FEATURE SafetySafety && EfficacyEfficacy ofof GlucosamineGlucosamine && ChondroitinChondroitin inin OsteoarthritisOsteoarthritis by DARRELL T. HULISZ, Pharm.D., R.Ph. Assistant Professor of Family Medicine Case Western Reserve University School of Medicine; Associate Clinical Professor of Pharmacy Practice, Ohio Northern University College of Pharmacy, Ada, OH

steoarthritis (OA), crepitus (crackling noise with movement) and soft also known as degen- tissue swelling.3 Inflammation, if present, is Oerative joint disease, is usually mild and localized to the affected joint. one of the most common Osteoarthritis commonly affects the knee, hip, chronic medical conditions hands, feet and spine. The disease generally pres- worldwide and is the most ents with unilateral or asymmetrical involvement common form of arthritis in of an affected joint, although bilateral or symmet- the United States.1 rical presentations may be observed in more Approximately 80% of advanced stages. The treatment of OA involves a people in Western countries combination of supportive treatment and pharma- age 75 or older have radi- cologic therapy. Additionally, nutraceutical ographic evidence of OA, alternatives, such as glucosamine and chondroitin, and about 11% of people are widely promoted and available to the general older than age 64 have public as a treatment for OA. Since pharmacists symptomatic OA of the are recognized as drug experts and are highly 2 knee. Risk factors for OA accessible to the public, they are likely to receive include obesity and activi- questions concerning the effectiveness and safety ties or occupations where Clinical studies of these agents. Thus, the purpose of this article is overuse of a joint is show these to equip pharmacists with updated information common. Those at risk agents are very concerning the safety and efficacy of glucosamine include baseball pitchers, well tolerated and chondroitin, alone and in combination, for the dancers, dock workers, and and may be management of OA. beneficial for marathon runners. osteoarthritis Osteoarthritis may also be OVERVIEW OF OSTEOARTHRITIS MANAGEMENT symptoms. the result of trauma, such as The treatment of OA involves a combination a motor vehicle accident. of supportive therapy and pharmacotherapy. The clinical features of OA include morning Nonpharmacologic measures include patient joint stiffness, joint pain that is usually worsened education, self-management programs, weight by movement and improved by rest, limited range loss (if overweight), aerobic exercise programs, of motion, gait instability, joint tenderness, bony physical therapy, range-of-motion exercises,

JANUARY/FEBRUARY 2003 7 Safety & Efficacy of Glucosamine & Chondroitin in Osteoarthritis muscle-strengthening exercises, assistive devices limited value, especially in more severe cases of for ambulation, and occupational therapy. The OA. Patients with OA may need to be treated with American College of Rheumatology recommends a more potent analgesic, such as tramadol and acetaminophen as initial treatment of early OA.3 opiates. These therapies carry additional risks, However, nonsteroidal anti-inflammatory drugs such as adverse central nervous system effects (NSAIDs), such as ibuprofen, naproxen and (e.g., sedation), and have the potential for addic- diclofenac, are perhaps the most widely prescribed tion or abuse. Intra-articular injections of steroids class of medications for OA. Approximately 73 and hyaluronate are also of limited value and million NSAID prescriptions are written for an cannot be used chronically. Furthermore, even estimated 17 million Americans, and over 30 when the aforementioned medications are billion over-the-counter tablets are sold annually prescribed with great diligence, many patients do in this country alone.4 NSAIDs, when used prop- not experience adequate relief of symptoms. Thus, erly, are generally safe and well-tolerated by most the quest for compounds that are both highly effi- patients. However, some users have experienced cacious and completely safe for OA remains serious, life-threatening adverse events with these elusive. medications, particularly dangerous gastrointesti- GLUCOSAMINE AND CHONDROITIN nal (GI) events. Using the definition of a 3-mm or AS DIETARY SUPPLEMENTS greater break in the gastric mucosa, about 25% of Recently, with the release of the book entitled chronic NSAID users will have endoscopically The Arthritis Cure, describing glucosamine and detected gastric ulcers, and up to 50% will have chondroitin sulfate as effective agents for OA either a gastric or duodenal ulcer.5 The majority of treatment, consumer interest in these compounds these gastric mucosal injuries are superficial, soared, especially in the U.S.15 Another factor that asymptomatic, and often self-limited. However, prompted increases in sales of these nutraceuticals some patients develop severe erosions, or even was the passage of the Dietary Supplement Health peptic ulcers leading to GI hemorrhage, perfora- and Education Act in 1994. This legislation tion, and death. The mortality rate for permits the marketing of products claiming to NSAID-induced GI bleeding is 5%?0%, with affect the structure or function of the body as a 107,000 hospitalizations per year, at an estimated dietary supplement without requiring FDA cost of $15,000?0,000 per event; however, total approval. Glucosamine and chondroitin are direct costs may exceed $2 billion annually.6,7 marketed as dietary supplements, and as such Additionally, NSAIDs have adverse renal effects, must contain a disclaimer stating that they are not which is a major concern in elderly individuals, intended to diagnose or treat any specific medical those who are volume-depleted, and patients with condition. underlying renal insufficiency. The use of glucosamine and chondroitin for A new class of compounds, the cyclooxyge- OA is not without controversy. To provide some nase-2 (COX-II) inhibitors (e.g., celecoxib, clarification, a special subcommittee of the rofecoxib), are at least as effective as NSAIDs for American College of Rheumatology released the OA, but have significantly less adverse GI following statement last year concerning use of toxicity.8-12 However, COX-II inhibitors are not these agents for OA: completely devoid of adverse renal effects and, While a number of studies support the effi- like the NSAIDs, are associated with other cacy of both glucosamine and chondroitin sulfate systemic side effects.13,14 Local therapies, such as for palliation of joint pain in patients with knee capsaicin cream and topical salicylates, are only of OA, the subcommittee believes that it is premature

