Glucosamine and Chondroitin shine in new study …

Gluco-Chondro Combo
Ties Osteoarthritic Drug


As good for pain as the leading osteoarthritis drug

By Will Block

A new study — designed to compare the efficacy and safety of the nutrients chondroitin sulfate plus glucosamine hydrochloride versus the drug celecoxib — has found that the nutrient combo works as well as the drug with knee osteoarthritis and severe pain.1 The new study is termed the MOVES trial (Multicenter Osteoarthritis interVEntion trial with SYSADOA). SYSADOA stands for symptomatic slow-acting drugs for osteoarthritis.

This sizeable intervention trial involving 606 patients was multi-centered and designed to evaluate treatment with either chondroitin sulfate plus glucosamine hydrochloride or celecoxib in 606 patients with moderate to near high levels of osteoarthritis and moderate-to-severe associated pain.

Osteoarthritis is Common, Widespread, and Costly

Arthritis is a form of joint malady that involves inflammation of the joints. There are many forms of arthritis, perhaps as great as 100 different types.2 The most common form of arthritis is osteoarthritis (degenerative joint disease), which usually affects the knees and the hips, leading to pain and loss of function. Osteoarthritis results from either trauma to the joint, infection of the joint, or age.

The progression of the disease typically starts with tenderness and pain, followed by limitations of movement and impairment of quality of life. It is a huge social and economic burden. By the age of 60, osteoarthritis affects 9.6% of men and nearly twice that (18%) of women.3

When total medical visits are considered, osteoarthritis ranks high in costs. And with increasing lifespan, it is expected to become the fourth leading cause of disability within the next 5 years.

Conventional Treatment

Standard treatment concentrates on symptom relief with analgesics and non-steroidal anti-inflammatory drugs (NSAIDs). Analgesics can cause a variety of side effects, such as allergic symptoms (difficulty breathing, hoarseness, swelling, itching, hives, and rash). They may precipitate stomach upset, constipation, diarrhea, dizziness, or headache. NSAIDS are much more problematic and can cause serious gastrointestinal and cardiovascular adverse effects, leading to deep concerns over long-term use.

In the prescription drug department celecoxib—used in the two principal studies reviewed in this article—is a COX-2 selective NSAID. It is used to treat the signs and symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute pain in adults, painful menstruation, and juvenile rheumatoid arthritis in patients two years or older.


In the GAIT study’s
primary outcome, a significant
difference was observed for the
gluco-chondro combo
in subjects with
moderate-to-severe pain, defined as a
20% decrease in pain.


Side effects include a 37% increase in incidence of major vascular events, which include nonfatal myocardial infarction, nonfatal stroke, or death from a blood vessel-related cause. Additionally, an 81% increase in incidence of upper gastrointestinal complications occurs, which include perforations, obstructions, or gastrointestinal bleeding as in all NSAIDs.

Benchmark Study

Assorted clinical trials have been performed with SYSADOA. The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT), published in The New England Journal of Medicine in 2006, utilized glucosamine hydrochloride and chondroitin sulfate, alone and in combination, and celecoxib for the treatment of knee osteoarthritis.4 This was a multicenter randomized, double-blinded, placebo-controlled study comparing the efficacy and safety of the nutrient combo and the drug. The subjects of the study — with a mean age of 59 years, 64 percent of whom were women — received 500 mg of glucosamine plus 400 mg of chondroitin sulfate three times daily, 200 mg of celecoxib (Celebrex®) daily, or placebo for 6 months. The study was quite similar to the MOVES study, with two main differences: there were separate nutrient groups (glucosamine and chondroitin alone) in the GAIT study and that in the MOVES study the measurement technology was more advanced.

Although no statistically significant effects were observed for the combination group in the overall study population, a significant difference was observed for the combination nutrient arm in patients with moderate-to-severe pain for the primary outcome, defined as a 20% decrease in a standard index that measured pain.

