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Chondroprotective agents: glucosamine and chondroitin
Foot Ankle Clin N Am 8 (2003) 201 – 219
Chondroprotective agents: glucosamine and chondroitin Marc W. Hungerford, MD*, Daniel Valaik, MD Johns Hopkins University, Suite G-1 Professional Office Building, 5601 Loch Raven Boulevard, Baltimore, MD 21239, USA
Osteoarthritis (OA) is the most common musculoskeletal disease in the United States [1]. It is estimated that 65% of people over the age of 65 have symptomatic OA in at least one joint [2]. The aging of western populations, coupled with increased longevity of those populations, has made OA one of the leading public health concerns [3], and yet, a disease-modifying treatment for this disorder has yet to be developed, or has it? The publication of a book entitled ‘‘The Arthritis Cure’’ by Theodosakis et al [4] in 1997 generated a strong public and media interest in glucosamine and chondroitin sulfate (CS), and nutritional supplements, in general; this helped to reinvigorate the search for disease-modifying treatments for this debilitating disorder. This article examines the data that support the use of these agents in the treatment of OA.
The structure and function of cartilage A discussion of the disease-modifying properties of an agent can only be understood in the context of the structure and function of normal cartilage and the pathologic mechanisms of OA. Normal articular cartilage is the most durable tissue in the body. It is avascular and aneural; all circulation within it must be accomplished by diffusion. Cartilage is composed of 5% chondrocytes and 95% extracellular matrix. The chondrocytes secrete and maintain the matrix, but the matrix gives cartilage its mechanical properties and allows it to function over a long period of time, despite a high degree of stress. Therefore, the importance of the proper function of the matrix cannot be overstated. The extracellular matrix is comprised of 70% water and 30% solid material, predominantly collagen II, proteoglycans, and other fibrillar and globular
* Corresponding author. E-mail address: [email protected] (M.W. Hungerford). 1083-7515/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1083-7515(03)00043-3
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Fig. 1. The structure of cartilage.
proteins. The proteoglycans are complex, high molecular weight macromolecules that consist of glycosaminoglycans (GAGs), such as chondroitin 4- and 6-sulfate, keratan sulfate or dermatan sulfate, and a protein core. Proteoglycans are, in turn, linked to a hyaluronan backbone to form the large aggrecan molecule. The proteoglycans carry a highly negative charge which gives them strong hydrophilic properties; this accounts for the high water content in cartilage. The glycosaminoglycans, especially CS, also form bonds with each other and with collagen II, thus limiting the amount of water imbibition and lending cartilage its turgor and resilience [5]. Without these bonds, the cartilage would absorb excessive water which results in chondromalacia. Because the structure and density of the matrix also determines the degree and rate of diffusion that is possible within it, normal extracellular matrix is vital not to the function of cartilage, as well as its survival (Fig. 1).
The nature and progression of osteoarthritis Great strides have been made in recent years in the understanding of the pathogenesis of OA. Although a small percentage of the population who has arthritis has suffered an antecedent injury (posttraumatic or secondary OA), most patients develop cartilage degeneration in the absence of any underlying cause. The incidence of OA increases with age; some estimates suggest that 85% percent of
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people aged 65 and older suffer from it to some degree. The relationship to age is an indirect one, however; it is just as inaccurate to regard cartilage degeneration as a normal consequence of aging cartilage as to consider it wear and tear. Osteoarthritis is a consequence of complex interactions between the chondrocytes and the extracellular matrix. Although the collagen in the matrix is static, the proteoglycans are actively maintained by the chondrocytes [6]. The balance between anabolic and catabolic processes in the matrix which determine the matrix’ fate. Although precise details of the processes that initiate cartilage degeneration remain undefined, it is known that chondrocytes in OA cartilage produce interleukin-1 (IL-1), which, in turn, releases a cascade of cytokines, including tumor necrosis factor-a (TNF-a), transforming growth factor-b, and several prostaglandins. These cytokines stimulate the chondrocytes to release lytic enzymes, such as the metalloproteinases, which degrade collagen II and proteoglycans [7 – 10]. Simultaneously, normal matrix synthesis by chondrocytes is inhibited [9]. In addition, the amount of chondroitin 4-sulfate is reduced and the ratio of keratan sulfate to CS is increased. CS binds to other GAGs and collagen II better than CS analogs. CS absence results in a weakness of the matrix and an increase in the amount of water in the matrix. These biochemical changes alters biomechanical competence of the matrix to transmit force and support the condrocytes, thus producing a vicious cycle. Once begun, there is no reliable way to reverse the process in man. Even small lesions demonstrate poor and incomplete healing. Although slow progression of disease is the rule, progression is not inexorable. In some instances, damaged cartilage can function without producing symptoms for remarkable periods of time. The disease typically progresses with loss of cartilage, microfracture and sclerosis of subchondral bone, and formation of bone cysts and osteophytes. In contrast to inflammatory arthritides, the synovium show minor changes, including congestion, minor inflammation, and fibrosis. The characteristic pathologic changes of OA are directly traceable to the initial degradation of the cartilage matrix [10].
Treatment of osteoarthritis Despite the large number of patients who suffer, and the staggering cost of treatments and days of work lost, the medical community has yet to devise a rational treatment for OA. Treatment efforts have been restricted to symptomatic amelioration. For mild, early OA, simple analgesics, such as acetaminophen or paracetamol, may suffice. When symptoms become more severe, the mainstay of treatment in the United States has been nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are problematic, at best, as a first line treatment for OA. Although the efficacy of NSAIDS, compared with placebo, has been well documented, evidence of superior efficacy compared with simple analgesics is largely lacking [11,12]. NSAIDs inhibit cyclo-oxygenase, which is the source of their anti-inflammatory properties, as well as their side effects. Inhibitory effects on
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cartilage have been noted by many investigators [13 – 19]. Catabolic and anabolic processes are inhibited [20,21]. The fear that inhibition of anabolic processes by NSAIDs may harm the cartilage led some investigators to postulate the possibility of an ‘‘NSAID arthropathy’’ [22,23]. Although this fear has not been realized, it seems clear that NSAIDs do not have any beneficial effects on the cartilage. Inhibition of the cyclooxygenase (COX) enzyme prevents secretion of prostaglandins that are vital to the maintenance of the gastric mucosa. In fact, NSAID gastropathy is the second most deadly rheumatic disease [24]; it accounted for 107,000 hospitalizations and 16,500 deaths according to one report [25]. The same investigators noted that the cumulative risk increases with time; 80% of patients with serious gastrointestinal (GI) complications had no previous symptoms. Thus, we are faced with a disease of epidemic proportions for which the mainline of treatment is purely symptomatic, expensive, and fraught with considerable danger for the patient. Clearly, there must be a better way.
