Chondroitin for the Treatment of Osteoarthritis Pain
August 2000; Volume 3; 85-89
By Teresa Klepser, PharmD, and Nicole Nisly, MD
The combination of glucosamine and chondroitin became a popular alternative therapy for the treatment of osteoarthritis following the 1997 publication of The Arthritis Cure by Jason Theodasakis, MD. Since then, full-page ads in the New York Times, displays at trade shows and medical conferences, and medical literature have promoted and examined glucosamine and chondroitin, which have reasonably well-established, if delayed, effectiveness as analgesics. (See Alternative Medicine Alert, November 1998, pp. 121-124.)
Chondroitin sulfate, which is extracted from the cartilage of the bovine trachea,1,2 consists of Type II collagen and glycosaminoglycans. What are the benefits of chondroitin among patients with osteoarthritis?
Prevalence and Etiology
Osteoarthritis is a serious disease. Up to 6% of the general population suffer from symptomatic osteoarthritis of the knee and hip.3 Approximately 100,000 Americans cannot ambulate because of hip or knee osteoarthritis symptoms.4 Men have a higher prevalence of osteoarthritis before age 50; women have a higher prevalence after age 50. A weight loss of 11 pounds has been reported to reduce the risk of symptomatic knee osteoarthritis by as much as 50%.4
Pharmacokinetics
Chondroitin, a glycosaminoglycan, is a large molecule that is poorly absorbed when administered orally—just 12%.5 However, animal studies using radiolabeled chondroitin sulfate have observed that more than 70% of the radioactive compound is absorbed after oral administration.6
The discrepancy may lie in the gastrointestinal tract: Chondroitin sulfate may undergo metabolism, resulting in more absorbable, active components.2 Its half-life is 5-10 hours,5,6 and it accumulates in synovial fluid and cartilage.5 Renal elimination accounts for approximately 20% of chondroitin clearance.5
Mechanism of Action
Chondroitins are the main glycosaminoglycans in human joints and connective tissue and play a role in cartilage formation through the stimulation of chondrocyte metabolism and synthesis of collagen and proteoglycan.1 Destructive synovial enzymes such as human leukocyte elastase and hyaluronidase are inhibited by chondroitins.7
Chondroitins may block the action of lytic enzymes and enhance cartilage repair by stimulating proteoglycan synthesis and by increasing levels of hyaluronic acid.5 Chondroitin may also exert a mild, direct anti-inflammatory effect mechanistically independent of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and indomethacin.5,8 Therefore, chondroitin may produce a synergistic effect in combination with NSAIDs. Older studies suggest that if enough chondroitin is used by cells to manufacture proteoglycan, matrix synthesis would occur and cartilage would be regenerated.9
Clinical Studies
McAlindon et al performed a meta-analysis to evaluate the effects of glucosamine and chondroitin for the treatment of osteoarthritis.10 Randomized, double-blind, placebo-controlled trials published from 1966 to June 1999 were included in this analysis. Duration of treatment with glucosamine (sulfate or hydrochloride) or chondroitin sulfate was at least four weeks. Studies also had a global pain score for index joint such as visual analog (VAS) or Likert scale, pain on walking for index joint, Western Ontario and McMaster Universities Osteoarthritis Index Pain Subscale, Lequesne Index, or pain in index joint during activities other than walking.
Separate meta-analyses were performed for glucosamine and chondroitin trials. Nine chondroitin and six glucosamine studies were included in the meta-analyses. Of the chondroitin studies, sample sizes ranged from 17 to 140. The mode of chondroitin administration was primarily oral (7/9). The majority of the studies (56%) evaluated arthritic pain as the primary outcome. Eight of the nine studies were affiliated with a chondroitin manufacturer. Only one study had an intention to treat analysis.
A large effect size (0.96; 95% confidence interval [CI], 0.63-1.3) was found for chondroitin. Unfortunately, the test for heterogeneity was significant (P < 0.001) among the chondroitin sample. One trial was identified that had a substantially larger effect than the others. When this trial was excluded and the studies reanalyzed, the test for heterogeneity became nonsignificant and the effect size was still significantly large at 0.78 (95% CI, 0.60-0.95). Potential limitations include: no intention to treat analysis, potential manufacturer bias, small sample size, insufficient reporting of allocation concealment, failure to report dropout rates, use of different dosage forms (oral and intramuscular), and evaluation of different endpoints.
A second recently published meta-analysis by Leeb et al evaluated seven studies that examined the effect of chondroitin for the treatment of osteoarthritis.11 Studies were at least three months in duration and tested oral chondroitin sulfate 800-1200 mg/d in subjects with chondropathia patellae, arthralgia, or osteoarthritis of the hip, knee, larger joints, or finger joints. Trials also had to have half of the following measured outcomes: investigator’s and/or patient’s global assessment, VAS for pain, walking time, functional index, Doyle index, loss of mobility, NSAID or analgesic consumption, number of flares over time, quality of life scale, walking or stair climbing time.