Plus, patients with moderate-to-severe pain showed significant differences in the combination versus placebo group for an outcome measured response, along with a 50% decrease in pain in accordance with a pain measurement, function measurement score, and a questionnaire pain score.


Also in the GAIT study, subjects with
moderate-to-severe pain
showed significant differences in the
nutrient combo versus placebo for an
outcome measured response, along
with a 50% decrease in pain.


To Confirm Results of the GAIT Study

To confirm the effects of the GAIT study, the current MOVES trial was conducted to test whether chondroitin sulfate plus glucosamine hydrochloride has comparable efficacy to celecoxib after 6 months of treatment in patients with painful knee osteoarthritis.

The MOVES trial was a phase IV trial (a study done after the drug has been marketed; from which safety has been evaluated),  multicenter, non-inferiority, randomized, parallel-group, double-blind study. Patients were recruited consecutively by physicians in public or private practice at sites in France, Germany, Poland and Spain.

Patient Criteria

Eligible patients were ≥40 years of age, with a diagnosis of primary knee osteoarthritis according to the American College of Rheumatology, with radiographic evidence of osteoarthritis, and severe pain score ≥301 on a 0 – 500 scale at the point of patient inclusion.

Patients were excluded if they had concurrent medical or arthritic conditions that could confound the evaluation of the index joint or coexisting disease that could preclude successful completion of the trial, such as history of cardiovascular or gastrointestinal events and were excluded due to use of celecoxib.

Treatment regimens for eligible subjects were randomized to receive 500 mg glucosamine hydrochloride plus 400 mg chondroitin sulfate three times a day (for a total of 1500 glucosamine HCl and 1200 mg chondroitin sulfate) or 200 mg celecoxib (Celebrex) every day for 6 months. The 200 mg dose of celecoxib is the recommended dose for osteoarthritis.

Subjects receiving combination therapy took six capsules of chondroitin sulfate 200 mg plus glucosamine hydrochloride 250 mg per day; those receiving celecoxib took one celecoxib 200 mg plus one placebo capsule (in the morning) and four further placebo capsules per day. To maintain the blind (among patients, physicians, site staff and contract research organization), celecoxib capsules were over-encapsulated and placebo capsules had an identical appearance to the combination product. Patients were allowed to take up to 3 g/day of acetaminophen as rescue medication, except during the 48 hours before clinical evaluation.


Patients were allowed to take up to
3 g/day of acetaminophen
as rescue medication, except
during the 48 hours
before clinical evaluation.


Outcome Measures

The primary outcome measure was defined as the mean decrease in a well-known arthritis index, the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale from baseline to 6 months. There was also a secondary outcome, for efficacy which measures such items as: stiffness and function (also from WOMAC); visual analogue scale; presence of joint swelling/effusion; use of rescue medication (according to diary entries and tablet counts); patients’ and investigators’ global assessments of disease activity and response to therapy, and health status at 6 months. All outcome measures were assessed at 30, 60, 120 and 180 days. Safety outcomes included discontinuation of study treatment due to adverse events (AEs), changes in various laboratory measures and vital signs.

Statistical Analysis

The main analyses were performed using the per-protocol population, defined as all randomized patients meeting the inclusion criteria, who received study medication, had a baseline and at least one post-baseline efficacy measurement (for the primary efficacy variable) and did not have major significant protocol violations.

In non-inferiority trials — where the design attempts to prove equivalency of treatment — the per-protocol set is used in the primary analysis as it is the most conservative approach. Furthermore, the primary efficacy analysis was performed according to intention to treat to test the robustness of the results.


Celecoxib inhibits
prostaglandin biosynthesis,
primarily through blocking the
cyclooxygenase-2 enzyme, thereby
achieving rapid reduction of
osteoarthritis of the knee,
but …
it does not alter other processes
underlying the disease.