Definition of chondroprotective agent Recognizing this dilemma, numerous researchers have been looking for a ‘‘chondroprotective agent’’ as a rational treatment for early OA. Cartilage researchers recognized that the ability to induce healing in damaged cartilage might be a long way off, but protecting that cartilage from further damage and preserving its function might be a considerably more achievable short-term goal. Ghosh and Brooks [26] made an attempt to define the characteristics of such an agent: A chondroprotective agent should
Enhance chondrocyte macromolecule synthesis Enhance synthesis of hyaluronan Inhibit degradative enzymes Mobilize thrombin, fibrin, lipids, and cholesterol deposits in blood vessels surrounding the joint Reduce joint pain Reduce synovitis
The remainder of this article examines the evidence of the clinical efficacy of glucosamine and chondroitin and whether they satisfy any of the criteria of a chondroprotective agent.
Glucosamine Glucosamine in an aminomonosaccharide which is a vital component of glycosaminoglycans and hyaluronan. Glucosamine is naturally synthesized by the chondrocyte, but when supplemented, it can be used directly to synthesize
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larger macromolecules. Most preparations for human use purify it from chitin that is derived from crustacean shells. Glucosamine has been available for human treatment since the 1950s, but it was not until an oral form was developed in Germany in the 1960s that clinical interest in this molecule developed in earnest. Intra-articular and intramuscular preparations are still available, but most studies use oral preparations of glucosamine sulfate, glucosamine hydrochloride, or a glucosamine analog, N-acetyl glucosamine. In vitro and animal studies documented a variety of glucosamine effects. These can be categorized into substrate effects, transcriptional effects, antiinflammatory effects, and anticatabolic or antiarthritic effects Substrate and transcriptional effects As early as 1956, Roden [27] noted an increased production of glycosaminoglycans and collagen when glucosamine sulfate was added to cartilage-derived fibroblast cell cultures. Other investigators confirmed this finding [28,29]. This effect was glucosamine-specific; N-acetyl glucosamine was far less active and glucuronic acid was without effect [30,31]. Besides functioning as a simple substrate, recent work showed that glucosamine affected gene transcription within the chondrocyte. Jimenez and Dodge [32] demonstrated a twofold increase in perlecan and aggrecan mRNA levels and a moderate increase in stromelysine mRNA in condrocyte cultures that were incubated with 50 mM glucosamine. The same investigators showed a dose-dependent down-regulation of metalloproteinase I and II (enzymes that are important in the degradation of cartilage) mRNA in the same model [32]. Anti-inflammatory, antireactive, and anticatabolic properties As early as 1980, Vidal y Plana and Karzel [33] demonstrated the ability of glucosamine to normalize cartilage metabolism and to prevent cartilage degradation. More recently, glucosamine was shown to inhibit aggrecanase mediated matrix destruction in rat chondrosarcoma cell line and cartilage explants [34]. A glucosamine relative, N-acetyl glucosamine, inhibits interleukin-b1 and TNF-a– induced nitric oxide production as well as down-regulating inducible nitric oxide synthetase mRNA in human articular chondrocytes [35]. Fenton et al [36] noted that 25 mg/mL of glucosamine prevented Lipopolysaccharide or IL-1– induced cartilage degeneration in equine cartilage explants. These anti-inflammatory effects support earlier work that demonstrated inhibition of inflammation in classic animal models of inflammation, such as carrageenin-induced plueritis or the rat paw model of inflammation [37]. Inflammation that was caused by inflammatory mediators, such as bradykinin, serotonin, or histamine, were not inhibited [37]. Specifically, glucosamine did not show any inhibition of the cyclo-oxygenase system, thus lending some credibility to the claim of GI tolerability.
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Glucosamine also increases the synovial production of hyaluronic acid, a substance that has been shown to have anti-inflammatory effects, induce anabolic activity in chondrocytes, decrease joint pain, and increase mobility in vivo and in clinical studies [38]. An antiarthritic effect of glucosamine was demonstrated in animal models for inflammatory arthritis, mechanical arthritis, immunoreative arthritis, and generalized inflammation. For example, in rabbits with transection of the anterior cruciate ligament, those who were treated with glucosamine demonstrated significantly less chondropathy than those who were treated with placebo [39]. In general, the efficacy of glucosamine in animal models was lower than indomethacin, but the toxicity was significantly lower; the overall therapeutic index was much more favorable [37]. Finally, glucosamine may have mild immunosuppressive activity. Hua et al [40] reported a variety of inhibitory effects of glucosamine on neutrophils, including supraoxide generation, phagocytosis, granule release, and chemotaxis, although it did not significantly affect bacteriocidal capability. N-acetyl glucosamine had no effect. Ma et al [41] showed dose-dependant suppression of T lymphocytes and allogeneic mixed leukocyte reactivity in vitro by glucosamine, as well as prolonged allogeneic cardiac allograft survival in vivo when subjects were treated with glucosamine; these effects were not seen with other amino sugars. Glucosamine sulfate has been studied in human arthritis sufferers over the past 25 years. Studies were performed in many countries, including Italy [42], Germany [43 –46], Spain [47], Portugal [48], China [49], and the Philippines [50]. Patients who had arthritis of the hand, spine, shoulders, hips, and knees were studied. The results were remarkably consistent; almost all studies showed a beneficial effect of glucosamine. Improvement in pain occurred slowly, over a period of several weeks. Subjects continued to improve while taking the study drug, compared with patients who took placebo. Subjects also maintained improvement for weeks to months after the drug was discontinued, whereas those who took placebo returned to baseline. Response to treatment was high, ranging from 56% to more than 90% [48,50] and no study encountered significant side effects with glucosamine. Interest in glucosamine accelerated in Europe with the synthesis of an easily absorbable oral preparation. Since the early 1980s, numerous controlled studies, including 12 double-blind studies (see references [42,47 – 49,51 – 58]) have been performed. At lease five of these were double-blind, single-joint, placebo-controlled, and randomized and used a validated outcomes tool [53 –57]. Reichelt and coauthors [57] reported a multicenter, double-blind, placebocontrolled study on the efficacy of intramuscular glucosamine in patients who had OA of the knee. One hundred fifty-five patients were treated with glucosamine sulfate, 400 mg, twice a week for 6 weeks, or placebo. The group who took glucosamine had a greater response and a higher rate of responders than the group who was given placebo. In 252 patients with OA of the knee, Noack et al [54] concluded that patients who were treated with glucosamine sulfate, 1500 mg,/day, for 4 weeks has a significantly greater improvement in Lesquesne’s index than those who were
