Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre randomised, double-blind, non-inferiority trial versus celecoxib

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Hochberg MC, et al. "Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre randomised, double-blind, non-inferiority trial versus celecoxib". Annals of Rheumatological Diseases. 2014. :.
PubMed

Clinical Question

Is combined chondroitin/glucosamine as safe and effective as celecoxib in reducing pain and improving function in patients with painful knee osteoarthritis?

Bottom Line

For patients with symptomatic knee osteoarthritis, high dose combination of glucosamine and chondroitin was as safe and effective as celecoxib at 6 months in decreasing pain while increasing the usability of the knee joint.

Major Points

Osteoarthritis is the most common form of arthritis and it affects mostly weight bearing joints, including the knees. It can restrict movement, cause a decrease in quality of life, and it is associated with morbidity and overall financial distress. Symptomatic relief is the primary goal of therapy with treatment options including analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs). The combination of chondroitin sulfate and glucosamine hydrochloride can offer benefits and decreased gastrointestinal side effects.[1]

The 2006 Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) randomized 1583 adults over the age of 40 with symptomatic knee osteoarthritis to receive glucosamine alone, chondroitin alone, glucosamine and chondroitin, celecoxib, or placebo for 24 weeks. Although treatment with celecoxib has as a faster response time, overall, differences between placebo and various agents were relatively small. This trial supports that chondroitin/glucosamine is as effective as celecoxib at 24 weeks.[2]

In this 2014 phase IV, multicentre, non-inferiority, randomized, parallel-group, double blind study (MOVES), chondroitin sulfate and glucosamine hydrochloride were compared to celecoxib to determine if there was a significant difference between the two medications in decreasing WOMAC pain score subscale from baseline to 6 months. In this study, 606 patients were divided into two study groups, one group receiving the combination of 400 mg chondroitin plue 500 mg glucosamine three times per day (n=304) and one group receiving 200 mg celecoxib once daily (n=302). At 180 days, there was no significant difference in WOMAC pain score from baseline (-185.7 in chondroitin/glucosamine vs. -186.8 in celecoxib).3

The MOVES trial found no significant difference in pain relief or increased function of the joint when using chondroitin/glucosamine combination or celecoxib alone. The trial contained criticisms including: an unclear allocation process and all of the authors had some affiliation with the manufacturers of chondroitin. In a 2015 Cochrane Review containing 43 randomized controlled trials, chondroitin appeared to improve pain in an adult patient with knee osteoarthritis when compared to placebo and celecoxib. Most trials in the Cochrane Review had at least one limitation including: unclear allocation concealment, unclear or no blinding, or a high dropout rate.4 Further research needs to be done to impact the confidence and quality of potential outcomes.[3]


Guidelines

In 2012, the American College of Rheumatology recommended that chondroitin sulfate and glucosamine should not be used for initial management (conditional recommendation).[4]

As of July 2016, there are no available guidelines addressing chondroitin/glucosamine versus celecoxib for treating symptoms of osteoarthritis.

Design

  • Multicentered, randomised, double-blind, non-inferiority trial
  • N=606
    • Chondroitin and glucosamine: n=304
    • Celecoxib: n=302
  • Setting: 42 practice sites in France, Germany, Poland and Spain
  • Enrollment: September 2011 - April 2013
  • Mean follow-up: 6 months
  • Analysis: Per-protocol
  • Primary outcome: Decrease in Western Ontario and McMaster osteoarthritis index (WOMAC) pain score at 6 months

Population

Inclusion Criteria

  • Patients ≥40 years of age
  • Diagnosis of primary knee osteoarthritis
  • Radiographic evidence (Kellgren and Lawrence Grade 2 or 3) of knee osteoarthritis
  • Severe pain (>301 on a 0-500 scale according to the WOMAC pain score)
  • Negative pregnancy test at screening and form of acceptable birth control

Exclusion Criteria

  • Patients having concurrent medical or arthritic conditions
  • Coexisting conditions such as:
    • Cardiovascular disease
    • Gastrointestinal disease
  • Allergy to shellfish or any other ingredient contained in the control and experimental medication
  • Fibromyalgia diagnosis
  • Patients who have uncontrolled hypertension (> 150/95) or diabetes mellitus (A1c level >8%)
  • Subjects who have a history of alcohol or substance abuse within 3 years
  • Female patients who are breastfeeding

Baseline Characteristics

From the chondroitin sulfate/glucosamine group. Both groups were similar

  • Mean age: 62 years
  • Women: 87%
  • White 98.5%
  • BMI: 31 kg/m2
  • Radiographic readings:
    • Grade 2: 63%
    • Grade 3: 37%
  • Analgesics used before inclusion:
    • Acetaminophen 28%
    • Ibuprofen 17% (17% in chondroitin sulfatae/glucosamine group vs 14.3% in celecoxib group)
    • Diclofenac 13%
  • WOMAC score (mean):
    • Pain 372
    • Stiffness 130
    • Function 1131
  • Joint swelling: 12.5%
  • Joint effusion: 6.8%
  • Health related quality of life - all elements similar between groups

