Treating Osteoarthritis with Chondroprotective Agents

David S. Hungerford, MD
Professor, Orthopaedic Surgery
Chief, Division of Arthritis Surgery
Johns Hopkins University
Baltimore, Maryland

Osteoarthritis (OA) is the most common form of joint disease in the United States. Because of its prevalence and the severe impact of its symptoms on patients’ quality of life, OA justly represents a major concern for health-care providers. 1,2  Recently, there has been a surge of interest in the use of chondroprotective agents to treat OA. To fully understand the definition and mechanism of action of these compounds, it is important to understand the biochemistry of normal articular cartilage.

Normal Articular Cartilage

Normal articular cartilage is composed of chondrocytes that occupy approximately 5% of the tissue volume, and the extracellular matrix, which composes the remaining 95% of the tissue. The chondrocytes secrete and maintain the matrix; the matrix in turn supplies the chondrocytes with an environment conducive to their continued existence in the face of a high level of mechanical stress. Because of its role in chondrocyte support, and because it physically forms such a large percentage of cartilage, the importance of the matrix in joint function cannot be overstated.

Water comprises approximately 70% of the matrix. The remainder of the matrix consists primarily of collagen, especially collagen II, and proteoglycans. Proteoglycans are composed of glycosaminoglycans (previously called mucopolysaccharides) attached to a linear core protein. The resulting structure resembles a "bottle brush." Proteoglycans are important in many body tissues. The proteoglycans that are specific to cartilage contain the glycosaminoglycans chondroitin sulfate-4, chondroitin sulfate-6, and keratan sulfate. In the matrix, numerous proteoglycans are attached end-on to a molecule of hyaluronan, forming a feathery structure called a proteoglycan aggregate (Figure 1). Because the glycosaminoglycans are negatively charged, they repel each other but attract polar molecules. Proteoglycan aggregates are therefore strongly hydrophilic. This is one reason for the high water content in the matrix. However, bonds that form between the individual glycosaminoglycans, especially chondroitin sulfate, and the collagen fibrils in the matrix limit water imbibition by limiting the degree to which the glycosaminoglycans can separate. Without this binding between collagen and chondroitin sulfate, and the physical integrity of the collagen network, the matrix absorbs excess amounts of water, and chondromalacia results. In short, normal matrix is necessary for normal cartilage and joint function.

Articular cartilage has no intrinsic blood supply, and all chondrocyte metabolites and nutrients must diffuse through the matrix from/to the joint space or the vasculature of the subchondral bone. Since the molecular structure of the matrix determines both the rate of diffusion as well as the nature of diffusible particles, normal matrix is also a prerequisite for chondrocyte survival.

Pathogenesis of Osteoarthritis

The importance of the matrix is evident in the pathogenesis of OA, which results when the cartilage matrix fails. 3,4  In about 5% of cases, OA affects individuals having some predisposing condition, such as a traumatic injury to a joint. These cases are referred to as secondary OA. In the majority of cases, OA appears insidiously, apparently as part of the aging process and without obvious initiating cause (primary or idiopathic OA). The association between OA and age is nonlinear, with incidence of disease increasing exponentially after age 50. By age 65, an estimated 85% of the population have some degree of OA. However, it would be an error to dismiss OA as simply an unavoidable result of cartilage senescence. The changes in articular cartilage seen in OA are the results of complex interplay between the macromolecules of the cartilage matrix (glycosaminoglycans, proteoglycans, and collagen) and the chondrocytes that produce the matrix and are in turn supported by it.

Chondrocytes play a fundamental role in the pathogenesis of OA. Although the precise biochemical events that initiate the process are as yet undefined, it is known that chondrocytes in OA cartilage produce interleukin-1, releasing a cascade of cytokines including TNF-alpha (tumor necrosis factor), TGF-beta (transforming growth factor), and various prostaglandin derivatives. These cytokines in turn induce chondrocytes to release lytic enzymes, including metalloproteinases, which degrade collagen II and proteoglycans. Simultaneously, normal matrix synthesis by chondrocytes is inhibited. 5  On the molecular level, these events result in a reduced amount of glycosaminoglycans in the matrix, decreased binding between glycosamino-glycans and collagen II, and an increase in the amount of water in the matrix. These biochemical changes in the cartilage matrix decrease its tensile strength and resiliency, preventing it from functioning normally in transmitting forces, supporting chondrocytes, and protecting subchondral bone. Thus, further injury to chondrocytes results and a vicious circle ensues.

