Glucosamine Sulfate for Treatment of Osteoarthritis
By Susan Brownsberger and Cydney E. McQueen PharmD
The 16 million americans afflicted with painful and often disabling osteoarthritis (OA) generate more than 7 million physician visits yearly.1,2 Since there is no cure and available pain medications have many side effects, OA is a prime disease candidate for alternative practices. Additionally, one study has suggested that long-term non-steroidal anti-inflammatory drug (NSAID) use may actually promote joint cartilage degeneration by inhibiting mucopolysaccharide synthesis needed in the production of new cartilage components.3 Glucosamine gained popularity among arthritis sufferers following the publication of The Arthritis Cure by Jason Theodosakis, MD.4 Although glucosamine may not provide the cure implied by Theodosakis’ title, the evidence supports its use in reducing OA symptoms.
Pharmacology/Mechanism of Action
Glucosaminoglycans, linear polymers of repeating disaccharides made from the amino sugar glucosamine and derived from glucose, are key components in human joint cartilage matrix. Ionization of sulfate molecules aids tensile strength and elasticity in the matrix. Supplemental glucosamine is proposed to provide the "building blocks" necessary to rebuild damaged cartilage. Animal and human evidence does lend support to the claim that progression of deleterious osteoarthritic cartilage changes is, at least, delayed, and, at best, reversed.3,5
Several glucosamine salt forms are available. This examination will be limited to glucosamine sulfate (GS), which has been widely tested in clinical trials and pharmacokinetic and safety studies. Concern over bioavailability of GS has been expressed, but pharmacokinetic studies (human and canine) using radiolabeled oral GS have shown fairly rapid absorption with 90-98% bioavailability.6,7
Clinical Trials
In 1994, Noack assessed 500 mg GS tid vs. placebo for four weeks for controlling OA symptoms.8 (See Table 1 for a summary of clinical trials.) Nine centers enrolled 252 patients with unilateral or bilateral OA of the knee based on radiological staging of 1-3 and a Lequesne index (a validated assessment scale commonly used in OA trials) score of at least 4 points. Patients must have had symptoms present for at least six months, be ambulatory with limited motion, and have an erythrocyte sedimentation rate < 30 mm/h with no external signs of active inflammation. Exclusion criteria included intra-articular corticosteroids within two months, NSAID use within two weeks, recent trauma or lesions, weight < 75 kg or > 150 kg, and other rheumatic, hematologic, hepatic, or renal disorders. Concurrent disease treatments were allowed and recorded. Primary efficacy outcome measures were mean change in Lequesne index and overall success rate. A successful responder was defined by both a decrease in Lequesne index of 3 or more points and investigator judgment of good or moderate efficacy at endpoint.
In both the intent-to-treat and evaluable population analyses, response rates were statistically significant in favor of GS at four weeks (P = 0.016 and P = 0.014, respectively). Safety was assessed based on an adverse event questionnaire, dropout rates, vital signs, and laboratory findings; there were no significant differences between groups. Of the dropouts, 5/8 in the GS group and 8/13 in the placebo group were due to adverse events. The investigators concluded that GS resulted in significantly better improvement than placebo with comparable tolerability. Level I, minor limitations (See Figure 1 on page 11.)
Müller-Faßbender’s 1994 study compared 500 mg GS tid to 400 mg ibuprofen (IBU) tid for four weeks in patients with OA of the knee.9 The 199 subjects were hospitalized in a physical rehabilitation program and had unilateral or bilateral OA of the knee with a Lequesne index (modified to assess each knee individually) score of at least 7 points. OA symptoms must have been present for at least three months prior to enrollment. Patients had mild inflammation based on joint swelling, effusion, and erythema. Exclusion criteria were identical to the Noack study. Overall success rate was based on a decrease in the modified Lequesne index of 2 points if the enrollment value was > 12 or 1 point if the enrollment value was £ 12, as well as an end of treatment investigator judgment of good efficacy.
Both groups improved by an average of 6 points and there was no significant difference in efficacy between the GS and IBU groups at week 4 (P = 0.67). GS demonstrated a slower onset of effect than IBU, with greater effect seen after week 2. Safety was assessed based on an adverse event questionnaire, dropout rates, and hematologic testing; the only statistically significant difference was in adverse events rates. Six adverse events were reported in the GS group, resulting in one withdrawal. In the IBU group, 35 adverse events were reported, resulting in seven dropouts. Reports included GI upset, pruritis, flushing, and fatigue. The authors concluded that GS was as effective as IBU in short-term symptom control of OA of the knee with slower onset of pain and symptom relief, but with better tolerability. Although the 1,200 mg/d IBU dose is not the maximum used by many OA patients, it is within therapeutic range. Level I, minor limitations
In 1998, Qiu also assessed efficacy and safety of 500 mg GS tid vs. 400 mg IBU tid in 178 patients for four weeks, with two week’s post-treatment observation.10 The inclusion/exclusion criteria were not stated in the article, nor was there an a priori power calculation. Efficacy was assessed by 0-3 ratings (non-validated instrument) in knee pain and swelling at rest, during movement, and with pressure. Additional efficacy measures included improvement ratings and therapeutic utility judgments by the investigator. No statistically significant differences were observed during treatment. GS patients had significantly better (P = 0.01) improvement ratings two weeks after treatment. Post-treatment pain and swelling ratings were also better in the GS group, but not significantly so. Safety was determined through an adverse event questionnaire, dropout rates, lab values, and an overall safety judgment. Five GS patients reported adverse events with no dropouts. In the IBU group, 9/14 reported adverse events resulted in dropouts. These results reflect both statistically and clinically significant differences in favor of GS. Level II, major limitations
