Glucosamine and Chondroitin Sulfate

RONALD A. NAVARRO

Osteoarthritis (OA) is an imbalance between the synthesis and degradation of cartilage that occurs in synovial joints.¹ It is characterized by disturbance in the smooth property of the cartilage, which results in the formation of subchondral cysts and marginal osteophytes.² Bone spurs may also form around the joint as the body’s response. This process occurs until all layers of cartilage are lost, leaving only the bone layer.

Currently, the aim of OA treatment is to reduce pain and stiffness. Its management consists of pharmacologic and nonpharmacologic therapies. Pharmacologic treatment of OA begins with acetaminophen, adding a low-dose nonsteroidal antiinflammatory drug (NSAID), salicylate, selective cyclooxygenase-2 (COX-2) inhibitor, or topical capsaicin cream if needed. Analgesics or NSAIDs are the most common subscribed noninvasive treatment for reducing pain associated with early cases of OA. Pain reduction can also be achieved by nonpharmacologic treatment, for example, physical therapy and decreasing the load on the joint by changing the patient’s lifestyle (e.g., weight loss and stress reduction). This can be challenging but of great benefit.³ In more severe cases joint injections, irrigation, or arthroscopy may be beneficial. In patients who continue to have pain and limited function despite these measures, surgical intervention should be considered.¹ Although NSAIDs have definite effect in pain reduction, up to 2% of patients per year have severe gastrointestinal problems after prolonged intake.⁴ Another important side effect is that with long-term usage of some of the NSAIDs, synthesis of cartilage matrix might be inhibited.⁵

The drawbacks of the long-term use of NSAIDs has inspired researchers to investigate agents that can help patients with OA with minimal or no side effects. A new class of agents termed symptomatic or disease modifying osteoarthritic drugs (S/DMOADs) is receiving wide publicity in the United States.⁶ The results of 10+ years of investigation including 40 human clinical trials and over 300 studies overall in animals and in vitro can be summarized as follows: S/DMOADs demonstrate clinical efficacy in symptomatic relief of OA with little or no side effects, retard progression of arthritic lesions in animal models of OA, and in at least one clinical study show evidence of cartilage regeneration. Studies were conducted on nutraceuticals, such as chondroitin sulfate and glucosamine, to demonstrate their efficacy in the symptomatic treatment of OA. Meta-analyses reviewed clinical trials of the glucosamine and chondroitin, S/DMOADs, in the treatment of osteoarthritis. It was concluded that clinical trials of these two agents showed substantial benefit in the treatment of osteoarthritis, although they provided insufficient information about study design and conduct.^6–8

Nutraceuticals and the Food and Drug Administration

The scientific community, nevertheless, expressed a high degree of skepticism toward nutraceuticals based on the concerns about the lack of quality control and of scientific testing of claims. The reason is that these substances are not Food and Drug Administration (FDA) regulated, and as a result, there is no requirement for rigorous scientific testing prior to marketing. The Dietary Supplement Health and Education Act (DSHEA) of 1994 established additional requirements for safety and made provisions for four categories of claims for nutritional support. However, because dietary supplements fall under the same general classification as “foods,” there are no specific regulations to assure product quality. What is stated on the label may not reflect the actual composition or purity of the product inside.

The other important factor to consider is the lack of good manufacturing practices that should be in place to guarantee high quality and batch-to-batch consistency. Last and not least is the absence of a validated analytic method for the raw materials, which is the only way manufacturers can verify the purity of their products. Recent published reports of the analysis of randomly purchased dietary supplements have shown a wide deviation from label claim by the majority of products tested. The University of Maryland School of Pharmacy analysis of 32 products containing glucosamine and chondroitin sulfate reported that 84% of tested products did not meet the label claims, and 40% of the products contained less than 30% of the label claims, regardless of retail price. In light of this, when selecting a dietary supplement with reported efficacy in clinical trials, patients should be advised that “brand” does matter. The only way to expect a result from a supplement that is equivalent to that reported in a controlled clinical study is to use the same brand of supplement as used in the study.9,¹⁰

Therefore, it is not surprising to know that the Arthritis Foundation has recommended that “when a supplement has been studied with good results, find out which brand was used in the study, and buy that.”¹¹

Glucosamine

Glucosamine (GA) is an amino-monosaccharide. It is a precursor of the disaccharide unit of glycosaminoglycan (GAGs) and is reported to stimulate the production of proteoglycans, which is the ground substance of the articular cartilage.^12,13 Glucosamine also stimulates synovial production of hyaluronic acid (HA), which is responsible for the lubricating and shock-absorbing properties of synovial fluid.¹⁴

Improvement in the symptoms of OA associated with the use of GA has been observed in several clinical trials.^15–17 Reported short-term adverse effects include mild gastrointestinal problems, drowsiness, skin reactions, and headache. Houpt et al¹⁸ conducted a double-blind study in Toronto, Canada investigating the efficacy of the hydrochloride salt of GA on pain and disability in knee OA. Although the primary end point was not met, a positive trend was noted for the GA group. In addition, the secondary end points of cumulative pain reduction as noted by the patient in a daily diary and as assessed by knee examination were favorable, suggesting that glucosamine hydrochloride benefits some patients with knee OA.

