knee osteoarthritisOsteoarthritis is a local disease of synovial joints, most commonly the hands, hips, knees, and spine. Loss of articular cartilage and new bone formation at the joint margins (osteophytes) with joint space narrowing characterize osteoarthritis.1

Osteoarthritis has several risk factors including age, gender, genetics, and behavioral influences. Before age 50, the prevalence of osteoarthritis in most joints is higher in men than women. After age 50, osteoarthritis of the hand, foot, and knee is more common in women.1

About 40% to 60% of patients with osteoarthritis of the hand, knee, hip, and spine have relatives with similar conditions. Genetic predisposition appears to be the product of multiple, not yet identified genes.2

About one-third of older adults in the U.S. are affected by knee osteoarthritis. Obesity is a well known risk factor for knee osteoarthritis. With the increasing health problem of obesity, knee osteoarthritis is like to become an even more common condition. Advanced knee osteoarthritis is the most common reason for elective joint replacement.2

Some clinical research suggests glucosamine can reduce joint space narrowing.3 Other clinical research suggests chondroitin may likewise have a disease-modifying effect.4 New research attempts to address the role of glucosamine and chondroitin in the treatment of knee osteoarthritis. Other researchers have associated a possible dietary deficiency with osteoarthritis.

The GAIT Study

Long awaited results of the NIH-funded study, the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) have recently become available in abstract form.5 NIH is withholding comment on the study until the full results are published in peer-reviewed form.

GAIT was a five-armed multicenter study that randomized 1,583 patients aged 40 years and older. Sixty-four percent were female. All subjects had at least six months duration of knee pain and radiographic evidence of knee osteoarthritis. Patients with mild knee pain, as classified by the Western Ontario and McMaster Universities (WOMAC) pain severity (125-300 mm) and moderate to severe pain score (WOMAC pain severity 301-400 mm) were included.

Patients were randomized to take glucosamine hydrochloride 500 mg three times daily, chondroitin sulfate 400 mg three times daily, a combination of glucosamine hydrochloride and chondroitin at these doses three times daily, celecoxib (Celebrex) 200 mg daily, or placebo. Acetaminophen, up to 4 grams per day, was allowed for additional pain relief.5

Patients were evaluated at baseline and at four, eight, 16, and 24 weeks. The primary outcome measure was a 20% improvement from baseline WOMAC pain severity at week 24.5

Celecoxib was better than placebo in all patients for pain relief (70.1% response rate for celecoxib compared with 60.1% response for placebo, p=0.008). Glucosamine hydrochloride, chondroitin sulfate, and the combination were no better than placebo for relieving pain in patients with mild pain. In the 20% of patients who had moderate to severe pain (WOMAC pain severity 301-400 mm), the combination of glucosamine and chondroitin was superior to placebo (79.2% response rate for the combination and 54.3% for placebo, p=0.002).5

The authors concluded that the combination of glucosamine hydrochloride and chondroitin sulfate is effective for treating moderate to severe knee pain caused by osteoarthritis.5

The GUIDE Study

Unlike GAIT, which was performed in the U.S., the Glucosamine Unum in Die Efficacy (GUIDE) trial was performed in Europe. This study used glucosamine sulfate, a product available by prescription only in Europe.6

GUIDE was a three-armed study that randomized 318 patients (88% women) with knee osteoarthritis as defined by American College of Rheumatology criteria. Treatments were glucosamine sulfate soluble powder 1500 mg per day, acetaminophen 1 g three times a day, or placebo for six months. For blinding, researchers used a double-dummy technique. Patients were allowed ibuprofen 400 mg as rescue medication.6

The primary outcome measure was changes from baseline in the Lequesne index at six months. Secondary outcomes were changes in WOMAC score and Osteoarthritis Research Society International (OARSI-A) responder criteria.6

Glucosamine sulfate was superior to placebo in all three outcome measures: Lequesne p=0.032 [difference = 1.2 (-2.3 to -0.80)], WOMAC p=0.039 [difference = -4.7 (-9.1 to -0.2)], and OARSI-A responders 39.6% versus 21.2% for placebo (p=0.007). Acetaminophen trended to more response than placebo, but reached statistical significance only for the OARSI-A measure.6

The authors concluded that glucosamine sulfate might be the preferred symptomatic medication for knee osteoarthritis.6

Selenium and Knee Osteoarthritis

This is an epidemiological study of 942 subjects with a mean age of 59.8 years. The group consisted of 33% males and 39.8% blacks. All submitted toenails for selenium assessment. All subjects underwent radiologic evaluation of the knees. Knee osteoarthritis was classified as none, unilateral, or bilateral; and severity as none, mild, moderate/severe.7

Mean selenium levels were 0.75 ppm. Selenium levels were lower for blacks versus whites (0.71 vs 0.78, p<0.0001), men versus women (0.73 vs 0.76, p<0.0001), and those with any knee osteoarthritis, bilateral knee ostearthritis, and severe knee osteoarthritis (p< =0.05).7

