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Chondroitin sulfate for the treatment of hip and knee osteoarthritis: Current status and future trends
Life Sciences 85 (2009) 477–483
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Life Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / l i f e s c i e
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Chondroitin sulfate for the treatment of hip and knee osteoarthritis: Current status and future trends Mitsuhiko Kubo, Kosei Ando, Tomohiro Mimura, Yoshitaka Matsusue, Kanji Mori ⁎ Department of Orthopaedic Surgery, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga, 520-2192, Japan
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Article history: Received 20 January 2009 Accepted 6 August 2009 Keywords: Chondroitin sulfate Osteoarthritis Articular cartilage Treatment
a b s t r a c t Aims: Osteoarthritis (OA) is a common joint disorder and a major socio-economic burden. Chondroitin sulfate (CS), which has chondroprotective properties, is a promising candidate for the therapeutic treatment of OA. Here, we summarize current knowledge as well as future trends of CS for the treatment of hip and knee OA. Main methods: We retrospectively reviewed pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of CS for the treatment of OA. Key findings: The safety and tolerability of CS are confirmed. CS is effective, at least in part, for the treatment of OA, and its therapeutic benefits occur through three main mechanisms: 1) stimulation of extracellular matrix production by chondrocytes; 2) suppression of inflammatory mediators; and 3) inhibition of cartilage degeneration. Significance: CS is a safe and tolerable therapeutic agent for the management of OA. Its effects include benefits that are not achieved by current medicines and include chondroprotection and the prevention of joint space narrowing. Such positive effects of CS represent a breakthrough in the treatment of hip and knee OA. © 2009 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . Current treatments of OA and their problems . Overview of the market . . . . . . . . . . . Introduction of the compound and its chemistry Pharmacodynamics . . . . . . . . . . . . . . Chondroprotective effects of CS . . . . . . . . Anti-inflammatory effects . . . . . . . . . . . Pharmacokinetics and metabolism . . . . . . . Clinical efficacy . . . . . . . . . . . . . . . . Safety and tolerability . . . . . . . . . . . . Summary and future trends . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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Introduction In developed countries, osteoarthritis (OA) is a common joint disorder. The most common symptoms are pain and functional disability resulting from destructive damage of joint cartilage. OA affects
⁎ Corresponding author. Tel.: +81 77 548 2252; fax: +81 77 548 2254. E-mail address: [email protected] (K. Mori). 0024-3205/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2009.08.005
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about 27 million people in the United States (US) (Lawrence et al. 2008), and the annual societal cost is estimated to be more than 60 billion dollars per year (Buckwalter et al. 2004). Significant advances in modern medicine have increased the average lifespan of humans, but have also contributed to the growing obesity epidemic. OA is a low mortality condition and its prevalence increases with age. It affects approximately 60% of the US population aged 65 years and older (CDC 2002), and the number of OA patients is expected to increase rapidly and double between 2005 and 2030 (CDC 2003). OA is therefore a major socio-economic burden.
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Current treatments of OA and their problems Current treatments for OA consist of non-surgical (physical, pharmacological) and surgical approaches. Surgical treatments are generally considered as final procedure when non-surgical treatments have failed to control pain and/or the function of the involved joint; however non-surgical approach should be tried at first. The optimal non-surgical management of OA patients requires a critical combination of both physical and pharmacological therapies. According to Lequesne et al, pharmacological approaches for the treatment of OA can be divided into three categories: 1) analgesics and non-steroidal anti-inflammatory agents (NSAIDs); 2) symptomatic slow-acting drugs for OA (SYSADOA); 3) chondroprotective or truly disease-modifying agents: disease-modifying OA drugs (DMOADs) (Lequesne et al. 1994). Recently, Steinmeyer et al. classified currently available drugs into 1) analgesics; 2) NSAIDs; 3) glucocorticoids; 4) slow-acting drugs for OA (SADOA); 5) herbal drugs; 6) diverse agents claiming to be effective (Steinmeyer and Konttinen 2006). Based on the fact that the central hallmark for the development of OA is the progressive destruction of joint tissue, the search for drugs with the ability to modulate the disease course is reasonable. DMOADs are such candidate drugs and are now under development (Qvist et al. 2008). Paracetamol is frequently used for self-medication and recommended as an oral analgesic to try at first according to EULAR and OARSI guidelines (Jordan et al. 2003; Zhang et al. 2007, 2008). However, paracetamol is not always sufficient for severe pain. OA is associated with significant inflammation such as synovitis and thus, NSAIDs appear to be rational drugs for the treatment of OA. Currently, this is the most popular pharmacological treatment for OA for the relief of both pain and inflammation. However, prolonged NSAIDs therapy is associated with several serious side-effects, including mucosal injury of the upper gastrointestinal tract (Laine 1996; Lanza et al. 2009; Silverstein et al. 2000) and nephropathy (Winkelmayer et al. 2008; Stürmer et al. 2001). As many as 25% of chronic NSAIDs users develop ulcer disease (Laine 1996) and approximately 1 in 200 patients aged more than 65 years develop acute renal complications within 45 days of a newly initiated NSAIDs regimen (Winkelmayer et al. 2008). The benefit of NSAIDs is palliative pain control, not primary care of the involved joint. Thus, safer and/or truly disease-modifying pharmacological agents for the management of OA are needed. Considerable attention has been paid to chondroitin sulfate (CS), a SYSADOA that has possible chondroprotective properties, as a good candidate for the pharmacological treatment of OA. In this review, we summarize current knowledge as well as future trends of CS for the treatment of hip and knee OA.
Conte 1993) are also commercially available in Europe. In contrast, CS is recognized as a “dietary supplement” in the US, and the Dietary Supplement Health and Education Act does not demand the same rigorous requirements for quality manufacturing as pharmaceuticals. Thus, the precise nature of the CS available in US is not published in the literature. Despite this clear difference, the market for CS is developing in both regions.