Chondroitin Sulfate

Chondroitin sulfate (CS) is an important component of cartilage. Two types of CS exist: chondroitin-4-sulfate and chondroitin-6-sulfate. They vary in molecular weight and thus differ in their bioavailability and purity.¹⁹ Chondroitin-4-sulfate is the most abundant GAG in growing mammalian hyaline cartilage. With age, chondrocytes secrete less chondroitin-4-sulfate and more amounts of the other GAGs. This change has been observed in the initiation and progression of the degenerative process within the cartilage in OA.²⁰

Omata et al²¹ injected bradykinin into the left knee articular cavities of rats three times a day for 2 days. Chondroitin sulfate was administered orally to rats for 14 days and was shown to inhibit the bradykinin-induced proteoglycan depletion of the articular cartilage in a dose-dependent manner. These results suggest that a reduction of the proteoglycan content of cartilage (similar to findings associated with osteoarthritis) can be inhibited by CS.

In another study, CS inhibited the aggrecanase enzyme in a dose-dependent manner, suggesting its protective effect. This is because aggrecanase has been believed to mediate aggrecans degradation in OA.²² Several other studies reported similar inhibitory effect of CS on many degradative enzymes.²³

Because of the large size of the CS, earlier reports voiced concerns about its bioavailability. However, radio-labeled CS given orally to humans was 70% absorbed. Its affinity for synovial fluid and articular cartilage has also been demonstrated.²⁴ In addition, many clinical trials have documented the clinical efficacy of CS in treating OA, showing significant symptomatic improvement and suggesting a structure modifying effect.^25,26

Combined Therapy with Glucosamine and Chondroitin Sulfate

From the previous sections, it is evident that both CS and GA are effective. Over the years, the combined use of these nutraceuticals in OA treatment has become extremely popular.³ This is because their use has much fewer side effects than do NSAIDs, and represents the only treatment suggested to prevent progression of the disease in preliminary reports.25–27

It is important to note that experimental studies have documented a synergistic effect when GA and CS are administered together. Lippiello et al²⁸ reported that the coadministration of TRH122(tm)(Nuttramax Laboratories, Edgewood, Maryland) low molecular weight sodium chondroitin-4-sulfate and FCHG49(tm) (Nutramax Laboratories, Edgewood, Maryland) glucosamine hydrochloride resulted in a greater increase of GAGs production (96.6%) than for either agent alone (GA, 32%; CS, 32%). The same study showed that while CS inhibited interleukin-1, GA did not. Therefore, it is not a matter of which one is superior; they have two different mechanisms of action, so both of them should be given together to get a better result.

In another study, Woodward et al²⁹ investigated the efficacy of the same combination of nutraceuticals in modifying the cartilage in an OA model. Fifty percent of the rabbits were fed a regular diet whereas the rest were fed the studied combination in an amount equivalent to 2% of their body weight. At week 16 of the study, samples from the animals’ medial condyles were evaluated histologically. The authors concluded that the studied combination has a significant structure-modifying effect in this OA model.

Two randomized, double-blind, placebo-controlled clinical trials investigated the efficacy of the same combination therapy in the management of OA. The first study was by Das et al,³⁰ who recruited 93 patients with knee OA. They found significant improvement in the treatment group of patients with mild or moderate knee OA at 4 and 6 months, compared with controls. The second 16-week crossover trial was conducted on 34 males from the U.S. Navy. It was also shown that the same combination therapy relieves symptoms of knee OA.³¹

Use of Glucosamine and Chondroitin Sulfate in Athletes

The use of S/DMOADs like GA and CS in sports injuries of athletes is a relatively new but promising application and a natural extension of their use in the treatment of osteoarthrosis.³²

Although clinical trials examining this application have not been performed, a published clinical case study reported on improvement of an osteochondral impaction injury of the femoral head in a female collegiate basketball player. Resolution of pain and physical improvement evidenced by magnetic resonance imaging (MRI) was documented.³³ Other mostly anecdotal reports suggest a need for further controlled clinical investigation.

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