Interventions

All capsules had identical appearance

Treatment with chondroitin sulfate/glucosamine (experimental)

  • 2 - 400mg/500mg capsules given three times a day
  • 6 capsules daaily

Treatment with celecoxib (control)

  • 200mg capsules given once daily
  • 1 active capsules daily + 5 placebo capsules

Outcomes

Comparisons are chondroitin sulfate+glucosamine hydrochloride vs. celecoxib

Primary Outcomes

WOMAC pain score
Baseline: 130.2±35.0 vs. 129.5±37.2
180 Days: 185.8 vs. 184.7 (-1.1; 95% CI -22.0 to 19.8; p=0.92)
Change: -185.7 vs -186.8

Secondary Outcomes

WOMAC stiffness score
1.41% vs. 1.14% (HR 1.22; 95% CI 1.01-1.46; P=0.04)
Baseline: 1131.4±242.7 vs. 1111.6±37.2
Change: -60.4 vs. -63.7
WOMAC function score
Baseline: 1131.4±242.7 vs. 1111.6±37.2
180 Days: 617.0 vs. 595.8 (-21.2; 95% CI -87.3 to 45.0; p=0.53)
Change: -504.4 vs. -525.6
Huskisson’s visual analogue scale
Baseline: 72.8±15.1 vs. 73.5±15.1
180 days: 617.0 vs. 595.8 (-0.22; 95% CI -4.8 to 4.3; p=0.92)
Change: -35.1 vs. -35.3
OMERACT-OARSI responders
188 vs. 175 (p=0.91)
Joint swelling
14 vs. 10 (p=0.91)
Joint effusion
7 vs. 9 (p=0.61)
Consumption of rescue medication (acetaminophen 500 mg)
Used days 120-180: 31 vs. 29 (p=0.58)
Patients’ global assessment of disease activity
Baseline: 69.1±17.3 vs. 69.4±16.4
180 days: 38.3 vs. 36.9 (-1.5; 95% CI -5.8 to 2.9; p=0.51)
Change: -31.0 vs. -32.4
Investigators’ global assessment of disease activity
Baseline: 63.2±15.5 vs. 63.3±14.7
180 days: 35.3 vs. 33.4 (-1.9; 95% CI -5.8 to 2.0; p=0.33)
Change: -27.8 vs. -29.7
Patients’ global assessment of response to therapy
180 days: 36.8 vs. 36.0 (-0.8; 95% CI -5.6 to 4.0; p=0.74)
Investigators’ global assessment of response to therapy
180 days: 34.7 vs. 33.8 (-0.9; 95% CI -5.4 to 3.6; p=0.70)
EuroQol-5D
Mobility: 1.5±0.03 vs. 1.5±0.03 (p=0.16)
Self-care: 1.2±0.03 vs. 1.2±0.03 (p=0.94)
Usual activities: 1.4±0.03 vs. 1.4±0.03 (p=0.73)
Pain/discomfort: 1.8±0.03 vs. 1.9±0.03 (p=0.60)
Anxiety/depression: 1.4±0.04 vs. 1.3±0.04 (p=0.21)
Visual analogue scale: 69.1±1.3 vs. 70.2±1.3 (p=0.54)

Adverse Events

Adverse events are chondroitin sulfate/glucosamine vs. celecoxib

  • Serious adverse events: 7 vs. 10 (2.7% vs. 3.9%)
    • 1 was judged as definitely related to celecoxib (allergic dermatitis)
    • 1 was judged as possibly related to celecoxib (dizziness)
    • 3 were judged as probably related to the study group
      • 2 in chondroitin+glucosamine group (Helicobacter pylori gastritis and allergic reaction)
      • 1 in celecoxib group (dermatitis psoriasiform)
    • Other 12 were deemed unlikely or unrelated to study medication
  • 44 of 603 patients dicontinued the study medication due to an AE
    • 22 in each treatment group

Criticisms

  • People with a history of cardiovascular disease and gastrointestinal disease were excluded from the study
  • Study was limited to primarily Caucasian woman
  • It was unclear if allocation was adequately concealed
  • Authors declared their conflict of interests, however, the authors received personal fees from Bioiberica SA (manufacturers of chondroitin sulfate)

Funding

  • Bioiberica SA (Barcelona, Spain) both sponsored and funded the trial by contributing necessary medications of no charge to the participants in this study
  • All expenses were accounted for by Bioiberica SA
  • The funding body participated in the study design as well as data interpretation

Further Reading

  1. Lawrence RC et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum. 1998. 41:778-99.
  2. Clegg DO et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N. Engl. J. Med. 2006. 354:795-808.
  3. Hochberg MC et al. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann. Rheum. Dis. 2016. 75:37-44.
  4. Hochberg MC 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 Res (Hoboken) 2012. 64:465-74.