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treated with placebo. Response rates were also better in the treated group (55% versus 37% in intention-to-treat analysis). More recently, Qiu and coauthors [49] studied 178 patients who had OA of the knee. Randomized cohorts received oral glucosamine, 1.5 g, or ibuprofen, 1.2 g, for a period of 4 weeks. Both groups had improvement in pain, mobility, and swelling, with trend that grew over time in favor of glucosamine. After discontinuation of treatment, glucosamine demonstrated a greater remnant therapeutic effect, although this was not statistically significant at 2 weeks. Glucosamine was significantly better tolerated than ibuprofen and the group who took glucosamine had fewer dropouts. In patients who had temporomandibular joint arthritis, Thie and coauthors [59] compared glucosamine to ibuprofen in a 3-month, randomized, controlled study. Thirty-nine patients were randomized to two groups: glucosamine, 1500 mg/day, or ibuprofen, 1200/day. Both groups showed clinical improvement. The degree of improvement was greater in the group who took glucosamine; persistent improvement was seen after discontinuation of the medication, compared with a return to baseline for the group who took ibuprofen. Criticism of the older literature on glucosamine and chondroitin centered on the small numbers of patients who were studied, the short time periods of the studies, and the relative lack of studies that were independent of corporate sponsorship [60,61]. Methodologic concerns, specifically the failure of most studies to specifically control for NSAID use, have also been raised [62,63]. Recent meta-analyses should help dispel some of the concern over the quality of the clinical evidence. Towheed et al [64], writing for the Cochrane Database, evaluated 16 Randomized Controlled Trials (RCTs); 12 compared glucosamine with placebo and four compared glucosamine with NSAIDs. The investigators concluded that glucosamine was safe and effective. McAlindon et al [65] reviewed six studies of glucosamine that involved 911 patients. Quality scores for these studies ranged from 12% to 52%. Combined results showed a moderate treatment effect of glucosamine. Perhaps the most convincing clinical reports are two recent studies that seem to demonstrate a chondroprotective effect in patients who had arthritis of the knee. Reginster and coauthors [56] randomized 212 patients to glucosamine sulfate (1500 mg/day) or placebo and followed them for 3 years. Standardized weight bearing knee radiographs were obtained and the minimum medial tibiofemoral joint space was measured using digital image analysis. The patients who took placebo showed progressive joint space narrowing of approximately 0.1 mm/y, whereas those who took glucosamine did not. Western Ontario and McMaster (WOMAC) scores decreased slightly in the group who took placebo compared with improvement in WOMAC scores in patients who took glucosamine. Reginster et al allowed the use of several different NSAIDs as rescue medications and some commentators were concerned that increased knee extension due to symptomatic relief in the group who took glucosamine could skew the results. To address some of these perceived deficiencies, Pavelka et al [55] performed a similar study with nearly identical results. In this study, 202 patients were randomized to glucosamine
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sulfate or placebo. Only acetaminophen was used for rescue analgesia. Minimal tibiofemoral compartment width, at a standard degree of knee flexion, and algofunctional scoring were used as endpoints. Progressive joint space narrowing was noted in the group who took placebo, whereas joint preservation was noted in the group who took glucosamine. Lequesne and WOMAC scores also showed statistically significant differences between the two groups.
Chondroitin CS is a sulfated glycosaminoglycan that consists of alternating residues of N-acetylgalactosamine and glucuronic acid. Chondroitin is one of the most abundant constituents of cartilage extracellular matrix and is also important in a variety of other connective tissues, including, cornea, heart valve, bone, skin, ligaments, and tendons. The high degree of sulfation lends the molecule a highly anionic character that accounts for its hydrophilicity. Chondroitin also binds to other GAGs and collagen II, thus serving an important function in matrix integrity [66]. Binding of CS to other GAGs and collagen II is better than keratan sulfate and other glycosamino glycans. In aging and OA, the ratio of keratan to chondroitin changes, reflecting a relative loss of chondroitin. The loss of chondroitin decreases the structural integrity of the matrix as a result of the loss of cross-links between chondroitin and collagen. When added to chondrocyte cell culture, metabolic effects of chondroitin have been noted. In a model of human articular chondrocytes, chondroitin increased the production of glycosaminoglycans with no noticeable effect on collagen II synthesis [67]. As a chondroprotective agent, chondroitin seems to competitively inhibit the action of many enzymes that degrade cartilage [67 –69]. Like other glycosaminoglycans and GAG precursors, a variety of anti-inflammatory activities have been described [70]. In animal models of arthritis, chondroitin affords the cartilage some protection from further degradation. For example, in rabbits who were injected with chymopapain into the knee, those who were preloaded with CS demonstrated less loss of proteoglycans from the cartilage than those who were not [101]. As with glucosmine, numerous clinical trials of chondroitin for the treatment of OA have been conducted [71 – 82], including at least four single joint, prospective, randomized, controlled studies that used a validated outcomes tool (see references [71,72,81,82]). All of these studies demonstrated some efficacy. Safety profiles were similar to placebo. In a characteristic pattern, a study that compared chondroitin with diclofenac showed a more rapid treatment response for diclofenac, but a more profound response to chondroitin. Further, the improvement persisted for 3 weeks after discontinuation in the group who took chondroitin group, whereas the group who took diclofenac returned to baseline [77]. Leeb and coathors [83] recently performed a meta-analysis of human RCTs that used CS. They pooled six studies (355 patients) using a visual analog scale or Lequesne index as an outcome measure. Subjects who took CS experienced
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improvement of 80% over baseline at 3 months versus a 51% improvement for the group who took placebo. Echoing other studies, the group who took CS had a persistent improvement after discontinuation of the drug, whereas the group who took placebo did not [53]. In another meta-analysis of studies that involved 799 patients, quality scores ranged from 14% to 55%. Chondroitin showed a large treatment effect in this analysis [65]. Most studies focused on symptomatic improvement for arthritis sufferers, primarily because such studies are much simpler and less time-consuming to execute. There is, however, some evidence that CS may have a disease-modifying effect in man. In a quantitative analysis of 140 patients who were treated with CS, 800 mg/d, or placebo, the group who took placebo showed decreased surface area, decreased mean thickness, and decreased minimum width of the medial tibiofemoral joint, whereas the group who took CS did not [82,85]. In another study, 119 patients who had OA of the hand were followed for 3 years. Only 9% of those who took CS, 1200 mg/d, developed new erosive lesions compared with 29% of those who took placebo [82]. Anticoagulant and antoatherosclerotic properties CS has also been studied for its anticoagulant and antiatherosclerotic effects [84 – 91]. Platelets normally secrete chondroitin and other GAGs (eg, heparin) as part of the body’s normal control of coagulation. With aging, the amount of chondroitin that is secreted decreases. Its function is assumed by less effective GAGs, such as keratan sulfate, thus predisposing the patient to microthrombus formation. By reversing this process, CS may improve the microcirculation to subchondral bone, synovium, and other tissues.