8 JANUARY/FEBRUARY 2003 Safety & Efficacy of Glucosamine & Chondroitin in Osteoarthritis to make specific recommendations about their use depleted in the matrix, which results in a loss of at this time because of methodologic considera- shock absorption and compressibility. Bone tions, including lack of standardized case responds to this with hypertrophic repair, increas- definitions and standardized outcome assess- ing the subcondral bone thickness.16,17 ments, as well as insufficient information about PROPOSED MECHANISMS OF ACTION FOR study design in a number of these published GLUCOSAMINE AND CHONDROITIN reports. A pivotal clinical trial being planned by Glucosamine is an aminomonosaccharide the NIH should help define the role of these that is part of almost all tissues in the human agents, singly and in combination, in the treatment body, including cartilage. Furthermore, it is the 3 of patients with knee OA. principal component of O- and N-linked Thus, it seems prudent and timely to review glycosaminoglycans, which form the connective the evidence from clinical trials to assist in provid- tissue matrix. Glucosamine sulfate, a salt of the ing recommendations to patients and healthcare natural aminomonosaccharide, has a relatively professionals for these compounds. low molecular weight. Following oral administra- PATHOPHYSIOLOGY tion, it is 90% absorbed, with about 8%?2% To better understand the potential for retained in the tissues.18 The chondrocytes incorpo- glucosamine and chondroitin to treat OA, a brief rate glucosamine into the proteoglycans, which overview of pathophysiology is necessary. are then excreted into the matrix. The sulfate Osteoarthritis is a degenerative disease affecting moiety specifically plays an important role in the articular cartilage, leading to acute periodic proteoglycan synthesis because the glycosamino- inflammation. Cartilage is made up of two compo- glycans are highly sulfated and may contribute to nents. The first are the chondrocytes, the cellular its therapeutic effect.18 Glucosamine bioavailability component, which are distributed in and actually after oral administration is about five times lower produce the second component, the matrix. The than after intravenous administration, likely due matrix is amorphous and made up of collagen and to the extensive first-pass effect in the liver. elastic fibers in a chondromucoid substance of Glucosamine is a slow-acting drug for OA treat- proteoglycans and glycoproteins. A protein back- ment; it may have a chondroprotective role in bone is formed from complex proteoglycans with OA.18 The chondroprotective effect includes an sulfated mucopolysaccharides, specifically chon- increase in proteoglycan synthesis that may be droitin sulfates A and C, and keratin sulfate, dose-dependent, along with effects on chondro- branching off laterally. cyte gene expression, thereby increasing levels of The presence of these sulfate groups allows mRNA and collagen synthesis. Glucosamine may binding that can result in a strongly electronega- also have an anti-inflammatory effect, although it tive structure with high water retention. This is 50?00 times lower than that of indomethacin.18 It ensures the elasticity and resistance of the carti- may also be related to reducing the formation of lage. During load bearing, the proteoglycans act as superoxide radicals by macrophages or inhibiting shock absorbers by slowly releasing this water.16 lysosomal enzymes. The pathophysiologic mechanism of cartilage Chondroitin sulfate is an important compo- degeneration appears to be linked to metabolic nent of the cartilaginous matrix. Chondroitin changes in the chondrocytes that disrupt the sulfate may be able to increase the synthesis of components and reduce the water content, leading RNA by chondrocytes, thereby leading to an to tissue damage by the leukocyte proteolytic increase also in proteoglycan concentration and enzyme elastase. The proteoglycan content is collagen synthesis. Furthermore, chondroitin