The safety population was defined as all randomized subjects who took at least one dose of the study medication. Continuous efficacy variables were analyzed by means of mixed models for repeated measurements (MMRM) approach — a mixed model is a statistical model containing both fixed effects and random effects, that is mixed effects. Included in the MMRM analysis were time, treatment-by-time interaction and baseline value as a covariate. The variance-covariance matrix was unstructured.

Other reasons were not imputed and were handled by the MMRM approach, which relies on the missing at random assumption. Sensitivity analyses were conducted using the baseline observation carried forward and the MMRM with no imputation.

Patient Characteristics

A total of 763 patients were screened and 606 underwent randomization. The principal reasons for the dropouts were high cardiovascular risk, patient decision and low WOMAC pain score. Of the 606 subjects randomized, 568 were included in the intention-to-treat analysis and 522 in the per-protocol analysis.

Of the 603 subjects included in the safety population, 465 completed the study, without differences between treatments. The mean ± SD age at baseline was 62.7±8.9 years, 438 (83.9%) who were women and 515 (98.7%) were Caucasian. The overall mean WOMAC pain score was 371.3±41.6.

The Non-Inferiority of the Outcomes

The mean change from baseline to 6 months in WOMAC pain score was −185.7 (−200.3 to −171.1) (a decrease of 50.1%) in the chondroitin sulfate plus glucosamine group and −186.8 (−201.7 to −171.9) (a decrease of 50.2%) in the celecoxib group. These were similar to the GAIT study.

The corresponding mean difference respected the non-inferiority margin of −40 units: −1.1 (−22.0 to 19.8) in the main analysis. All sensitivity analyses confirmed the non-inferiority conclusion. There were no differences at 6 months between treatment groups in the WOMAC stiffness score, with a decrease of 46.9% in the combination group, compared with a decrease of 49.2% in the celecoxib group; WOMAC function score, with a decrease of 45.5% in the combination group compared with a decrease of 46.4% in the celecoxib group and visual analogue scale, with a decrease of 48.0% in the combination group versus a decrease of 48.8% in the celecoxib group. Similarly, there were no differences in patients’ and physicians’ global assessments of disease activity or response to therapy. Over 70% of patients fulfilled alternative pain, physical function, and structure criteria in both treatments from 120 days onwards.

At 6 months, both treatments achieved a 79% response rate. Both groups elicited a reduction from baseline >50% in joint swelling, from 12.5% to 5.9% for chondroitin sulfate plus glucosamine, and from 14.0% to 4.5% for celecoxib. A similar reduction was also seen for effusions, from 6.8% to 3.0% and from 7.8% to 4.1% respectively. The consumption of rescue medication throughout the study was low and similar between treatments, except for the first month when use was higher in the combination group.


Celecoxib increases the risk of
cardiovascular thrombotic events,
congestive heart failure, and
major gastrointestinal events
compared with placebo, and
in the European Union
is contraindicated in patients with
known cardiovascular and
peripheral vascular disease.


Health-Related Quality of Life

All components of the test measuring quality of life showed improvements over the treatment period in both groups. At 6 months, no differences were apparent between groups in terms of mobility, self-care, usual activities, pain/discomfort, anxiety/depression or general health status measured by the visual analogue score (see Fig. 1).

Figure 1. Western Ontario and McMaster osteoarthritis index (WOMAC) (A) pain, (B) stiffness and (C) function subscales, and (D) visual analogue scale by visit; (E) Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) responder criteria, (F) joint swelling, (G) joint effusion and (H) consumption of rescue medication, by visit. The p values compare values between treatments. Data are least-square means±SEM. CE, celecoxib; CS+GH, chondroitin sulfate plus glucosamine hydrochloride.
LEM1503GlucoFig1_274.gif
(click on thumbnail for full sized image)

