A review of evidence-based medicine for glucosamine and chondroitin sulfate use in knee osteoarthritis

A Review of Evidence-Based Medicine for Glucosamine and Chondroitin Sulfate Use in Knee Osteoarthritis C. Thomas Vangsness Jr., M.D., William Spiker, M.D., and Juliana Erickson, B.A.
Abstract: The investigation of disease-modifying treatment options for osteoarthritis (OA) has
become an important aspect of orthopaedic care. The purpose of this review is to critically evaluate
the evidence for the use of glucosamine and chondroitin sulfate for knee OA with the goal of
elucidating their indications for clinical use. The published clinical studies of glucosamine and
chondroitin sulfate on OA are reviewed within the context of evidence-based medicine. Almost every
included trial has found the safety of these compounds to be equal to placebo. In the literature
satisfying our inclusion criteria, glucosamine sulfate, glucosamine hydrochloride, and chondroitin
sulfate have individually shown inconsistent efficacy in decreasing OA pain and improving joint
function. Many studies confirmed OA pain relief with glucosamine and chondroitin sulfate use. The
excellent safety profile of glucosamine and chondroitin sulfate therapy should be discussed with
patients, and these supplements may serve a role as an initial treatment modality for many OA
patients. Key Words: Glucosamine sulfate—Glucosamine hydrochloride—Chondroitin sulfate—
Knee osteoarthritis—Nutritional supplement.
As the most common musculoskeletal disease in status quo despite questionable efficacy and signifi-
the United States, osteoarthritis (OA) has long cant risks such as peptic ulcer disease, renal failure, been a topic of intense research and debate. Knowl- edge about the biomechanical and biochemical pro- pected to double in the next 20 years and NSAID- gression of the disease continues to improve but re- related gastropathy currently the second most deadly rheumatic the investigation of disease-mod- Americans incurring pain and disability from the dis- ifying treatment options for OA has become an im- ease, research has resulted in only minimal advances Glucosamine and chondroitin sulfate (CS), both roidal anti-inflammatory drugs (NSAIDs) remains the components to the extracellular matrix of articularcartilage, have been used for medicinal purposes fornearly 40 After gaining popularity in Europeand Asia for the treatment of arthritis for the last 20 From the Department of Orthopaedic Surgery, Keck School of years, they gained popularity in the United States after Medicine, University of Southern California, Los Angeles, Califor- the release of several lay publications in the late The authors report no conflict of interest.
Address correspondence and reprint requests to C. Thomas One of the earliest studies to use glucosamine and Vangsness Jr., M.D., Department of Orthopaedic Surgery, Keck CS for the treatment of the signs and symptoms of OA School of Medicine, University of Southern California, 1520 SanPablo St, Suite 2000, Los Angeles, CA 90033, U.S.A. E-mail: was a 1969 study by that showed a decrease in joint symptoms with topical application. In the fol- 2009 by the Arthroscopy Association of North America lowing decades, numerous studies were designed to 0749-8063/09/2501-7234$36.00/0doi:10.1016/j.arthro.2008.07.020 investigate the effects of glucosamine hydrochloride Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol 25, No 1 (January), 2009: pp 86-94 GLUCOSAMINE AND CHONDROITIN SULFATE (GH), glucosamine sulfate (GS), and CS on outcomes ble-blind, placebo-controlled, randomized controlled such as joint space narrowing, functionality, and pain.
trials (RCTs) using glucosamine and CS for knee OA Although many trials have been published showing that have incorporated established outcome measure- significant treatment effects with these nutritional sup- plements, they have been largely ignored by the med-ical community in the United States because of theirquestionable quality.