JANUARY/FEBRUARY 2003 9 Safety & Efficacy of Glucosamine & Chondroitin in Osteoarthritis sulfate may have some inhibitory activity on the glucosamine group as well as improved range of degradation of elastase. The activity of chondroitin motion compared to the placebo.20 All the patients sulfate has been postulated to decrease the inflam- were diagnosed with gonarthrosis, a common matory response in arthritis as well. Marketed problem in Thailand due to their typical sitting chondroitin sulfate extracts contain mostly chon- position, which requires acute flexion of the knee. droitin-4 sulfate and chondroitin-6 sulfate, both of The investigator concluded that the metabolic which are large molecules and absorbed mini- action of glucosamine partially succeeded in mally, only about 10%, from the GI tract.18 restoring the articular function of cartilage and Although chondroitin is sold as an oral dietary relieving pain. A small number of patients with supplement, the compound was usually adminis- very specific OA in a limited area were selected tered by injection in clinical trials. for this study. As a result, the outcomes of this test may not be applicable to the population as a CLINICAL EVIDENCE FOR GLUCOSAMINE whole. Furthermore, parenteral glucosamine is A double-blind, placebo-controlled study generally not used or available in the U.S. conducted by Drovanti et al. compared 1.5 g/day In a study from Portugal, 40 patients diag- of glucosamine sulfate in three divided doses with nosed with unilateral knee OA were treated with placebo in 80 patients with OA for one month.19 glucosamine 1.5 g daily or ibuprofen 1.2 g daily to The results of this study showed that symptom compare the efficacy and tolerance of oral treat- scores decreased more in the glucosamine sulfate ment.21 In this double-blind trial, pain scores group compared to the placebo group, 72% and improved in both groups, with a more rapid result 36%, respectively, with symptoms continuing to seen in the ibuprofen group. However, continual improve at 30 days. Improvement was measured improvement was noted throughout the eight by assessing decreases in swelling and tenderness, weeks with the glucosamine group. Differences and increases in range of motion. Tissue was also observed in swelling and other parameters were examined under an electron microscope. This not noted to be significant in this trial, suggesting study showed an improvement in pain after seven that glucosamine has less anti-inflammatory action days, improvements in tenderness, swelling, and and more effect on normalizing the cartilage active range of motion after 14 days, and passive metabolism through stimulation of proteoglycan range of motion improving in 21 days. Electron synthesis and inhibition of degradation, allowing microscopy of cartilage also yielded favorable partially restored articular function. The results results in the glucosamine sulfate group, relative showed better tolerability with glucosamine, to placebo. Limitations to this study include the which was also the case in the overall evaluation small sample size, short study duration, and the by the physician, compared to ibuprofen. The fact that cartilage samples were obtained from investigator concluded that outcomes may be opti- only four subjects, two from each study group. mal if the patient is started on glucosamine and Another double-blind study evaluating 54 NSAID treatment initially to ensure rapid reduc- outpatients to determine the efficacy and tolerance tion of pain, and then continued on glucosamine of intra-articular glucosamine versus placebo was alone for a longer period depending on patient conducted in Thailand. After baseline measure- needs. ments of pain, swelling, range of motion and other A study done by Rindone et al. was symptoms were documented, patients were conducted in 98 patients to determine the efficacy injected with either a commercial dosage form of of glucosamine in reducing pain from OA of the glucosamine salts or 0.9% NaCl. Results showed knee.22 This double-blind, randomized, parallel significant improvement in pain for the