Introduction of the compound and its chemistry CS is naturally found in the extracellular matrix (ECM) of articular cartilage. Articular cartilage is composed of abundant ECM and chondrocytes and has two main components: collagen and proteoglycan (PG). Whereas collagen fibrils are mainly composed of type II collagen that form the framework of articular cartilage and resist tensile stress, PGs are hydrated and resist compression stress (Kubo et al. 2003). Many glycosaminoglycans (GAGs) gather on the core protein and mass attach to hyaluronan (HA) via a link protein, which makes PG. CS is a GAG of the same class as glucosamine (Fig. 1). CS is a GAG that is composed of alternate sequences of differently sulfated residues of D-glucuronic acid and N-acetyl-D-galactosamine linked by β bonds, thus making a disaccharide. Sequences of these disaccharides are formed into polysaccharide chains (Murata and Yokoyama 1985). The most abundant disaccharides in joint tissue are chondroitin sulfate A (CS A; chondroitin-4-sulfate) and chondroitin sulfate C (CS C; chondroitin-6-sulfate). CS A and CS C have a sulfate (SO3−) group at R4 and R6, respectively and a hydroxyl group at R2 (Fig. 2). Disaccharides
Overview of the market The occurrence of several serious side-effects of NSAIDs, the most common pharmacological agent for the treatment of OA, has led to the use of SADOA, an approach officially accepted by the WHO/ILAR Task Force in 1994 (Lequesne et al. 1994). SADOA are divided into two categories: SYSADOA and DMOAD; however DMOAD does not exist at the moment. Therefore, current interest has focused on SYSADOA. SYSADOA are characterized by their slow mode of action in humans. Their benefit is observed approximately 6 weeks after the start of therapy and they improve the pain and functional symptoms associated with OA. CS is a SYSADOA and is one of the most widely used SYSADOA for the treatment of OA (Uebelhart 2008). There is a discrepancy regarding the use of CS between the US and Europe. In Europe, CS is marketed as a SYSADOA and is widely used for the treatment of OA. Condrosulf® is a representative CS in Europe. The origin of Condrosulf® is bovine and the molecular mass is about 25,000–30,000 Da (Uebelhart 2008; Volpi 2002). Other CSs of different origin such as Matrix® (shark, 75,000 Da) (Ronca and
Fig. 1. Schematic presentation of cartilage structure (a) and magnification of proteoglycan (PG) (b). Collagen fibrils are mainly type II collagens that form the framework of articular cartilage and resist tensile stress, whereas PGs are hydrated and resist compression stress (a). Many glycosaminoglycans (GAGs) gather on the core protein and the mass attach to hyaluronan via a link protein, which makes PG. Chondroitin sulfate is a GAG (b).
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Fig. 2. Chemical structure of one unit in a chondroitin sulfate (CS) chain. A sulfate group can be located at R2, R4, R6 or by any combination of these positions. At the other site there is a hydroxyl group. Polysaccharide chains of CS will have repeating units with varying R groups of this disaccharide molecule. The heterogeneity of this primary structure is responsible for the different and specific biological and pharmacological functions of these GAGs. R2: the carbon 2 radial of the glucuronic acid, R4: the carbon 4 radial of the N-acetylgalactosamine and R6: the carbon 6 radial of the N-acetylgalactosamine.
with different numbers and positions of sulfate groups can be located inside the polysaccharide chain with varying percentages. This heterogeneity in primary structure is responsible for the different and specific biological and pharmacological functions of these GAGs (Volpi et al. 1993). Pharmacodynamics The benefits of CS for the treatment of OA occur through three main mechanisms: 1) stimulation of ECM (PG, CS, hyaluronan) production by chondrocytes (Bassleer et al. 1992, 1998; Johnson et al. 2001; Lippiello et al. 2000; Uebelhart et al. 1998); 2) suppression of inflammatory mediators (myeloperoxidase, N-acetyl glucosaminidase, collagenase, hyaluronidase, elastase) (Baici and Bradamante 1984; Ronca et al. 1998; Verbruggen and Veys 1977) and 3) inhibition of cartilage degeneration (Bassleer et al. 1992, 1998; Lippiello et al. 2000). Inflammatory mediators have a key role in the development of OA. Myeloperoxidase produces hypochlorous acid from hydrogen peroxide and chloride anions. Furthermore, it oxidizes tyrosine to tyrosyl radical using hydrogen peroxide as an oxidizing agent. Hypochlorous acid and tyrosyl radicals are cytotoxic. N-acetyl-beta-D-glucosaminidase, a glycolytic enzyme, is distributed in various tissue cells. It is released from macrophages especially at inflammation sites and resolves N-acetyl glucosamine, which is a component of the cartilage matrix. Collagenase and hyaluronidase resolve collagen and hyaluronan, which are the main structural components of articular cartilage extracellular matrix, respectively. Leukocyte elastase is a protease and resolves proteoglycans at sites of inflammation. Chondroprotective effects of CS Loss of articular cartilage is the major cause of joint dysfunction and disability in OA. Most current theories on the pathogenesis of cartilage degradation focus on the enzymatic degradation of the extracellular matrix and the suppression of matrix synthesis. Chondrocytes are crucial for adequate matrix balance and function because chondrocytes are the only cells in articular cartilage. Recently, extensive apoptotic cell death has been reported in OA cartilage (Hashimoto et al. 1998). Apoptotic cell death is an obvious central factor in both the initiation and progression of OA, because dead
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articular chondrocytes cannot be replaced in adults (Meachim et al. 1965). Studies that have used chondrocytes cultured in monolayers have revealed several benefits of CS (Hung 1974; Schwartz and Dorfman 1975). Interestingly, a recent study that used rabbit chondrocytes cultured in monolayers showed that CS does not induce chondrocyte proliferation but reduces apoptosis (Jomphe et al. 2008). This result is very promising, since apoptosis plays a pivotal role in the progression of articular cartilage degeneration in OA (Kubo et al. 2002). Although chondrocyte cultured in monolayers have been used in many studies, chondrocytes are surrounded with abundant ECM in vivo. Moreover, it is well known that chondrocytes cultured in monolayers de-differentiate into fibroblastic cells and lose their chondrocyte characteristics (Lin et al. 2008). However, 3D-culture conditions maintain the phenotypic characteristics of chondrocytes (Takahashi et al. 2007). Thus, results obtained from studies using 3Dcultures, i.e., cultures in cluster (Bassleer et al. 1992, 1998) or alginate beads (Legendre et al. 2008) are more credible for evaluating the real effects of CS on chondrocytes. Whereas CS significantly and dosedependently induces PG production in differentiated human articular chondrocytes cultured in cluster compared to untreated controls, DNA synthesis and type II collagen production are not affected. Furthermore, CS significantly decreases collagenolytic activity (Bassleer et al. 1992, 1998). These results indicate that CS stimulates ECM production by chondrocytes and inhibits cartilage degeneration in 3D-cultured chondrocytes. The other limitation of in vitro studies is the type of chondrocytes used. Many studies have used normal chondrocytes to evaluate the effects of CS (Bassleer et al. 1992; Nishimoto et al. 2005). To elucidate whether CS has benefits in the treatment of OA, the effects of CS on degenerated chondrocytes have been investigated. Indeed, cartilage explants and chondrocytes obtained from young or old animals displayed different responses to CS treatment (Legendre et al. 2008; Lippiello 2003). Interestingly, the benefits of CS on degenerative chondrocytes are larger than those