International Journal of Rheumatic Diseases 2011; 14: 152158

REVIEW ARTICLE

What about supplements for osteoarthritis? A critical and evidenced-based review

Evan S. VISTA1 and Chak S. LAU2
Joint & Bone Center, University of Santo Tomas Hospital, Espana, Manila, Philippines, and 2Division of Rheumatology and Clinical Immunology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
1

Abstract
Dietary supplements have inundated the commercial market in recent times. These so called health supplements are being marketed as benecial in the prevention and regression of several common medical conditions that include osteoarthritis. This review provides an overview of osteoarthritis as a common disease and elucidates the disease process in relation to conventional therapeutic approaches. We also attempt to present perspectives about the dietary industry, focusing on the widely available dietary supplements for osteoarthritis; then we discuss the current available evidence regarding these common dietary supplements which are nally consolidated and enumerated as major key points. Key words: chondroitin sulfate, dietary supplement, glucosamine, osteoarthritis.

Osteoarthritis (OA) is the most common type of arthritis which is characterized by degenerative changes of the joint.1,2 OA usually affects adults from middle-age. Taking into account a global trend in increased life expectancy, the disease burden has risen remarkably in recent years. OA is now a leading cause of chronic disability.1,2 Unfortunately, the projected increase in the number of people suffering from OA has been met with limited therapeutic successes. Based on the 2004 mean disability-adjusted life year calculation, a measure of overall disease burden reported by the World Health Organization, OA sufferers lose around 278 cumulative years per 100 000 persons.3

OSTEOARTHRITIS: THE DISEASE

Prevention of articular cartilage degradation, the main pathology change of OA, has not been addressed satisCorrespondence: Dr Evan S. Vista, Joint & Bone Center, University of Santo Tomas Hospital, Espana, Manila, Philippines 1008. Email: evan-vista@omrf.org

factorily by the present conventional treatments available for this condition.4 The minimal therapeutic efcacy of these drugs is further aggravated by the inherent toxicity demonstrated by their long-term use.5 OA is thought to be due to long-standing mechanical stress that leads to chondrocyte activation and cartilage breakdown.6 Current research impetus is geared toward the development of drugs that would prevent, slow down, or reverse joint damage. Dietary supplements (DS) developed for OA patients are popular and are claimed to address the disease by directly providing the natural components that inhibit or enhance the role of biologic mediators in preserving the structural integrity of the joint. The rising incidence of OA cases with refractory response to available drugs approved for the treatment of this condition fuels the unprecedented growth of the dietary supplement industry. These OA supplements have now been considered by many patients and even healthcare providers as an alternative treatment modality; in fact, OA supplements have been labeled in several studies with new terms such as structure/disease-modifying OA drugs.7

2011 The Authors International Journal of Rheumatic Diseases 2011 Asia Pacic League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd

Review of supplements for OA

Table 1. Examples of available commercial OA supplement preparations Commercial preparation GNC Triple Strength Fish Oil GNC Salmon Oil GNC Omega-3 Soft Chews GNC Triex Fast-Acting OA supplement component Eicosapentaenoic acid (EPA) 647 mg Docosahexaenoic acid (DHA) 253 mg EPA 180 mg DHA 120 mg EPA and DHA 120 mg Glucosamine hydrochloride (GHCL) 375 mg Chondroitin sulfate (CS) 300 mg Methylsulfonylmethane (MSM) 60 mg Cutch tree extract (Acacia catechu) and Chinese skullcap root extract (Scutellaria baicalenis) 60 mg Sodium hyaluronate 1.25 mg GHCL 375 mg CS 300 mg MSM 60 mg Shark cartilage powder 750 mg Glucosamine sulfate (GS) 250 mg capsule GS 500 mg capsule GS 1500 mg capsule GS 1500 mg powder sachet GS 400 mg ampule GHCL 500 mg and CS 400 mg GHCL 750 mg and CS 600 mg GHCL 1000 mg MSM 1000 mg MSM 500 mg and GS 500 mg Glucosamine 2800 mg and chondroitin 865 mg S-adenosyl-methionine 200 mg Avocado/soybean unsaponiables 300 mg tablet Recommended dosage One softgel capsule daily 12 softgel capsule daily 13 soft chews daily Four capsules daily

GNC Triex

Three tablets daily

Natural Brand Shark Cartilage ROTTA research group (multiple preparations) Viartril-S (multiple preparations) DONA Xicil GNC Glucosamine/CS GNC Glucosamine HCL GNC MSM GNC MSM/GS GLC 2000 GNC SAM-e 200 Piascledine

15 tablets daily 1500 mg daily

7501500 mg GHCL and 6001200 mg CS daily 12 tablets daily One or two capsules daily 13 capsules daily Two capsules daily 28 tablets daily One tablet daily

Source: General Nutrition Centers (GNC), Rotta Pharmaceuticals, Inc. and Laboratories Expanscience.

