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Home , Chondroitin sulfate, Glucosamine, Methylsulfonylmethane

Dietary Supplements for Philip J. Gregory, PharmD; Morgan Sperry, PharmD; and Amy Friedman Wilson, PharmD Creighton University School of Pharmacy and Health Professions, Omaha, Nebraska

A large number of dietary supplements are promoted to patients with osteoarthritis and as many as one third of those patients have used a supplement to treat their condition. -containing supplements are among the most commonly used products for osteo- . Although the evidence is not entirely consistent, most research suggests that glucos- amine sulfate can improve symptoms of related to osteoarthritis, as well as slow disease progression in patients with osteoarthritis of the knee. sulfate also appears to reduce osteoarthritis symptoms and is often combined with glucosamine, but there is no reliable evi- dence that the combination is more effective than either agent alone. S-adenosylmethionine may reduce pain but high costs and product quality issues limit its use. Several other supplements are promoted for treating osteoarthritis, such as , Harpagophytum pro- cumbens (devil’s claw), Curcuma longa (turmeric), and Zingiber officinale (ginger), but there is insufficient reliable evidence regarding long-term safety or effectiveness. Am( Fam Physician. 2008;77(2):177-184. Copyright © 2008 American Academy of Family Physicians.)

ietary supplements, commonly , which are found in referred to as natural medicines, , ligaments, and other joint herbal medicines, or alternative structures. Exogenous glucosamine is derived medicines, account for nearly from marine exoskeletons or produced syn- D $20 billion in U.S. sales annually.1 These thetically. Exogenous glucosamine may have products have a unique regulatory status that anti-inflammatory effects and is thought to allows them to be marketed with little or no stimulate of .4 credible scientific research. Since 2000, more Glucosamine is available in multiple than 800 brand name forms. The most common are glucosamine formulations targeting patients with osteo- hydrochloride and glucosamine sulfate. arthritis have been introduced.2 Although a Some products contain a blend of these, and handful of these have some evidence of long- many combine one of the forms with a vari- term safety and effectiveness, most do not. ety of other ingredients. Approximately 30 percent of patients with osteoarthritis have used a supplement to EFFECTIVENESS treat their condition.3 Unlike many supplements that reach the This article is a review of dietary supple- market completely untested in clinical tri- ments commonly used by patients with als, glucosamine has been the subject of osteoarthritis (Table 1). Searches were done considerable research. More than 20 ran- using evidence-based databases (Natural domized controlled trials involving over Medicines Comprehensive Database and The 2,500 patients have evaluated the use of glu- Cochrane library) and bibliographic data- cosamine for osteoarthritis.5-7 Most of the bases (PubMed, International Pharmaceuti- research has focused on glucosamine sulfate cal Abstracts, the International Bibliographic and its role in treating osteoarthritis of the Information on Dietary Supplements). knee and hip, the two most studied and most commonly afflicted joints. Glucosamine Despite extensive research, study findings Glucosamine is the supplement most com- have been inconsistent, possibly because of monly used by patients with osteoarthri- the different products and methodologies tis. It is an endogenous amino sugar that is used in trials and/or issues of publication required for synthesis of and or industry bias. in 2005, a high-quality

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Evidence Clinical recommendation rating References Comments

Glucosamine sulfate may be used for reducing B 5-7, 11, 12 Evidence mostly positive, but with some symptoms and possibly slowing disease progression inconsistencies in patients with osteoarthritis of the knee. Chondroitin may provide modest benefit in some B 7, 16-19 Inconsistent evidence; analysis of all studies patients with osteoarthritis, but it does not appear shows benefit, but analysis of higher- to offer any advantage over glucosamine sulfate. quality studies shows no benefit S-adenosylmethionine may reduce osteoarthritis B 23-29 Evidence consistently shows reduced pain, pain, but it is a less appropriate treatment option but there are concerns about product for most patients. quality and high cost

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease- oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 131 or http:// www.aafp.org/afpsort.xml.