on normal chondrocytes (Legendre et al. 2008; Lippiello 2003). However, optimal culture conditions, i.e., 3Dcultured degenerative chondrocytes should be used in future studies to elucidate more reliably the capability of CS as a therapeutic agent for the treatment of OA. In vivo studies have also demonstrated the capability of CS to treat OA. In a rabbit proteolytic degradation model, PG content in cartilage was demonstrated to be significantly higher in animals treated by oral administration (80 mg/day) or intramuscular injection (80 mg/day) of CS than that in untreated animals (Uebelhart et al. 1998). Anti-inflammatory effects In addition to these chondroprotective effects, Ronca et al. demonstrated the anti-inflammatory effects of CS both in vitro and in vivo (Ronca et al. 1998). It is noteworthy that oral administration of CS results in significantly higher anti-inflammatory activity compared with NSAIDs in rabbit models. The precise mechanisms of how CS achieves its multiple activities remain unknown. However, one possible mechanism has been proposed (Jomphe et al. 2008). Interleukin-1β (IL-1β) is considered a key factor in the development of OA by inducing both articular inflammation and cartilage degradation (Aigner et al. 2006). It has been reported that CS counteracts these adverse effects induced by IL-1β (Jomphe et al. 2008; Legendre et al. 2008). After IL-1β binds to cell membrane receptors (IL-1βR), it directly activates the intracellular signal transduction molecule nuclear factor-κB (NF-κB). In addition, IL-1β activates mitogen activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK) 1/2 and p38 MAPK, both of which can transactivate NF-κB and c-Jun N-terminal kinase (JNK), which in turn activate the activator protein-1 (AP-1) transcription factor. These transcription factors (NF-κB and AP-1)
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initiate and maintain the inflammatory response in chondrocytes (Agarwal et al. 2004; Roman-Blas and Jimenez 2006). Jomphe et al. suggest that CS acts as an anti-inflammatory agent by attenuating IL1β-induced p38 MAPK and ERK 1/2 phosphorylation, and NF-κB nuclear translocation, but not AP-1 translocation (Jomphe et al. 2008) (Fig. 3). Further studies are needed to determine the precise mechanism of the various activities of CS. Pharmacokinetics and metabolism The bioavailability of oral CS in human and animals is a subject under debate (Andermann and Dietz 1982; Baici et al. 1992; Conte et al. 1991a,b, 1955; Dohlman 1956; Dziewiatkowski 1956; Konador and Kawiak 1976, 1977; Palmieri et al. 1990). The likely explanations for this discrepancy are differences in analytical methods, the nature of the CS used for experimentation (Baici et al. 1992; Volpi 2002, 2003) and the animal species used (Conte et al. 1991b, 1995; Palmieri et al. 1990). Even in humans, different bioavailabilities of orally administered CS have been reported. Baici et al. reported that the serum concentration of CS is statistically unchanged after oral administration of 1 to 2 g of CS (Baici et al. 1992). In contrast, Conte et al. reported that administration of 0.8 g (single daily dose or two daily dose; 0.4 g × 2) of CS induces a significant increase in plasma concentrations as compared to predose values (Conte et al. 1995). Ronca et al. (1998) and Conte et al. (1991a,b) reported that the actual bioavailability of CS is 12% and 13.2%, respectively. Despite using CS of different origins (bovine, shark), oral administration of 4 g of CS resulted in an increase in serum CS levels compared to predose endogenous CS (Volpi 2002, 2003). Recent reports tend to reveal positive bioavailability of orally administered CS in humans (Conte et al. 1995; Volpi 2002, 2003). Orally administered CS is partially absorbed in the gastrointestinal tract and the rest is excreted in the feces. In mammals, the major site of metabolism for circulating CS is the liver, but the exact mechanism is unclear. The majority of orally administered CS is hydrolyzed into monosaccharides during the digestive process. Smaller amounts of di-, oligo-, and polysaccharides survive intact throughout the digestive process. About 10% of orally administered CS is absorbed as highmolecular-weight compounds and 20% is absorbed as low-molecular-weight compounds. A relevant fraction reaches tissues with
Fig. 3. Schematic presentation of chondroprotection at the level of signal transduction induced by chondroitin sulfate (CS). After binding its surface receptor Interleukin (IL)1β receptor 1 (IL-1βR1), IL-1β induces and maintains an inflammation response, which results in cartilage degeneration by activating NF-κB, extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). CS discloses chondroprotective effect by attenuating NF-κB, ERK 1/2 and p38 MAPK signals induced by IL-1β.
particular tropism for cartilage and other glycosaminoglycan-rich tissues. The absorption of orally administered CS depends on the length of polysaccharide chains (i.e., molecular mass) and charge density (Ronca and Conte 1993). Interestingly, the tropism of CS for joints was demonstrated after its oral administration. When 131I labeled CS was administered by an oral rout in humans, a high level of 131I labeled CS was observed in the synovial fluid and articular cartilage. This tropism was also documented in humans by SPECT analysis with oral administration of 99m Tc-CS (Ronca et al. 1998). Clinical efficacy A large variety of efficacies of CS with different degrees have been reported. Three major clinical efficacies of CS as a SYSADOA are 1) reduction of pain, 2) improvement of function (Lequesne index) and 3) reduction of NSAID or analgesic consumption (Bellamy 1997). The Lequesne index deals with pain, maximum walking distance and some activities associated with daily living (Lequesne et al. 1987). This index has been used to evaluate clinical assessment for knee and hip OA with satisfactory reproducibility (Lequesne et al. 1994). Five meta-analyses that included some double-blind, randomized and controlled studies have revealed positive effects of CS for the treatment of OA; however the benefits of CS tend to be milder (Bjordal et al. 2007; Leeb et al. 2000; McAlindon et al. 2000; Reichenbach et al. 2007; Richy et al. 2003). It was suggested that the advantage of CS in earlier trials could be related to lower methodological quality (Reichenbach et al. 2007). However, Monfort et al. critically appraised these five meta-analyses and concluded that CS has slight to moderate efficacy in the treatment of symptomatic OA with an excellent safety profile (Monfort et al. 2008). The SADOA guideline recommends evaluating the consumption of NSAIDs and/or analgesics regarding clinical outcome measurements for OA trials (Lequesne et al. 1994). Leeb et al. reviewed 7 publications and evaluated the consumption of NSAIDs and/or analgesics. A statistically significant reduction compared to baseline in CS groups, and a much less marked reduction for placebo was confirmed (Leeb et al. 2000). In addition, a recent study with high methodological quality reported very encouraging effects of CS, such as the prevention of joint space narrowing (Michel et al. 2005; Uebelhart et al. 2004). Thus, Uebelhart, who published significant numbers of papers in this field, appreciated CS as a SYSADOA as well as DMOADs in his latest review (Uebelhart 2008). DMOADs are by nature different from currently available pharmaceutical treatments. Currently, new potential DMOADs are being developed. Current treatment options focus on the relief of pain and improvement of joint function; however DMOADs have the ability to slow degeneration in OA. Matrix-metalloproteinase inhibitors, bisphosphonate, cytokine inhibitors, and calcitonin are now under development as such agents (Qvist et al. 2008). Notably, the intermittent oral administration of CS (800 mg CS per day for two periods of 3 months during 1 year) for the treatment of OA significantly improves pain and function due to knee OA compared to placebo (Uebelhart et al. 2004). Additionally, in another series, OA patients treated for 3 months with CS followed by a 3-month drug free period maintained significant pain reduction and improvement of clinical symptoms at the last follow-up period (Mazieres et al. 2001; Morreale et al. 1996. These findings suggest that the favorable effect of CS for the treatment of OA could be sustained for several months following cessation of treatment. This unique effect of CS is called the carry-over effect (Fajardo and Di Cesare 2005; Mazieres et al. 2001; Morreale et al. 1996; Uebelhart et al. 2004). Conversely, some recent studies failed to demonstrate the significant benefit of CS for the treatment of OA in terms of pain relief. The multi-center, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT), founded
