Summary
Symptomatic slow-acting drugs for the treatment of osteoarthritis (SYSADOA; OA) are compounds which are prescribed as drugs in European countries since many years, whereas they are sold as nutraceuticals in USA. In Europe, the publication of the EULAR Recommendations for the Treatment of Knee OA in 2003 has listed oral chondroitin sulfate (CS) as evidence 1A and strength of recommendation A which represents the highest level for a therapeutic strategy.
Symptomatic slow-acting drugs are intended to be used as ground therapy for OA; these compounds are not rapidly acting agents such as Non Steroidal Anti-Inflammatory Drugs (NSAIDs), and their clinical efficacy on algo-functional symptoms can only be demonstrated after a couple of weeks of regular intake. Interestingly, once the administration is stopped, they do show carry-over effects of various durations, from about 3 months with the oral formulations to 6–9 months with intra-articular formulations. The main rationale behind the use of the SYSADOA therapeutic class is the reduction of NSAIDs in the overall drug management of OA disease and therefore consequently to limit the very significant risks of upper Gastro-intestinal (GI) tract erosions, ulcers with bleeding and/or deleterious renal effects in elderly patients.
The evidence for clinical efficacy of oral CS as a drug able to significantly improve the algo-functional symptoms of OA disease does come from a set of randomized clinical studies published a couple of years ago. Indeed, it was demonstrated that the drug was effective in knee and finger OA, whereas previous data suggested that hip OA patients could also benefit from it. In addition, oral CS supported the comparison with NSAIDs such as diclofenac sodium in a medium/long-term clinical study in patients with knee OA. A dose-finding study in patients with knee OA did provide strong data supporting the administration of 800 mg of CS orally which had nearly the same effects as 1200 mg/day, whereas the use of a sequential 3 months administration mode, twice a year was also shown to provide the same results as a continuous treatment. The good tolerability and safety aspects of oral CS were largely documented in these CTs. Taking these important points into account, we definitively have enough clinical data available supporting the view that oral CS is a valuable and safe symptomatic treatment for OA disease.
More recent data based on a couple of previous trials and two pivotal studies do provide further evidence that oral CS does also have structure-modifying effects in knee OA patients.
A couple of other compounds such as hyaluronan, diacerein, avocado and soya unsaponifiables, doxycycline have also been tested with respect to their potential disease-modifying effects. Additional compounds including receptor activator of NF-κB (RANK) ligand inhibitors, cathepsin K inhibitors, bisphosphonates are further assessed regarding their potential structure-modifying effect.
Key words
Introduction
Symptomatic slow-acting drugs for the treatment of osteoarthritis (SYSADOA; OA) are compounds which are prescribed as drugs in European countries since many years, whereas they are sold as nutraceuticals in USA. In Europe, the publication of the EULAR Recommendations for the Treatment of Knee OA in 2003 has listed oral chondroitin sulfate (CS) as evidence 1A and strength of recommendation A which represents the highest level for a therapeutic strategy.
Symptomatic slow-acting drugs are intended to be used as ground therapy for OA; these compounds are not rapidly acting agents such as Non Steroidal Anti-Inflammatory Drugs (NSAIDS) and their clinical efficacy on algo-functional symptoms can only be demonstrated after a couple of weeks of regular intake. Interestingly, once the administration is stopped, they do show carry-over effects of various durations, from about 3 months with the oral formulations to 6–9 months with intra-articular formulations. The main rationale behind the use of the SYSADOA therapeutic class is the reduction of NSAIDs in the overall drug management of OA disease and therefore consequently to limit the very significant risks of upper Gastro-intestinal (GI) tract erosions, ulcers with bleeding and/or deleterious renal effects in elderly patients.
Oral CS as a SYSADOA
CS belongs to the oral SYSADOA and the substance does have a delayed mode of action in OA which means that the first effects on pain and mobility can only be assessed after a couple of weeks of therapy (2–3 weeks), in sharp contrast with analgesics and NSAIDs, which do act more rapidly (1–3 days). Importantly, when stopped after 3 months of continuous daily administration, CS will present in most cases with a remanent effect which can last for a couple of months in some cases, a feature which is never observed with analgesics and NSAIDs, substances which need to be continuously administered in order to provide relief from pain and increased mobility in OA patients.