The disease typically progresses inexorably, with sloughing of cartilage, proliferation and microfractures of subchondral bone, formation of bone cysts and osteophytes, and the production of "joint mice." In most cases, the synovium shows relatively minor changes which include congestion, secondary inflammation, and fibrosis. The pathologic changes characteristic of OA are directly traceable to the initial degradative changes in the cartilage matrix. 6


Treatment of Osteoarthritis

The two goals of OA therapy should be: 1) to decrease the symptoms of the disease, and 2) to control the progression of the disease process. 7

Conventional therapies for OA are largely palliative and focus on the reduction of pain and suppression of inflammation via surgery, changes in lifestyle, and pharmaceutical approaches.

It is beyond the scope of this review to address the many applications of surgery in the treatment of OA. Certainly, with current advances and improvements in techniques and available technology, surgery has been proven to be of great benefit in a wide range of joint conditions, including cases of joint instability. However, surgery generally addresses the symptoms of OA, but can do little to change the biochemical events that lead to progression of the disease.8

Changes in lifestyle may include weight loss, diet changes, controlled exercise (physical therapy), and stress reduction. Although these modifications can be of huge benefit to OA sufferers, they are unfortunately also the most difficult changes to implement. In the Western world, blessed with a surfeit of food and an apparent scarcity of time, it is much easier to recommend weight loss and stress reduction than to achieve them. In spite of this difficulty, the relationships between lifestyle, body weight, and joint disease should be remembered and addressed when possible.

Pharmaceutical approaches are well known and consist largely of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. While these pharmaceuticals have definite beneficial symptomatic effects, their use is also associated with a relatively high rate of side effects. 9  For example, the tendency of NSAIDs to cause gastrointestinal ulceration, renal necrosis, and platelet dysfunction is well known. Similarly, corticosteroids are known to decrease immune function and slow healing of injured tissues. Less well known, but equally important, is the effect of corticosteroids and some NSAIDs on chondrocyte metabolism; recent research has shown that some of these drugs can down-regulate chondrocyte metabolism and actually decrease glycosaminoglycan synthesis.10,11  For these reasons, it is recommended that the use of NSAIDs and corticosteroids be minimized.

Chondroprotective Agents

Problems associated with currently available therapies, along with the expanding knowledge of cartilage biochemistry and OA pathogenesis, has focused research on slowing the progression of OA and promoting cartilage matrix synthesis.12  This research has identified substances, termed chondroprotective agents, which counter arthritic degenerative processes and encourage normalization of the synovial fluid and cartilage matrix.13 Ghosh defines chondroprotective agents as compounds that: 1) stimulate chondrocyte synthesis of collagen and proteoglycans, as well as synoviocyte production of hyaluronan; 2) inhibit cartilage degradation; and 3) prevent fibrin formation in the subchondral and synovial vasculature.14 Examples of compounds that exhibit some of these characteristics are the endogenous molecules of articular cartilage, including hyaluronic acid, glucosamine, and chondroitin sulfate.

Hyaluronic Acid

Hyaluronic acid (HA) is a glycosamino-glycan that is composed of glucuronic acid and N-acetylglucosamine. It differs from other glycosaminoglycans in that it is unsulfated; also, it does not bind covalently with proteins to form proteoglycan monomers, serving instead as the backbone of proteoglycan aggregates. It is the only glycosaminoglycan that is not limited to animal tissues, being found also in bacteria. It serves as a lubricant and shock absorber in the synovial fluid, and is found in the vitreous humor of the eye. HA is not well absorbed orally, but has been widely used intraarticularly in the treatment of OA in animals15  and, more recently, in humans.16  Possible mechanisms by which HA may act therapeutically include 1) providing additional lubrication of the synovial membrane; 2) controlling permeability of the synovial membrane, thereby controlling effusions; and 3) directly blocking inflammation by scavenging free radicals. Other possible, though less certain, mechanisms include promotion of cartilage matrix synthesis and reaggregation of proteoglycans. HA is well tolerated with no demonstrable toxicity and few side effects. 17  Because it is injected directly into the joint, its onset of action is rapid. Conversely, its route of administration does limit its therapeutic applications to some degree, and high cost is also a factor.


