The use of nutritional supplements as pharmaceutical agents, or nutraceuticals, in disease management is not new. Over 250 years ago, a British naval surgeon named James Lind designed and conducted the first documented controlled, prospective clinical trial in an attempt to treat scurvy.1 Through this trial he realized that the condition was a result of a deficiency, and could be cured with the administration of citrus fruits. Since this time, researchers have determined that a number of diseases have dietary insufficiencies at the center of their pathogenesis, and can be treated by correcting these insufficiencies. However, despite the recognition that nutritional abnormalities may be a major contributor in the pathogenesis of osteoarthritis, dietary supplements have had a secondary role in its management.
Hyaline cartilage lines the bony surfaces of all synovial joints and consists of chondrocytes, which produce a matrix of type II collagen fibers and proteoglycans, and water. The network of type II collagen fibers provides the tensile strength and rigidity of cartilage, while the hydrated proteoglycan gel occupies the interstices. Proteoglycans have a protein core and many negatively charged glycosaminoglycan chains that allow them to retain water. In weight bearing, proteoglycans serve as a shock absorber by slowly releasing this water.2
Osteoarthritis is the most common form of articular disease, causing greater morbidity than any other condition with the exception of cardiovascular disease. Radiological studies have proposed that >70% of the population aged >65 years have osteoarthritis.1,2 In osteoarthritis, the amount of proteoglycan is depleted gradually, leading to a loss of compressibility and shock absorption. Once cartilage begins to break down, the joint space becomes narrowed and the underlying bone responds to the increased stress with hypertrophic repair. This ongoing process leads to sclerosis of subchondral bone (eburnation), cyst formation, and osteophyte formation in an effort to distribute the load through the joint.2,3
Currently, nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids remain the most common therapies to achieve symptomatic relief from osteoarthritis. They function as anti-inflammatory and analgesic agents by inhibiting the synthesis of prostaglandins. However, some evidence has suggested that this impairment of prostaglandin synthesis may exacerbate cartilage loss and therefore encourage progression of the disease process.4-7 This makes the prospect of alternate therapies devoid of this effect, and possibly even able to hinder disease progression, extremely attractive. Nutraceuticals that have been the subject of clinical trials for use in the management of osteoarthritis are listed in the Table.
Glucosamine has been the subject of more laboratory and clinical trials than any other nutraceutical currently on the market. It is an amino monosaccharide sugar and a precursor component in the synthesis of glycosaminoglycans, which form proteoglycans, as well as hyaluronic acid in articular cartilage.8,9 A variety of commercially available preparations of glucosamine exist; however, the majority of clinical trials have been conducted using the sulfated form. The mechanism of action in the treatment of osteoarthritis has been largely unclear, though recent studies have proposed some answers.
At the molecular level, studies have demonstrated that glucosamine is capable of stimulating synthesis and inhibiting the degradation of proteoglycans in vitro, and ultimately stimulating the regeneration of cartilage in vivo.10-12 The process through which this occurs is thought to exist, at least in part, at a transcription level. Dodge and Jimenez9 demonstrated that glucosamine stimulates the production of chondrocyte aggrecan mRNA and protein, as well as inhibiting the production and activity of matrix degrading enzymes in vitro. Additionally, glucosamine has been found to inhibit the synthesis of pro-inflammatory mediators that induce the synthesis of the degrading enzymes as well as inhibiting chondrocyte proliferation.9,13,14
The above molecular evidence is translatable into improved clinical outcome as demonstrated by several well-designed clinical trials. These have been carried out with an oral dosage regimen of 1500 mg daily, or 500 mg three times daily. Prospective evaluation of radiographic changes by analysis of joint space narrowing associated with articular cartilage degeneration is an accepted method for examining the modification of structure in vivo. A comprehensive meta-analysis of results from recent trials demonstrated that glucosamine might effectively prevent the long-term progression of osteoarthritis, with a mean difference in joint space narrowing of 0.27 mm over 3 years.15 In the two most recent clinical trials, radiographs were taken of the knees in full extension during weight bearing.16,17 This measure has been criticized to some extent; with an argument that better knee extension secondary to symptom improvement leads to a decrease in the apparent joint space narrowing. However, this has since been refuted by further radiologic studies comparing symptom and structural change in fully-extended and semi-flexed joint views.18,19
As eluded to above, glucosamine has further been shown to have an analgesic effect, and in association with a decrease in joint space narrowing, result in improved joint mobility and function.20,21 In 2001, Towheed et al22 demonstrated in a review of recent randomized controlled trials that the analgesic properties of glucosamine were substantial and may compare favorably to conventional NSAIDs. In addition, function is improved by a moderate to large degree when measured by Lequesnes indices.
