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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Roman-Blas JA, et al. "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". Arthritis & Rheumatology. 2017. 69(1):77-85.
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Clinical Question

In patients with osteoarthritis of the knee, does the use of glucosamine plus chondroitin decrease pain and improve functionality?

Bottom Line

Combined treatment with Chondroitin Sulfate and Glucosamine Sulfate were inferior to placebo for reduction of joint pain and functional impairment in patients with knee osteoarthritis.

Major Points

Background: Although there are contradictory results in regards to the use of CS/GS treatment for OA, it is widely used in Western countries. This study aims to further clarify whether or not this treatment is beneficial by avoiding bias, maintaining concealment and randomization, and using products of high quality. Patients with symptomatic knee OA, who met the inclusion criteria and had no exclusion criteria, were randomly assigned into a treatment arm, whether it was the CS plus GS or the placebo.

Study Design: The design of the study was a randomized, double blind, placebo controlled trial taking place at multiple centers over a period of six months. A total of 158 patients participated with 80 receiving treatment and 78 receiving placebo. The primary outcome measured was a reduction of pain using a pain scale from 0-100. The results of the study were that the reduction of pain was actually greater in the placebo group than in the treatment group, rendering it ineffective. The placebo group had a pain score reduction of 20.5 (33%) while the treatment group only had a reduction of 11.8 (19%).

Interpretation: Although the study size was small and there were a large number of dropouts, the results from this study are still significant. These results resemble another study conducted by the National Center for Complementary and Integrative Health and in addition support the recommendations made by the American College of Rheumatology.

Guidelines

According to the American College of Rheumatology guidelines of 2012, patients with osteoarthritis should not use chondroitin sulfate, glucosamine, or topical capsaicin. New guidelines for 2018 will be posted later this year.

Design

• Trial type- A Six Month Multicenter, Randomized, Double-Blind, Placebo Controlled Clinical Trial
• N=158 patients
• Experimental arm= 80 patients with CS/GS
• Standard=78 patients with placebo
• Setting: 9 rheumatology referral centers and one orthopedic surgery referral center in Spain
• Enrollment- unknown
• Mean follow up- 6 months
• Analysis populations:

                       1) modified intent-to-treat: includes patients that received at least one dose of treatment and had at least one follow up
                       2) Per-protocol 
                       3) Safety population: all patients that received at least one dose of treatment

• Primary outcome: mean difference between the baseline pain score and the pain scores at the end of the trial assessed by a VAS with a range of 0-100.

Population

Inclusion Criteria

• Patients with primary symptomatic knee OA, diagnosed according to the American College of Rheumatology criteria for knee OA, who were classified as having radiographic grade 2 or grade 3 knee OA according to the Kellgren/Lawrence scale.
• During the pre-inclusion week, all recruited patients were required to have moderate-to-severe knee pain defined by a self-reported global pain scale of 40-80 mm on a 100 mm visual analog scale

Exclusion Criteria

• Obesity (BMI ≥ 35 kg/m2), concurrent arthritic conditions, or any coexisting disease that could prevent successful completion of the study.

Baseline Characteristics

• Duration of knee OA (years) - 6.1 ± 5
• Global pain scale (0-100 mm VAS) - 62.0 ± 11.7
• Investigator’s global assessment of disease activity (0-100 mm VAS) - 56.9 ± 14.8
• WOMAC score (0-100 mm VAS):

                            1) Total 52.0 ± 15.3
                            2) Pain 53.2 ± 15.5
                            3) Function 51.7 ± 16.1

Interventions

The intervention made was using 1,200 mg of Chondroitin sulfate from bovine tracheal cartilage and 1,500 mg of glucosamine sulfate of crustacean origin, both made by Tedec Meiji Farma, in combination to reduce pain associated with osteoarthritis. This was formulated and taken once daily, as was the placebo. In addition, the patients were able to use acetaminophen as needed for breakthrough pain for a maximum dose of 3 grams per day, and all other medications taken for symptoms were discontinued. The patients were followed over a period of six months with follow up occurring after the baseline visit at 4, 12, and 24 weeks.

Outcomes

Comparisons are dietary supplements vs. placebo.

Primary Outcomes

Modified intent-to-treat population

Global pain score

Placebo (n=78): -20.5 ± 2.4 CS/GS (n=80): -11.8 ± 2.4 P= 0.029

Per-Protocol completes

Global pain score

Placebo (n=64): -20.1 ± 2.6 CS/GS (n=55): -13.6 ± 2.8 P= 0.072

Secondary Outcomes

Modified intent-to-treat population

Investigator’s global assessment of disease activity

Placebo: -21.7 ± 2.1 CS/GS: -15.1 ± 2.1 P= 0.039

WOMAC score

Total

Placebo: -14.8 ± 2.0 CS/GS: -8.9 ± 2.0 P= 0.047

Pain

Placebo: -15.7 ± 2.2 CS/GS: -8.8 ± 2.2 P= 0.043

Function

Placebo: -14.3 ± 2.0 CS/GS: -9.0 ± 2.0 P= 0.068

Per-protocol completes

Investigator’s global assessment of disease activity

Placebo: -20.8 ± 2.2 CS/GS: -17.3 ± 2.4 P= 0.154

WOMAC score

Total

Placebo: -15.2 ± 2.0 CS/GS: -11.6 ± 2.4 P= 0.129

Pain

Placebo: -16.0 ± 2.4 CS/GS: -11.2 ± 2.6 P= 0.127

Function

Placebo: -14.7 ± 2.2 CS/GS: -11.8 ± 1.4 P= 0.175

Adverse Events

There was a higher incidence of dropout in the CS/GS combination therapy group consisting mainly due to abdominal symptoms such as diarrhea, upper abdominal pain, and constipation. There was, however, few withdrawals associated with other reasons in the CS/GS combination therapy group compared to the placebo group. AE related to treatment: Placebo: 19 (24.35%) CS/GS: 33 (41.25%) Total: 52 (32.91%) P= 0.0181

Criticisms

Some limiting factors of this study were:

• The small size and large number of dropouts. Osteoarthritis is a disease that can hinder daily life tasks, and if patients are not feeling relief, they will not continue with treatment.
• CS/GS therapy caused adverse events in some patients which could have skewed the pain score with the stomach pain acting as a counterirritant.
• In previous studies, the same daily dose was studied but given twice a day unlike the once daily dosing of this study. There was no difference found in the efficacy of once daily dosing and divided daily dosing so these results cannot be explained by the change in the dosage regimen.

Funding

“Tedec Meiji Farma provided the study drug but had no role in the study design or in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit the manuscript for publication. Publication of this article was not contingent upon approval by Tedec Meiji Farma.”

Further Reading

References:

1. Glucosamine and Chondroitin for Osteoarthritis.” National Center for Complementary and Integrative Health, U.S. Department of Health and Human Services, 24 Sept. 2017, nccih.nih.gov/health/glucosaminechondroitin

2. Hochberg, Marc C., et al. “American College of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and Knee.” Arthritis Care & Research, vol. 64, no. 4, 2012, pp. 465–474., doi:10.1002/acr.21596.