Glucosamine chondroitin synergy Looking back to the proposed definition of a chondroprotective agent, it is clear that neither glucosamine nor CS meet the criteria by themselves (Table 1). A combination treatment of the two agents addresses all of the requirements for a chondroprotective agent in Table 1. Furthermore, cell culture and animal experiments suggest a possible synergistic, rather than merely additive, effect of glucosamine and chondroitin on cartilage metabolism. In bovine cartilage explants, synergy that was measured by maximal uptake of 35-sulfate was optimum at a dose of glucosamine, 150 mg/mL, and chondroitin, 140 mg/mL. Uptake when both Table 1 Postulated mechanism of synergy between glucosamine and chondroitin sulfate Proposed chondroprotective agents
Chondroprotective characteristics identified
Glucosamine Chondroitin sulfate Chondroitin sulfate
Stimulate chondrocyte and synoviocyte metabolism Inhibition of degradative enzymes Prevent peri-articular fibrin thrombi
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Figure 2: Saffranin-O stain of normal articular cartilage. (From Lippiello L, Woodward J, Karpman R, et al.In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop 2000;381:229 – 40; with permission.)
agents were administered was 96.6% greater than controls compared with only a 32% improvement compared with controls for either agent alone [92]. In a rabbit instability model of knee OA, the chondroprotective efficacy of glucosamine, chondroitin, and the combination were compared with placebo. Evidence of chondroprotection of both agents compared with placebo was noted, but dramatic,
Figure 3: Saffranin-O stain of articular cartilage of an animal treated with placebo (From Lippiello L, Woodward J, Karpman R, et al.In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop 2000;381:229 – 40; with permission.)
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Figure 4: Saffranin-O stain of articular cartilage of animal treated with Cosamine (From Lippiello L, Woodward J, Karpman R, et al.In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop 2000;381:229 – 40; with permission.)
near complete preservation of the cartilage was seen when both agent were given together (Figs. 2 –4) [92]. Numerous studies that used a combinination therapy have been reported in man (see references [78,93 – 95]) and in veterinary practice. Results are similar to those that used glucosamine or chondroitin alone. There has yet to be a study that compares the effects of each agent individually to the combination therapy and placebo in man. For this reason, the National Institutes of Health has funded an ongoing, four-arm, multi-year study to compare glucosamine, chondroitin, combination, and placebo in the treatment of OA of the knee.
Nutraceutical caveats There are several caveats a clinician must consider before recommending glucosamine or chondroitin to patients in clinical practice. These include concerns over safety, efficacy, purity, and labeling, to name a few. Although there is credible evidence to support the efficacy of both of these agents, the literature is not without negative results [96]. A few experimental papers suggested toxic effects of high doses of glucosamine on chondrocytes [97]. The investigators suggested that the decrease in cartilage breakdown that is seen in
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cartilage culture, in the presence of IL-1 and Lipo-Polysaccharide (LPS), is due to increased apoptosis when cultures were treated with glucosamine. The safety of these agents has also been called into question (see references [61,98,99]). Glucosamine and chondroitin are sugars. There has been legitimate concern that these agents might cause or exacerbate diabetes. Neither glucosamine nor chondoitin produced insulin resistance in a study of Sprague Dawley and spontaneous hypertensive rats. Both breeds are highly sensitive to changes in glucose metabolism [100]. Glucosamine is a simple sugar that may be synthesized or derived from the chitin that is found in crustacean shells. Chondroitin, is usually derived from animal sources; the most common is bovine trachea. There has been concern that cross contamination with Bovine Spongiform Encephalopathy (BSE) could occur. The infective agent in BSE is a nearly indestructible denatured protein, termed a prion. It is found primarily in bovine neuronal tissue, but protein source must also be treated with care. Cartilage is less problematic, having been found to be BSE-free, even in infected animals [101]. A recent review of safety concerns for these agents, including possible hypercholestrerolemia, anticoagulation, prostate cancer, and sodium content, found that both agents were remarkably safe [98]. In contradistinction to most other countries, including all of Europe, glucosamine and chondroitin are considered dietary supplements in the United States. Their regulation falls under the Dietary Supplement Health Education Act, rather than under direct Food and Drug Administration control. Dietary supplements are not required to meet the same standards of purity and labeling as pharmaceuticals. Independent laboratory analysis revealed that many available supplements do not reach their stated label claim for purity and quantity. Some of them have no active ingredient (Fig. 5) [102]. Furthermore, the bioavailability of off label brands is far from assured. Well constructed animal bioavailability and human clinical trials were conducted using pharmaceutical grade glucosamine and chondroitin. The assumption that a generic brand as compared with Cosamin DS is equally efficacious is suspect. This is especially true for chondroitin; the low molecular weight compound is absorbed by the gut, whereas the high molecular weight variety is not [102,103]. Because of the lack of regulation or guarantee of purity and consistency, general objections to the use of nutritional supplements as a mainline treatment for OA have been raised [61]. Reginster et al [104], in a recent review, pointed out that almost all of the reported studies in the literature used glucosamine and chondroitin that were licensed as a pharmaceutical (as it is in Europe) rather than an unregulated neutraceutical that is sold in the United States.
Bioavailability CS is a large molecule that ranges in size from 15 kilo Dalton (kDa) to 45 kDa. Oral bioavailability depends on molecular weight [102,103]. With low molecular
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Fig. 5. Relationship between percentage label claim and retail price for chondroitin sulfate supplements. (From Adebowale A, Cox DS, Zhongming L, et al. Analysis of glucosamine and chondroitin sulfate content in marketed products and the Caco-2 permeability of chondroitin sulfate raw materials. JAMA 2000;3(1):37 – 44; with permission.)
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weight CS, bioavailability is approximately 20% [105]. After absorption, only about 10% to 15% remains CS, the remainder exists as depolymerized derivatives; this suggests an important first-pass effect. CS demonstrates tropism to cartilage [106]. Significant intra-articular accumulation of CS is noted 2 hours after administration. Although the oral bioavailability of CS is low, significant accumulation after multiple dosing was noted in animal models [107]. Glucosamine is a simple hexosamine, and as such, is rapidly and nearly completely absorbed from the GI tract. Bioavailability after a first-pass effect is 26% [108]. Bioavailability of intramuscular and intra-articular routes are 96% and 100%, respectively [109]. Active uptake by the cartilage was demonstrated by using radiolabeling techniques [109].
Summary The near universal finding of the safety of glucosamine and chondroitin combined with some compelling evidence of their efficacy should spur further research into their mechanism of action, optimal dosing, long-term effects on disease modification, and clinical applicability. When recommending a supplement to patients, the clinician should take into account the purity of the ingredients, reputation of the manufacturer, and the molecular weight of chondroitin supplied.
