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Data Synthesis: Quality scores ranged from 12.3% to 55.4% of the maximum, with a mean (SD) of 35.5% (12%). Only 1 study described adequate allocation concealment and 2 reported an intent-to-treat analysis. Most were supported or performed by a manufacturer. Funnel plots showed significant asymmetry (P.01) compatible with publication bias. Tests for heterogeneity were nonsignificant after removing 1 outlier trial. The aggregated effect sizes were 0.44 (95% confidence interval [CI], 0.24-0.64) for glucosamine and 0.78 (95% CI, 0.60-0.95) for chondroitin, but they were diminished when only high-quality or large trials were considered. The effect sizes were relatively consistent for pain and functional outcomes.

Conclusions: Trials of glucosamine and chondroitin preparations for OA symptoms demonstrate moderate to large effects, but quality issues and likely publication bias suggest that these effects are exaggerated. Nevertheless, some degree of efficacy appears probable for these preparations.

Radiographic Outcomes of a 2-Year Prospective Study

Michel B¹, Vignon E², de Vathaire F³, Frey D⁴, Hauselmann HJ¹, Stucki G¹, Bruhimann P¹, Uebelhart D¹,⁴

1Dept. of Rheumatology and Institute of Physical Med., University Hospital Zurich, Switzerland; 2 Dept. of Rheumatology, CHU Lyon-Sud, Pierre Benite, France;3 1NSERM Unit 521, Gustave Roussy Institute, University of Paris XI, Villejulf, France:4 Dept. of Biochemistry, Rush Presbyterian St. Luke's Medical Centre, Chicago, IL, USA

Objectives: To evaluate the efficacy of chondroitin sulphate (CS, Chondrosulf® 800, tablets) as potential Disease Modifying Drug in knee OA (DMOAD), by assessing femorotibial joint space narrowing using quantitative radiology.

Methods: One-center, randomized, double-blind, placebocontrolled (PBO), two-year prospective (Phase III) clinical trial. Between 1996-99, a total of 300 patients of both gender, aged > 40 with clinically symptomatic knee OA, Kellgren & Lawrence score I-III, were recruited and randomly allocated to CS or PBO groups. Both knees were radiographed in standard upright and in Schuss position (20% flexion) at entry and after 2 years. The target knee was defined upon entry. X-rays were blindly measured at the end of the study using a validated digitized image analysis system.

Results: Regarding 1° efficacy outcome criteria, a total of 210 patients completed the two-year treatment period. Data of the femorotibial joint space of the target knee in Schuss (20% flexion) incidence are provided, a total of 151 completers (78 CS; 73 PBO) did have a min. JS width > = 1 mm at entry and were therefore analysed in PR The minimum JS width significantly decreased (p= 0.04) in the PBO group whereas it did not change in the CS group. The evolution was significantly different between both groups (p= 0.03). The mean JS thickness also significantly decreased (p=0.02) in the PBO group whereas it did not change in the CS group. The evolution was also significantly different between both groups (p=0.01). The JS surface area showed a trend to decrease in the PBO group (ns) whereas it did not vary in the CS group. The evolution between both groups was not significantly different.

Conclusion: These quantitative X-ray data originating from the first 2-year duration trial with oral CS confirm previous results of our group. Based upon the available data, chondroitin sulphate, a well-known SYSADOA could therefore also qualify as a Disease Modifying Drug for the treatment of OA (DMOAD).

Osteoarthritis & Cartilage. 2001:9(suppl B):S68

Chondroitin Sulfate: S/DMOAD (Structure/Disease Modifying Anti-Osteoarthritis Drug) in the Treatment of Finger Joint OA

Gust Verbruggen, Stefan Goemaere and Eric M. Veys

Department of Rheumatology, Ghent University Hospital, Ghent, Belgium

Summary:

A total of 119 patients were included in a randomized, double-blind, placebo-controlled trial in order to assess the S/DMOAD properties in OA of chondroitin sulfate (CS 4&6, 3 x 400 mg/day, Condrosulf® IBSA, Lugano, CH).

Posteranterior roentgenographies of the interphalangeal (IP) joints were carried out at the start of the study and at yearly intervals. This enabled the investigators to document the radiological progression of the anatomical lesions in the pathological finger joints over a 3-year period. It was shown that the progression of OA in the IP finger joints in an individual can be determined by the evolution of his finger joints through previously described anatomical phases: ‘N’ (not affected), 'S' (classical OA), ‘J’ (loss of joint space), ‘E’ (erosive OA) and ‘R’ (remodeled joint).

Structure/disease-modifying anti-OA drug (S/DMOAD) properties were searched for by assaying the number of patients developing OA in previously normal IP joints ('N' > 'S'), or progressing through the described anatomical phases of the disease ('S' > ‘J’, 'S' > ‘E’, ‘J’ > ‘E’, 'S' > ‘R’, ‘J’ > ‘R’, ‘E’ > ‘R’). In the CS 4&6 group we observed a significant decrease in the number of patients with new 'erosive' OA finger joints. This result is particularly important since OA of the finger joints becomes a clinical problem (pain, functional loss) when 'S' joints progress to ‘J’ and especially 'E' phases. During and after these ‘E’ phases, joints will remodel and show the nodular deformities characteristic of Heberden's and Bouchard's nodes.