Table 1. Selected Supplements for Osteoarthritis

Supplement Typical dosage Comments Monthly cost*

Glucosamine 1,500 mg once daily or Glucosamine sulfate preferred $9 to 35 (combination drugs appear 500 mg three times daily over glucosamine hydrochloride to be in the same price range) Chondroitin 200 to 400 mg two or Combination chondroitin/ $10 to 25 three times daily glucosamine no better than glucosamine sulfate alone S-adenosylmethionine 200 mg three times daily Butanedisulfonate form $60 to 120 preferred for best stability and bioavailability Methylsulfonylmethane 500 mg three times daily Not recommended because $5 to 35 to 3 g two times daily of insufficient evidence Harpagophytum 2.4 to 2.6 g daily Not recommended because $15 to 40 procumbens standardized extract of insufficient long-term (devil’s claw) safety data Curcuma longa No typical dosage for Not recommended because $8 to 23 (for one tablet daily) (turmeric) osteoarthritis of insufficient evidence Zingiber officinale 510 mg daily standardized Not recommended because $2 to 3 (ginger) extract of insufficient evidence

*—Average retail cost (rounded to the nearest dollar) based on a search of common Internet stores, including http://www.vitacost.com and http://www.vitaminshoppe.com. Product quality may vary.

systematic review of glucosamine trials for assessment of patients with osteoarthritis of osteoarthritis identified some interesting the knee or hip. The Lequesne index assesses patterns in the research.6 The pooled data pain and discomfort, maximal walking from all glucosamine trials, regardless of distance, and activities of daily living. The product type, trial quality, or assessment WOMAC index assesses pain, stiffness, and instrument, show that glucosamine sig- physical disability. one pooled analysis nificantly reduces pain. a previous meta- found that studies using the Lequesne index analysis found similar results.7 showed benefit, whereas those using the A subgroup analysis of studies shows dif- WOMAC index did not.6 However, a differ- ferent outcomes depending on whether the ent analysis did show improvement in out- study used the Lequesne index or the West- comes when using the WOMAC index as an ern ontario and McMaster Universities assessment tool.7 (WOMAC) osteoarthritis index to assess The type of glucosamine product used outcomes. Both are validated scales for the appears to have a significant impact on

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outcomes. Many studies used a specific com- evidence and animal research suggesting mercial glucosamine sulfate product called increased . However, clin- Dona. Pooled findings from these stud- ical research shows that glucosamine does ies, regardless of the assessment scale used, not increase blood glucose suggest that this formulation significantly or A1C levels in patients with reduces osteoarthritis pain. Findings from type 2 diabetes.13,14 Because Glucosamine sulfate is studies using different formulations suggest glucosamine is derived from effective for reducing no significant improvement.6 the exoskeleton of shellfish, osteoarthritis pain and Consistent with this analysis are results of there is also concern that glu- improving function, and the highly-publicized Glucosamine/chon- cosamine may cause reactions might have disease- droitin arthritis intervention Trial, which in persons who are allergic to modifying effects. did not use a glucosamine sulfate formula- shellfish. however, shellfish tion, but rather a glucosamine hydrochlo- allergies are caused by antigens ride product.8 The investigators found that in the meat of the shellfish (not the shell) when used alone or in combination with and there have been no reports of reactions chondroitin, glucosamine hydrochloride in persons with shellfish allergies who take does not reduce symptoms of knee osteoar- glucosamine.15 thritis; however, subgroup analysis suggests that the combination does reduce pain in CLINICAL RECOMMENDATIONS patients with severe symptoms. Of note, the Overall, the evidence supports the use of placebo response rate in this trial was high; glucosamine sulfate for modestly reducing approximately 60 percent of patients in the osteoarthritis symptoms and possibly slow- placebo group had a 20 percent decrease in ing disease progression. however, there is the WOMAC index. it would be difficult not enough evidence to recommend the use for a treatment to surpass this effect, which of other glucosamine formulations. Patients may also explain the negative findings of should be advised that they may need addi- this trial.9 tional pain relief from analgesics on an as- Glucosamine sulfate has been compared needed basis. with acetaminophen and the nonsteroidal anti-inflammatory drugs (NSAIDs), ibupro- Chondroitin fen (Motrin) and (Feldene), in Chondroitin, an endogenous glycosamino- the treatment of osteoarthritis. These trials glycan, is a building block for the formation show that glucosamine sulfate is effective for of the joint matrix structure.4 Chondroitin reducing pain and improving function.6,10 is almost always combined with other ingre- The effect of glucosamine sulfate on joint- dients in commercial products; however, space narrowing has been evaluated in two most research on chondroitin has focused studies; the results of both studies sug- on single-ingredient gest that glucosamine sulfate significantly preparations. reduces knee-joint–space narrowing over three years of treatment.11,12 Similar long- EFFECTIVENESS term research using other formulations has Less research is available on chondroi- not been conducted. tin than on glucosamine sulfate. also, the research findings have been inconsistent. SAFETY Most early clinical trials conducted from Glucosamine has been safely used in long- the 1980s to 2001 show that a combination term clinical trials. Side effects from glucos- of chondroitin and conventional analgesics amine occurred at a rate similar to that of more effectively reduces pain compared with placebo and less than that of NSAIDs.6 analgesics alone.7,16 Preliminary evidence There have been concerns that glucos- also shows that long-term use of chondroitin amine worsens glycemic control in patients may slow joint-space narrowing, suggesting with diabetes. This is based on anecdotal that the supplement could also slow disease