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Chondroprotective agents: glucosamine and chondroitin Marc W. Hungerford, MD*, Daniel Valaik, MD Johns Hopkins University, Suite G-1 Professional Office Building, 5601 Loch Raven Boulevard, Baltimore, MD 21239, USA
Osteoarthritis (OA) is the most common musculoskeletal disease in the United States [1]. It is estimated that 65% of people over the age of 65 have symptomatic OA in at least one joint [2]. The aging of western populations, coupled with increased longevity of those populations, has made OA one of the leading public health concerns [3], and yet, a disease-modifying treatment for this disorder has yet to be developed, or has it? The publication of a book entitled ‘‘The Arthritis Cure’’ by Theodosakis et al [4] in 1997 generated a strong public and media interest in glucosamine and chondroitin sulfate (CS), and nutritional supplements, in general; this helped to reinvigorate the search for disease-modifying treatments for this debilitating disorder. This article examines the data that support the use of these agents in the treatment of OA.
The structure and function of cartilage A discussion of the disease-modifying properties of an agent can only be understood in the context of the structure and function of normal cartilage and the pathologic mechanisms of OA. Normal articular cartilage is the most durable tissue in the body. It is avascular and aneural; all circulation within it must be accomplished by diffusion. Cartilage is composed of 5% chondrocytes and 95% extracellular matrix. The chondrocytes secrete and maintain the matrix, but the matrix gives cartilage its mechanical properties and allows it to function over a long period of time, despite a high degree of stress. Therefore, the importance of the proper function of the matrix cannot be overstated. The extracellular matrix is comprised of 70% water and 30% solid material, predominantly collagen II, proteoglycans, and other fibrillar and globular
* Corresponding author. E-mail address: [email protected] (M.W. Hungerford). 1083-7515/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1083-7515(03)00043-3
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Fig. 1. The structure of cartilage.
proteins. The proteoglycans are complex, high molecular weight macromolecules that consist of glycosaminoglycans (GAGs), such as chondroitin 4- and 6-sulfate, keratan sulfate or dermatan sulfate, and a protein core. Proteoglycans are, in turn, linked to a hyaluronan backbone to form the large aggrecan molecule. The proteoglycans carry a highly negative charge which gives them strong hydrophilic properties; this accounts for the high water content in cartilage. The glycosaminoglycans, especially CS, also form bonds with each other and with collagen II, thus limiting the amount of water imbibition and lending cartilage its turgor and resilience [5]. Without these bonds, the cartilage would absorb excessive water which results in chondromalacia. Because the structure and density of the matrix also determines the degree and rate of diffusion that is possible within it, normal extracellular matrix is vital not to the function of cartilage, as well as its survival (Fig. 1).
The nature and progression of osteoarthritis Great strides have been made in recent years in the understanding of the pathogenesis of OA. Although a small percentage of the population who has arthritis has suffered an antecedent injury (posttraumatic or secondary OA), most patients develop cartilage degeneration in the absence of any underlying cause. The incidence of OA increases with age; some estimates suggest that 85% percent of
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people aged 65 and older suffer from it to some degree. The relationship to age is an indirect one, however; it is just as inaccurate to regard cartilage degeneration as a normal consequence of aging cartilage as to consider it wear and tear. Osteoarthritis is a consequence of complex interactions between the chondrocytes and the extracellular matrix. Although the collagen in the matrix is static, the proteoglycans are actively maintained by the chondrocytes [6]. The balance between anabolic and catabolic processes in the matrix which determine the matrix’ fate. Although precise details of the processes that initiate cartilage degeneration remain undefined, it is known that chondrocytes in OA cartilage produce interleukin-1 (IL-1), which, in turn, releases a cascade of cytokines, including tumor necrosis factor-a (TNF-a), transforming growth factor-b, and several prostaglandins. These cytokines stimulate the chondrocytes to release lytic enzymes, such as the metalloproteinases, which degrade collagen II and proteoglycans [7 – 10]. Simultaneously, normal matrix synthesis by chondrocytes is inhibited [9]. In addition, the amount of chondroitin 4-sulfate is reduced and the ratio of keratan sulfate to CS is increased. CS binds to other GAGs and collagen II better than CS analogs. CS absence results in a weakness of the matrix and an increase in the amount of water in the matrix. These biochemical changes alters biomechanical competence of the matrix to transmit force and support the condrocytes, thus producing a vicious cycle. Once begun, there is no reliable way to reverse the process in man. Even small lesions demonstrate poor and incomplete healing. Although slow progression of disease is the rule, progression is not inexorable. In some instances, damaged cartilage can function without producing symptoms for remarkable periods of time. The disease typically progresses with loss of cartilage, microfracture and sclerosis of subchondral bone, and formation of bone cysts and osteophytes. In contrast to inflammatory arthritides, the synovium show minor changes, including congestion, minor inflammation, and fibrosis. The characteristic pathologic changes of OA are directly traceable to the initial degradation of the cartilage matrix [10].
Treatment of osteoarthritis Despite the large number of patients who suffer, and the staggering cost of treatments and days of work lost, the medical community has yet to devise a rational treatment for OA. Treatment efforts have been restricted to symptomatic amelioration. For mild, early OA, simple analgesics, such as acetaminophen or paracetamol, may suffice. When symptoms become more severe, the mainstay of treatment in the United States has been nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are problematic, at best, as a first line treatment for OA. Although the efficacy of NSAIDS, compared with placebo, has been well documented, evidence of superior efficacy compared with simple analgesics is largely lacking [11,12]. NSAIDs inhibit cyclo-oxygenase, which is the source of their anti-inflammatory properties, as well as their side effects. Inhibitory effects on
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cartilage have been noted by many investigators [13 – 19]. Catabolic and anabolic processes are inhibited [20,21]. The fear that inhibition of anabolic processes by NSAIDs may harm the cartilage led some investigators to postulate the possibility of an ‘‘NSAID arthropathy’’ [22,23]. Although this fear has not been realized, it seems clear that NSAIDs do not have any beneficial effects on the cartilage. Inhibition of the cyclooxygenase (COX) enzyme prevents secretion of prostaglandins that are vital to the maintenance of the gastric mucosa. In fact, NSAID gastropathy is the second most deadly rheumatic disease [24]; it accounted for 107,000 hospitalizations and 16,500 deaths according to one report [25]. The same investigators noted that the cumulative risk increases with time; 80% of patients with serious gastrointestinal (GI) complications had no previous symptoms. Thus, we are faced with a disease of epidemic proportions for which the mainline of treatment is purely symptomatic, expensive, and fraught with considerable danger for the patient. Clearly, there must be a better way.