On review of the literature, glucosamine generally has been well tolerated; however, adverse effects have been documented. These have occurred in approximately 12% of patients enrolled in the randomized controlled trials reviewed by Towheed et al,22 were generally mild in severity, and principally involved the gastrointestinal tract. Symptoms have included dyspepsia, abdominal discomfort, and diarrhea, with all adverse effects resolving promptly on cessation of glucosamine without further intervention.16 A case report of asthma being exacerbated by the combination of glucosamine and chondroitin sulfate also was published.23 However, despite some limited evidence that these agents may lead to atopy and increased respiratory tract secretions in asthmatic patients, there remains no definitive link between the two. In addition, glucosamine was thought to contribute to insulin resistance and the development of diabetes mellitus following animal trials, although this has not been replicated in human trials.17
Chondroitin has received almost as much attention as glucosamine in both medical and lay circles. It often is marketed as a combined preparation with the latter; however, it is also available as a sole product, and like glucosamine, is most widely available in its sulfated form. The oral dosage used in clinical trials generally is 1200 mg daily, or 400 mg three times daily, with bioavailability after oral administration documented to be as great as 70%.24,25
Chondroitin is a glycosaminoglycan found in the proteoglycans that make up the aggrecan of articular cartilage.15 In vitro and animal studies have demonstrated that supplementation acts to retard the process of osteoarthritis by increasing the synthesis of proteoglycan in articular cartilage.26 In particular, effects include contributing to cartilage matrix deposition, inhibition of proteolytic enzymes, and stimulation of glycosaminoglycan and collagen synthesis.27,28 Furthermore, glucosamine and chondroitin appear to act in a synergistic manner by stimulating glycosaminoglycan synthesis in chondrocytes, with chondroitin having anti-inflammatory activity and glucosamine influencing cellular metabolism.12 This has been shown in studies comparing monotherapy and the combination of each of these products.
To date no long-term, prospective, placebo-controlled trials have examined the effect that chondroitin may have on joint space narrowing, although two smaller trials have shown promise.27,28 Clinical trials analyzing its effect on improved joint function and symptomatic relief have been well documented. In 2000, two independent comprehensive meta-analyses both demonstrated significant analgesic properties when compared with placebo, as well as a large increase in the degree of function as measured by Lequesnes indices.20,21 In these trials, adverse effects associated with chondroitin use were less than the placebo group. Documented adverse effects include atopy and asthma, and interaction with anticoagulants such as warfarin and heparin, leading to excessive bleeding.23,29 However, until clinical trials are undertaken to examine these effects, the long-term safety profile of chondroitin remains uncertain.
S-adenosylmethionine (SAMe) has been used historically in the treatment of arthritis, depression, fibromyalgia, liver disease, and migraine headaches.30 S-adenosylmethionine is found in every living cell, particularly in the brain and liver, and is involved in a broad range of important biochemical pathways. It is a sulfur-containing compound synthesized from the amino acid L-methionine and adenosine triphosphate.30,31 In vitro studies demonstrate that SAMe appears to enhance the synthesis of proteoglycans in cultures of chondrocytes obtained from the articular cartilage of patients with osteoarthritis.32,33 Animal studies have demonstrated that SAMe has anti-inflammatory and analgesic properties, and furthermore, progression of surgically induced osteoarthritis is prevented, or at the very least slowed.32,34,35 Despite these findings, its mechanism of action in analgesia remains unknown. Clinical trials, with a dosage of 800 mg per day for 2 weeks, followed by a maintenance dosage of 400 mg per day, reduced pain and functional limitation in patients with osteoarthritis.31 This effect is greater than placebo and comparable to that of NSAIDs. Symptoms usually are improved within the initial 2-week period, although the onset of action appears to be slower than that of NSAIDs.31,32
Adverse effects are significantly (58%) less likely to occur than those treated with NSAIDs.31 The main adverse effects are mild nausea or heartburn, which is self-limiting by cessation of the product.36,37 Cases of agitation and manic reactions in patients with bipolar disorder have been documented, and therefore the use of SAMe in such patients should be avoided.38 Toxicological studies in animals indicate that SAMe is non-toxic at relatively high dosages, and there are no known confirmed drug interactions involving SAMe.30
A confounding factor in clinical trials involving the use of SAMe as an agent for osteoarthritis is its effect on alleviating depression. That is, SAMe may not be acting directly on the joint to improve pain and function, but indirectly by decreasing the perception of pain through an elevated mood.31 The long-term effectiveness relating to analgesia may therefore diminish with time, and consequently further studies are required to examine this phenomenon prior to any recommendation of the product for routine use.