For every increase of 0.1 ppm of selenium, the odds of knee osteoarthritis, bilateral knee ostearthritis, and severe knee osteoarthritis were decreased by approximately 15% to 20%. The adjusted odds ratio (95% confidence interval) was 0.85 (0.72-1.00) for knee osteoarthritis; 0.79 (0.65-0.96) for bilateral knee osteoarthritis; and 0.82 (0.69-0.98) for severe knee osteoarthritis. Compared with those in the lowest tertile, for those in the highest tertile the odds of knee osteoarthritis were 0.62 (0.37-1.02); for bilateral knee osteoarthritis 0.54 (0.31-0.97); and severe knee osteoarthritis 0.56 (0.34-0.94).7

The authors concluded that low toenail selenium levels are associated with increased risk of knee osteoarthritis, bilateral knee osteoarthritis, and severe knee osteoarthritis.7

The Bottom Line

Clinical trials looking at glucosamine or chondroitin or the combination for osteoarthritis pain and disease progression have produced mixed findings.8 Newly available research, unfortunately, does little to clarify the issue.

Most studies that have found benefit from glucosamine have used the sulfate salt, which was used in the GUIDE study. However these studies have been criticized for being sponsored by industry (mostly Rotta Pharmaceutical Company, which makes a prescription-only glucosamine sulfate product in Europe).9

A recent meta-analysis indicates that that glucosamine sulfate (Rotta brand) is superior to placebo in the treatment of pain and functional impairment caused by osteoarthritis. But, no glucosamine product improved WOMAC outcomes of pain, stiffness and function better than placebo.10

Until more details of the GAIT trial are available, it is not possible to tell how glucosamine hydrochloride plus chondroitin compares with celecoxib. Also, the GAIT trial suggests that the combination might be effective for moderate to severe osteoarthritis, how this combination compares with glucosamine sulfate is unknown. There are no head-to-head trials of glucosamine sulfate and glucosamine hydrochloride.

For now, recommend glucosamine sulfate as an initial choice for patients who are interested in a dietary supplement to treat osteoarthritis. For patients with more severe disease, moving to a combination glucosamine/chondroitin product may be worth a try.

The actual content (versus the labelled content) of glucosamine and chondroitin products varies widely.10 Tell patients to stick to products that have been evaluated by USP.

Tell patients to avoid products with extra ingredients such as manganese and methylsulfonylmethane (MSM). There’s no reliable evidence that they work better than glucosamine or chondroitin alone, but may increase the risk of adverse effects.8

Avoid using chondroitin in men with prostate cancer. Preliminary clinical research suggests that chondroitin may cause the spread or recurrence of prostate cancer. This effect has not been shown with supplemental chondroitin sulfate. But until more is known, advise men with prostate cancer or those at increased risk for prostate cancer to avoid chondroitin.8

If patients ask about selenium and osteoarthritis, suggest increasing intake of foods that contain high amounts of selenium. Although selenium content varies with geographical areas, crab, liver, fish, poultry, and wheat are generally good selenium sources.8 Tell patients that research is needed to tell if selenium supplements can prevent osteoarthritis.

Project Leader in preparation of this Detail-Document: Gayle Nicholas Scott, Pharm.D., BCPS, ELS

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1 Neame R, Doherty M. Osteoarthritis update. Clin Med 2005;5:207-10.

2 Wu CW, Kalunian KC. New developments in osteoarthritis. Clin Geriatr Med 2005;21:589-601.

3 Richy F, Bruyere O, Ethgen O, et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med 2003;163:1514-22.

4 Michel BA, Stucki G, Frey D, et al. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized, controlled trial. Arthritis Rheum 2005;52:779-86.

5 Clegg DO, Reda DJ, Harris CL, et al. The efficacy of glucosamine and chondroitin sulfate in patients with painful knee osteoarthritis (OA) The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT). American College of Rheumatology Annual Meeting. San Diego November 12 – 17, 2005. Abstract 622.

6 Herrero-Beaumont G, Roman JA, Trabado MC, et al. Effects of glucosamine sulfate on a 6-month control of knee osteoarthritis symptoms vs placebo and acetaminophen: Results from the Glucose Unum in Die Efficacy (GUIDE) Trial. American College of Rheumatology Annual Meeting. San Diego November 12 – 17, 2005. Abstract 1203.

7 Jordan JM, Fang F, Arab L, et al. Low selenium levels are associated with increased risk for osteoarthritis of the knee. American College of Rheumatology Annual Meeting. San Diego November 12 – 17, 2005. Abstract 1189.

8 Jellin JM, Gregory PJ, Batz F, et al. Pharmacist’s Letter/Prescriber’s Letter Natural Medicines Comprehensive Database. Chondroitin sulfate monograph. (Accessed November 16, 2005).

9 Chard J, Dieppe P. Glucosamine for osteoarthritis: magic, hype, or confusion? It’s probably safe-but there’s no good evidence that it works. BMJ 2001;322:1439-40.

10 Towheed TE, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005;(2):CD002946