Definition of chondroprotective agent Recognizing this dilemma, numerous researchers have been looking for a ‘‘chondroprotective agent’’ as a rational treatment for early OA. Cartilage researchers recognized that the ability to induce healing in damaged cartilage might be a long way off, but protecting that cartilage from further damage and preserving its function might be a considerably more achievable short-term goal. Ghosh and Brooks [26] made an attempt to define the characteristics of such an agent: A chondroprotective agent should
Enhance chondrocyte macromolecule synthesis Enhance synthesis of hyaluronan Inhibit degradative enzymes Mobilize thrombin, fibrin, lipids, and cholesterol deposits in blood vessels surrounding the joint Reduce joint pain Reduce synovitis
The remainder of this article examines the evidence of the clinical efficacy of glucosamine and chondroitin and whether they satisfy any of the criteria of a chondroprotective agent.
Glucosamine Glucosamine in an aminomonosaccharide which is a vital component of glycosaminoglycans and hyaluronan. Glucosamine is naturally synthesized by the chondrocyte, but when supplemented, it can be used directly to synthesize
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larger macromolecules. Most preparations for human use purify it from chitin that is derived from crustacean shells. Glucosamine has been available for human treatment since the 1950s, but it was not until an oral form was developed in Germany in the 1960s that clinical interest in this molecule developed in earnest. Intra-articular and intramuscular preparations are still available, but most studies use oral preparations of glucosamine sulfate, glucosamine hydrochloride, or a glucosamine analog, N-acetyl glucosamine. In vitro and animal studies documented a variety of glucosamine effects. These can be categorized into substrate effects, transcriptional effects, antiinflammatory effects, and anticatabolic or antiarthritic effects Substrate and transcriptional effects As early as 1956, Roden [27] noted an increased production of glycosaminoglycans and collagen when glucosamine sulfate was added to cartilage-derived fibroblast cell cultures. Other investigators confirmed this finding [28,29]. This effect was glucosamine-specific; N-acetyl glucosamine was far less active and glucuronic acid was without effect [30,31]. Besides functioning as a simple substrate, recent work showed that glucosamine affected gene transcription within the chondrocyte. Jimenez and Dodge [32] demonstrated a twofold increase in perlecan and aggrecan mRNA levels and a moderate increase in stromelysine mRNA in condrocyte cultures that were incubated with 50 mM glucosamine. The same investigators showed a dose-dependent down-regulation of metalloproteinase I and II (enzymes that are important in the degradation of cartilage) mRNA in the same model [32]. Anti-inflammatory, antireactive, and anticatabolic properties As early as 1980, Vidal y Plana and Karzel [33] demonstrated the ability of glucosamine to normalize cartilage metabolism and to prevent cartilage degradation. More recently, glucosamine was shown to inhibit aggrecanase mediated matrix destruction in rat chondrosarcoma cell line and cartilage explants [34]. A glucosamine relative, N-acetyl glucosamine, inhibits interleukin-b1 and TNF-a– induced nitric oxide production as well as down-regulating inducible nitric oxide synthetase mRNA in human articular chondrocytes [35]. Fenton et al [36] noted that 25 mg/mL of glucosamine prevented Lipopolysaccharide or IL-1– induced cartilage degeneration in equine cartilage explants. These anti-inflammatory effects support earlier work that demonstrated inhibition of inflammation in classic animal models of inflammation, such as carrageenin-induced plueritis or the rat paw model of inflammation [37]. Inflammation that was caused by inflammatory mediators, such as bradykinin, serotonin, or histamine, were not inhibited [37]. Specifically, glucosamine did not show any inhibition of the cyclo-oxygenase system, thus lending some credibility to the claim of GI tolerability.
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Glucosamine also increases the synovial production of hyaluronic acid, a substance that has been shown to have anti-inflammatory effects, induce anabolic activity in chondrocytes, decrease joint pain, and increase mobility in vivo and in clinical studies [38]. An antiarthritic effect of glucosamine was demonstrated in animal models for inflammatory arthritis, mechanical arthritis, immunoreative arthritis, and generalized inflammation. For example, in rabbits with transection of the anterior cruciate ligament, those who were treated with glucosamine demonstrated significantly less chondropathy than those who were treated with placebo [39]. In general, the efficacy of glucosamine in animal models was lower than indomethacin, but the toxicity was significantly lower; the overall therapeutic index was much more favorable [37]. Finally, glucosamine may have mild immunosuppressive activity. Hua et al [40] reported a variety of inhibitory effects of glucosamine on neutrophils, including supraoxide generation, phagocytosis, granule release, and chemotaxis, although it did not significantly affect bacteriocidal capability. N-acetyl glucosamine had no effect. Ma et al [41] showed dose-dependant suppression of T lymphocytes and allogeneic mixed leukocyte reactivity in vitro by glucosamine, as well as prolonged allogeneic cardiac allograft survival in vivo when subjects were treated with glucosamine; these effects were not seen with other amino sugars. Glucosamine sulfate has been studied in human arthritis sufferers over the past 25 years. Studies were performed in many countries, including Italy [42], Germany [43 –46], Spain [47], Portugal [48], China [49], and the Philippines [50]. Patients who had arthritis of the hand, spine, shoulders, hips, and knees were studied. The results were remarkably consistent; almost all studies showed a beneficial effect of glucosamine. Improvement in pain occurred slowly, over a period of several weeks. Subjects continued to improve while taking the study drug, compared with patients who took placebo. Subjects also maintained improvement for weeks to months after the drug was discontinued, whereas those who took placebo returned to baseline. Response to treatment was high, ranging from 56% to more than 90% [48,50] and no study encountered significant side effects with glucosamine. Interest in glucosamine accelerated in Europe with the synthesis of an easily absorbable oral preparation. Since the early 1980s, numerous controlled studies, including 12 double-blind studies (see references [42,47 – 49,51 – 58]) have been performed. At lease five of these were double-blind, single-joint, placebo-controlled, and randomized and used a validated outcomes tool [53 –57]. Reichelt and coauthors [57] reported a multicenter, double-blind, placebocontrolled study on the efficacy of intramuscular glucosamine in patients who had OA of the knee. One hundred fifty-five patients were treated with glucosamine sulfate, 400 mg, twice a week for 6 weeks, or placebo. The group who took glucosamine had a greater response and a higher rate of responders than the group who was given placebo. In 252 patients with OA of the knee, Noack et al [54] concluded that patients who were treated with glucosamine sulfate, 1500 mg,/day, for 4 weeks has a significantly greater improvement in Lesquesne’s index than those who were