DIETARY SUPPLEMENTS: THE INDUSTRY

Dietary supplements are considered as natural biological compounds that are harmless for human consumption. Despite the increasing popularity of DS among the general public, there is widespread scepticism among the scientic community. Numerous DS commercial preparations for OA that have not been properly tested are currently available (Table 1); this adds further confusion among general consumers. Trials that aim to measure product superiority are warranted. In the USA, the so-called nutrients are dened by the 1994 DS Health and Education Act as a product that is intended to supplement the diet, contains one or more dietary ingredients, is intended to be taken by mouth in forms such as tablet, capsule, powder, softgel, gelcap, or liquid and should be labeled as being a DS. In 2007, the US public spent $14.8 billion to

purchase non-vitamin, non-mineral, natural products, about 31% of the amount that the public spent outof-pocket to buy pharmaceutical drugs.8 Fish oil (37.4%) and glucosamine (19.9%) are the two most popular products marketed for persons with OA.9 In other countries, the lack of appropriate government regulation could be attributed to the industrys large impact on the economy. In most parts of Asia, Africa and Latin America, DS are widely available in several commercial preparations of varying potency and quality marketed by major multinational corporations. Many institutional drug regulatory agencies are less stringent as compared to prescription drugs, and in many cases, non-prescription drugs. A manufacturer does not have to prove the safety and efcacy of a DS before it is marketed. If a particular health benet is being claimed by a product, it must be followed by a disclaimer clause. In the US, good manufacturing practice standards that ensure the quality of a DS has been

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in place only since 2008.10 An agency is tasked to monitor accuracy of product advertising and labeling. Despite these measures, it has not prevented the DS industry thriving and being advocated by the general public.

DIETARY SUPPLEMENTS FOR OA: THE SCIENTIFIC EVIDENCE

A search for evidence in the literature was conducted using the computer databases of MEDLINE, Cochrane and the International Bibliographic Information on DS. The free text and Mesh terms for osteoarthritis and dietary supplement/s were used. Among these searched articles, studies on vitamins which are considered as traditional DS for general health wellness were excluded. Critical appraisal of the reports were restricted to the most recently published randomized control trials (RCTs) and meta-analysis for OA supplements that contained the most common commercial preparations seen in most retail-based, online and direct selling companies worldwide. The selected publications have been evaluated as having the latest best available evidence. Most efcacy studies in OA utilize multiple standard assessment tools that measure relief of pain and improvement of physical function. These instruments vary considerably in terms of methodology and although standardized and validated individually, full integration across each outcome measure has yet to be fully achieved.11 The selected studies in this review used outcome variables from the oldest and simplest scales (Likert and visual analog or VAS) combined with global assessments and quality of life questionnaires (SF36, HAQ) to the more detailed but complex instruments such as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne Functional Severity Index and the Outcome Measures in Rheumatology (OMERACT) with an attempt to harmonize scoring systems by the development into Osteoarthritis Research Society International (OARSI) responder criteria.12 However, the development of updated versions of these outcome measures confounds the results across ongoing and completed OA therapeutic trials. In addition, several groups solely advocate the delay of radiographic evidence of joint space narrowing, pioneered by Kellgren and Lawrence,13 as a measure of efcacy. All these standardized scoring systems have been adapted in the research design for trials involving DS for OA. Several studies that attempt to introduce new endpoint mea-

sures specic for OA supplements further add to the heterogeneity of the study results.14,15 All these variations have impacted the assessment of DS for OA as reected in the current OARSI recommendations for hip and knee OA.16 It is therefore not surprising that results from most of the main studies have not been consistent despite numerous case reports and anecdotal evidence reporting efcacy. This discord raises the question on the applicability of these standardized efcacy measures for trials involving DS for OA. It could be deduced that the DS industry ultimately derive benet from this impasse since proven efcacy of an OA supplement is generally not required in most countries as compared to the rigid stages of pharmaceutical drug development.