10 JANUARY/FEBRUARY 2003 Safety & Efficacy of Glucosamine & Chondroitin in Osteoarthritis trial of 500 mg of glucosamine sulfate, given three respond as well to glucosamine due to more times a day, compared to a placebo, showed no extensively damaged cartilage. Further, this study statistical benefit with glucosamine over the two- was only conducted for two months, which may month period. Mean scores on both visual analog not be long enough to produce beneficial results, scales for resting and walking were taken at 30 especially in more severe cases. and 60 days with no statistical differences noted Arecent three-year, double-blind study in 212 when compared to the baseline in either group. Belgian patients with OA randomized subjects to Side effects were mild and self-limiting in both receive either oral glucosamine sulfate 1,500 mg groups. One suggested reason for this negative QD or placebo.23 After three years, patients who result was that the patients in this study were received placebo had a mean joint space loss of 0.3 older, heavier, and had arthritis longer than many mm (tibiofemoral joint), whereas those receiving patients evaluated in other studies. This may glucosamine had no significant loss of joint space. suggest that more pronounced arthritis does not Standard, validated symptom scores for OA pain ROLE OF THE PHARMACIST and disability were significantly improved in the AND PATIENT COUNSELING glucosamine group and slightly worse in the placebo group at the end of the study. There were Pharmacists are consulted regularly for information on no significant differences between groups in the dietary supplements; they are likely to receive questions frequency or pattern of adverse events. This about glucosamine and chondroitin. Patients should be should be considered a landmark study since it encouraged to discuss their use of glucosamine and demonstrates that glucosamine provides sympto- chondroitin with their physicians. Patients should be matic improvement and is well-tolerated and safe reminded that these therapies have a gradual onset of for long-term use. This well-designed study also therapeutic effect; other agents such as NSAIDs will suggests that glucosamine may have disease- provide more immediate relief of acute symptoms. Generally, patients should use glucosamine or chon- modifying properties in OA as well. droitin for at least a continuous 8?2 week trial before CLINICAL EVIDENCE FOR CHONDROITIN AND discontinuing use, and should be counseled to remain COMBINATION THERAPY compliant. Relative to glucosamine, there is even less While these supplements are used predominantly in compelling evidence to support chondroitin older patients with OA, pharmacists should advise monotherapy as a primary treatment for OA. A against the use of these supplements during pregnancy study performed by Morreale et al. was designed or lactation since their effects on fetal development and to assess the clinical efficacy of chondroitin sulfate, breast milk excretion are unknown. Patients should also when compared to the NSAID diclofenac sodium, be advised to take the same dosage and frequency that in patients with knee OA.17 This was a random- has been studied in clinical trials, and not to exceed ized, double-blind, parallel group study that labeled amounts. Pharmacists should discourage the collected data from 126 patients and lasted six sale and use of glucosamine and chondroitin products that do not list the exact amount or dosage contained months. Patients were divided into two groups. in the product. Finally, pharmacists should remind For the first month, the chondroitin sulfate group patients that glucosamine and chondroitin are not received 400 mg of chondroitin sachet three times regulated by the FDA in the same manner as prescrip- a day and a placebo (diclofenac dummy) three tion products for OA. However, good scientific evidence times a day. The diclofenac sodium group was now exists to support the use of glucosamine as a safer, given 50 mg of diclofenac three times a day and a effective alternative to NSAIDs or as an adjunct to a placebo sachet (chondroitin dummy) three times a comprehensive OA management plan. day. For months two and three, the chondroitin