Sample sizes ranged from 23 to 72. Pain assessed by VAS had an overall mean Glass score of 0.9; approximately 65% of patients taking chondroitin had pain reduction superior to placebo. The Glass score for the Lequesne Index was 0.74; an estimated 55% of patients would benefit from chondroitin compared to placebo. Limitations include small sample size, no intention to treat analysis, and possible publication bias.
Studies comparing chondroitin to NSAIDs were included in the Leeb meta-analysis. Morreale et al conducted a randomized, multicenter, double-blind, double-dummy, six-month parallel trial comparing the anti-inflammatory properties of chondroitin and diclofenac in 146 patients with osteoarthritis of the knee.12 Patients were randomized to receive 400 mg chondroitin and placebo or 50 mg diclofenac and placebo tid for one month. During the second and third months, patients continued taking chondroitin or diclofenac but no placebo. During the last three months both groups took placebo only.
The Lequesne Index, the Huskisson VAS, supplemental intake of acetaminophen, and pain on load were statistically significantly improved with chondroitin. Diclofenac gave prompt immediate reduction of clinical symptoms when patients consumed the NSAID. In contrast, chondroitin demonstrated slower onset of symptomatic improvement, but its effects persisted for up to three months following its discontinuation.
Two published trials evaluated the combination of chondroitin and glucosamine. Shankland enrolled 50 patients suffering from various temporomandibular disorders with a diagnosis of osteoarthritis.13 Patients were given chondroitin (1,200 mg), glucosamine (1,600 mg), and calcium ascorbate (1,000 mg) bid. The main endpoint evaluated was joint noise described as "Same," "Improved," or "Better." Eighty percent of the patients reported a decrease in joint noise. Limitations to this study include no placebo group, open trial, lack of therapy duration description, and results that may not be extrapolated to the general public with osteoarthritis.
The other combination trial was a randomized, double-blind, placebo-controlled 16-week crossover trial comparing Cosamin® (a combination of 1,500 mg/d glucosamine, 1,200 mg/d chondroitin, and 228 mg/d manganese ascorbate) or placebo in 34 males (mean age 43.5 years) with degenerative joint disease of the knee or lower back.14 Endpoints included Lequesne Index, patient’s assessment, physician’s overall assessment, VAS for pain, tenderness with movement of the low back and with firm pressure on the knees, time to run 100 yards and to run up and down a tower with 80 stairs, physical examination of tenderness, range of motion, warmth, crepitus, effusion, swelling, muscle atrophy, and knee active range of motion.
Chondroitin was statistically significantly better than placebo in patient’s assessment of treatment result (total and knee), VAS for pain based on clinic visit and diary (total and knee), and physical examination score of the knee. Limitations include small sample size, an all-male study population, and possible carryover effects in a crossover design.
Adverse Effects
Occasional mild gastrointestinal disturbances such as dyspepsia and nausea have been reported. Other reported adverse effects include headache, motor uneasiness, euphoria, and allergic reactions.1,2,15
Since chondroitin is a small component (approximately 4%) of the low molecular weight heparinoid mixture danaparoid (Orgaran®), there is a concern that chondroitin may have anticoagulant properties. However, hematological changes and bleeding have not been observed in clinical studies.2
Contraindications/Precautions
Persons who have had previous hypersensitivity to chondroitin sulfate should avoid its use. Teratogenesis studies in rats and rabbits found no malformation of fetuses. However, the newborns of chondroitin sulfate-treated pregnant animals did weigh approximately 10-20% less than untreated controls. For this reason, chondroitin cannot be recommended for pregnant women. Since safety has not been established in children, during lactation, or in the presence of severe liver or renal disease, chondroitin should be avoided there.15 Patients with bleeding disorders should use chondroitin with caution because of the potential risk of anticoagulation.1
Drug Interactions
No drug interactions have been reported. But because chondroitin is component of the low molecular weight heparinoid mixture, anticoagulants such as warfarin and aspirin may potentiate the risk of bleeding.1
Dosage
The reported daily dosage range for chondroitin is 300-1,500 mg.7 However, the usual dosage of chondroitin is 400 mg tid. Some authors suggest that 1,200 mg/d may be equally effective.15 Allow at least three months for chondroitin to achieve its full analgesic effect. (See Table 1 for product comparisons.)