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treated with placebo. Response rates were also better in the treated group (55% versus 37% in intention-to-treat analysis). More recently, Qiu and coauthors [49] studied 178 patients who had OA of the knee. Randomized cohorts received oral glucosamine, 1.5 g, or ibuprofen, 1.2 g, for a period of 4 weeks. Both groups had improvement in pain, mobility, and swelling, with trend that grew over time in favor of glucosamine. After discontinuation of treatment, glucosamine demonstrated a greater remnant therapeutic effect, although this was not statistically significant at 2 weeks. Glucosamine was significantly better tolerated than ibuprofen and the group who took glucosamine had fewer dropouts. In patients who had temporomandibular joint arthritis, Thie and coauthors [59] compared glucosamine to ibuprofen in a 3-month, randomized, controlled study. Thirty-nine patients were randomized to two groups: glucosamine, 1500 mg/day, or ibuprofen, 1200/day. Both groups showed clinical improvement. The degree of improvement was greater in the group who took glucosamine; persistent improvement was seen after discontinuation of the medication, compared with a return to baseline for the group who took ibuprofen. Criticism of the older literature on glucosamine and chondroitin centered on the small numbers of patients who were studied, the short time periods of the studies, and the relative lack of studies that were independent of corporate sponsorship [60,61]. Methodologic concerns, specifically the failure of most studies to specifically control for NSAID use, have also been raised [62,63]. Recent meta-analyses should help dispel some of the concern over the quality of the clinical evidence. Towheed et al [64], writing for the Cochrane Database, evaluated 16 Randomized Controlled Trials (RCTs); 12 compared glucosamine with placebo and four compared glucosamine with NSAIDs. The investigators concluded that glucosamine was safe and effective. McAlindon et al [65] reviewed six studies of glucosamine that involved 911 patients. Quality scores for these studies ranged from 12% to 52%. Combined results showed a moderate treatment effect of glucosamine. Perhaps the most convincing clinical reports are two recent studies that seem to demonstrate a chondroprotective effect in patients who had arthritis of the knee. Reginster and coauthors [56] randomized 212 patients to glucosamine sulfate (1500 mg/day) or placebo and followed them for 3 years. Standardized weight bearing knee radiographs were obtained and the minimum medial tibiofemoral joint space was measured using digital image analysis. The patients who took placebo showed progressive joint space narrowing of approximately 0.1 mm/y, whereas those who took glucosamine did not. Western Ontario and McMaster (WOMAC) scores decreased slightly in the group who took placebo compared with improvement in WOMAC scores in patients who took glucosamine. Reginster et al allowed the use of several different NSAIDs as rescue medications and some commentators were concerned that increased knee extension due to symptomatic relief in the group who took glucosamine could skew the results. To address some of these perceived deficiencies, Pavelka et al [55] performed a similar study with nearly identical results. In this study, 202 patients were randomized to glucosamine
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sulfate or placebo. Only acetaminophen was used for rescue analgesia. Minimal tibiofemoral compartment width, at a standard degree of knee flexion, and algofunctional scoring were used as endpoints. Progressive joint space narrowing was noted in the group who took placebo, whereas joint preservation was noted in the group who took glucosamine. Lequesne and WOMAC scores also showed statistically significant differences between the two groups.
Chondroitin CS is a sulfated glycosaminoglycan that consists of alternating residues of N-acetylgalactosamine and glucuronic acid. Chondroitin is one of the most abundant constituents of cartilage extracellular matrix and is also important in a variety of other connective tissues, including, cornea, heart valve, bone, skin, ligaments, and tendons. The high degree of sulfation lends the molecule a highly anionic character that accounts for its hydrophilicity. Chondroitin also binds to other GAGs and collagen II, thus serving an important function in matrix integrity [66]. Binding of CS to other GAGs and collagen II is better than keratan sulfate and other glycosamino glycans. In aging and OA, the ratio of keratan to chondroitin changes, reflecting a relative loss of chondroitin. The loss of chondroitin decreases the structural integrity of the matrix as a result of the loss of cross-links between chondroitin and collagen. When added to chondrocyte cell culture, metabolic effects of chondroitin have been noted. In a model of human articular chondrocytes, chondroitin increased the production of glycosaminoglycans with no noticeable effect on collagen II synthesis [67]. As a chondroprotective agent, chondroitin seems to competitively inhibit the action of many enzymes that degrade cartilage [67 –69]. Like other glycosaminoglycans and GAG precursors, a variety of anti-inflammatory activities have been described [70]. In animal models of arthritis, chondroitin affords the cartilage some protection from further degradation. For example, in rabbits who were injected with chymopapain into the knee, those who were preloaded with CS demonstrated less loss of proteoglycans from the cartilage than those who were not [101]. As with glucosmine, numerous clinical trials of chondroitin for the treatment of OA have been conducted [71 – 82], including at least four single joint, prospective, randomized, controlled studies that used a validated outcomes tool (see references [71,72,81,82]). All of these studies demonstrated some efficacy. Safety profiles were similar to placebo. In a characteristic pattern, a study that compared chondroitin with diclofenac showed a more rapid treatment response for diclofenac, but a more profound response to chondroitin. Further, the improvement persisted for 3 weeks after discontinuation in the group who took chondroitin group, whereas the group who took diclofenac returned to baseline [77]. Leeb and coathors [83] recently performed a meta-analysis of human RCTs that used CS. They pooled six studies (355 patients) using a visual analog scale or Lequesne index as an outcome measure. Subjects who took CS experienced
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improvement of 80% over baseline at 3 months versus a 51% improvement for the group who took placebo. Echoing other studies, the group who took CS had a persistent improvement after discontinuation of the drug, whereas the group who took placebo did not [53]. In another meta-analysis of studies that involved 799 patients, quality scores ranged from 14% to 55%. Chondroitin showed a large treatment effect in this analysis [65]. Most studies focused on symptomatic improvement for arthritis sufferers, primarily because such studies are much simpler and less time-consuming to execute. There is, however, some evidence that CS may have a disease-modifying effect in man. In a quantitative analysis of 140 patients who were treated with CS, 800 mg/d, or placebo, the group who took placebo showed decreased surface area, decreased mean thickness, and decreased minimum width of the medial tibiofemoral joint, whereas the group who took CS did not [82,85]. In another study, 119 patients who had OA of the hand were followed for 3 years. Only 9% of those who took CS, 1200 mg/d, developed new erosive lesions compared with 29% of those who took placebo [82]. Anticoagulant and antoatherosclerotic properties CS has also been studied for its anticoagulant and antiatherosclerotic effects [84 – 91]. Platelets normally secrete chondroitin and other GAGs (eg, heparin) as part of the body’s normal control of coagulation. With aging, the amount of chondroitin that is secreted decreases. Its function is assumed by less effective GAGs, such as keratan sulfate, thus predisposing the patient to microthrombus formation. By reversing this process, CS may improve the microcirculation to subchondral bone, synovium, and other tissues.