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progression.17-19 Two clini- SAMe S-adenosylmethionine has cal trials evaluating a specific S-adenosylmethionine (SAMe) is produced been used to treat osteo- combination product contain- in the liver from methionine. SAMe appears arthritis, as well as other ing chondroitin, glucosamine to increase chondrocytes and thick- conditions such as depres- hydrochloride, and ness and may also decrease cytokine-induced sion and liver disease. (Cosamin-DS) show that this damage.4 SAMe has been used combination reduces knee pain to treat osteoarthritis, as well as other condi- in patients with osteoarthritis.20,21 of note, tions such as depression and liver disease. these studies used glucosamine hydrochlo- ride and did not include a comparison with EFFECTIVENESS glucosamine sulfate alone. Research on the use of SAMe for osteoarthri- Many of the early trials were of moderate tis has been consistently positive. a review or poor quality. The results of more recent and meta-analysis conducted by the Agency research (published since 2005) have been for Healthcare Research and Quality, as well negative. One analysis shows that when the as several randomized clinical trials, have results of all chondroitin studies are pooled, shown that SAMe is more effective than pla- this supplement appears to improve symp- cebo and comparable to NSAIDs in reducing toms of pain; however, when only higher- osteoarthritis pain.23-29 In a recent trial, SAMe quality studies are pooled, chondroitin does (1,200 mg per day) was compared with the not appear to be beneficial.22 cyclooxygenase (COX)-2 inhibitor (Celebrex; 200 mg per day). Celecoxib was SAFETY much more effective than SAMe in reduc- Chondroitin has been safely used and well ing pain during the first month of treatment; tolerated in clinical trials. however, chon- however, after two months of use, no differ- droitin is often derived from animal sources, ence in pain relief was noted between the two such as bovine cartilage, which has raised agents.29 Although SAMe does provide pain questions about the possibility of contamina- relief, it can take several weeks of treatment tion from animal diseases (e.g., bovine spon- before symptoms substantially improve. giform encephalopathy). Although cartilage tissue is not associated with bovine spon- SAFETY giform encephalopathy, there are concerns SAMe appears to be safe and is possibly that the lack of stringent manufacturing better-tolerated than nSAIDs.23-29 in addi- practices in the industry could potentially ­tion to its effects on cartilage, SAMe also result in cross-contamination with high-risk affects several neurotransmitters. SAMe tissue types. These concerns are purely theo- increases serotonin turnover and may retical. no reports of disease transmission increase norepinephrine and dopamine lev- exist and such risks are probably low. els; therefore, it has the potential to cause central nervous system side effects such as CLINICAL RECOMMENDATIONS anxiety, headache, insomnia, and nervous- The evidence for chondroitin is inconsistent. ness. it also has the potential to interact Chondroitin does not offer an advantage with other serotoninergic drugs, such as over glucosamine sulfate, and there is no evi- antidepressants, tramadol (Ultram), and dence that combining chondroitin with any meperidine (Demerol), possibly resulting in formulation of glucosamine is more effective serotonin syndrome (Table 2).4 There also than glucosamine sulfate alone. Chon- have been reports of hypomania and mania droitin also has the disadvantage of being in patients with depression who took SAMe.4 harvested from animal sources. although chondroitin may provide modest benefit for CLINICAL RECOMMENDATIONS some patients, glucosamine sulfate is more SAMe is an effective treatment for osteo- appropriate for patients interested in trying arthritis, but it can be expensive. a one- a dietary supplement for osteoarthritis. month supply typically costs between