Treated patients were protected against erosive evolution.

Source: Osteoarthritis and Cartilage (1998) 6, (Supplement A), 37-38. Osteoarthritis Research Society

Dr. Theo’s comments: This very well designed Belgium study proves that chondroitin sulfate can modify cartilage erosion and may prevent osteoarthritis in the finger joints. This erosion is what leads to crooked and enlarged finger joints. This type of study design provides a high level of medical evidence.

Effects of Oral Chondroitin Sulfate on the Progression of Knee Osteoarthritis: A Pilot Study

Daniel Uebelhart, Eugene J-M. A. Thonar, Pierre D. Delmas,

Alex Chantraine and Eric Vignon Division of Physical Medicine & Rehabilitation, Department Neuclid, University Hospital of Geneva, Switzerland; Department of Biochemistry and WHO Collaborating Center for the Field of Osteoarthritis, Rush Presbyterian-St. Luke's Medical Center, Chicago, IL, USA; INSERM 403 Unit and Division of Rheumatology, E. Herriot Hospital, Lyon, France; and Division of Rheumatology, Lyon-Sud Hospital, France

Summary:

The aim of this study was to assess the clinical, radiological and biological efficacy and tolerability of the SYSADOA, chondroitin 4- and 6-sulfate (CS, Condrosulf, IBSA, Lugano, Switzerland), in patients suffering from knee osteoarthritis.

This was a 1-year, randomized, double-blind, controlled pilot study which included 42 patients of both sexes, aged 35-78 years with symptomatic knee OA. Patients were treated orally with 800 mg chondroitin sulfate (CS) per day or with a placebo (PBO) administered in identical sachets. The main outcome criteria were the degree of spontaneous joint pain and the overall mobility capacity. Secondary outcome criteria included the actual joint space measurement and the levels of biochemical markers of bone and joint metabolism.

This limited study confirmed that chondroitin sulfate was well-tolerated and both significantly reduced pain and increased overall mobility capacity. Treatment with CS was also associated in a limited group of patients with a stabilization of the medial femoro-tibial joint width, measured with a digitized automatic image analyzer, whereas joint space narrowing did occur in placebo-treated patients. In addition, the metabolism of bone and joint assessed by various biochemical markers also stabilized in the CS patients whereas it was still abnormal in the PBO patients.

These results confirm that oral chondroitin 4- and 6-sulfate is an effective and safe symptomatic slow-acting drug for the treatment of knee OA. In addition, CS might be able to stabilize the joint space width and to modulate bone and joint metabolism. This is the first preliminary demonstration that a SYSADOA might influence the natural course of OA in humans.

Source: Osteoarthritis and Cartilage (1998) 6, (Supplement A), 39-46 1998 Osteoarthritis Research Society

Dr. Theo’s comments: This is another study that shows chondroitin sulfate can beneficially modify cartilage tissue. This is more evidence that chondroitin may be structure-modifying and not just a symptomatic treatment for osteoarthritis. It is obviously a small study and should be considered to be a pilot, warranting a larger trial.

Glucosamine Sulfate Significantly Reduces Progression Of Knee Osteoarthritis Over 3 Years: A Large, Randomised, Placebo-Controlled, Double-Blind, Prospective Trial. J Y Reginster, R Deroisy, I Paul, R L Lee, Y Henrotin, G Giacovelli, J Dacre, L C Rovati, C Gosset.

Conclusions: Combined Structure and Symptom Modifying effects suggest that glucosamine sulfate may be a possible Disease Modifying agent in OA.

Discolsure: Work reported in this abstract was supported by the Rotta Research Group

Source: American College of Rheumatology 1999 Annual Meeting, Boston, MA Presentation Date: Wednesday, November 17, 1999 Arthritis & Rheumatism 1999;42(suppl)

GLUCOSAMINE SULFATE DECREASES PROGRESSION OF KNEE OSTEOARTHRITIS IN A LONG-TERM, RANDOMIZED, PLACEBO-CONTROLLED, INDEPENDENT, CONFIRMATORY TRIAL.