| Table 1-Chondroitin price and formulation comparison | ||||
| Manufacturer/Product | Per Tablet Formulation | Manufacturer's Recommended Dose | Price/Quantity | |
| Twinlab/Maxilife Gluco/Chond | 500 mg glucosamine sulfate, 400 mg chondroitin sulfate (pure pharmaceutical grade) | 3 tablets/d | $46.95/60 tablets | |
| Schiff/Chondroitin Sulfate | 500 mg chondroitin sulfate | 2 capsules/d | $31.82/60 capsules | |
| Futurebiotics/Glucosamine Chondroitin | 500 mg glucosamine sulfate, 250 mg chondroitin sulfate | 2 capsules/d | $29.95/50 capsules | |
| The Vitamin Shoppe/Chondroitin Sulfate CSA | 500 mg chondroitin sulfate | 1-3 tablets/d | $23.95/100 tablets | |
| Cardiovascular Research/Chondroitin Sulfate | 250 mg chondroitin-4-sulphate (natural constituent of connective tissue) | 2 capsules/d | $15.95/60 capsules | |
| Amerifit/Glucosamine Chondroitin | 200 mg chondroitin, 250 mg glucosamine | 6 caplets/d | $14.98/60 caplets | |
| Source: Online mail-order firms | ||||
There are large differences between chondroitin products, based on molecular weight and sulfation, leading to differences in absorption and hence effectiveness. The products most commonly used in double-blind trials are proprietary, and it is not clear if competing products are equally effective.15
For retail sale, chondroitin is often combined with glucosamine, at a dose of 500 mg tid. As mentioned earlier, the chondroitin/glucosamine combination may be superior to either treatment alone.15
In December 1999 and January 2000, Consumerlab.com purchased 25 brands of glucosamine, chondroitin, and combination products to test whether the products contained the amounts listed on their respective labels.16 Almost 33% of the products did not contain the stated amounts. Some of the combination products and both of the chondroitin-only products contained lower levels of chondroitin than advertised.
Conclusion
Chondroitin, alone or in combination with glucosamine, has been used in the treatment of osteoarthritis. Clinical data to support its use for this indication are good and side effects appear to be rare. Improvement in osteoarthritis symptoms should begin within a month.
Recommendation
Chondroitin may be considered a first-line agent for the treatment of osteoarthritis given the minimal concerns regarding contraindications and precautions, the minimal potential for drug interactions, and the rarity of side effects. Since both chondroitin-alone and combination chondroitin/glucosamine products have been studied, either formulation is recommended. However, it would be easier to track potential side effects and drug interactions if patients were using chondroitin alone.
Dr. Klepser is Assistant Professor, University of Iowa College of Pharmacy, Division of Clinical and Administrative Pharmacy, and College of Medicine, Department of Family Medicine; Dr. Nisly is Assistant Professor, University of Iowa College of Medicine, Department of Internal Medicine in Iowa City.
References
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2. Natural Medicines Comprehensive Database. Stockton, CA: Therapeutic Research Center, Inc.; 1999.
3. Felson DT, Zhang Y. An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis Rheum 1998;41:1343-1355.
4. Gaby AR. Natural treatments for osteoarthritis. Altern Med Rev 1999;4:330-341.
5. Ronca F, et al. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage 1998;6(Suppl A):14-21.
6. Conte A, et al. Biochemical and pharmacokinetic aspects of oral treatment with chondroitin sulfate. Arzneimittelforschung 1995;45:918-925.
7. LaValle JB, et al. Natural Therapeutics Pocket Guide. Hudson, OH: Lexi-Comp, Inc.; 2000.
8. Pipitone VR. Chondroprotection with chondroitin sulfate. Drugs Exp Clin Res 1991;17:3-7.
9. Chondroitin. In: The Review of Natural Products. St. Louis, MO: Facts and Comparisons; 1998.
10. McAlindon TE, et al. Glucosamine and chondroitin for treatment of osteoarthritis: A systematic quality assessment and meta-analysis. JAMA 2000;283:1469-1475.
11. Leeb BF, et al. A meta-analysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheumatol 2000;27:205-211.
12. Morreale P, et al. Comparison of the anti-inflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee arthritis. J Rheumatol 1996;23:1385-1391.
13. Shankland WE 2nd. The effects of glucosamine and chondroitin sulfate on osteoarthritis of the TMJ: A preliminary report of 50 patients. Cranio 1998;16:230-235.
14. Leffler CT, et al. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: A randomized, double-blind placebo-controlled study. Mil Med 1999;164:85-91.
15. Chondroitin Sulfate. Professional monographs. The Natural Pharmacist. Available at: http://www.tnp.com/propages.asp?ID=12. Accessed July 11, 2000.
16. Product review: Glucosamine and chondroitin. Consum-erlab.com. Available at: http://www.consumerlab.com/results/gluco.html. Accessed July 11, 2000.
August 2000; Volume 3; 85-89
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