Glucosamine chondroitin synergy Looking back to the proposed definition of a chondroprotective agent, it is clear that neither glucosamine nor CS meet the criteria by themselves (Table 1). A combination treatment of the two agents addresses all of the requirements for a chondroprotective agent in Table 1. Furthermore, cell culture and animal experiments suggest a possible synergistic, rather than merely additive, effect of glucosamine and chondroitin on cartilage metabolism. In bovine cartilage explants, synergy that was measured by maximal uptake of 35-sulfate was optimum at a dose of glucosamine, 150 mg/mL, and chondroitin, 140 mg/mL. Uptake when both Table 1 Postulated mechanism of synergy between glucosamine and chondroitin sulfate Proposed chondroprotective agents
Chondroprotective characteristics identified
Glucosamine Chondroitin sulfate Chondroitin sulfate
Stimulate chondrocyte and synoviocyte metabolism Inhibition of degradative enzymes Prevent peri-articular fibrin thrombi
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Figure 2: Saffranin-O stain of normal articular cartilage. (From Lippiello L, Woodward J, Karpman R, et al.In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop 2000;381:229 – 40; with permission.)
agents were administered was 96.6% greater than controls compared with only a 32% improvement compared with controls for either agent alone [92]. In a rabbit instability model of knee OA, the chondroprotective efficacy of glucosamine, chondroitin, and the combination were compared with placebo. Evidence of chondroprotection of both agents compared with placebo was noted, but dramatic,
Figure 3: Saffranin-O stain of articular cartilage of an animal treated with placebo (From Lippiello L, Woodward J, Karpman R, et al.In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop 2000;381:229 – 40; with permission.)
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Figure 4: Saffranin-O stain of articular cartilage of animal treated with Cosamine (From Lippiello L, Woodward J, Karpman R, et al.In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop 2000;381:229 – 40; with permission.)
near complete preservation of the cartilage was seen when both agent were given together (Figs. 2 –4) [92]. Numerous studies that used a combinination therapy have been reported in man (see references [78,93 – 95]) and in veterinary practice. Results are similar to those that used glucosamine or chondroitin alone. There has yet to be a study that compares the effects of each agent individually to the combination therapy and placebo in man. For this reason, the National Institutes of Health has funded an ongoing, four-arm, multi-year study to compare glucosamine, chondroitin, combination, and placebo in the treatment of OA of the knee.
Nutraceutical caveats There are several caveats a clinician must consider before recommending glucosamine or chondroitin to patients in clinical practice. These include concerns over safety, efficacy, purity, and labeling, to name a few. Although there is credible evidence to support the efficacy of both of these agents, the literature is not without negative results [96]. A few experimental papers suggested toxic effects of high doses of glucosamine on chondrocytes [97]. The investigators suggested that the decrease in cartilage breakdown that is seen in
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cartilage culture, in the presence of IL-1 and Lipo-Polysaccharide (LPS), is due to increased apoptosis when cultures were treated with glucosamine. The safety of these agents has also been called into question (see references [61,98,99]). Glucosamine and chondroitin are sugars. There has been legitimate concern that these agents might cause or exacerbate diabetes. Neither glucosamine nor chondoitin produced insulin resistance in a study of Sprague Dawley and spontaneous hypertensive rats. Both breeds are highly sensitive to changes in glucose metabolism [100]. Glucosamine is a simple sugar that may be synthesized or derived from the chitin that is found in crustacean shells. Chondroitin, is usually derived from animal sources; the most common is bovine trachea. There has been concern that cross contamination with Bovine Spongiform Encephalopathy (BSE) could occur. The infective agent in BSE is a nearly indestructible denatured protein, termed a prion. It is found primarily in bovine neuronal tissue, but protein source must also be treated with care. Cartilage is less problematic, having been found to be BSE-free, even in infected animals [101]. A recent review of safety concerns for these agents, including possible hypercholestrerolemia, anticoagulation, prostate cancer, and sodium content, found that both agents were remarkably safe [98]. In contradistinction to most other countries, including all of Europe, glucosamine and chondroitin are considered dietary supplements in the United States. Their regulation falls under the Dietary Supplement Health Education Act, rather than under direct Food and Drug Administration control. Dietary supplements are not required to meet the same standards of purity and labeling as pharmaceuticals. Independent laboratory analysis revealed that many available supplements do not reach their stated label claim for purity and quantity. Some of them have no active ingredient (Fig. 5) [102]. Furthermore, the bioavailability of off label brands is far from assured. Well constructed animal bioavailability and human clinical trials were conducted using pharmaceutical grade glucosamine and chondroitin. The assumption that a generic brand as compared with Cosamin DS is equally efficacious is suspect. This is especially true for chondroitin; the low molecular weight compound is absorbed by the gut, whereas the high molecular weight variety is not [102,103]. Because of the lack of regulation or guarantee of purity and consistency, general objections to the use of nutritional supplements as a mainline treatment for OA have been raised [61]. Reginster et al [104], in a recent review, pointed out that almost all of the reported studies in the literature used glucosamine and chondroitin that were licensed as a pharmaceutical (as it is in Europe) rather than an unregulated neutraceutical that is sold in the United States.
Bioavailability CS is a large molecule that ranges in size from 15 kilo Dalton (kDa) to 45 kDa. Oral bioavailability depends on molecular weight [102,103]. With low molecular
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Fig. 5. Relationship between percentage label claim and retail price for chondroitin sulfate supplements. (From Adebowale A, Cox DS, Zhongming L, et al. Analysis of glucosamine and chondroitin sulfate content in marketed products and the Caco-2 permeability of chondroitin sulfate raw materials. JAMA 2000;3(1):37 – 44; with permission.)
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weight CS, bioavailability is approximately 20% [105]. After absorption, only about 10% to 15% remains CS, the remainder exists as depolymerized derivatives; this suggests an important first-pass effect. CS demonstrates tropism to cartilage [106]. Significant intra-articular accumulation of CS is noted 2 hours after administration. Although the oral bioavailability of CS is low, significant accumulation after multiple dosing was noted in animal models [107]. Glucosamine is a simple hexosamine, and as such, is rapidly and nearly completely absorbed from the GI tract. Bioavailability after a first-pass effect is 26% [108]. Bioavailability of intramuscular and intra-articular routes are 96% and 100%, respectively [109]. Active uptake by the cartilage was demonstrated by using radiolabeling techniques [109].
Summary The near universal finding of the safety of glucosamine and chondroitin combined with some compelling evidence of their efficacy should spur further research into their mechanism of action, optimal dosing, long-term effects on disease modification, and clinical applicability. When recommending a supplement to patients, the clinician should take into account the purity of the ingredients, reputation of the manufacturer, and the molecular weight of chondroitin supplied.
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