AEs were about the same in the nutrient and drug groups. Only 2.3% were serious in the chondroitin sulfate plus glucosamine group compared with 3.3% in the celecoxib group. One serious AE was judged as definitely related to the study medication (allergic dermatitis) and one as possibly related (dizziness) (both in the celecoxib group); three serious AEs were judged to be most likely related to the study group, two in the chondroitin sulfate plus glucosamine group (Helicobacter pylori gastritis and allergic reaction) and one in the celecoxib group (dermatitis psoriaform). The other 12 were deemed to be unlikely or unrelated to study medication. No deaths occurred in this study. A total of 44 of 603 patients discontinued the study medication due to an AE, 22 in each treatment group. Parameters determined from blood and urine, vital signs and physical examination were similar in both groups.

Comparable Efficacy

The MOVES trial found that a fixed-dose combination of chondroitin sulfate plus glucosamine has comparable efficacy to celecoxib in reducing pain in patients with osteoarthritis of the knee with moderate-to-severe pain after 6 months of treatment. The reduction in pain was both clinically important and statistically significant (50% reduction in both groups), as was the improvement in stiffness (46.9% reduction with the combination vs 49.2% with celecoxib), and function (45.5% vs 46.4%), respectively. Similar improvements were seen in visual analogue scale, the pain/discomfort dimension of and patients’ and investigators’ assessments of disease activity and response to therapy without differences between treatments.

Indeed, four-fifths of patients met the responder criteria (in both groups). Other clinical symptoms, such as swelling/effusion, improved to the same extent in both groups and the consumption of rescue medication was similar. These results both confirm and extend those from the GAIT study in patients with severe knee pain.

Chondroitin sulfate and glucosamine have a slow onset of response and provide long-lasting pain relief and functional improvement in osteoarthritis. In the current study, celecoxib was superior to chondroitin sulfate and glucosamine at 1 – 4 months (in terms of WOMAC scores and the visual analogue scale), but by 6 months, response to the combo glucosamine HCl and chondroitin sulfate was similar to celecoxib (see Fig. 1).

Studies have demonstrated antiinflammatory effects of both glucosamine HCl and chondroitin sulfate. Both inhibit metalloproteinase activity (capable of degrading all kinds of extracellular matrix proteins, including a number of bioactive molecules), prostaglandin E2 release (induces fever and suppresses T cell receptor signaling), nitric oxide production and degradation of glycosaminoglycans (these long unbranched polysaccharides attract water and are therefore useful in the body as a lubricant or as a shock absorber), as well as stimulate the synthesis of hyaluronic acid in the joint. Chondroitin sulfate stimulates collagen synthesis, while glucosamine inhibits prostaglandin release.

However, while each substance exerts beneficial effects on the processes underlying osteoarthritis, a number of studies have demonstrated that many of these effects benefit from the synergy observed with combined glucosamine and chondroitin sulfate treatment. In contrast, celecoxib inhibits prostaglandin biosynthesis, primarily through blocking the cyclooxygenase-2 enzyme, thereby achieving rapid reduction in signs and symptoms of osteoarthritis of the knee, but it does not alter other processes underlying the disease. This difference in the mechanisms of action is supported by the present results, which indicate more substantial and faster response for celecoxib than for chondroitin sulfate plus glucosamine up to 120 days, but by 6 months there are no significant differences between the two treatments across all outcomes. Indeed, the overall pain improvement calculated using area under the curve analyses was superior with celecoxib than with the combination.


The use of a placebo arm
was not considered necessary, as the
design of the MOVES study was
similar to that of the GAIT study,
which already compared both active
treatments with placebo.


Both treatments had a good safety profile and tolerability in this population, which excluded patients with high cardiovascular or gastrointestinal risk. However, celecoxib is recognized to increase the risk of cardiovascular thrombotic events, congestive heart failure and major gastrointestinal events compared with placebo, and in the European Union is contraindicated in patients with known cardiovascular and peripheral vascular disease. Around half of the patients in each group had at least one AE, most of which were of mild or moderate intensity, with only 17 events classified as serious. The observed tolerability in both groups was as expected from previous studies, such as GAIT.