Boswellia serrata is a tree of intermediate height found in hilly areas of India. Dried gum resin (guggulu) extracted from Boswellia serrata has been claimed to possess good anti-inflammatory, anti-arthritic, and analgesic activity. Despite these claims, a lack of studies examining the effect of Boswellia in the treatment of osteoarthritis existed until a randomized, double-blind, placebo-controlled trial examining its effect on knee osteoarthritis was published in early 2003.39 With a dosage of 1000 mg per day (333 mg three times daily), Boswellia was observed to result in a decrease in severity of pain and swelling, as well as a return of function and range of movement; this being both clinically and statistically significant when compared to placebo. The frequency of joint swelling was also decreased; however, no change in joint space narrowing in affected joints was observed radiologically. Adverse drug reactions of Boswellia therapy were uncommon and included diarrhea, epigastric pain, and nausea, all of which responded to simple symptomatic treatments.
In an in vitro study examining the effects of Boswellia on the complement system, the extract demonstrated a marked inhibitory effect on both classical and alternate pathways.40 Animal studies have supported this finding as well as demonstrated that ingestion of Boswellia decreases polymorphonuclear leukocyte chemotaxis and primary antibody synthesis.41,42 It also inhibits human leukocyte elastase, which in combination with the latter may make it of assistance in the management of autoimmune disorders such as rheumatoid arthritis.43 Animal studies further demonstrated the existence of marked sedative and analgesic effects, and at a structural level Boswellia has been claimed to decrease the glycosaminoglycan degradation; thereby assisting in keeping articular cartilage in good condition.39,44 This is hypothesized to be responsible for the recovery of the patients with osteoarthritis and may prevent progression of the disease.
Hydrolyzed gelatin products have been used in pharmaceuticals and foodstuffs for many years. Collagen hydrolysate used in medications is manufactured by the hydrolysis of pharmaceutical-grade gelatin.45 The rationale for investigation of this agent in the management of osteoarthritis centers around hydrolyzed collagen containing a large quantity of amino acids that participate in the synthesis of collagen; one of two major protein components of the cartilage matrix. Although its specific action remains largely unknown, it has been hypothesized that administration of this agent may stimulate chondrocytes to synthesize collagen matrix and thus provide symptomatic improvement in osteoarthritis.24 This hypothesis is supported by collagen hydrolysate having no known direct analgesic or general anti-inflammatory properties.24 Clinical trials have suggested that the ingestion of 10 g of collagen hydrolysate daily decreases pain in patients with osteoarthritis of the knee or hip. Furthermore, increased efficacy for collagen hydrolysate compared to placebo is observed in patients with more severe symptomatology. It is associated with minimal adverse effects, which are mainly characterized by a sensation of fullness or unpleasant taste.45
In vitro studies have demonstrated that diacereins metabolite rhein inhibits the activity of interleukin-1, thereby reducing collagenase production in the articular cartilage. Furthermore, it inhibits superoxide anion production and the chemotactic and phagocytic properties of neutrophils and macrophages.46,47 Clinical trials using a dosage of 50 mg orally twice a day have shown an efficacy similar to that of NSAIDs, only with a slower onset of action.47 A decrease in pain and increase in function as measured by Lequesnes indices, corresponded with improved quality-of-life scores and a decrease in NSAID and analgesic consumption.48,49 Joint space narrowing is also significantly reduced when compared with placebo.50 Diacerein does not alter renal or platelet cyclooxygenase activity as do NSAIDs, and may therefore be tolerated by patients with impaired renal function.47 Adverse effects include mild to moderate changes in bowel habits (diarrhea) at doses higher 50 mg twice per day, which is promptly reversible on cessation of the agent.47,49,50
Oxaceprol is derived from the amino acid L-proline, and functions in osteoarthritis to inhibit leukocyte adhesion and migration, and therefore impede the inflammatory process.51,52 In clinical trials, this nutraceutical has been as effective in its analgesic properties, and tolerated better than diclofenac in the management of osteoarthritis of the hip or knee.53,54 It has further been demonstrated to increase function to a clinically relevant degree as measured by Lequesnes indices. What makes it particularly attractive in the management of osteoarthritis is that it appears to have no adverse effects on the gastrointestinal system when compared with NSAIDs.52-54 The dose used in these clinical trials varies between 200 to 400 mg orally three times a day.
