In 1993, the publication of a survey on the use of what was then termed “unconventional medicine”¹ surprised many in the traditional medical community. The report showed that in a nationwide sample of 1539 adults, 34% said they used some form of what has come to be known as complementary and alternative medicine (CAM) in the preceding year. In addition, it was estimated that expenditures on these types of therapies cost close to $14 billion, more than out-of-pocket annual expenditures on hospitalizations in the United States. In the ensuing years, it has become clear that the use of CAM has grown. More recently, the 2002 Centers for Disease Control National Health Interview Survey estimated from a sample of 31,044 U.S. adults that 49.8% have used CAM for health reasons.² Furthermore, a number of studies looking specifically at patients with rheumatic diseases, including osteoarthritis (OA), have found that they use CAM more frequently than the general public.³ A 1997 survey showed that 63% of 232 patients surveyed with either rheumatoid arthritis (RA) or OA used some type of alternative care for their arthritis.⁴ A 2001 survey of 480 elderly subjects with arthritis showed that 66% had used CAM for their arthritis.⁵ The array of therapies has expanded as well. The Institute of Medicine estimated that in 2004, 29,000 products were on the market with 1,000 new products being developed annually.⁶ Sales of dietary supplements alone accounted for $16 billion in annual sales,⁶ and others have estimated that total costs for CAM to be comparable to the total out-of-pocket expenditures for physician services in the United States.⁷

The National Center for Complementary and Alternative Medicine (NCCAM) was established by Congress in 1998 to explore CAM therapies in a rigorous scientific context, train researchers, and disseminate authoritative information to the public and to health care professionals. NCCAM has defined CAM as a group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine. This definition is subject to change over time as various therapies are adopted into the standard treatment for OA or other diseases. The NCCAM divides these therapies into five categories: biologically based therapies such as dietary supplements and herbal products; alternative medicine systems such as homeopathy, naturopathy, traditional Chinese medicine, and Ayurvedic medicine; manipulative and body-based therapies such as chiropractic, osteopathy, and massage; mind-body interventions such as meditation and prayer; and energy therapies such as qi gong, Reiki, therapeutic touch, and the application of magnetic fields.

The reasons patients give for choosing CAM therapies are varied. Many arthritis patients cite “pain control” as the most important reason.⁴ This may reflect the inadequacy of their current analgesia, but might also reflect the sense that patients using CAM are doing so on their own initiative. In addition, patients may view CAM therapies as less toxic than prescription medications.⁴ Nonetheless, most CAM users are likely to be taking prescription medications along with their alternative therapies and to be under the care of medical physicians.⁵ In fact, CAM users often feel that CAM used in combination with conventional medicine is more likely to help than either alone.²

OA patients are cited as frequent CAM users in large part because of their high rate of consumption of glucosamine compounds. Glucosamine and chondroitin are used by over 5 million Americans each year² and accounted for close to $750 million in annual sales in 2004.⁸ Glucosamine is an amino-monosaccharide and one of the basic constituents of the disaccharide units of articular cartilage glycosaminoglycans. Glucosamine is reduced in osteoarthritic cartilage, and, therefore, the notion of replenishing glucosamine by taking dietary supplements is appealing. However, just how useful glucosamine is as a therapy for OA, either for symptom relief or disease modification, remains controversial.

A considerable amount of in vitro and animal data has been amassed regarding potential mechanisms of action by which glucosamine could treat OA. Work from the 1990s suggested that glucosamine could stimulate proteoglycan synthesis by human chondrocytes and become incorporated into glycosaminoglycans.⁹

However, some have questioned whether or not glucosamine is absorbed in amounts large enough to significantly influence macromolecular synthesis in humans and whether glucosamine would be likely to arrive intact within articular cartilage and become available to the chondrocytes there. In vitro experiments in human chondrocytes show that more than 99% of the galactosamine in chondroitin sulfate (CS) is produced from endogenously produced glucose rather than from exogenously available H-glucosamine.^3,10 The circumstances under which proteoglycan production by chondrocytes would preferentially rely on exogenously administered glucosamine are unclear.¹¹

Experiments have shown that orally administered glucosamine is detectable in rats given about 17 times the usual human dose (maximum level 100 μmol/L)¹² and in dogs given 8 times the human dose (maximum level 50 μmol/L).¹³ Recently, glucosamine has been detected in human serum using high performance liquid chromatography after oral glucosamine ingestion.¹⁴ Glucosamine levels were initially undetectable in all 18 subjects with OA tested. Subjects received 1500 mg of crystalline glucosamine sulfate mixed in water. In one subject, glucosamine levels remained undetectable throughout the subsequent 3 hours of testing. In the others, serum glucosamine levels reached a maximum of 4.8 (range 0-11.5) μmol/L at a mean of 2 hours after ingestion. Interestingly, subjects who had previously taken glucosamine had an earlier onset of a detectable level, delayed time to maximum level, and higher maximum levels. In two subjects, additional measurements showed a considerable reduction in glucosamine levels at 5 hours and a return to baseline undetectable levels at 8 hours. Based on these pharmacokinetic data, the investigators felt it was unlikely that glucosamine contributes to chondroitin synthesis in vivo.