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by the National Institutes of Health (NIH), was performed to evaluate the efficacy and safety of CS as a therapeutic agent for knee pain due to OA. In this trial, 1583 patients were randomized and received 1500 mg of glucosamine daily, 1200 mg of CS daily, both glucosamine and CS, 200 mg celecoxib daily or placebo for 24 weeks. Interestingly, subjects treated with CS alone or glucosamine alone showed any significant improvement of knee pain compared to placebo. However, caution is warranted when interpreting this result, since most patients presented only mild pain with an unusual response to placebo in this trial (60%) (Clegg et al. 2006). In patients with moderate-severe pain at baseline, a combination of CS with glucosamine significantly reduced pain and the response rate was higher than that of placebo (Clegg et al. 2006). Furthermore, there was a significant difference (p = 0.01) in the incidence of joint swelling and/or effusion between treated and placebo groups. Thus, it appears that CS is effective, at least in part, for the treatment of OA. Taking into account these reports, two major organizations: The Osteoarthritis Research Society International (OARSI) and the European League Against Rheumatism (EULAR) ranked CS treatment for OA as ‘‘Recommendations’’ with the level of evidence as Ia (Jordan et al. 2003; Zhang et al. 2007, 2008). OARSI advocated evidence-based, expert consensus guidelines in 2008 with 25 recommendations. These guidelines describe CS as follows: ‘Treatment with glucosamine and/or CS may provide symptomatic benefit in patients with knee OA. If no response is apparent within 6 months treatment should be discontinued’ (Zhang et al. 2007). The final recommendation of CS from EULAR ranked CS with the highest “A” grade and CS is included as one of the best 10 recommendations (Jordan et al. 2003). Nevertheless, we have to remember that the benefit of CS is not accepted by all guidelines. Indeed, CS is recommended by only 2 out of 7 guidelines in which the modalities of therapy were considered, and there is continuing controversy as to the efficacy of these agents as modifying drugs (Zhang et al. 2007). Moreover, a meta-analysis of five placebo-controlled RCTs yielded that CS may also have structure-modifying effects and smaller than expected beneficial effects (Reichenbach et al. 2007). Safety and tolerability Good tolerability and safety is a great concern in medicine, especially for chronic clinical manifestations such as OA. Previous reports confirmed the safety and tolerability of CS regardless of its origin (Bourgeois et al. 1998; Bucsi and Poor 1998; Volpi 2003). Two independent randomized double-blind, placebo-controlled studies confirmed very good tolerability of CS treatment by the assessment of both physicians and patients (Bourgeois et al. 1998; Bucsi and Poor 1998). The rate of adverse drug events was 15% (6/40), 23% (10/43) and 27% (12/44) (1200 mg/day, 3 × 400 mg/day and placebo, respectively) and almost all cases (89%) were digestive and cutaneous problems (Bourgeois et al. 1998). Severe adverse drug events were not found. EULAR ranked the potential toxicity of each intervention by VAS (0 was ‘‘not toxic at all’’ and 100 was ‘‘very toxic’’) according to 23 expert opinions. The potential toxicity of CS was estimated to be less than 10/100. This score was identical with that of ultrasound treatment, electromagnetic and orthotics, and significantly lower than that of NSAIDs (51/100) (Jordan et al. 2003). In addition, the adverse effect of CS was not reported in OARSI recommendations (Zhang et al. 2007). Despite this evidence, observations such as hair loss, edema of ankles and extrasystoles, which were not reported with placebo, were indicated in a report (Bourgeois et al. 1998). The potential mechanism of these adverse effects is unknown. However careful attention must be paid for the appearance of such unfavorable events. The dropout rate was also investigated in a meta-analysis of CS for the treatment of OA. The dropout rate in 7 double-blind, randomized
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controlled studies was 27% in the CS group and 39% in the placebo group, respectively (Leeb et al. 2000). This result further indicates its good tolerability as well as its benefits.
Summary and future trends In the next 5–10 years, the prevalence of OA will increase with the aging world population and the socio-economic burden of this disease will also increase steadily. Thus, more safe and effective medicines for the treatment of OA need to be produced. When CS is orally administered in humans, it is absorbed and reaches the articular joint. CS demonstrates clinical benefits such as reduction of NSAID or analgesic consumption for the treatment of OA. Moreover, other benefits, which were not achieved by current standard medicines, such as prevention of joint space narrowing have been reported. These benefits by means of CS result from three mechanisms: 1) direct stimulation of ECM production by chondrocytes; 2) suppression of inflammatory mediators and 3) inhibition of cartilage degeneration. Furthermore, we believe there is broad agreement in the field regarding the safety and tolerability of CS. Altogether, the use of CS is rational, and it is a good candidate for the treatment of OA. In recent publications, the beneficial effects of CS have been found to be smaller than previously thought. However, the quality of the research and the sponsorship of such studies remain questionable. Reichenbach et al. analyzed the quality of trials and suggested that most trials had poor methodological quality or inadequate reporting (Reichenbach et al. 2007). McAlindon et al. evaluated trials using the assessment by Chalmers et al. (1981) and produced quality scores expressed as a percentage of the maximum possible score. Quality scores ranged from 12.3% to 55.4% with a mean of 35.5% (McAlindon et al. 2000). Moreover, they examined the presence of industrial sponsorships. Among 9 trials, 5 studies received direct financial support from manufacturers, 2 articles included investigators from the companies as co-authors, and the manufacturers conducted key aspects of the trials such as randomization, data collection or statistical analysis in 4 studies (McAlindon et al. 2000). High quality, unsponsored, human clinical trials are needed to evaluate the true efficacy of CS for the treatment of OA. Currently, the rout of CS administration is oral, but the digestive process has a significant impact on its absorption. To obtain the desired benefits of CS, other delivery routs, i.e., intra-articular inoculation, should be addressed to deliver higher concentrations of intact CS without hydrolyzation. Current standard medicines have several serious side-effects. Safe medicines with chondroprotective effects such as CS may be the first line of medical treatment for OA in the future. It is possible that CS in combination with other agents such as glucosamine will be a standard regimen for the treatment of OA.