SPECIFIC SUPPLEMENT STUDIES
Glucosamine and CS studies have been criticized Chondroitin Sulfate
for small sample sizes, confirmation of supplementquality, short length of therapy, potential bias be- In 1998 Bucsi and evaluated the use of CS cause of manufacturer’s sponsorship of the studies, inadequate masking of the study agent, and failure symptoms via Lequesne’s index, the occurrence of to adhere to the intention-to-treat principle. Despite spontaneous joint pain, and 20-minute walk time in these weaknesses, meta-analyses have concluded 80 OA patients who underwent 6 months of therapy that these supplements likely have some efficacy with 800 mg of CS sulfate or placebo. A statistically in treating the symptoms of OA with possible dis- significant improvement was shown in all 3 tested ease-modifying effects. Combined with a strong measurements over placebo with no difference in safety profile, such conclusions have created sup- side effects. In the same year Bourgeois et port for glucosamine and CS in medical circles and performed a similar study to determine whether the dosing schedule of CS had any impact on the effi- The purpose of this review is to critically evaluate the cacy of the treatment. In this 3-month trial, 1,200 evidence for the use of glucosamine and CS for OA with mg of CS (administered either as a single dose or as the goal of elucidating their indications for clinical use. It 3 equally divided doses) reduced Lequesne’s index is necessary to evaluate each supplement independently and spontaneous joint pain scores versus placebo (GS, GH, and CS) and jointly as a pair (glucosamine plus (P Ͻ .01). Dosing schedules supported once-a-day CS). Although placebo-controlled, “randomized,” dou- administration. In a randomized clinical trial, Con- ble-blind studies date back 25 years, many of the older used an 800-mg dose in 104 patients treated trials are difficult to analyze because of sponsorship for 1 year. Functional impairment recovered by from manufacturers and inadequate product conceal- approximately 50%, with significant improvement ment. Specifically, this review article focuses on dou- over placebo for all clinical criteria.
and (2) walking time, globaljudgment, and acetaminophenconsumption spontaneous joint pain (visualanalog scale) 400 mg CS 2 times per day v placebo pain (visual analog scale), and 20-min walk time In a study by Mazieres et published in 2001, Michel et performed an RCT in 300 patients 130 patients were randomized to receive 1,000 mg of with OA, testing 800 mg of CS against placebo for CS daily for 3 months and were followed up for an 2 years. They evaluated joint space narrowing as a additional 3 months after therapy. Lequesne’s index primary outcome, with pain and function as second- significantly improved (P ϭ .02) and remained ele- ary outcomes. They found no significant symptom- vated for 1 month after treatment. These findings did atic effects between the treatment groups and con- not reach significance when the results were viewed cluded that CS may retard radiographic progression with an intention-to-treat analysis. Mazieres et in patients with OA of the knee. Future evaluation also evaluated 307 patients with knee OA for 6 of these structural observations was recommended.
months using CS. They failed to show any efficacy However, large well-designed studies are necessary to prove such an effect, especially with respect to Uebelhart et randomized 120 patients to re- the reproducibility and consistent measurement of ceive placebo or 800 mg of CS for two 3-month periods during a period of 1 year. They showed a 36%improvement in Lequesne’s index scores in the CS Glucosamine Sulfate
group whereas the placebo group only improved by26%. This significant decrease in pain with improved GS is one of the most studied dietary supplements function showed a long-term benefit with intermittent available today In the last 30 years, many trials have been conducted and published on the effects of glucosamine on the signs and symptoms of 300 patients in 2002, showed that over a 2-year pe- riod, CS reduced the radiographic progression of OA 4-week effects of 1,200 mg of GS using Lequesne’s when compared with controls. In the CS group the severity index and looked at the relative risks of side radiologic parameters remained stable. These results effects in the GS group versus the ibuprofen group. In were further supported by the 2005 study of Michel et this short 1-month study, GS was as effective as which also showed a retardation of joint space ibuprofen and significantly better tolerated (P Ͻ .001).
narrowing in patients who received the same nutri- Only 6% of patients taking GS reported adverse tional supplement for a 2-year period. Together, these events, whereas 35% of ibuprofen users had an ad- studies suggest a disease-modifying role of CS.
verse event (mainly gastrointestinal in origin).