Other work has suggested that glucosamine might have additional effects and some of these might be relevant to a potential beneficial mechanism of action in OA. They include countering enzymatic or inflammatory processes leading to degradation of cartilage. At concentrations of 50 to 400 μmol/L, glucosamine inhibits IL-1β-induced matrix metalloproteinase activity in human OA articular chondrocytes.¹⁵ At concentrations of 5 mmol/L, glucosamine inhibits aggrecanase-mediated degradation of aggrecan in explant cultures of bovine articular cartilage.¹⁶ Glucosamine at concentrations of 1 to 4.5 mg/mL in culture with rat chondrocytes antagonizes IL-1β-induced nitric oxide and prostaglandin E2 production.¹⁷ It was recently shown that glucosamine effects on MMP-13, aggrecanase 1, and IL-1β-induced expression of inducible nitric oxide synthase and cyclooxygenase 2 may occur at the level of gene expression. Reductions in corresponding levels of mRNA were detected in normal equine chondrocyte culture at glucosamine concentrations of only 10 μg/mL.¹⁸ Interestingly, it has recently been shown that orally administered glucosamine sulfate, dosed at 1500 mg/d for 14 days, is detectable in the plasma and synovial fluid of subjects with knee OA at concentrations of 7.9 ± 3.9 μM and 7.2 ± 3.2 μM, respectively,¹⁹ 3 hours after the last dose has been given.

Many short term clinical trials were carried out over a number of years to assess the analgesic efficacy of glucosamine in the treatment of osteoarthritis. Each was small and short term and meta-analyses were subsequently carried out on a number of these trials to clarify their conclusions. One meta-analysis of many of the early trials²⁰ suggested that there was short-term analgesic benefit from the use of glucosamine and that short-term use was safe. The magnitude of the effect was comparable to that seen with nonsteroidal anti-inflammatory drugs (NSAIDs) but delayed in onset by weeks by comparison. Larger trials have since been carried out and further meta-analyses done. The first of the larger and longer term trials involved 212 subjects with osteoarthritis of the knee who received either oral glucosamine at a dose of 1500 mg daily or placebo for 3 years.²¹ Subjects were evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and with weight-bearing anteroposterior view radiographs of the knees. Fluoroscopy was used to correct lower limb positioning for the radiographs. The trial showed that subjects who received glucosamine had modest pain reduction based on the WOMAC (average of 11.7% reduction in WOMAC score in the intention to treat analysis), while those in the placebo group worsened (average of 9.8% worsening) and the difference between these average scores was statistically significant. Radiographs of those who received placebo showed a mean of 0.31 mm (range: 0.13–0.48 mm loss) of joint space narrowing in the medial joint compartment at the end of 3 years in the intention to treat analysis. Those who received glucosamine had a mean of 0.06 mm of joint space narrowing (range: 0.22-mm loss to 0.09-mm gain). The difference between these two mean figures was statistically significant. Interestingly, there was no correlation between the improvement of symptoms and radiographic findings. The side effects of glucosamine did not differ from those of placebo.

A subsequent study of 202 subjects used a similar trial design and got similar results.²² Participants were randomized to receive either 1500 mg of crystalline glucosamine
sulfate or placebo for 3 years. In the intention to treat analysis at 3 years, the subjects treated with glucosamine had a mean reduction of 8 points in their WOMAC total scores (from a total of 30.48 points at baseline), while those in the placebo group had a mean reduction of 4.9 points (from a total of 30.70 points at baseline). This was a statistically significant difference. Intention to treat analysis of radiographs of those who received placebo showed a mean of 0.19 mm (range: 0.09–0.29 mm loss) of joint space narrowing on anteroposterior weight-bearing radiographs of the knee in full extension with fluoroscopic positioning of the center of the x-ray beam. In the glucosamine treated group, there was a mean gain in joint space of 0.04 mm (range: 0.06 mm loss to 0.14 mm gain). This difference was statistically significant. Again, glucosamine did not differ from placebo in the frequency or type of side effects noted.

Both of these studies have been interpreted to support the contention that glucosamine is a disease-modifying treatment for osteoarthritis. Acceptance of this conclusion hinges on the interpretation of the radiographic outcome measures used. Subsequent studies have suggested that the reliability and reproducibility of the anteroposterior knee radiograph as a measure of OA progression can be influenced by a number of technical²³ and patient specific²⁴ factors. Unequivocal evidence of the ability of glucosamine to modify structure in OA awaits the development of more precise outcome measures.