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Life Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / l i f e s c i e
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Chondroitin sulfate for the treatment of hip and knee osteoarthritis: Current status and future trends Mitsuhiko Kubo, Kosei Ando, Tomohiro Mimura, Yoshitaka Matsusue, Kanji Mori ⁎ Department of Orthopaedic Surgery, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga, 520-2192, Japan
a r t i c l e
i n f o
Article history: Received 20 January 2009 Accepted 6 August 2009 Keywords: Chondroitin sulfate Osteoarthritis Articular cartilage Treatment
a b s t r a c t Aims: Osteoarthritis (OA) is a common joint disorder and a major socio-economic burden. Chondroitin sulfate (CS), which has chondroprotective properties, is a promising candidate for the therapeutic treatment of OA. Here, we summarize current knowledge as well as future trends of CS for the treatment of hip and knee OA. Main methods: We retrospectively reviewed pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of CS for the treatment of OA. Key findings: The safety and tolerability of CS are confirmed. CS is effective, at least in part, for the treatment of OA, and its therapeutic benefits occur through three main mechanisms: 1) stimulation of extracellular matrix production by chondrocytes; 2) suppression of inflammatory mediators; and 3) inhibition of cartilage degeneration. Significance: CS is a safe and tolerable therapeutic agent for the management of OA. Its effects include benefits that are not achieved by current medicines and include chondroprotection and the prevention of joint space narrowing. Such positive effects of CS represent a breakthrough in the treatment of hip and knee OA. © 2009 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . Current treatments of OA and their problems . Overview of the market . . . . . . . . . . . Introduction of the compound and its chemistry Pharmacodynamics . . . . . . . . . . . . . . Chondroprotective effects of CS . . . . . . . . Anti-inflammatory effects . . . . . . . . . . . Pharmacokinetics and metabolism . . . . . . . Clinical efficacy . . . . . . . . . . . . . . . . Safety and tolerability . . . . . . . . . . . . Summary and future trends . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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Introduction In developed countries, osteoarthritis (OA) is a common joint disorder. The most common symptoms are pain and functional disability resulting from destructive damage of joint cartilage. OA affects
⁎ Corresponding author. Tel.: +81 77 548 2252; fax: +81 77 548 2254. E-mail address: [email protected] (K. Mori). 0024-3205/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2009.08.005
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about 27 million people in the United States (US) (Lawrence et al. 2008), and the annual societal cost is estimated to be more than 60 billion dollars per year (Buckwalter et al. 2004). Significant advances in modern medicine have increased the average lifespan of humans, but have also contributed to the growing obesity epidemic. OA is a low mortality condition and its prevalence increases with age. It affects approximately 60% of the US population aged 65 years and older (CDC 2002), and the number of OA patients is expected to increase rapidly and double between 2005 and 2030 (CDC 2003). OA is therefore a major socio-economic burden.
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Current treatments of OA and their problems Current treatments for OA consist of non-surgical (physical, pharmacological) and surgical approaches. Surgical treatments are generally considered as final procedure when non-surgical treatments have failed to control pain and/or the function of the involved joint; however non-surgical approach should be tried at first. The optimal non-surgical management of OA patients requires a critical combination of both physical and pharmacological therapies. According to Lequesne et al, pharmacological approaches for the treatment of OA can be divided into three categories: 1) analgesics and non-steroidal anti-inflammatory agents (NSAIDs); 2) symptomatic slow-acting drugs for OA (SYSADOA); 3) chondroprotective or truly disease-modifying agents: disease-modifying OA drugs (DMOADs) (Lequesne et al. 1994). Recently, Steinmeyer et al. classified currently available drugs into 1) analgesics; 2) NSAIDs; 3) glucocorticoids; 4) slow-acting drugs for OA (SADOA); 5) herbal drugs; 6) diverse agents claiming to be effective (Steinmeyer and Konttinen 2006). Based on the fact that the central hallmark for the development of OA is the progressive destruction of joint tissue, the search for drugs with the ability to modulate the disease course is reasonable. DMOADs are such candidate drugs and are now under development (Qvist et al. 2008). Paracetamol is frequently used for self-medication and recommended as an oral analgesic to try at first according to EULAR and OARSI guidelines (Jordan et al. 2003; Zhang et al. 2007, 2008). However, paracetamol is not always sufficient for severe pain. OA is associated with significant inflammation such as synovitis and thus, NSAIDs appear to be rational drugs for the treatment of OA. Currently, this is the most popular pharmacological treatment for OA for the relief of both pain and inflammation. However, prolonged NSAIDs therapy is associated with several serious side-effects, including mucosal injury of the upper gastrointestinal tract (Laine 1996; Lanza et al. 2009; Silverstein et al. 2000) and nephropathy (Winkelmayer et al. 2008; Stürmer et al. 2001). As many as 25% of chronic NSAIDs users develop ulcer disease (Laine 1996) and approximately 1 in 200 patients aged more than 65 years develop acute renal complications within 45 days of a newly initiated NSAIDs regimen (Winkelmayer et al. 2008). The benefit of NSAIDs is palliative pain control, not primary care of the involved joint. Thus, safer and/or truly disease-modifying pharmacological agents for the management of OA are needed. Considerable attention has been paid to chondroitin sulfate (CS), a SYSADOA that has possible chondroprotective properties, as a good candidate for the pharmacological treatment of OA. In this review, we summarize current knowledge as well as future trends of CS for the treatment of hip and knee OA.
Conte 1993) are also commercially available in Europe. In contrast, CS is recognized as a “dietary supplement” in the US, and the Dietary Supplement Health and Education Act does not demand the same rigorous requirements for quality manufacturing as pharmaceuticals. Thus, the precise nature of the CS available in US is not published in the literature. Despite this clear difference, the market for CS is developing in both regions.