1,500 mg GS per day v placebo Minimal joint space width and 1,500 mg GS per day v placebo Lequesne’s index, WOMAC, 1,500 mg GS per day v placebo WOMAC and minimal joint GLUCOSAMINE AND CHONDROITIN SULFATE Noack et published a 4-week study comparing sion of Johnson & Johnson, Guelph, Ontario, Canada), GS with placebo rather than ibuprofen. This short and placebo. After 6 months, 1,500 mg of GS was study of 252 patients showed that GS was more ef- found to be better than placebo and acetaminophen by fective than placebo in improving OA symptomatol- use of Lequesne’s index and the WOMAC.
ogy. Patients in the GS arm of the trial enjoyed a Hughes and performed a randomized clinical 3.3-point drop in Lequesne’s severity index, whereas trial with GS in 80 OA patients for 24 weeks. They those taking the placebo improved by 2.0 points. A found a 33% placebo response rate and no statistical 6-week study by Reichelt et showed GS to de- improvement over placebo as a symptom modifier.
crease Lequesne’s index over placebo in 155 patients.
Collectively, these GS studies showed that GS as an Unfortunately, these studies are too short to make individual agent may have some effect on the progres- sion of the disease and was as safe as placebo at a dose In 2001 Reginster et published the results of a of 1,200 to 1,500 mg/d for up to 3 years. Many studies trial in which 212 patients were randomized to receive had a short-term follow-up, and the evidence inconsis- placebo or GS daily for 3 years. Glucosamine was tently supported the use of glucosamine as an effective shown to protect the joint space from the narrowing alternative to higher-risk medications such as NSAIDs effects of OA. A trend toward improving Western and cyclooxygenase II inhibitors for knee OA.
Ontario and McMaster Universities Osteoarthritis In-dex (WOMAC) scores was seen without any statisti- Glucosamine Hydrochloride
The hydrochloride salt of glucosamine is a common A similar study by Pavelká et supported the glucosamine product, yet it has received relatively findings of Reginster et proving statistically sig- little attention from researchers Houpt et nificant effects of glucosamine on both radiographic were unable to show statistically significant changes in the WOMAC pain score subset versus Bruyere et used the same outcome measures of placebo after a short period of therapy with GH (8 joint space narrowing and WOMAC scores to prove weeks). All tested parameters tended to show im- that the disease-modifying effects seen in the study of provement, and GH did significantly reduce the daily Pavelká et were also found in the older postmeno- pain reported by patients (P ϭ .018) and improved pausal female population. Bruyere et investigated findings on clinical knee examination (P ϭ .026). GH joint space narrowing in 212 knee OA patients at 3 was shown to be as safe as placebo. Though failing to years. Patients with less severe radiographic knee OA prove its primary outcome measure, this study sug- had the most dramatic disease progression as seen by gested that GH benefited some patients with OA with- joint space narrowing. The GS group, compared with out the side effects of other treatment modalities.
the placebo group, showed a nonstatistical trend in McAlindon et performed a 12-week GH study on significant reduction of joint space narrowing.
205 patients, recruited over the Internet. By use of the Cibere et tested GS in a 4-center 6-month WOMAC as the primary outcome, GH was safe but randomized, double-blind, placebo-controlled study.
no more effective than placebo in treating symptoms No differences were found in the severity of disease pain episodes (flare-ups) or other secondary outcomesbetween placebo- and glucosamine-treated patients.