JANUARY/FEBRUARY 2003 11 Safety & Efficacy of Glucosamine & Chondroitin in Osteoarthritis sulfate group received chondroitin sulfate sachets superior to the placebo in reducing pain scores in only while the diclofenac sodium group received those with OA of the knee on the visual analog placebo sachets only. During months four, five, scale after eight weeks of treatment. However, it is and six, only placebo chondroitin sulfate sachets unclear whether the addition of chondroitin were given to both groups. Scores on the Lequesne contributed to this decrease or not. Changes from Index (a series of questions that rates pain during baseline measurements of pain along with func- activity) decreased sharply during the first month tional questionnaires, physical exam scores, and in both groups. This decrease was greater in the running times were presented as a percentage of diclofenac sodium group; however, by the end of the average score of each patient. However, this the first month, the score evened out in the same benefit was neither demonstrated nor diclofenac sodium group. This group was treated excluded for degenerative joint disease of the for the next five months with placebo and showed spine. Also, running times were not significantly a continual increase in pain scores through the rest different. of the study. On the other hand, the chondroitin Ameta-analysis of 15 double-blind, random- sulfate group showed a continual decrease in pain ized, placebo-controlled trials of oral or parenteral scores through the next two months of continued glucosamine sulfate or chondroitin sulfate for chondroitin sulfate treatment. At the end of the knee or hip osteoarthritis has recently been study, the scores were 64.4% lower overall published.25 Studies were included in this analysis compared to baseline in the chondroitin sulfate only if they were placebo-controlled and of at least group, and 29.7% lower in the diclofenac sodium four weeks in duration. This meta-analysis group. When spontaneous pain was measured, concluded that some degree of efficacy was likely, both groups showed a decrease progressively despite quality concerns, such as publication bias through the first two months; however, patients in (manufacturers of glucosamine or chondroitin the chondroitin sulfate group had a higher funded all but one trial). consumption of acetaminophen for breakthrough A randomized, controlled trial was conducted pain. The remainder of the study showed a in 95 patients with OA of the knee using a combi- progressive decrease in mean values for sponta- nation product (Cosamin DS) containing neous pain in the chondroitin sulfate group and glucosamine HCl 1,000 mg, sodium chondroitin an increase in mean values for the diclofenac sulfate 800 mg, and manganese ascorbate 152 mg sodium group. This difference proved to be statis- given BID, compared to placebo.26 Patients were tically significant during the last four months of evaluated at baseline and then every two months the study. From the results of this study, the for six months using the Lesquene Index. conclusion was made that chondroitin sulfate has Statistical improvement was seen in the active slow but gradually increasing effectiveness in OA. treatment group beginning at four months. The Combinations of chondroitin with response rate to the combination product was glucosamine are advertised extensively in stores 52%, versus 28% with placebo in 72 patients with across the U.S. Only one controlled study has mild to moderate OA. In the remaining 23 patients compared this combination with a placebo in with severe OA there was no significant difference patients with OA.24 This double-blind, placebo- in efficacy between the two groups. The incidence controlled, crossover trial evaluated 21 males with of adverse reactions was comparable between the chronic pain and OA of the knee or low back. The two groups. The investigators concluded that the results of this trial showed that the combination of combination of glucosamine HCl, sodium chon- glucosamine sulfate and chondroitin sulfate was droitin sulfate, and manganese ascorbate was

12 JANUARY/FEBRUARY 2003 Safety & Efficacy of Glucosamine & Chondroitin in Osteoarthritis effective in mild to moderate OA of the knee. reported. Similarly, glucosamine in clinical trials A meta-analysis of seven double-blind, causes a less than 4% incidence of GI effects, simi- randomized, controlled trials using chondroitin lar to placebo.28 Because glucosamine is an amino sulfate for OA was recently published.26 When saccharide, some authorities recommend using results of these studies were pooled, following this product with caution in diabetics; however, patients to 120 or more days, chondroitin showed hyperglycemia has not been observed in patients at least a 50% improvement in pain scores using glucosamine.28 Areasonable recommenda- compared to placebo. It should be noted, however, tion is for diabetic patients receiving glucosamine that in most of these trials chondroitin was given products to increase the frequency of blood along with other analgesics and NSAIDs, glucose monitoring, especially when first initiating confounding the exact magnitude of treatment glucosamine therapy. effect due to chondroitin alone. CONCLUSION ADVERSE EFFECTS The clinical trials of glucosamine and chon- It should be encouraging to pharmacists, droitin in the use of OA treatment collectively other healthcare providers and patients that demonstrate that their effects may be beneficial for glucosamine and chondroitin have been very well- OA symptoms. Based on available evidence, it tolerated in research trials and in clinical practice.25 appears that glucosamine monotherapy is prefer- Chondroitin appears to be especially safe, with the able to chondroitin monotherapy. Combination incidence of adverse reactions being similar to therapy is promising, but clinical data is inconclu- placebo; no serious side effects have been sive. The National Institutes of Health has recently funded a randomized, double-blind, placebo- controlled trial comparing glucosamine sulfate 500 mg TID to chondroitin sulfate 400 mg TID, versus a combination of the two.29 Both treatments are being given orally, and the study results should be available later this year. It is unknown whether these products are actually “disease-modifying,” and it is uncertain if combination products are superior to glucosamine alone. Using these agents appears to be relatively safe; however, drug interaction studies have not been carried out. Pharmacists should recommend these products only for confirmed cases of OA and suggest products that are marketed by reputable manufacturers. Glucosamine and chondroitin should not be recommended for acute pain or other inflammatory bone and joint diseases. ■

Acknowledgment The author wishes to thank Gail Stitt for her contribution in preparing this manuscript.