Introduction of the compound and its chemistry CS is naturally found in the extracellular matrix (ECM) of articular cartilage. Articular cartilage is composed of abundant ECM and chondrocytes and has two main components: collagen and proteoglycan (PG). Whereas collagen fibrils are mainly composed of type II collagen that form the framework of articular cartilage and resist tensile stress, PGs are hydrated and resist compression stress (Kubo et al. 2003). Many glycosaminoglycans (GAGs) gather on the core protein and mass attach to hyaluronan (HA) via a link protein, which makes PG. CS is a GAG of the same class as glucosamine (Fig. 1). CS is a GAG that is composed of alternate sequences of differently sulfated residues of D-glucuronic acid and N-acetyl-D-galactosamine linked by β bonds, thus making a disaccharide. Sequences of these disaccharides are formed into polysaccharide chains (Murata and Yokoyama 1985). The most abundant disaccharides in joint tissue are chondroitin sulfate A (CS A; chondroitin-4-sulfate) and chondroitin sulfate C (CS C; chondroitin-6-sulfate). CS A and CS C have a sulfate (SO3−) group at R4 and R6, respectively and a hydroxyl group at R2 (Fig. 2). Disaccharides
Overview of the market The occurrence of several serious side-effects of NSAIDs, the most common pharmacological agent for the treatment of OA, has led to the use of SADOA, an approach officially accepted by the WHO/ILAR Task Force in 1994 (Lequesne et al. 1994). SADOA are divided into two categories: SYSADOA and DMOAD; however DMOAD does not exist at the moment. Therefore, current interest has focused on SYSADOA. SYSADOA are characterized by their slow mode of action in humans. Their benefit is observed approximately 6 weeks after the start of therapy and they improve the pain and functional symptoms associated with OA. CS is a SYSADOA and is one of the most widely used SYSADOA for the treatment of OA (Uebelhart 2008). There is a discrepancy regarding the use of CS between the US and Europe. In Europe, CS is marketed as a SYSADOA and is widely used for the treatment of OA. Condrosulf® is a representative CS in Europe. The origin of Condrosulf® is bovine and the molecular mass is about 25,000–30,000 Da (Uebelhart 2008; Volpi 2002). Other CSs of different origin such as Matrix® (shark, 75,000 Da) (Ronca and
Fig. 1. Schematic presentation of cartilage structure (a) and magnification of proteoglycan (PG) (b). Collagen fibrils are mainly type II collagens that form the framework of articular cartilage and resist tensile stress, whereas PGs are hydrated and resist compression stress (a). Many glycosaminoglycans (GAGs) gather on the core protein and the mass attach to hyaluronan via a link protein, which makes PG. Chondroitin sulfate is a GAG (b).
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Fig. 2. Chemical structure of one unit in a chondroitin sulfate (CS) chain. A sulfate group can be located at R2, R4, R6 or by any combination of these positions. At the other site there is a hydroxyl group. Polysaccharide chains of CS will have repeating units with varying R groups of this disaccharide molecule. The heterogeneity of this primary structure is responsible for the different and specific biological and pharmacological functions of these GAGs. R2: the carbon 2 radial of the glucuronic acid, R4: the carbon 4 radial of the N-acetylgalactosamine and R6: the carbon 6 radial of the N-acetylgalactosamine.
with different numbers and positions of sulfate groups can be located inside the polysaccharide chain with varying percentages. This heterogeneity in primary structure is responsible for the different and specific biological and pharmacological functions of these GAGs (Volpi et al. 1993). Pharmacodynamics The benefits of CS for the treatment of OA occur through three main mechanisms: 1) stimulation of ECM (PG, CS, hyaluronan) production by chondrocytes (Bassleer et al. 1992, 1998; Johnson et al. 2001; Lippiello et al. 2000; Uebelhart et al. 1998); 2) suppression of inflammatory mediators (myeloperoxidase, N-acetyl glucosaminidase, collagenase, hyaluronidase, elastase) (Baici and Bradamante 1984; Ronca et al. 1998; Verbruggen and Veys 1977) and 3) inhibition of cartilage degeneration (Bassleer et al. 1992, 1998; Lippiello et al. 2000). Inflammatory mediators have a key role in the development of OA. Myeloperoxidase produces hypochlorous acid from hydrogen peroxide and chloride anions. Furthermore, it oxidizes tyrosine to tyrosyl radical using hydrogen peroxide as an oxidizing agent. Hypochlorous acid and tyrosyl radicals are cytotoxic. N-acetyl-beta-D-glucosaminidase, a glycolytic enzyme, is distributed in various tissue cells. It is released from macrophages especially at inflammation sites and resolves N-acetyl glucosamine, which is a component of the cartilage matrix. Collagenase and hyaluronidase resolve collagen and hyaluronan, which are the main structural components of articular cartilage extracellular matrix, respectively. Leukocyte elastase is a protease and resolves proteoglycans at sites of inflammation. Chondroprotective effects of CS Loss of articular cartilage is the major cause of joint dysfunction and disability in OA. Most current theories on the pathogenesis of cartilage degradation focus on the enzymatic degradation of the extracellular matrix and the suppression of matrix synthesis. Chondrocytes are crucial for adequate matrix balance and function because chondrocytes are the only cells in articular cartilage. Recently, extensive apoptotic cell death has been reported in OA cartilage (Hashimoto et al. 1998). Apoptotic cell death is an obvious central factor in both the initiation and progression of OA, because dead
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articular chondrocytes cannot be replaced in adults (Meachim et al. 1965). Studies that have used chondrocytes cultured in monolayers have revealed several benefits of CS (Hung 1974; Schwartz and Dorfman 1975). Interestingly, a recent study that used rabbit chondrocytes cultured in monolayers showed that CS does not induce chondrocyte proliferation but reduces apoptosis (Jomphe et al. 2008). This result is very promising, since apoptosis plays a pivotal role in the progression of articular cartilage degeneration in OA (Kubo et al. 2002). Although chondrocyte cultured in monolayers have been used in many studies, chondrocytes are surrounded with abundant ECM in vivo. Moreover, it is well known that chondrocytes cultured in monolayers de-differentiate into fibroblastic cells and lose their chondrocyte characteristics (Lin et al. 2008). However, 3D-culture conditions maintain the phenotypic characteristics of chondrocytes (Takahashi et al. 2007). Thus, results obtained from studies using 3Dcultures, i.e., cultures in cluster (Bassleer et al. 1992, 1998) or alginate beads (Legendre et al. 2008) are more credible for evaluating the real effects of CS on chondrocytes. Whereas CS significantly and dosedependently induces PG production in differentiated human articular chondrocytes cultured in cluster compared to untreated controls, DNA synthesis and type II collagen production are not affected. Furthermore, CS significantly decreases collagenolytic activity (Bassleer et al. 1992, 1998). These results indicate that CS stimulates ECM production by chondrocytes and inhibits cartilage degeneration in 3D-cultured chondrocytes. The other limitation of in vitro studies is the type of chondrocytes used. Many studies have used normal chondrocytes to evaluate the effects of CS (Bassleer et al. 1992; Nishimoto et al. 2005). To elucidate whether CS has benefits in the treatment of OA, the effects of CS on degenerated chondrocytes have been investigated. Indeed, cartilage explants and chondrocytes obtained from young or old animals displayed different responses to CS treatment (Legendre et al. 2008; Lippiello 2003). Interestingly, the benefits of CS on degenerative chondrocytes are larger than those on normal