MAJOR OA SUPPLEMENTS STUDIES: GLUCOSAMINE AND CHONDROITIN SULFATE

The most popular among OA supplements, glucosamine and chondroitin, are natural components of human cartilage found also in shark cartilage, shellsh, swine ears and noses. Glucosamine is a water-soluble amino monosaccharide (2-amino-2-deoxy-D-glucose) while chondroitin is a disaccharide polymer component of glycosaminoglycan. It is hypothesized that substrate availability of these compounds are the limiting factor in the synthesis of the glycosaminoglycan component of cartilage.17,18 These supplements act by suppressing or reducing the expression of several cytokine mediators of articular cartilage degradation (i.e., metallomatrix proteinase, interleukins [IL]1b and 8, cyclooxygenase [COX]-2, tumor necrosis factor [TNF]-a) and combined together it has been shown to act synergistically to modulate articular cartilage matrix metabolism.19 During the last decade, different groups around the world conducted trials to evaluate the efcacy of glucosamine among OA patients and were recently consolidated.20,21 Although there is evidence of efcacy in some of these studies, several variables inherent to each trial design act as qualiers to each study conclusion, and thus hinder the outright recommendation for the use of glucosamine and chondroitin in OA. Glucosamine sulfate (GS) has been demonstrated to have an adequate oral bioavailability22 and its prescription formulation has been found to be associated with better Lequesne and WOMAC scores than placebo but inferior to the non-steroidal anti-inammatory drug (NSAID) comparators in some studies,23

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while others did not show signicant symptom improvement among specic groups of OA patients when compared to placebo.24,25 On the other hand, the study by Bruyere et al. observed that treatment of knee OA with GS for at least 12 months and up to 3 years may prevent total joint replacement in an average follow-up of 5 years.26 Finally, in the last updated Cochrane review of glucosamine therapy for OA, encompassing 25 studies and comprising a total of 4963 pooled sample population of OA subjects, the review failed to show benet of glucosamine use (WOMAC).27 A meta-analysis which included 20 trials with a pooled population of 3486 knee and hip OA patients, evaluated the clinical efcacy of chondroitin. However, no recommendations were given, mainly due to the heterogeneity of trial designs and minimal benets seen on some studies.28 These ndings were echoed in the review chapter by Bana et al.29 assessing 7/26 RCTs using CS comprising a pooled sample size of 909 OA patients. Other RCTs have shown patients with a chronic co-morbidity (psoriasis) reporting improvement of quality of life scores30 but improvement of pain and function (VAS and Lequesne) was not achieved by using CS (1 g/day) alone after 6 months.31 A delay in radiographic joint space narrowing has been implied to be the benet of longterm CS use as seen in the study by Kahan et al., using CS 4 and 6 preparations daily for 2 years. The most recent meta-analysis of Hochberg conrmed this benet for joint space preservation with pooled results showing a signicant delay (P = 0.00001).32 The Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) sponsored by the US National Institute of Health is one of the largest, multicenter, randomized, placebo-controlled trials assessing DS for OA.33 The trial is composed of a primary study assessing relief of pain and an ancillary study assessing prevention of structural damage of the knee among OA patients. A total of 1583 patients with knee pain and documented X-ray evidence of OA participated in this study. The average age was 59 years and 64% were composed of women, 78% were in the mild pain subgroup and 22% in the moderate-to-severe pain subgroup. Participants were randomly assigned to receive one of ve treatments: 1500 mg of glucosamine alone, CS alone (1200 mg), glucosamine and CS combined (same doses), a placebo, or a 200 mg dose of NSAID as a positive control. Although glucosamine and CS alone or in combination showed no signicant relief from pain as compared to placebo, the smaller subgroup of

OA patients with moderate-to-severe pain taking glucosamine plus CS showed signicant improvement in pain scores (P = 0.002). There were no signicant differences in the rate of adverse events among all treatment groups and from a total of 77 reports of serious adverse effects only three were attributed to study treatments. In the ancillary study, enrolled patients had an X-ray evidence of moderate (grade 2) or severe (grade 3) knee OA in one or both knees. The results showed that glucosamine and CS, alone or in combination, had a similar outcome to placebo in delaying the progression of cartilage loss in knee OA.34 More recently, the long-term (2 years) results of this trial were released, revealing that OA patients who took the supplements (alone or in combination) had no signicant difference in outcomes as compared to NSAID and the placebo arm.35