Shortcomings common to the trials above include relatively short duration and a connection to Rotta Research Laboratorium, which manufactures a GS product. These shortcomings were not present in a study by Lopes Vaz.11 Study design and limitations were very similar to previously mentioned trials, doses of GS and IBU were identical, and results were also very similar. Level II, major limitations
The limitation of short duration was overcome in a recent study by JY Reginster, et al.12 The three-year study tested 1,500 mg/d GS vs. placebo in 212 patients. At the end of treatment, placebo patients had a 6-10% worsening of symptoms, while GS patients improved 15-24% (JY Reginster, written communication, February, 2000). Endpoint radiographic evidence demonstrated joint space narrowing of 0.08-0.1 mm in the placebo group, matching the normal average loss in OA. No narrowing occurred in the GS patients. On the contrary, there was an increase of 0.07-0.12 mm, although this was not statistically significant. Level and limitations unknown
Radiographic evidence of the effects of GS on cartilage is also confirmed by results of another oral GS vs. placebo study.5 Although clinical endpoints were in favor of GS, the study’s primary significance comes from electron microscopy examination of cartilage from two GS and two IBU patients after 30 days of treatment. Cartilage in the GS patients appeared smooth with ordered collagen fibrils, while cartilage in the placebo patients had the typical rough arthritic appearance with disordered fibrils. The small number of subjects makes these results hard to generalize, but they also confirm animal studies demonstrating similar positive changes with GS supplementation. Level II, major limitations
Side Effects
The most commonly reported side effects are mild GI upset, diarrhea, pruritis, and headache.4,5,8-10 GI effects are the most common; the highest overall incidence rate observed in trials was 6%.9,10
Contraindications
Concern has existed that competitive inhibition of glucose conversion to glucosamine could raise blood sugar levels in diabetics. The only study to monitor glucose found no problems (JY Reginster, written communication, February, 2000); however, extra initial monitoring in diabetic patients is prudent.
A diagnosis of OA should be determined before recommending therapy; GS has not been studied for other types of arthritis.
Interactions
No known interactions have been identified.
Pregnancy/Lactation
GS has not been tested in pregnancy or lactation and should be avoided in this population without physician recommendation and supervision.
Formulation and Dosage
The most commonly studied dose is 500 mg tid. A 1,500 mg daily dose may be taken, but there are anecdotal reports of increased diarrhea and flatulence with this regimen.
Glucosamine is available in several salt forms—sulfate, N-acetyl-glucosamine (NAG), and HCl. NAG may be a future option as serum glucosamine levels increase after ingestion of both NAG and a polymeric form,13 but no clinical trial data are yet available. A recent trial of glucosamine HCl vs. placebo did not show differences between groups, lending credence to the claim that the sulfate moiety is important for efficacy.14
Glucosamine is commonly marketed in combination with chondroitin sulfate, a large molecule with restricted bioavailability.15 It is not yet known if combination products are more effective than GS alone. A large, four-year NIH study currently is testing GS and GS plus chondroitin against placebo.
Conclusion
Clinical studies have shown GS to be effective in reducing the symptoms of OA and to have similar efficacy as IBU 400 mg tid with significantly fewer side effects.
Recommendation
The available evidence supports a Grade A recommendation for short-term GS use for mild-to-moderate OA symptoms. When full results of the Belgian study12 become available for evaluation, it may be possible to recommend long-term use.
Additional long-term studies are needed to further characterize any disease-modification potential and to determine if a lower maintenance dose is effective. Comparisons to other NSAIDs, acetaminophen, and COX-2 inhibitors are also needed, and use in severe OA has yet to be examined. Grade A
Ms. Brownsberger is a doctoral candidate at the University of Missouri-Kansas City School of Pharmacy.
References
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2. Young L, Koda-Kimble M. Applied Therapeutics: The Clinical Use of Drugs. 4th ed. Vancouver, WA: Applied Therapeutics Inc.; 1992.
3. Vidal Y, et al. Glucosamine: Its importance for the metabolism of articular cartilage. Studies on articular cartilage. Fortschr Med 1980;98:801-806.
4. Theodosakis, J. The Arthritis Cure. New York: St. Martin’s Press; 1997.
5. Drovanti A, et al. Therapeutic activity of oral glucosamine sulfate in osteoarthrosis: A placebo-controlled double-blind investigation. Clin Ther 1980;3:260-272.
6. Setnikar I, et al. Pharmacokinetics of glucosamine in man. Arzneimittelforschung 1993;43:1109-1113.
7. Setnikar I, et al. Antireactive properties of glucosamine sulfate. Arzneimittelforschung 1991;41: 157-161.
8. Noack W, et al. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage 1994;2:51-59.
9. Müller-Faßbender H, et al. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage 1994;2:61-69.
10. Qiu G, et al. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforschung 1998;48:469-474.
11. Lopes Vaz A, et al. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulfate in the management of the knee in outpatients. Cur Med Res Opin 1982;8:145-149.
12. Reginster JY, et al. Glucosamine sulfate significantly reduces progression of knee osteoarthritis over 3 years: A large, randomised, placebo-controlled, double-blind, prospective trial. Presented at American College of Rheumatology Annual Scientific Meeting. Boston, MA; November 1999. Abstract accessed online at www.rheumatology.org on February 14, 2000.
13. Talent JM, Gracy RW. Pilot study of oral polymeric N-acetyl-D-glucosamine as a potential treatment for patients with osteoarthritis. Clin Ther 1996;18: 1184-1190.
14. Houpt JB, et al. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J Rheumatol 1999;26:2423-2430.
15. Murray M. Which is better: Aged versus fresh garlic; glucosamine sulfate versus chondroitin sulfate. Am J Nat Med 1997;4:5-8.
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