chondrocytes (Legendre et al. 2008; Lippiello 2003). However, optimal culture conditions, i.e., 3Dcultured degenerative chondrocytes should be used in future studies to elucidate more reliably the capability of CS as a therapeutic agent for the treatment of OA. In vivo studies have also demonstrated the capability of CS to treat OA. In a rabbit proteolytic degradation model, PG content in cartilage was demonstrated to be significantly higher in animals treated by oral administration (80 mg/day) or intramuscular injection (80 mg/day) of CS than that in untreated animals (Uebelhart et al. 1998). Anti-inflammatory effects In addition to these chondroprotective effects, Ronca et al. demonstrated the anti-inflammatory effects of CS both in vitro and in vivo (Ronca et al. 1998). It is noteworthy that oral administration of CS results in significantly higher anti-inflammatory activity compared with NSAIDs in rabbit models. The precise mechanisms of how CS achieves its multiple activities remain unknown. However, one possible mechanism has been proposed (Jomphe et al. 2008). Interleukin-1β (IL-1β) is considered a key factor in the development of OA by inducing both articular inflammation and cartilage degradation (Aigner et al. 2006). It has been reported that CS counteracts these adverse effects induced by IL-1β (Jomphe et al. 2008; Legendre et al. 2008). After IL-1β binds to cell membrane receptors (IL-1βR), it directly activates the intracellular signal transduction molecule nuclear factor-κB (NF-κB). In addition, IL-1β activates mitogen activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK) 1/2 and p38 MAPK, both of which can transactivate NF-κB and c-Jun N-terminal kinase (JNK), which in turn activate the activator protein-1 (AP-1) transcription factor. These transcription factors (NF-κB and AP-1)
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initiate and maintain the inflammatory response in chondrocytes (Agarwal et al. 2004; Roman-Blas and Jimenez 2006). Jomphe et al. suggest that CS acts as an anti-inflammatory agent by attenuating IL1β-induced p38 MAPK and ERK 1/2 phosphorylation, and NF-κB nuclear translocation, but not AP-1 translocation (Jomphe et al. 2008) (Fig. 3). Further studies are needed to determine the precise mechanism of the various activities of CS. Pharmacokinetics and metabolism The bioavailability of oral CS in human and animals is a subject under debate (Andermann and Dietz 1982; Baici et al. 1992; Conte et al. 1991a,b, 1955; Dohlman 1956; Dziewiatkowski 1956; Konador and Kawiak 1976, 1977; Palmieri et al. 1990). The likely explanations for this discrepancy are differences in analytical methods, the nature of the CS used for experimentation (Baici et al. 1992; Volpi 2002, 2003) and the animal species used (Conte et al. 1991b, 1995; Palmieri et al. 1990). Even in humans, different bioavailabilities of orally administered CS have been reported. Baici et al. reported that the serum concentration of CS is statistically unchanged after oral administration of 1 to 2 g of CS (Baici et al. 1992). In contrast, Conte et al. reported that administration of 0.8 g (single daily dose or two daily dose; 0.4 g × 2) of CS induces a significant increase in plasma concentrations as compared to predose values (Conte et al. 1995). Ronca et al. (1998) and Conte et al. (1991a,b) reported that the actual bioavailability of CS is 12% and 13.2%, respectively. Despite using CS of different origins (bovine, shark), oral administration of 4 g of CS resulted in an increase in serum CS levels compared to predose endogenous CS (Volpi 2002, 2003). Recent reports tend to reveal positive bioavailability of orally administered CS in humans (Conte et al. 1995; Volpi 2002, 2003). Orally administered CS is partially absorbed in the gastrointestinal tract and the rest is excreted in the feces. In mammals, the major site of metabolism for circulating CS is the liver, but the exact mechanism is unclear. The majority of orally administered CS is hydrolyzed into monosaccharides during the digestive process. Smaller amounts of di-, oligo-, and polysaccharides survive intact throughout the digestive process. About 10% of orally administered CS is absorbed as highmolecular-weight compounds and 20% is absorbed as low-molecular-weight compounds. A relevant fraction reaches tissues with
Fig. 3. Schematic presentation of chondroprotection at the level of signal transduction induced by chondroitin sulfate (CS). After binding its surface receptor Interleukin (IL)1β receptor 1 (IL-1βR1), IL-1β induces and maintains an inflammation response, which results in cartilage degeneration by activating NF-κB, extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). CS discloses chondroprotective effect by attenuating NF-κB, ERK 1/2 and p38 MAPK signals induced by IL-1β.
particular tropism for cartilage and other glycosaminoglycan-rich tissues. The absorption of orally administered CS depends on the length of polysaccharide chains (i.e., molecular mass) and charge density (Ronca and Conte 1993). Interestingly, the tropism of CS for joints was demonstrated after its oral administration. When 131I labeled CS was administered by an oral rout in humans, a high level of 131I labeled CS was observed in the synovial fluid and articular cartilage. This tropism was also documented in humans by SPECT analysis with oral administration of 99m Tc-CS (Ronca et al. 1998). Clinical efficacy A large variety of efficacies of CS with different degrees have been reported. Three major clinical efficacies of CS as a SYSADOA are 1) reduction of pain, 2) improvement of function (Lequesne index) and 3) reduction of NSAID or analgesic consumption (Bellamy 1997). The Lequesne index deals with pain, maximum walking distance and some activities associated with daily living (Lequesne et al. 1987). This index has been used to evaluate clinical assessment for knee and hip OA with satisfactory reproducibility (Lequesne et al. 1994). Five meta-analyses that included some double-blind, randomized and controlled studies have revealed positive effects of CS for the treatment of OA; however the benefits of CS tend to be milder (Bjordal et al. 2007; Leeb et al. 2000; McAlindon et al. 2000; Reichenbach et al. 2007; Richy et al. 2003). It was suggested that the advantage of CS in earlier trials could be related to lower methodological quality (Reichenbach et al. 2007). However, Monfort et al. critically appraised these five meta-analyses and concluded that CS has slight to moderate efficacy in the treatment of symptomatic OA with an excellent safety profile (Monfort et al. 2008). The SADOA guideline recommends evaluating the consumption of NSAIDs and/or analgesics regarding clinical outcome measurements for OA trials (Lequesne et al. 1994). Leeb et al. reviewed 7 publications and evaluated the consumption of NSAIDs and/or analgesics. A statistically significant reduction compared to baseline in CS groups, and a much less marked reduction for placebo was confirmed (Leeb et al. 2000). In addition, a recent study with high methodological quality reported very encouraging effects of CS, such as the prevention of joint space narrowing (Michel et al. 2005; Uebelhart et al. 2004). Thus, Uebelhart, who published significant numbers of papers in this field, appreciated CS as a SYSADOA as well as DMOADs in his latest review (Uebelhart 2008). DMOADs are by nature different from currently available pharmaceutical treatments. Currently, new potential DMOADs are being developed. Current treatment options focus on the relief of pain and improvement of joint function; however DMOADs have the ability to slow degeneration in OA. Matrix-metalloproteinase inhibitors, bisphosphonate, cytokine inhibitors, and calcitonin are now under development as such agents (Qvist et al. 2008). Notably, the intermittent oral administration of CS (800 mg CS per day for two periods of 3 months during 1 year) for the treatment of OA significantly improves pain and function due to knee OA compared to placebo (Uebelhart et al. 2004). Additionally, in another series, OA patients treated for 3 months with CS followed by a 3-month drug free period maintained significant pain reduction and improvement of clinical symptoms at the last follow-up period (Mazieres et al. 2001; Morreale et al. 1996. These findings suggest that the favorable effect of CS for the treatment of OA could be sustained for several months following cessation of treatment. This unique effect of CS is called the carry-over effect (Fajardo and Di Cesare 2005; Mazieres et al. 2001; Morreale et al. 1996; Uebelhart et al. 2004). Conversely, some recent studies failed to demonstrate the significant benefit of CS for the treatment of OA in terms of pain relief. The multi-center, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT), founded