Glucosamine is an aminomonosaccharide that functions in the body as the precursor of the disaccharide unit in glycosamino-glycans. Normally, chondrocytes synthesize glucosamine from glucose. Supplying exogenous glucosamine provides the body with additional raw materials for matrix production. However, as a chondro-protective agent, glucosamine has a second function beyond its structural role. In contrast to HA, numerous in vitro studies have demonstrated that glucosamine stimulates the synthesis of proteoglycans and collagen by chondrocytes.18  Since OA results when cartilage breakdown exceeds the chondrocytes’ synthetic capacity, providing exogenous glucosamine increases matrix production and seems likely to alter the natural history of OA. Glucosamine also has a mild anti-inflammatory activity that is unrelated to prostaglandin metabolism, probably via a free-radical scavenging effect.19

The effects of glucosamine have been studied using intravenous, intramuscular, and oral routes of administration. Absorption of radiolabeled glucosamine from the gut, and tropism of the compound to joint tissues, has been verified using radiolabeling techniques. When administered orally as a salt (glucosamine hydrochloride, glucosamine sulfate, or glucosamine hydroiodide), approximately 87% of the administered dose is absorbed. Its excretion is primarily via urine, with only a small percentage being excreted unchanged in the stool.20,21  In randomized, double-blinded, placebo-controlled clinical trials using oral preparations, glucosamine salts have been verified as efficacious in the management of OA, and have not demonstrated any toxicity, severe side effects, or abnormal clinical, biochemical, or hematological changes.22-26  A minimum of 1g of glucosamine daily is the standard dose, bearing in mind that the inorganic moiety of the salt occupies a significant part of the compound’s total molecular weight. For example, the sulfate moiety contributes one third of the total molecular weight of glucosamine sulfate. The use of glucosamine salts for treatment of osteoarthritis is convenient, cost-effective, and well tolerated by patients.

Chondroitin Sulfate

Chondroitin sulfate, as previously stated, is the most abundant glycosaminoglycan in articular cartilage. It is composed of repeating disaccharide units of glucuronic acid and galactosamine sulfate, and is a natural component of several tissues in the body in addition to cartilage, including tendon, bone, intervertebral disk, the cornea, and heart valve.

As a glycosaminoglycan, chondroitin sulfate plays an important structural role in articular cartilage, notable for its role in binding with collagen fibrils. However, as a chondroprotective agent, it has a metabolic effect as well; its action is to competitively inhibit many of the degradative enzymes that break down the cartilage matrix and synovial fluid in OA.27,28  An additional mechanism of action by which chondroitin sulfate may benefit joint tissues is via the prevention of fibrin thrombi in synovial or subchondral microvasculature.29  Platelets normally secrete chondroitin sulfate and other glycosaminoglycans (eg, heparin) as part of the body’s normal control of thrombogenesis. With aging, chondroitin sulfate production by body cells decreases, to be replaced by less effective glycosaminoglycans like keratan sulfate, which predisposes to pathologic thrombus formation.