OTHER OA SUPPLEMENT STUDIES

The popularity of sh oil among other DS could be due to its claims of multiple health benets for different disease conditions other than OA. Fish oil contains the polyunsaturated fatty acid (PUFA) omega-3 and this lipid has been found to be anti-inammatory and chondroprotective in animal and in vitro studies.36,37 One mechanism is suggested to be through the action of its oxygenated derivatives named resolvins that binds to G protein-coupled receptors acting as potent antagonists of inammation.38 The clinical utility of sh oil alone for OA remains to be seen; the study by Gruenwald et al.39 combines PUFA omega 3 with GS 1500 mg/day, and a recent RCT about a proprietary DS named Phytalgic contains sh oil as just one of the components in achieving pain/function WOMAC improvement scores.40 S-adenosylmethionine (SAMe), derived from the liver metabolism of methionine, has been postulated to prevent cytokine expression that promotes chondrocyte damage as well as increases articular cartilage thickness.41 A total of 11 RCTs reported in the metaanalysis by Soeken et al. showed only efcacy equivalence of SAMe to NSAIDs for short-term pain relief of OA42 but with fewer side effects. This was reinforced in the latest phase 4 RCT by Kim et al. that showed no signicant benet in Korean OA patients given SAMe versus NSAIDs.43 In the Cochrane review of SAMe for OA of the knee or hip, four trials comprising 656 patients were included and compared with placebo.44 In terms of effects on pain, function and safety outcomes, these experiments achieved inconclusive

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results and routine use of SAMe for OA patients was not recommended. Methylsulfonylmethane (MSM) occurs naturally as a phytochemical found in human adrenal glands and is the oxidised form of dimethyl sulfoxide (DMSO). In the meta analysis by Brien et al. in combination with DMSO for the treatment of knee OA, results were inconclusive.45 Only three short-term RCTs (3 months) have shown efcacy of MSM in improving pain and function. The RCT for knee OA by Usha et al.46 utilized 500 mg of MSM three times/day, used alone or in combination with 500 mg of glucosamine HCl three times/ day, and showed improved Likert scale and Lequesne index. In the RCT by Kim et al., 3 g of MSM given twice daily was more efcient than placebo in decreasing WOMAC pain and function scores47 and lastly, the study by Xie et al. used AR7 joint complex which contains MSM given one capsule daily.48 The major components of avocado/soybean unsaponiables (ASU) are considered anti-inammatory compounds with antioxidant properties that also provide analgesia (phytosterols). This compound blocks the activation of TNF-a, IL-1b, inducible nitric oxide synthase COX-2 transcripts and secretion of prostaglandin E2.49 Among the ASU experiments for OA, four highquality RCTs were considered in the meta-analysis by Christensen et al.50 A total of 664 OA subjects with either hip (41.4%) or knee (58.6%) OA were grouped to either 300 mg ASU (336) or placebo (328) arm for an average trial duration of 6 months. The combined pain reduction favored ASU (P = 0.04) and the number of responders following ASU is signicantly higher compared to placebo (odds ratio [OR] 2.19, P = 0.007). These results were corroborated on a Cochrane review on herbal therapy for treating OA. The two combined studies of ASU in this meta-analysis showed benecial effects on functional index, pain, intake of NSAIDs and global evaluation with no serious side effects.51 Although the safety prole for its long-term use is well supported, the non-uniformity of trial designs and inconsistencies of experimental results combined with the numerous commercial preparations with varying pharmaceutical grades, could all sum up the confounding therapeutic efcacy of DS for OA. Historically, marketing strategies by companies relied on common perceptions by the general public for maximizing return of investments. For DS, this is achieved mainly through multi-media advertising that employs accumulating claims of benets directly from the consumers and at times, endorsed by persons of

interests (e.g., athletes, professionals, artists) without full regard to the scientic process. Unfortunately, this method also provides a personal appeal to the end user, sacricing veracity of experimental data, thus contributing to the widely perceived placebo effect among persons taking DS. It is therefore imperative upon the prescribing physician to recognize discretion among patients regarding the use of OA supplements by providing them with a well-informed choice.

KEY POINTS
 Routine use of dietary supplements is not recommended for the treatment of OA.  Several OA supplements in combined preparation and appropriate dosage could play a role among certain groups of OA patients in the reduction of moderate to severe pain.  Long-term use of OA supplements is generally safe.  Uniformity among research design trials is warranted to investigate the potential of all commercially available OA supplements for the management of OA.  General agreement among outcome measures use in the efcacy studies for OA supplements must be promoted.  Stringent approach and consensus among international regulatory bodies are required at the present times to control misconceptions by the general public regarding use of OA supplements.

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