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$60 and $120, which is comparable to the occurs naturally in small amounts in some cost of celecoxib and higher than that of green plants, fruits and vegetables, and other nSAIDs or acetaminophen. Because human adrenal glands. MSM is promoted SAMe is an unstable compound, product as having anti-inflammatory and analgesic quality is another concern; products on store effects. Preliminary animal research sug- shelves may contain little or none of the active gests that it may decrease degenerative pro- ingredient. Although it is helpful to choose cesses in joints.4 a SAMe product that has been reviewed for quality and contents by a reputable indepen- EFFECTIVENESS dent company, it is still unclear how long this Two preliminary clinical trials have evalu- product remains stable on the shelf. Until ated MSM alone and in combination with these concerns have been resolved, SAMe may glucosamine in the treatment of patients not be a reliable alternative treatment option. with osteoarthritis. Results show that MSM If patients are interested in using SAMe, the modestly reduces pain and swelling, but it butanedisulfonate salt formulation should be does not reduce joint stiffness.30,31 recommended because it is more stable and has a higher bioavailability.4 SAFETY MSM has been well tolerated in clinical tri- MSM als and does not appear to cause side effects Methylsulfonylmethane (MSM) is usually more often than placebo. Clinical trials have found in combination supplements con- lasted 12 weeks or less; therefore, more data taining glucosamine and/or chondroitin. It are needed to assess long-term safety.

Table 2. Potential Interactions Between Supplements and Conventional Drugs

Supplement Potential interaction Level of evidence

Glucosamine Antimitotic In vitro Chondroitin (Coumadin)* Case report S-adenosylmethionine Serotoninergic drugs (e.g., antidepressants, Case reports dextromethorphan [Delsym], meperidine [Demerol], tramadol [Ultram]) Levodopa (Larodopa; brand not available Theoretical in the United States)† Monoamine oxidase inhibitors Theoretical Methylsulfonylmethane None (known or suspected) — Harpagophytum procumbens Antihypertensive drugs Theoretical (devil’s claw) substrates In vitro Hypoglycemic drugs Theoretical Warfarin Case report Curcuma longa (turmeric) Antiplatelet/ drugs Theoretical Zingiber officinale (ginger) Antiplatelet/anticoagulant drugs Theoretical channel blockers Theoretical Hypoglycemic drugs Theoretical Warfarin Case report

*—Case involved very high dosages of chondroitin/glucosamine combination product. There is no evidence that typi- cal dosages of chondroitin cause this potential interaction. †—Levodopa is only available in the United States as a combination drug product (e.g., carbidopa/levodopa [Sinemet]). Information from reference 4.