An important consideration to be made at this stage is that oral CS is registered as a drug in many European countries, whereas it is sold since many years as a prescription-free and over the counter (OTC) substance in all drugstores in the USA. The differences between both markets are obvious. The oral CS sold and used on the European market has been fully registered as a drug, which means that it had to fulfill severe criteria of quality and safety and was fully analyzed regarding its pharmacotoxicologic characteristics and industrial processing. These requirements are not applied to the CS sold as OTC on the American market. There is no doubt that the actual content of active substance and its quality in various brands of CS sold on the US market are not directly comparable with the CS at disposal in the European countries, which might also explain why the results of the clinical trials might differ significantly between both North America and Europe.
We did recently perform a survey of the available randomized clinical trials (RCTs) to assess the clinical efficacy and tolerability of oral CS and did choose to review the evidence on the basis of the published literature which was critically analyzed. The results of this review were published in 2006
1
. Briefly, the authors did assess the effects of oral CS on OA of the knee using the available outcome criteria such as the Lequesne's Algo-functional Index (AFI), the Huskisson Visual Analog Scale for Pain, the Walking Time, the Western Ontario MacMaster score (WOMAC) Score as well as analyzing the safety and tolerability data.Two independent reviewers did assess the methodological quality of the studies according to the Delphi Criteria List
2
, which consists of a set of nine criteria for quality assessment from 1 (use of randomization) to 9 (use of an intention-to-treat analysis). For each quality criterion, three rating categories were available: yes, met criteria, no, did not meet the criteria, and does not know. In addition, percentage agreement and Cohen's Kappa statistic were calculated with GRAPHPAD Software (Version 2002) and were interpreted with Landis and Koch's benchmarks for assessing the agreement between the two raters3
.The literature search yielded 11 reports that met the basic eligibility criteria of being an RCT which assessed the effects of oral CS on knee OA. A total of 1443 patients were included originating from France: Mazières et al.
4
; Bourgeois et al.5
; Conrozier, 19986
; and L'Hirondel, 19927
; Switzerland: Michel et al.8
; Uebelhart et al.9
; Uebelhart et al.10
, and Uebelhart et al.11
; Belgium: Malaise et al.12
; Hungary: Bucsi and Poor13
; Tschech Republic: Pavelka et al.14
. Several varieties of CS were used (bovine, shark, and avian) which also differed in dosage (500–1200 mg/day), treatment time (3–24 months) and mode of administration, daily continuously (3–24 months) or intermittently (2×3 months).The results of this survey exclusively taking RCTs into account, 10 published in peer-reviewed journals and one study not yet published, having the highest methodological quality, can be qualified overall as very positive for CS as an oral SYSADOA for the treatment of knee OA. Indeed, they did prove that the long-term administration of oral CS is safe, well tolerated and fully indicated to control the symptoms of pain and increase the overall mobility of knee OA patients.
Oral CS as a disease or structure-modifying drug in osteoarthritis (SMOAD)
Oral CS was also checked by humans as a disease or structure-modifying drug (SMOAD) in the treatment of OA. Using the same analytic method described above for the RCTs concerning the symptomatic effects of oral CS, we were able to identify a total of six published studies in which the SMOAD effect was assessed as primary or secondary evaluation outcome. These RCTs were performed in patients suffering from knee and finger OA. The main idea behind the potential SMOAD effect of oral CS is that the drug might be able to modify the course of the OA disease, may stop its progression and not only positively act on symptoms and mobility of the OA patients.