Glucosamine and CS
They concluded that there was no evidence of symp-tomatic benefits from continued GS use from this The highly publicized Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) was published in Herrero-Beaumont et evaluated 318 patients the New England Journal of Medicine early in 2006 with knee OA in an RCT comparing GS, acetamino- phen (Tylenol; McNeil Consumer Healthcare, a divi- tients to randomly receive 1,500 mg glucosamine; sodium 2 times per day for 1 mo and then1 time per day for 5 mo v diclofenacsodium 1,500 mg GH v 1,200 mg CS v GH plus CS v 200 mg celecoxib v placebo 1,200 mg CS; both GH and CS; 200 mg of celecoxib patients with more severe OA. Questions remain (Celebrex; Pfizer, New York, NY); or placebo for 24 about the usefulness of glucosamine and CS in mild weeks. Patients were allowed to take up to 4,000 mg OA and their effect on other parameters such as joint of acetaminophen for rescue analgesia daily (no pain function, stiffness, and joint space narrowing. Limita- medications were taken within 24 hours of clinical tions of the study noted by the authors were the high examination). All patients in the study were aged at rate of response to placebo (60%) and the relatively least 40 years, had both clinical evidence (knee pain mild degree of OA pain among the participants. Con- for most days of the month for Ն6 months) and comitant treatments, such as physical therapy, were radiographic evidence of OA (osteophytes Ն1 mm), not clarified. These limitations decreased the ability of and WOMAC scores from 125 to 400. The primary the study to detect the benefits of treatment. Studies outcome measure was a 20% decrease in the summed with alternative medical therapies have shown a score for the WOMAC pain subscale from baseline to higher placebo response Celecoxib at 200 mg/d week 24. Over 40 secondary outcome measures were had noticeably smaller effects in the GAIT study In the subgroup of 79 patients with moderate to The GAIT study was designed to include 1,588 severe pain (determined by a score of 300-400 on the patients to provide the study with statistical power to WOMAC pain scale), GH and CS significantly reduced detect 1 or more clinically meaningful differences knee pain. In this subgroup of patients receiving GH and based on an assumed placebo response rate of 35%.
CS, 79% showed a 20% reduction in knee pain, whereas When this placebo response rate nearly doubled, the only 54.3% of the placebo group showed this improve- number of participants needed to obtain a similar ment. However, GH and CS were not found to be sig- statistical power increased substantially. With far too nificantly better than placebo in reducing knee pain by few patients given its placebo response rate, the data 20% from baseline in the pooled analysis of patients.
were barely able to prove its control (celecoxib) in the Adverse effects were mild, infrequent, and evenly dis- primary outcome measure (P ϭ .04) and was unable tributed across all groups tested, supporting the safety of to do so in the moderate/severe pain subgroup. Fur- thermore, the choice of the product tested (GH) has Celecoxib was found to yield a statistically signif- been called into question given the fact that GS has icant decrease in pain scores in the combined mild been more rigorously studied in the literature. The pain and moderate/severe pain subgroups but failed to GAIT authors also chose less sophisticated methods have a significant effect on the pain scores in the for dealing with missing data, using the last observa- moderate/severe pain subgroup. Celecoxib was also tion– carried forward method rather than the multiple found to yield a faster decrease in pain scores, show- ing substantial decreases in pain scores at 4 weeks of Alekseeva et alexamined 90 women aged between treatment. Overall, celecoxib was found to have a 40 and 75 years with Kellgren-Lawrence stage II or III significant effect on 6 of the 42 outcome measures knee OA who had pain after 40 minutes of walking and followed in the study, whereas glucosamine and CS regularly took NSAIDs for pain relief. The patients were were found to have a significant effect on 14 of the 42 randomly selected either to receive 500 mg of the glu- cosamine and CS supplements with optional diclofenac This study, the largest and most rigorous of its kind, (50 mg) or to receive a placebo and optional diclofenac showed that GH and CS had a significant effect on for a total of 3 months. The results were measured by the GLUCOSAMINE AND CHONDROITIN SULFATE WOMAC, daily need for NSAIDs, and evaluation of Richy et examined both structural and symp- efficacy by the patient and the physician after 1 and 3 tomatic efficacy of CS and glucosamine. By examin- months of treatment and again 3 months after the oral ing structural changes via radiographic progression of supplementation had been stopped. The true WOMAC joint space narrowing, this analysis was the first to score decreased after 3 months of therapy and 3 months evaluate the disease-modifying effects of these sup- after the supplementation had been stopped (P Ͻ .03). At plements. Evaluating the results of 15 studies that the end of the 3 months of therapy, the study group included data from 1,775 patients, the authors showed exhibited decreases in pain scores (P ϭ .008) and in- a statistically significant improvement in symptom creases in subjective functional ability. The patients tak- scores with both glucosamine and CS therapy. They ing the glucosamine and CS supplementation required also were able to show a significant effect of glu- less diclofenac. After 1 month of therapy, 4.5% stopped cosamine on the progression of joint space narrowing taking diclofenac and nearly 40% stopped taking it by over a 3-year period, suggesting a disease-modifying the end of the study. Although limited by its size and the effect of the compound (no such studies existed for small subgroup that was studied (older women), this CS). Importantly, the tolerance for these supplements study showed that combined medications offer signifi- was again shown to be equal to that of placebo.