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by the National Institutes of Health (NIH), was performed to evaluate the efficacy and safety of CS as a therapeutic agent for knee pain due to OA. In this trial, 1583 patients were randomized and received 1500 mg of glucosamine daily, 1200 mg of CS daily, both glucosamine and CS, 200 mg celecoxib daily or placebo for 24 weeks. Interestingly, subjects treated with CS alone or glucosamine alone showed any significant improvement of knee pain compared to placebo. However, caution is warranted when interpreting this result, since most patients presented only mild pain with an unusual response to placebo in this trial (60%) (Clegg et al. 2006). In patients with moderate-severe pain at baseline, a combination of CS with glucosamine significantly reduced pain and the response rate was higher than that of placebo (Clegg et al. 2006). Furthermore, there was a significant difference (p = 0.01) in the incidence of joint swelling and/or effusion between treated and placebo groups. Thus, it appears that CS is effective, at least in part, for the treatment of OA. Taking into account these reports, two major organizations: The Osteoarthritis Research Society International (OARSI) and the European League Against Rheumatism (EULAR) ranked CS treatment for OA as ‘‘Recommendations’’ with the level of evidence as Ia (Jordan et al. 2003; Zhang et al. 2007, 2008). OARSI advocated evidence-based, expert consensus guidelines in 2008 with 25 recommendations. These guidelines describe CS as follows: ‘Treatment with glucosamine and/or CS may provide symptomatic benefit in patients with knee OA. If no response is apparent within 6 months treatment should be discontinued’ (Zhang et al. 2007). The final recommendation of CS from EULAR ranked CS with the highest “A” grade and CS is included as one of the best 10 recommendations (Jordan et al. 2003). Nevertheless, we have to remember that the benefit of CS is not accepted by all guidelines. Indeed, CS is recommended by only 2 out of 7 guidelines in which the modalities of therapy were considered, and there is continuing controversy as to the efficacy of these agents as modifying drugs (Zhang et al. 2007). Moreover, a meta-analysis of five placebo-controlled RCTs yielded that CS may also have structure-modifying effects and smaller than expected beneficial effects (Reichenbach et al. 2007). Safety and tolerability Good tolerability and safety is a great concern in medicine, especially for chronic clinical manifestations such as OA. Previous reports confirmed the safety and tolerability of CS regardless of its origin (Bourgeois et al. 1998; Bucsi and Poor 1998; Volpi 2003). Two independent randomized double-blind, placebo-controlled studies confirmed very good tolerability of CS treatment by the assessment of both physicians and patients (Bourgeois et al. 1998; Bucsi and Poor 1998). The rate of adverse drug events was 15% (6/40), 23% (10/43) and 27% (12/44) (1200 mg/day, 3 × 400 mg/day and placebo, respectively) and almost all cases (89%) were digestive and cutaneous problems (Bourgeois et al. 1998). Severe adverse drug events were not found. EULAR ranked the potential toxicity of each intervention by VAS (0 was ‘‘not toxic at all’’ and 100 was ‘‘very toxic’’) according to 23 expert opinions. The potential toxicity of CS was estimated to be less than 10/100. This score was identical with that of ultrasound treatment, electromagnetic and orthotics, and significantly lower than that of NSAIDs (51/100) (Jordan et al. 2003). In addition, the adverse effect of CS was not reported in OARSI recommendations (Zhang et al. 2007). Despite this evidence, observations such as hair loss, edema of ankles and extrasystoles, which were not reported with placebo, were indicated in a report (Bourgeois et al. 1998). The potential mechanism of these adverse effects is unknown. However careful attention must be paid for the appearance of such unfavorable events. The dropout rate was also investigated in a meta-analysis of CS for the treatment of OA. The dropout rate in 7 double-blind, randomized
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controlled studies was 27% in the CS group and 39% in the placebo group, respectively (Leeb et al. 2000). This result further indicates its good tolerability as well as its benefits.
Summary and future trends In the next 5–10 years, the prevalence of OA will increase with the aging world population and the socio-economic burden of this disease will also increase steadily. Thus, more safe and effective medicines for the treatment of OA need to be produced. When CS is orally administered in humans, it is absorbed and reaches the articular joint. CS demonstrates clinical benefits such as reduction of NSAID or analgesic consumption for the treatment of OA. Moreover, other benefits, which were not achieved by current standard medicines, such as prevention of joint space narrowing have been reported. These benefits by means of CS result from three mechanisms: 1) direct stimulation of ECM production by chondrocytes; 2) suppression of inflammatory mediators and 3) inhibition of cartilage degeneration. Furthermore, we believe there is broad agreement in the field regarding the safety and tolerability of CS. Altogether, the use of CS is rational, and it is a good candidate for the treatment of OA. In recent publications, the beneficial effects of CS have been found to be smaller than previously thought. However, the quality of the research and the sponsorship of such studies remain questionable. Reichenbach et al. analyzed the quality of trials and suggested that most trials had poor methodological quality or inadequate reporting (Reichenbach et al. 2007). McAlindon et al. evaluated trials using the assessment by Chalmers et al. (1981) and produced quality scores expressed as a percentage of the maximum possible score. Quality scores ranged from 12.3% to 55.4% with a mean of 35.5% (McAlindon et al. 2000). Moreover, they examined the presence of industrial sponsorships. Among 9 trials, 5 studies received direct financial support from manufacturers, 2 articles included investigators from the companies as co-authors, and the manufacturers conducted key aspects of the trials such as randomization, data collection or statistical analysis in 4 studies (McAlindon et al. 2000). High quality, unsponsored, human clinical trials are needed to evaluate the true efficacy of CS for the treatment of OA. Currently, the rout of CS administration is oral, but the digestive process has a significant impact on its absorption. To obtain the desired benefits of CS, other delivery routs, i.e., intra-articular inoculation, should be addressed to deliver higher concentrations of intact CS without hydrolyzation. Current standard medicines have several serious side-effects. Safe medicines with chondroprotective effects such as CS may be the first line of medical treatment for OA in the future. It is possible that CS in combination with other agents such as glucosamine will be a standard regimen for the treatment of OA.
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