SMOAD effect of CS in knee OA
A total of three RCTs originating from Switzerland and which did evaluate the chondroprotective aspects of oral CS as primary or secondary outcome were available including 462 knee OA patients. One study was a one-center study
8
, whereas the two other studies9
, 10
were multicentric and included OA patients from various countries (France, Italy, and Belgium) as well. In addition, two treatment modalities were used which differed in their administration sequence. One study reported an intermittent treatment schedule of oral CS of 2×3 months daily oral CS 800 mg during 1 year9
, whereas the two other studies used a treatment schedule of oral CS 800 mg daily given continuously for a total of 1210
vs 248
consecutive months.Importantly, only one
8
out of these three studies had disease-modifying effect as a primary outcome, whereas in the two other ones this was a secondary outcome. The radiological progression was assessed in all three studies using the medial femoro-tibial joint space narrowing (JSN) measured with a digitalized analysis of high-quality knee X-rays. The results of the digitized X-rays analysis of the JSN were identical in these studies, originally shown in the two earlier and confirmed in the third one.The newest Study on Osteoarthritis Progression Prevention (STOPP) multicentric international study was designed as a RCT with the aim to test the SMOAD effect of oral CS 800 mg daily vs placebo during a 2-year survey in a total of 600 symptomatic knee OA patients. The recruitment of the OA patients who had to be symptomatic was performed on the basis of a blinded knee X-rays analysis performed in the Lyon-Schuss view. Only those patients who complied with the very strict inclusion criteria were enrolled and followed for 2 years after having been randomized to both CS or placebo (PBO) treatment groups. The results were already partially presented in some international meetings, but the publication is still in preparation. The main outcome of the STOPP study was the evolution of the medial femoro-tibial JSN over 2 years of treatment with oral CS as compared to PBO and did confirm that oral CS was able to significantly stabilize the JSN whereas PBO did not. A recent survey of the available RCTs to assess the structure-modifying effect of oral was published in 2006
15
.SMOAD effect of CS in finger joint OA
A total of two RCTs could be identified including a total of 284 patients. Both studies were performed at the Department of Rheumatology of the University of Ghent, Belgium. A first study was based on the use of a numerical scoring system for the anatomical evolution of finger joint OA developed by Verbruggen and Veys
16
. A total of 119 patients suffering from finger OA were included in this RCT with primary outcome being SMOAD effect of oral CS given 3×400 mg/day over a period of 3 years assessed on standard PA X-rays of the interphalangeal joints. The results of this study showed that in the CS treated group of patients, there was a significant decrease in the number of patients with new erosive OA finger joints17
, 18
. Two additional studies were conducted by Verbruggen et al.19
to assess the progression of finger OA using different Disease Modyfying Anti-Osteoarthritic Drugs (DMOADs) (polysulfated chondroitin sulfate (CPS) and CS) including oral CS 3×400 mg daily for a total duration of 3 years. In this study, the 34 patients treated with oral CS presenting with the classical OA anatomical lesions presented with less progressive evolution with both CPS and oral CS. In addition, fewer patients of both CPS and oral CS treated groups developed erosive OA of the finger joints. Even if additional studies are needed, the SMOAD effect of oral CS in finger OA was clearly demonstrated in these studies.Meta-analyses on CS in OA
Before the last meta-analysis of Reichenbach et al.
20
was published, two other ones were available. Based on data originating from published studies available at the time of the publication, both Leeb et al.21
and McAlindon et al.22
did provide some positive effects (moderate to large) of oral CS on the relief of painful symptoms in OA patients.The latest published meta-analysis by Reichenbach et al.
20
did provide some more critical insights in the effects of oral CS in OA pain. The authors did analyze 20 trials including a total of 3846 patients originating from randomized and quasi-randomized published studies focusing on pain relief in patients suffering from knee and hip OA as well. The authors did find for CS a pooled effect size of −0.75 (95% confidence interval [CI], −0.99–0.50) corresponding to a large symptomatic effect of the substance. This very positive result definitively goes along with the previous published meta-analyses, but the final interpretation of the authors was surprisingly negative about a symptomatic effect of the substance. It is worth noting that this meta-analysis presented with numerous bias and methodological problems which were also addressed as sound critics by some experts in the field of OA therapy who wrote letters to the Editor.The only way to solve the problem raised by this controversial publication and to become a clear picture of the effects of oral CS in OA patients would be to perform a high-quality new meta-analysis based on the raw data of the RCTs on CS and not based on the extracted data from the publications which are always incomplete.
Conclusion
Based upon published peer-reviewed RCTs and all available meta-analyses, oral CS has proven efficacy in symptomatic knee OA and structural-modifying effects in finger and knee OA. In addition, the tolerability and safety profile of the substance were found to be very favorable in all available RCTs performed. Additional work related to both the symptomatic and the structure-modifying effects of oral CS in OA patients is currently ongoing and should help to further clarify the situation of the substance in this indication.