cant safety and effective pain relief in the short term with Bjoral et reviewed 63 RCTs using opioids, NSAIDs, glucosamine, CS, and acetaminophen (Ty- Messier et in a double-blind 12-month GH/CS lenol; McNeil Consumer Healthcare) for knee OA study with 80 patients, incorporated 6 months of ex- including some 14,060 total patients. Acetaminophen, ercise after 6 months of a non-exercising treatment.
GS, and CS had maximum efficacies at 1 to 4 weeks The primary end-point was the WOMAC and func- with mild pain improvements. Overall clinical effects tional measures such as the 6-minute walk. At 12 from these knee pharmacologic arthritic interventions months, there was no difference between groups for were found to be small and limited to the first 2 to 3 the 6-minute walk, knee strength, mobility, and func- dence for glucosamine and CS studies analyzing Meta-Analyses of Glucosamine and CS Studies
RCTs. Their results were inconclusive regarding thecontinuous use of these nutraceuticals because of Several important meta-analyses have been pub- lished in recent years about the efficacy of glu- Reichenbach et performed a meta-analysis of cosamine and CS therapy. By performing exhaustive CS for OA of the knee or hip in 20 trials involving searches in the literature and applying systematic 3,846 patients. After analyzing the small and large quality assessment of these studies, these meta-anal- studies, they found the trial quality to generally be yses provided pooled information from the many pre- low. They concluded that with the large-scale, meth- odologically sound trials, CS had minimal to nonex- McAlindon et examined 15 double-blind, ran- istent symptomatic benefit. They discouraged CS use domized, placebo-controlled trials of 4 weeks’ dura- by itself in routine clinical practice.
tion or longer for their impact on the symptoms of hip Leeb et performed a meta-analysis of 7 trials of and/or knee OA. They included studies of glucosamine CS including 372 patients. They cited the difficulties and CS with various routes of administration, including in design with co-mixing of medications in several oral, intramuscular, intravenous, and intra-articular. Very studies using the visual analog scale and Lequesne’s few of the examined studies described adequate alloca- index. The findings in the CS groups were signifi- tion concealment or use of an intention-to-treat analysis.
cantly superior to those in the placebo groups. They They also found evidence of significant publication bias, called for better and longer time periods for symptom- likely because of manufacturer’s sponsorship of trials and the financial interests of the authors. When only the The Cochrane Review is perhaps the most thorough larger high-quality studies were evaluated, the effects of of the meta-analyses performed on glucosamine’s ef- glucosamine and CS persisted, although they were no- fect on Updated in January 2005, this meta- ticeably diminished. This study also suggested that the analysis followed 3 selection criteria: they were full therapeutic benefit of these supplements likely did RCTs, they were either placebo controlled or compar- not occur in the first 4 weeks and that longer studies ative, and they were blinded (single or double were both accepted). Twenty articles were found to meet the selection criteria, representing 2,570 patients. Cu- measured by the Short Form 36 score (P ϭ .05), but this mulatively, these articles showed that glucosamine study found no significant improvement in the total ag- induced a 28% improvement from baseline in pain and a 21% improvement in function by use of Lequesne’sindex. In 8 articles that showed adequate allocation DISCUSSION
concealment, glucosamine failed to show a benefit foreither pain or function. The Cochrane Review con- This review looked at the current research on the firmed the safety findings of the incorporated studies, sulfur-containing nutraceuticals and their effects on finding glucosamine to have adverse events equal to proven outcome measures. In the literature satisfying the placebo. Although these conclusions were signif- our inclusion criteria, GS and CS have shown an icant for the number of studies they incorporate, they inconsistent yet overall positive efficacy in decreasing did have their limitations. This review was designed to OA pain and improving joint function. Most trials include a broad selection of clinical trials, accepting found the safety of these compounds to be equal to short-term studies, comparative control studies, and that of placebo. The literature on GH, GS, or CS as an single-blind studies. In accepting these lower-quality individual supplement suggests a therapeutic value but articles, the power of the pooled results was nega- falls short of proving a role for its independent use.