Chondroitin sulfate has also been investigated for its antiatherosclerotic effect.30  It is theorized that chondroitin sulfate supplementation maximizes blood circulation to the tissues, including subchondral bone and synovium. Although it is a large molecule, chondroitin sulfate’s bioavailability after oral administration has been well documented using radiolabeled compound. In humans and experimental animals, approximately 70% of orally administered chondroitin sulfate was absorbed. Tropism to synovial fluid and cartilage has also been demonstrated.31

As might be expected of an endogenous molecule, chondroitin sulfate has an excellent safety record, with no demonstrable toxicity. In repeated clinical studies, oral chondroitin sulfate (1200 mg qd) was consistently effective in reducing OA symptoms, and was very well tolerated, without local or systemic side effects. These studies uniformly refer to a reduction of pain and an increase in normal function, in many cases with a concurrent reduction in use of NSAIDs or other analgesics. In most studies, the incidence of side effects was similar to those seen in the placebo groups.32-36  Several medical products containing chondroitin sulfate are being prescribed to patients with osteoarthritis in Europe.37


TABLE 1. Postulated Mechanism of Synergy Between Glucosamine and Chondroitin Sulfate

Chondroprotective Agents
Characteristics of
Chondroprotective Agents

Glucosamine Stimulate chondrocyte and synoviocyte metabolism
Chondroitin sulfate Inhibit degradative enzymes
Chondroitin sulfate Prevent fibrin thrombi in periarticular tissues


While studies performed using either glucosamine or chondroitin sulfate uniformly showed beneficial results, no single compound has yet been found that meets all the defining characteristics of a chondroprotective agent such as was mentioned earlier. However, by combining agents, all criteria can be met. This is exemplified in the combination of glucosamine and chondroitin sulfate. When used together, the effects of these 2 compounds combine to 1) stimulate the metabolism of chondrocytes and synoviocytes; 2) inhibit degradative enzymes; and 3) reduce fibrin thrombi in periarticular microvasculature. Providing both compounds together is therefore more beneficial than supplying either separately.38

Because glucosamine induces increased synthesis of matrix compounds, and chondroitin sulfate inhibits breakdown, their concurrent use results in a net increase in the amount of normal cartilage matrix, thus slowing the progression of osteoarthritis (OA) as well as reducing the symptoms of the disease. However, the combined effects of these 2 compounds may not be merely additive. Several factors, including chondroitin sulfate’s effects on the microvasculature, create the expectation that the effects of these 2 compounds in combination could be synergistic. Research with cell culture and animal models using a patented combination of glucosamine hydrochloride and chondroitin sulfate (Cosamin® DS, Nutramax Laboratories, Inc.) has supported this.39,40  Numerous clinical studies performed at US veterinary schools using the veterinary equivalent (Cosequin®, Nutramax Laboratories, Inc.) also documented positive effects.41-46  A review of veterinary studies and applications of the discussed agents in animal health is presented elsewhere.47,48  Human randomized, double-blind clinical trials are currently under way.

Purity and Labeling

Glucosamine and chondroitin sulfate are both obtained from animal tissue sources, and purity can vary widely depending on extraction techniques and analysis technology. The studies of glucosamine and chondroitin sulfate referenced in this article were all conducted using carefully assayed, purified compounds. The purity of the compounds used can certainly be expected to affect efficacy. Furthermore, glucosamine and chondroitin sulfate are considered dietary supplements, and are therefore not regulated by the Food and Drug Administration. Although many brands of chondroitin sulfate and glucosamine are available over the counter, independent laboratory analysis has shown that many products do not actually contain the amounts claimed on the label.49  It is definitely a case of caveat emptor. Purchasers of dietary supplements should be careful to buy from a reputable manufacturer that uses quality-control programs to validate raw material and finished product purity.


Clinicians should be aware of chondroprotective agents such as hyaluronic acid, glucosamine, and chondroitin sulfate, because these compounds are receiving increasing attention from both laypersons and health professionals as therapeutic agents for the management of osteoarthritis (OA). Further investigative work is certainly justified, but current information suggests that intraarticular hyaluronic acid improves lubrication in the joint and helps decrease swelling and inflammation. Special attention focuses on oral chondroprotectives, and extensive research supports the concurrent use of oral glucosamine and chondroitin sulfate. These dietary supplements, when used correctly, appear to work synergistically together to cause a net increase in the amount of healthy articular cartilage, thus slowing the progression of OA. Because of their convenience, cost-effectiveness, expected synergistic efficacy, and exceptional safety record, the use of these combined oral chondroprotective agents presents an exciting new approach in the treatment of OA and opens the possibility of doing more than merely addressing the symptoms of this disease.

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