Conflict of interest
The author declares that he is responsible for its design and content and the corrections of the proofs and approval of its final version.
References
- Treatment of knee osteoarthritis with oral chondroitin sulfate.in: Chondroitin Sulfate: Structure, Role and Pharmacological Activity. Elsevier Inc, Amsterdam2006
- The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus.J Clin Epidemiol. 1998; 51: 1235-1241
- The measurement of observer agreement for categorical data.Biometrics. 1977; 33: 159-174
- Chondroitin sulfate in osteoarthritis of the knee: a prospective, double blind, placebo controlled multicenter clinical study.J Rheumatol. 2001; 28: 173-181
- Efficacy and tolerability of chondroitin sulfate 1200 mg/day vs chondroitin sulfate 3×400 mg/day vs placebo.Osteoarthritis Cartilage. 1998; 6A: 25-30
- Anti-arthrosis treatments: efficacy and tolerance of chondroitin sulfates (CS 4&6).Presse Med. 1998; 27: 1862-1865
- Klinische Doppelblindstudie mit oral verabreichtem Chrondointinsulphat gegen Placebo bei der tibiofemoralen Gonarthrose.Litera Rheumatol. 1992; 14: 77-85
- Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized controlled trial.Arthritis Rheum. 2005; 52: 779-786
- Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo.Osteoarthritis Cartilage. 2004; 12: 269-276
- Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study.Osteoarthritis Cartilage. 1998; 6A: 39-46
Uebelhart D, Knüsel O, Osterkorn K, Berz S, Przybylski C, Theiler R. Oral chondroitin sulfate in patients with femorotibial osteoarthritis: a six-month multicentre, randomised double-blind, placebo-controlled, parallel-group study, unpublished (personal communication).
- Efficacy and tolerability of 800 mg oral chrondroitin 4&6 sulfate in the treatment of knee osteoarthritis: a randomised, double blind, multicentre study versus placebo.Litera Rheumatol. 1999; 24: 31-42
- Efficacy and tolerability of oral chondroitin sulfate as a symptomatic slow-acting drug for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis.Osteoarthritis Cartilage. 1998; 6A: 31-36
- Double-blind, dose-effect study of oral chondroitin 4&6 Sulfate 1200 mg, 800 mg, 200 mg and placebo in the treatment of knee osteoarthritis.Litera Rheumatol. 1999; 24: 21-30
- Chondroitin sulfate as a structure-modifying agent.in: Chondroitin Sulfate: Structure, Role and Pharmacological Activity. Elsevier Inc., Amsterdam2006
- Numerical scoring systems for the anatomical evolution of osteoarthritis of the finger joint.Arthritis Rheum. 1996; 39: 308-320
- Influence of chondroitin 4&6 sulfate on finger osteoarthritis in a double blind, controlled study versus placebo.Litera Rheumatol. 1998; 24: 43-47
- Chondroitin sulfate: S/DMOAD (structure/disease modifying anti-osteoarthritis drug) in the treatment of finger joint OA.Osteoarthritis Cartilage. 1998; 6: 37-38
- Systems to assess the progression of finger joint osteoarthritis and the effects of disease modifying osteoarthritis drugs.Clin Rheumatol. 2002; 21: 231-243
- Meta-analysis: chondroitin for osteoarthritis of the knee or hip.Ann Int Med. 2007; 146: 580-590
- A meta-analysis of chondroitin sulfate in the treatment of osteoarthritis.J Rheumatol. 2000; 27: 205-211
- Glucosamine and chondroitin for the treatment of osteoarthritis: a systematic quality assessment and meta-analysis.JAMA. 2000; 283: 1469-1475
Article info
Publication history
Published online: August 04, 2008
Received:
June 17,
2008
Identification
Copyright
© 2008 Osteoarthritis Research Society International. Published by Elsevier Inc.
User license
Elsevier user license | How you can reuse 
Elsevier's open access license policy
Elsevier user license
Permitted
For non-commercial purposes:
- Read, print & download
- Text & data mine
- Translate the article
Not Permitted
- Reuse portions or extracts from the article in other works
- Redistribute or republish the final article
- Sell or re-use for commercial purposes
Elsevier's open access license policy