JANUARY/FEBRUARY 2003 13 Safety & Efficacy of Glucosamine & Chondroitin in Osteoarthritis

REFERENCES 15. Theodosakis J, Adderly B, Fox B. The Arthritis Cure. New York, NY: St. Martin’s Press; 1997. 1. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthri- tis and selected musculoskeletal disorders in the United States. Arthritis Rheum 16. Runkel DR, Cupp MJ. Glucosamine sulfate use in osteoarthritis. Am J Health-Syst 1998;41:778-99. Pharm 1999;56:267-9. 2. Manek NJ, Lane NE. Osteoarthritis: Current concepts in diagnosis and manage- 17. Morreale P, Manopulo R, Galati M, et al. Comparison of the anti-inflammatory ment. Am Fam Phys 2000;61:1795-1804. efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. J Rheumatol 1996;23:1385-91. 3. American College of Rheumatology. Recommendations for the medical manage- ment of osteoarthritis of the hip and knee arthritis. Arthritis Rheum 18. Deal CL, Moskowitz RW. Nutraceuticals as therapeutic agents in osteoarthritis. 2000;43:1905-1915. Rheum Dis Clin N Amer 1999;25:379-95. 4. Geis GS. Update on clinical developments with celecoxib, a new specific COX-2 19. Drovanti A, Bignamini AA, Rovati AL. Therapeutic activity of oral glucosamine inhibitor: What can we expect? J Rheumatol 1996; 26(Suppl 56):31-26. sulfate in osteoarthritis: A placebo-controlled double-blind investigation. Clin Ther 1980;3:260-7. 5. Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropa- thy. Am J Med 19998;105:1B):31S-38S. 20. Vajaradul Y. Double-blind clinical evaluation of intra-articular glucosamine in outpatients with gonarthrosis. Clin Ther 1981;3:336-43. 6. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol 1996;26(Suppl 56):18-24. 21. Vaz AL. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthrosis of the knee in out- 7. Wolfe MM, Lichenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal patients. Curr Med Res Opin 1982;8:145-9. antiinflammatory drugs. N Engl J Med 1999;340:1888-1899. 22. Rindone JP, Hiller D, Collacott E, et al. Randomized, controlled trials of 8. Simon LS, Weaver AL, Grahma DY, et al. Anti-inflammatory and upper gastroin- glucosamine for treating osteoarthritis of the knee. West J Med 2000;172:91-4. testinal effects of celecoxib in rheumatoid arthritis: A randomized controlled trial. JAMA 1999;282:1921-28. 23. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: A randomised, placebo-controlled trial. 9. Emery P, Zeidler H, Kvien TK, et al. Celecoxib versus diclofenac in long-term Lancet 2001;357:251-6. management of rheumatoid arthritis: Randomized double-blind comparison. Lancet 1999;354:2106-11. 24. Leffler CT, Philippi AF, Leffler SG, et al. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: A 10. Silverstein F, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib randomized double-blind, placebo-controlled pilot study. Mil Med 1999;164:85-91. versus nonsteroidal anti-inflammatory drugs for osteo-arthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. JAMA 2000;284:1247- 25. MacAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin 55. for treatment of osteoarthritis. A systematic quality assessment and meta-analysis. JAMA 2000;283:1469-75. 11. Laine L, Harper S, Simon T, et al. A randomized trial comparing the effect of rofe- coxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the 26. Das A, Hammad TA. Efficacy of a combination of FCHG49 glucosamine gastroduodenal mucosa of patients with osteoarthritis. Gastroenterology hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and 1999;117:776-83. manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage 2000;8:343-50. 12. Hawkey C, Laine L, Simon T, et al. Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal 27. Leeb BF, Schweitzer H, Montag K, Smolen JS. A meta-analysis of chondroitin mucosa of patients with osteoarthritis: A double-blind, placebo-controlled trial. sulfate in the treatment of osteoarthritis. J Rheumatol 2000;27:205-11. Arthritis Rheum 2000;43:370-7. 28. Schiedermayer D. Glucosamine sulfate for the treatment of osteo-arthritis. Alt 13. Hawkey CJ. COX-2 inhibitors. Lancet 1999: 353:307-314. Med Alert 1998;1(11):122-4. 14. Lichtenstein DR, Wolfe MM. COX-2-selective NSAIDs: new and improved? 29. Towheed TE, Anastassiades TP. Glucosamine and chondroitin for treating symp- JAMA 2000;284:1297-99. toms of osteoarthritis. Evidence is widely touted but incomplete. JAMA 2000;283:1483-4.

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