Additional studies and meta-analyses have cast doubt on the ability of glucosamine to modify symptoms in a meaningful way in OA. One discontinuation trial has recently been published.²⁵ This study enrolled 137 current users of glucosamine (whether subjects used the sulfate or hydrochloride formula was not specified) who had experienced subjective improvement in their knee pain when they started using glucosamine. Participants were randomized to receive either 1500 mg of glucosamine sulfate in tablet form or placebo for 6 months. They were assessed throughout the trial for the presence of a disease flare, defined as either the patient’s perception of worsening of symptoms with a concomitant increase of at least 20 mm in WOMAC pain on walking (using a visual analog scale) or a worsening of the physician global assessment by at least 1 grade (on a 1 to 5 scale). In the intention to treat analysis, 28 (42%) of the 66 subjects in the placebo group and 32 (45%) of the 71 subjects in the glucosamine group experienced a disease flare. These were statistically indistinguishable.

Many had hoped that the National Institutes of Health-sponsored Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) would clarify whether or not glucosamine was a significant agent for symptom or structure modification. Radiographic data have yet to be published, but the data on symptom relief recently reported failed to end the controversy about the utility of glucosamine.²⁶ The GAIT trial was innovative in its use of a five-arm intervention of either glucosamine 1500 mg daily; chondroitin 1200 mg daily; the combination of glucosamine and chondroitin; a cyclooxygenase inhibitor; and placebo. Overall, glucosamine, chondroitin, and the combination of the two were no better at relieving OA symptoms than placebo measured by WOMAC, health assessment questionnaire, or patient or physician global assessments. Use of chondroitin, but not glucosamine or the combination, was associated with a statistically significant reduction in the number of patients found to have a joint effusion or swelling on clinical examination. In subjects with moderate to severe pain, the combination of glucosamine and chondroitin, but neither alone nor the cyclooxygenase inhibitor, was better than placebo at relieving symptoms in this group. The high placebo response in this trial, as well as the relatively mild degree of pain among many of the participants, makes meaningful interpretation of these findings limited.

The most recent meta-analysis to review the glucosamine literature was published through the Cochrane Collaboration.²⁷ This update reviewed 20 randomized, controlled trials that included 2570 subjects. Collectively, the studies showed that glucosamine favored placebo with a 28% improvement in pain and a 21% improvement in function using the Lequesne Index, but that WOMAC pain, function, and stiffness outcomes did not reach statistical significance. When the analysis was restricted to eight studies with adequate allocation concealment, none showed improvement in pain or function. Ten trials used the crystalline glucosamine preparation available from Rotta Pharmaceuticals. When these trials were analyzed separately, glucosamine was found to be superior to placebo in improving pain and function using the Lequesne Index. Two of the latter trials were also those that have suggested a slowing of radiographic progression. The authors noted that compared to the 1999 Cochrane review, this updated analysis suggested that there was high-quality evidence that glucosamine was not as useful for symptom improvement as had previously been thought. The potential impact of the involvement of glucosamine manufacturers in the sponsorship, design, or reporting of clinical trials of glucosamine has been discussed elsewhere.²⁸

Like glucosamine, CS is an important constituent of normal joint tissue. CS levels are altered in OA cartilage, plasma, and synovial fluid.²⁹ In vitro work has similarly suggested a variety of mechanisms, in addition to a contribution to structural integrity, through which this glycosaminoglycan might be useful in the treatment of OA. However, the link between potential therapeutic effects and a definitive demonstration of efficacy in OA is no clearer for CS than for glucosamine. In part, this is because there have been fewer clinical trials examining the utility of CS than that of glucosamine, and the CS trials have generally been of short duration.

CS appears to be less readily absorbed after oral administration than glucosamine.³⁰ After oral administration of CS from shark cartilage, healthy volunteers showed considerable variability in absorption measured by disaccharide pattern evaluation on agarose gel electrophoresis and high
performance liquid chromatography. All subjects had detectable levels of CS by 48 hours, but some had peak levels as early as 4 hours postingestion. The t_max of shark-derived cartilage was estimated to be 8.7 hours, compared with 2.4 hours for bovine CS.

Addition of CS to cultured chondrocytes derived from osteoarthritic joints results in significant increases in total proteoglycan production.^9,31 This effect occurs at concentrations as low as 100 μg/mL. When mixed in chondrocyte culture with interleukin-1β, CS will counteract the effects of IL-1β.³¹ This includes reversing the decrease in proteoglycan production seen with IL-1β. Interestingly, although CS itself does not affect collagen II production, it inhibits the reduction in collagen II production caused by IL-1β. Furthermore, CS itself decreases prostaglandin E2 production and counters IL-1β-induced increases as well. Higher concentrations of CS, up to 500 to 1000 μg/mL, are needed to inhibit some of these IL-1β-induced effects. CS may also inhibit collagenolytic activity⁹ and matrix metalloproteinase production in chondrocyte culture derived from patients with hip OA.³² Data can be found to support and to refute the contention that CS has an effect on pretranslational regulation of genes for matrix metalloproteinases, aggrecanase, nitric oxide synthase, or cyclooxygenase.^18,33