Karel Pavelka, Jindriska Gatterova, Marta Olejarova, Stanislav Machacek, Giampaolo Giacovelli, Lucio C Rovati Prague, Czech Republic and Monza, Milan, Italy

Background. glucosamine sulfate was proposed to improve knee osteoarthritis (OA) symptoms and to prevent radiological mean joint space narrowing (JSN), as assessed by digital image analysis, over 3 years [Arthritis Rheum 1999; 42(suppl): 1975]. This independent study was conducted to confirm and extend those results by slightly different techniques. Methods. 202 patients with knee OA diagnosed according to the ACR criteria were randomized to double-blind treatment with oral glucosamine sulfate 1500 mg once-a-day, or placebo for 3 years. The minimum joint space width (JSW) of the narrowest medial compartment of the tibio-femoral joint was measured visually by a 0.1 mm graduated magnifying glass, on standardised weight-bearing antero-posterior radiographs of each knee in full extension. Symptoms were assessed by both the WOMAC (LK 3.0 version) and the Lequesne indices. Final changes from enrollment (JSN, or  ) were analysed by a worst case scenario intention-to-treat (ITT), assigning to missing values the final average change observed with placebo. Results. The two groups were comparable for demographic and disease characteristics. The 3-year JSN observed with placebo was approximately 0.2 mm and significantly higher than with glucosamine sulfate, for which no JSN occurred in average. Symptoms improved in both groups, but significantly more with glucosamine sulfate.

Slightly more patients left the study prematurely with placebo than with glucosamine sulfate (total 46% vs. 35%, with 10% vs. 8% for adverse events, respectively): results on per-protocol completers were even slightly more favorable to glucosamine sulfate, but with a similar degree of significance than in ITT.

Conclusions. This study confirmed that the natural JSN in knee OA is slow (<0.1 mm/year in average), but can be prevented by glucosamine sulfate that also induces a significant symptom improvement.

Disclosure: Work reported in this abstract was supported by the Rotta Research Group. G. Giacovelli and L.C. Rovati belong to the Dept. Clinical Pharmacology of Rotta Research Lab., i.e. the research center of the Rotta Research Group.

Source: Arthritis & Rheumatism 2000;49(suppl). Presented at the American College of Rheumatology 2000 Annual Meeting in Philadelphia, Nov. 2000.

Dr. Theo’s Comments: This first study confirms the 1999, 3-year trial suggesting that glucosamine is not only symptom-improving, but structure-improving for osteoarthritis. This is a very well-designed study, about as good as an osteoarthritis study gets. The data is far better than the studies done for the pharmaceutical products such as Celebrex and Vioxx (in which no structure-modifying data exists).

No loss of cartilage loss was seen (on average) in the glucosamine users (as determined by joint space narrowing on X-Ray). A side note: the side effect profile and drop-out rate for the patients was higher in those using the placebo than in those taking the glucosamine. This also alludes to the safety and tolerability of long-term glucosamine use (3-year). One major drawback to interpreting these results is that the study was funded by the company that makes and sells glucosamine sulfate (outside the US only).

Beneficial Effect Of Cartilage Disease-Modifying Agents Tested In Chondrocyte Cultures And A Rabbit Instability Model Of Osteoarthrosis.

L Lippiello, J Woodward, R Karpman, T A Hammad. Phoenix, AZ, Edgewood, Md.

Dietary supplements of disease-modifying agents were tested separately and in combination for their ability to retard progression of cartilage lesions in a rabbit instability model of osteoarthritis. Surgical instability (Hulth) was induced in 2-3 Kg NZW rabbits. Post-operatively, animals were exercised for 1 hour 3 times per week. Group 1 controls (12) were fed standard Teklad diet; group 2 (12), 3 (6) and 4 (6) had diets supplemented with 2% by weight Cosamin DS*, and comparable levels of chondroitin sulfate or glucosamine HCl respectively. Animals were sacrificed at 16 weeks and the weight-bearing portion of the medial condyles evaluated quantitatively with a modified Mankin grading system using Safranin-O stained slides. The extent and severity of lesions was measured as mm linear involvement for each grade of severity using Image Pro software and a Polaroid Slide Scanner. Lesions were grouped as mild (1-3), moderate (4-7) or severe (>8). Statistical analysis utilized Student t-test and Wilcoxon rank sum test. Results: Cosamin DS fed animals had no severe lesions and a significant substantial reduction in the extent of moderate lesions compared to controls (p<0.003). Chondroitin sulfate and glucosamine-fed animals had less moderate and severe tissue involvement than controls but not to the extent of the Cosamin? DS group. No metabolic changes were noted in noninvolved normal humeral cartilage nor was there any apparent organ pathology upon necropsy. In vitro studies with isolated chondrocytes confirmed a synergistic effect of glucosamine HCL + chondroitin sulfate on stimulation of proteoglycan synthesis (p<0.04). The data suggests that the disease-modifying effect of a mixture of glucosamine HCL and chondroitin sulfate was synergistic and superior than either agent alone insofar as stimulating proteoglycan synthesis and retarding the development of cartilage lesions.

*A combination of glucosamine HCl and low molecular weight chondroitin sulfate. Nutramax Laboratories, Edgewood, MD.

Discolsure: Study supported by Nutramax Laboratories, Edgewood, Maryland

Source: American College of Rheumatology 1999 Annual Meeting, Boston, MAPresentation Date: Monday, November 15, 1999

Dr. Theo rips on topical (rub-on) glucosamine/ chondroitin/ MSM products that are defrauding people of $millions.