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CLINICAL RECOMMENDATION it may improve symptoms of rheumatoid MSM was popular for treating osteoarthritis, arthritis.36 Turmeric is safe when consumed even before any clinical trials were published. as a spice in foods, and it also appears to be Based on limited research, MSM modestly safe and well tolerated when used in the short reduces some osteoarthritis symptoms but, term for medicinal purposes.4 However, until because these trials have been short term there is reliable clinical evidence, turmeric is and there is no reliable evidence of long-term not recommended for osteoarthritis. safety, MSM should not be recommended to treat osteoarthritis. GINGER Zingiber officinale (ginger) is best known Other Products as a soothing remedy for motion or morn- DEVIL’S CLAW ing sickness. it is also used for rheumatic Harpagophytum procumbens (devil’s claw) is conditions such as osteoarthritis and rheu- an African plant that gets its name from the matoid arthritis. Ginger may have anti- “claws” found on the fruit. The tuber is what inflammatory effects by inhibiting COX and is used for medicinal purposes. The pharma- lipoxygenase. It may also affect tumor necro- cologic activity of devil’s claw is attributed to sis factor and decrease synthesis of inflam- iridoid glycosides, particularly harpagoside. matory prostaglandins.4 Two manufacturer- Some products are standardized to contain a sponsored trials have evaluated specific gin- specific amount of these components.4 ger extracts called eurovita extract 33 and Devil’s claw is thought to have anti- Eurovita extract 77. Taking these extracts inflammatory effects, possibly because of for three to six weeks appears to provide inhibition of COX and lipoxygenase; how- no relief to modest improvement in osteo- ever, it appears to inhibit COX-2, but not arthritis pain after standing or walking.37,38 COX-1.4 Three moderate- to high-quality Ginger is safe and has been well tolerated in clinical trials have evaluated devil’s claw clinical trials; however, there is not enough extracts standardized to contain 2.0% to evidence to support recommending ginger 2.5% harpagoside. These extracts taken alone for the treatment of osteoarthritis. or in combination with an NSAID decrease This is one in a series of “Clinical Pharmacology” articles symptoms of osteoarthritis pain and are coordinated by Allen F. Shaughnessy, PharmD, Tufts Uni- 32-35 well tolerated. Devil’s claw can cause versity Family Medicine Residency at Cambridge Health side effects including diarrhea, abdominal Alliance, Malden, Mass. pain, and skin reactions. in one trial, pur- purea was reported in a patient on warfarin The Authors (Coumadin).4 although devil’s claw seems PHILIP J. GREGORY, PharmD, is an assistant professor of promising, more evidence on effectiveness pharmacy practice at the School of Pharmacy and Health and long-term safety is needed before it can Professions and the coordinator of the Drug Information be recommended. Residency Program at the Center for Drug Information and Evidence-Based Practice at Creighton University in TURMERIC Omaha, Neb. He is also editor of the Natural Medicines Comprehensive Database. Dr. Gregory received his doctor Curcuma longa (turmeric) is a spice com- of pharmacy degree from the University of the Pacific in monly used in curry powders. The pharma- Stockton, Calif., and completed a drug information resi- cologically active constituent is curcumin, a dency at Creighton University. pigment that gives the yellow color to some MORGAN SPERRY, PharmD, is assistant director of the mustards, broth, and other foods. Cur- Drug Information Center and a clinical assistant profes- sor at the University of Missouri–Kansas City School of cumin appears to have anti-inflammatory Pharmacy. At the time of writing this article, she was an effects because of inhibition of COX-2, pros- instructor of pharmacy practice at the School of Pharmacy taglandins, and leukotrienes.4 Clinical tri- and Health Professions and a drug information specialist als have not evaluated the effectiveness of at the Center for Drug Information and Evidence-Based Practice at Creighton University. Dr. Sperry received her turmeric for osteoarthritis; however, some doctor of pharmacy degree from and completed a drug preliminary clinical research suggests that information residency at Creighton University.