The combination of avocado and soybean used as a preparation for osteoarthritis is manufactured from unsaponifiable fractions of one-third avocado oil and two-thirds soybean oil. In vitro studies have demonstrated that this agent inhibits the deleterious effects of different mediators on joint structures.55 Clinical trials using an oral dosage regimen of 300 mg daily have further shown that this agent is superior to placebo in patients with hip or knee osteoarthritis.55,56 This is quantified by a decrease in use of NSAIDs with a significant improvement in pain scores and a significant improvement in function as measured by Lequesnes indices. Side effects are gastrointestinal in nature, and are thought to be rare as well as mild in severity. Furthermore, the effect on clinical symptoms appears to be prolonged, with ongoing benefit existing 2 months after cessation of the agent in one study.55
Other less-investigated nutraceuticals include curcum (turmeric), ginger, evening primrose oil, tipi, willow bark, and horse-chestnut seed.29,57-59 A lack of scientific evidence exists to support their use in osteoarthritis management.
Sulfur Amino Acids
Articular cartilage requires a source of inorganic sulfate for the ongoing synthesis of glycosaminoglycans as well as for other important metabolic intermediates of the cartilage matrix.60 Extracellular storage of sulfates in humans is relatively low when compared to other species, and therefore humans require a sustained supply of dietary sulfur.61 The primary source of sulfur in our diet is from sulfur amino acids (cysteine, methionine). Ingestion of suboptimal quantities may not lead to significant manifestations in healthy cartilage; however, with progression of osteoarthritis, glycosaminoglycan turnover is greatly enhanced and correspondingly sulfate stores are rapidly depleted.62 Therefore, dietary sulfur may play an important role in the progression of osteoarthritis. This may be exacerbated by concurrent use of analgesics such as acetaminophen, where approximately 40% of this medication is excreted in the urine conjugated with sulfate.63
Many of the aforementioned nutraceuticals (glucosamine sulfate, chondroitin sulfate, and SAMe) used in the management of osteoarthritis contain large quantities of sulfur. The possibility that a large part of their therapeutic value may be the result of their sulfate moieties now arises, and by serving as a source of inorganic sulfur, they may be compensating for a suboptimal or marginal intake of sulfur amino acids. Also supporting these findings is a study using glucosamine hydrochloride, where a lesser therapeutic value is achieved than studies where its sulfated form have been examined.64 This leads to the suggestion that increasing the intake of dietary protein or mineral water containing high quantities of inorganic sulfates may have similar effects to the administration to a number of nutraceuticals.60
Nutraceuticals offer the promise of new options in the treatment of osteoarthritis. They may modify the indication for joint surgery, time to substantial disability, or at least reduce the reliance on NSAIDs. Substantial evidence exists that glucosamine sulfate can improve symptoms, structure, and function of joints affected by osteoarthritis, and it is associated with a good long-term efficacy and safety profile. Further long-term trials need to be conducted for chondroitin sulfate to support short-term trends.
The evidence for other nutraceuticals remains lacking in terms of the small number of studies and the variability in their quality of design and reporting. However, some of these studies are sufficiently convincing to encourage further high-quality clinical trials. Questions that need to be answered by these trials include: What is the long-term efficacy and safety of the various nutraceuticals? Are glucosamine and other nutraceuticals helpful for all patients with osteoarthritis involving different joints and at different stages of severity? Which agents affect structural change in joints as opposed to those that are solely involved in symptom management? Should patients with particular medical disorders or taking prescription medications avoid use of these agents? In particular, future trials should monitor the sulfur intake in participating individuals, also comparing sulfated with non-sulfated compounds, as this factor may play a large role in nutraceutical efficacy, especially in those with marginal protein consumption.