Although the study by Clegg et called into question the efficacy of GH and CS in mild OA, it Other Sulfur-Containing Compounds
showed the effectiveness of these supplements in themoderate/severe pain subgroup. Their study lacked the S-adenosylmethionine (SAMe) and methylsulfonyl- size to make up for a placebo response rate of over 60% methane (MSM) are market leaders among the sulfur- and the relatively mild disease state of the study partic- containing compounds advertised for joint health.
ipants. When considered within the context of the other Despite the public interest in these compounds, few studies reviewed, it serves as another study to confirm well-designed studies have been completed. An open- the safety profile of glucosamine and CS and shows a label study in 1987 showed that SAMe increased joint reduction in pain scores with consistent use.
The scant literature on the sulfur-containing com- Subsequent double-blind placebo-controlled studies pounds SAM-e and MSM shows trends toward de- have supported the use of SAMe and shown it was creased pain and increased function with consistent use effective as many anti-inflammatory and pain-reliev- but fall short of proving any therapeutic benefit. How- ever, they have a documented 3-month safety profile; there is a need for more randomized clinical trials.
SAMe with Celebrex (Pfizer) for the symptoms of Perhaps the most important trend seen in the current OA. In the first month of their 4-month study, cele- literature on nutraceutical use for OA is the impor- coxib showed significantly more reduction in subjec- tance of length of therapy. Although some studies tive pain reports by the participants (P ϭ .024). By the have shown significant improvement in OA symptoms second month, both study arms were equally effective during a short time period, these studies involved the in reducing pain (P Ͻ .01). This study noted increased use of concomitant pain relievers, were poorly con- functional health measures and increasing joint mo- cealed for allocation, or were monetarily supported by bility in both treatment groups, without significant manufacturers. In the more rigorous and lengthy stud- differences in side effects. These trends were not ies comparing these compounds, effectiveness was not shown to be statistically significant.
seen until several months into therapy. For example, Despite the presence of several studies suggesting in studies on CS significant effects were not seen until the efficacy of MSM in reducing joint pain and en- 3 to 6 months of treatment. In other studies the effec- tiveness of CS was not shown until month 9 of the cient. With a paucity of research, as well as the short treatment phase or month 4 of the post-treatment length of follow-up, it is difficult to recommend MSM at phase. In glucosamine studies a similar trend can be this time as an efficacious therapy for OA. Kim et noted because treatment effects can be delayed until showed significant decreases in WOMAC pain (decrease post-treatment follow-up. These findings support the of 25% from baseline) and physical function subcatego- need for more long-term trials and the importance of ries with MSM versus placebo. Improved performance consistent use in patients who select these compounds of MSM users was seen in activities of daily life as GLUCOSAMINE AND CHONDROITIN SULFATE It is important to understand that many of these glu- CONCLUSIONS
cosamine and CS studies have been financed and spon-sored by industry and specific manufacturers. Not all In the literature satisfying our inclusion criteria, GS, studies document this well, and financial relationships GH, and CS have individually shown inconsistentefficacy in decreasing OA pain and improving joint with industry, scientific investigators, and academic in- function. Many studies confirmed OA pain relief with stitutions are widespread. These potential conflicts influ- glucosamine and CS use. The excellent safety profile of glucosamine and CS therapy should be discussed When considering the use of vitamin or nutrient with patients, and these supplements may serve a role supplementation, it is important to realize that the as an initial treatment modality for many OA patients.
supplements tested in trials are not necessarily thesame as the supplements sold in To reduceany potential complicating factors, clinical trials must REFERENCES
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