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AMY FRIEDMAN WILSON, PharmD, is an associate profes- 12. Reginster JY, Deroisy R, Rovati LC, et al. Long-term sor of pharmacy practice at the School of Pharmacy and effects of glucosamine sulfate on osteoarthritis pro- Health Professions and director of the Center for Drug gression: a randomised, placebo-controlled trial. Lan- Information and Evidence-Based Practice at Creighton Uni- cet. 2001;357(9252):251-256. versity. She received her doctor of pharmacy degree from 13. Scroggie DA, Albright A, Harris MD. The effect of glu- Creighton University and completed a pharmacy practice cosamine-chondroitin supplementation on glycosylated residency at the University of Iowa in Iowa City. hemoglobin levels in patients with type 2 diabetes mel- litus: a placebo-controlled, double-blinded, randomized Address correspondence to Philip J. Gregory, PharmD, . Arch Intern Med. 2003;163(13):1587-1590. Creighton University School of Pharmacy and Health 14. Yu JG, Boies SM, Olefsky JM. The effect of oral glucos- Professions, 2500 California Plaza, Omaha, NE 68178 amine sulfate on insulin sensitivity in human subjects. (e-mail: [email protected]). Reprints are not Diabetes Care. 2003;26(6):1941-1942. available from the authors. 15. Gray HC, Hutcheson PS, Slavin RG. Is glucosamine safe in patients with seafood allergy? [letter]. J Allergy Clin Author disclosure: Nothing to disclose. Immunol. 2004;114(2):459-460. 16. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glu- REFERENCES cosamine and chondroitin for treatment of osteoarthri- tis: a systematic quality assessment and meta-analysis. 1. Natural and Nutritional Products Industry (NPI) Center. JAMA. 2000;283(11):1469-1475. NMI Reports 2005 Health & Wellness Industry Sales at 17. Uebelhart D, Thonar EJ, Delmas PD, Chantraine A, $79 billion. The Natural Marketing Institute. February Vignon E. Effects of oral chondroitin sulfate on the pro- 28, 2006. http://www.npicenter.com. 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28. Caruso I, Pietrogrande V. Italian double-blind multicenter Pollak S. Comparison of outcome measures during study comparing S-adenosylmethionine, naproxen, and treatment with the proprietary Harpagophytum extract placebo in the treatment of degenerative joint disease. doloteffin in patients with pain in the lower back, knee Am J Med. 1987;83(5A):66-71. or hip. Phytomedicine. 2002;9(3):181-194. 29. Najm WI, Reinsch S, Hoehler F, Tobis JS, Harvey PW. 34. Gagnier JJ, Chrubasik S, Manheimer E. Harpgophytum pro- S-adenosyl methionine (SAMe) versus celecoxib for the cumbens for osteoarthritis and low back pain: a systematic treatment of osteoarthritis symptoms: a double-blind review. BMC Complement Altern Med. 2004;4:13. cross-over trial. BMC Musculoskelet Disord. 2004;5:6. 35. Wegener T, Lüpke NP. Treatment of patients with 30. Usha PR, Naidu MU. Randomised, double-blind, par- arthrosis of hip or knee with an aqueous extract of dev- allel, placebo-controlled study of oral glucosamine, il’s claw (Harpagophytum procumbens DC.). Phytother methylsulfonylmethane and their combination in osteo- Res. 2003;17(10):1165-1172. arthritis. Clin Drug Investig. 2004;24(6):353-363. 36. Deodhar SD, Sethi R, Srimal RC. Preliminary study on 31. Kim LS, Axelrod LJ, Howard P, Buratovich N, RF. antirheumatic activity of curcumin (diferuloyl methane). Efficacy of methylsulfonylmethane (MSM) in osteoar- Indian J Med Res. 1980;71:632-634. thritis pain of the knee: a pilot clinical trial. Osteoarthri- 37. Bliddal H, Rosetzsky A, Schlichting P, et al. A random- tis Cartilage. 2006;14(3):286-294. ized, placebo-controlled, cross-over study of ginger 32. Chantre P, Cappelaere A, Leblan D, Guedon D, Vander- extracts and ibuprofen in osteoarthritis. Osteoarthritis mander J, Fournie B. Efficacy and tolerance or Harpag- Cartilage. 2000;8(1):9-12. ophytum procumbens versus diacerhein in treatment of 38. Altman RD, Marcussen KC. Effects of a ginger extract osteoarthritis. Phytomedicine. 2000;7(3):177-183. on knee pain in patients with osteoarthritis. Arthritis 33. Chrubasik S, Thanner J, Künzel O, Conradt C, Black A, Rheum. 2001;44(11):2531-2538.

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