Standardized preparations of glucosamine and other nutraceuticals are already available in Europe, but in Australia and the United States these products are considered dietary supplements. Since the dietary supplement industry is not as well regulated as the companies that manufacture prescription medications, quality and consistency may vary between brands, and many may not contain exactly what is advertised on product labels. Accordingly, patients directed by their treating physician that a particular nutraceutical may be of benefit to them should also be advised to purchase these products from reputable sources, and that symptom improvement may take several months.
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- Van Kuijk C, Cheng X, Hottya G, et al. The effects of rofecoxib and diclofenac on knee osteoarthritis articular cartilage: the results from one-year prospective clinical trials. Arthritis Rheum. 2000; 43(suppl):924.
- Towheed TE, Anastassiades TP. Glucosamine and chondroitin for treating symptoms of osteoarthritis: evidence is widely touted but incomplete. JAMA. 2000; 283:1483-1484.
- Dodge GR, Jimenez SA. Glucosamine sulfate modulates the levels of aggrecan and matrix metalloproteinase-3 synthesised by cultured human osteoarthritis articular chondrocytes. Osteoarthritis Cartilage. 2003; 11:424-432.
- Basleer C, Rovati L, Frachimont P. Stimulation of proteoglycan production by glucosamine sulfate in chondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthritis Cartilage. 1998; 6:427-434.
- Piperno M, Reboul P, Hellio Le Gaverand MP, et al. Glucosamine sulfate modulates dysregulated activities of human chondrocytes in vitro. Osteoarthritis Cartilage. 2000; 8:207-212.
- Lippiello L, Woodward J, Karpman R, et al. In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop Relat Res. 2000; 381:229-240.
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- Largo R, Alvarez-Soria MA, Diez-Ortego I, et al. Glucosamine inhibits IL-1-induced NFB activation in human osteoarthritic chondrocytes. Osteoarthritis Cartilage. 2003; 11:290-298.
- Richy F, Bruyere O, Ethgen O, et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis:a comprehensive meta-analysis. Arch Int Med. 2003; 163:1514-1522.
- Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulfate on osteoarthritis progression: a randomized, placebo-controlled clinical trial. Lancet. 2001; 357:251-256.
- Pavelka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate delays progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002; 162:2113-2123.
- Buckland-Wright JC, Wolfe F, Ward RJ, et al. Substantial superiority of semiflexed (MTP) views in knee osteoarthritis: a comparative radiographic study, without fluoroscopy, of standing extended, semiflexed (MTP), and schuss view. J Rheumatol. 1999; 26:2664-2674.
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- Leeb BF, Schweitzer H, Montag K, et al. A meta-analysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheumatol. 2000; 27:205-211.
- Towheed TE, Anastassiades TP, Shea B, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev. 2001; 1:CD002946.
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- Uebelhart D, Thonar EJ, Zhang J, et al. Protective effect of exogenous chondroitin 4,6-sulfate in the acute degradation of articular cartilage in the rabbit. Osteoarthritis Cartilage. 1998; 6(suppl A):6-13.
- Verbruggen G, Goemaere S, Veys EM. Chondroitin sulfate SYSMOAD (structure/disease modifying antiosteoarthritis drug) in the treatment of finger joint OA. Osteoarthritis Cartilage. 1999; 6(suppl A):37-38.
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Dr Clayton is from the Department of Orthopedics and Trauma, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
Dr Clayton has disclosed no relevant financial relationships. Dr Morgan, CME Editor, has disclosed the following relevant financial relationships: Stryker, speakers bureau; Smith & Nephew, speakers bureau, research grant recipient; AO International, speakers bureau, research grant recipient; Synthes, institutional support. Dr DAmbrosia, Editor-in-Chief, has disclosed no relevant financial relationships. The staff of Orthopedics have disclosed no relevant financial relationships.
The material presented at or in any Vindico Medical Education continuing education activity does not necessarily reflect the views and opinions of Vindico Medical Education or Orthopedics. Neither Vindico Medical Education or Orthopedics, nor the faculty endorse or recommend any techniques, commercial products, or manufacturers. The faculty/authors may discuss the use of materials and/or products that have not yet been approved by the US Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or utilizing any product.
Correspondence should be addressed to: James J. Clayton, BSc(Med), MB,BS, Dept of Orthopedics and Trauma, Royal Adelaide Hospital, North Terrace Adelaide, SA 5000 Australia.