While the present results are consistant with data from other studies for the nutrient combination, and for celecoxib in painful knee osteoarthritis at the same dosage, direct comparisons are limited by differences in study designs and drug formulations. The only randomized double-blind study that allows the comparison of the combination of chondroitin sulfate plus glucosamine with celecoxib was the GAIT study. The data of efficacy and safety in the present study are consistent with those from GAIT in patients with severe knee pain.

Chondroitin and glucosamine have been recommended in some practice guidelines for the treatment of osteoarthritis. Both chondroitin sulfate and the two commercially available salts of glucosamine hydrochloride or sulfate are available as prescription medicines in the European Union for the treatment of osteoarthritis. In the USA, prescriptions are not required. The clinical evidence to support these nutrients is, however, conflicting. Consequently, current evidence-based guidelines on the management of osteoarthritis focus on topical treatments and oral analgesics, and some advise against treatment with chondroitin sulfate and glucosamine on the basis of lack of efficacy evidence, but not on potential harm. Conversely, the suboptimal efficacy and possibility of serious adverse drug reactions with long-term use of analgesics, NSAIDs and opioids are well recognized.


Overall, the results
confirm that the combination of
chondroitin sulfate plus glucosamine
hydrochloride has proven
to be equal to celecoxib in
reducing pain.


Long-Term Efficacy and Safety Demonstrated

The present study, conducted in patients with osteoarthritis of the knee with severe pain, provides robust data to demonstrate the long-term efficacy and safety of glucosamine HCl plus chondroitin sulfate in the management of these patients, and suggests that this combination may offer an alternative, especially for individuals with cardiovascular or gastrointestinal conditions who have contraindications for treatment with NSAIDs.

This study has some limitations, including the fact that the present results cannot be generalized to other compound mixtures, such as commercially available dietary supplements in the UK and the USA, or to the individual components themselves.

As patients with known cardiovascular disease and those at high risk for both cardiovascular and gastrointestinal disease were not included, it is not possible to extend the safety of the combination to this population. Yet other studies with the two nutrients have not found any safety concerns.

The study was designed as a non-inferiority trial with two active treatment arms. The use of a placebo group was not considered appropriate for ethical and methodological reasons. The reason: a non-inferiority trial requires that the reference treatment’s efficacy is established or is in widespread use, as is the case for celecoxib, so that a placebo or untreated control group would be deemed unethical. This is of special relevance in this specific patient population with moderate-to-severe pain. Furthermore, the use of a placebo arm was not considered necessary, as the design of the MOVES study was similar to that of the GAIT study, which already compared both active treatments with placebo. Additionally, both treatment groups have already demonstrated superiority compared with placebo in former randomized controlled trials.

GAIT Non-Inferior Results Confirmed

Overall, the results confirm that the combination of chondroitin sulfate plus glucosamine hydrochloride has proven non-inferior (or equal) to celecoxib in reducing pain. No differences were found for stiffness, functional limitations, joint swelling and effusion after 6 months of treatment in patients with severe pain from osteoarthritis of the knee, and the combination has a similar good safety profile and tolerability. This combination of SYSADOA appears to be beneficial in the treatment of patients with osteoarthritis of the knee and should offer a safe and effective alternative for those patients with cardiovascular or gastrointestinal conditions.

References

  1. Hochberg MC, Martel-Pelletier J, Monfort J, et al. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis. 2015 Jan 14. pii: annrheumdis-2014-206792. doi: 10.1136/annrheumdis-2014-206792. [Epub ahead of print]
  2. Arthritis: Joint inflammation; Joint degeneration [Internet]. Bethesda (MD): National Institutes of Health; January 22, 2014. [updated 2014 Jan 22; cited 2015 Feb 26]. Available from: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002223/
  3. Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ. 2003;81(9):646-56.
  4. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795 – 808.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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