term efficacy of the intervention is undetermined due to only a 6 month period in the study.
Funding
Tedec Meiji Farma provided the study drug but had no other role. Publication of this article was not contingent upon approval by Tedec Meiji Farma