Glucosamine and chondroitin sulfate, Type II collagen hydrolysates, Methylsulfonylmethane: International Clinical giudelines review. Vitaminized

REVIEW OF CLINICAL GUIDELINES FOR ELGENOFLEX COMPONENTS

Elgenoflex contains the following active ingredients: hydrolyzed type II collagen from chicken (which also naturally contains chondroitin sulfate and hyaluronic acid), glucosamine, and methylsulfonylmethane (MSM). In this article, the existing guidelines and regulations for the use of Elgenoflex components are considered.

 

Glucosamine and chondroitin sulfate

Most of the available guidelines regarding the use of Elgenoflex components concern the use of glucosamine and chondroitin sulfate in patients with osteoarthritis. Glucosamine and chondroitin sulfate, as well as their combinations, are widely used as supplements in patients with osteoarthritis, and their beneficial effects have been documented in multiple clinical trials (see a review by Iovu and colleagues [1] and references therein). Despite a large number of clinical trials, their efficiency is a subject of controversy. This can be illustrated by simultaneous publication in 2007 of reviews of available clinical trials by two different groups: a group from Belgium concluded that glucosamine and chondroitin sulfate are effective in slowing the progression of osteoarthritis [2,3], whereas a group from Switzerland concluded that chondroitin sulfate has only minimal or no beneficial effects in osteoarthritis patients [4]. Possible causes of confusion include the “placebo effect” (improvements seen in groups taking a placebo; see below) and the difficulty in quantitatively assessing pain.

 

Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), a placebo-controlled study conducted by the National Center for Complementary and Integrative Health of the US National Institutes of Health (NIH) at 16 US universities and health centers, investigated the effectiveness of glucosamine and chondroitin sulfate (1500 mg and 1200 mg daily, respectively, for up to 24 weeks) in relieving pain in patients with knee osteoarthritis [5]. Patients who had mild pain or moderate-to-severe pain were considered separately; celecoxib, an approved nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, was used as a positive control. The results of GAIT indicated that the glucosamine / chondroitin sulfate combination but not each supplement separately statistically significantly reduced pain in patients with moderate-to-severe pain in comparison with the placebo group. No significant improvement in pain was found in patients with mild pain. It should be noted however that GAIT also found only a minimal beneficial effect of celecoxib in comparison with a placebo (a 10 percentage points difference), and that the placebo effect in this study was very large (60% of the patients in the placebo group reported alleviation of pain) [5]. A later reanalysis of the data also suggested a beneficial effect of chondroitin sulfate on knee joint swelling, particularly in patients with milder pain [6].

 

On the basis of the GAIT results, the NIH guidelines recommend taking glucosamine plus chondroitin sulfate as a possible component of a comprehensive management plan (along with the right diet, weight loss, exercise, and pain medications) for osteoarthritis patients with moderate-to-severe pain [7]. Despite these NIH guidelines, the US Food and Drug Administration (FDA) considers glucosamine and chondroitin sulfate as food supplements and does not regulate them as medications. The FDA also considers that the link between glucosamine and chondroitin sulfate and a reduced risk of osteoarthritis has not been reliably established [8].

 

The British National Health Service (NHS) considers chondroitin and glucosamine treatments not to be cost-effective enough in patients with osteoarthritis to warrant their prescription under the NHS scheme [9]. However, the NHS guidelines issued in 2010 and reviewed in 2012, which are based on recommendations by the National Institute for Health and Clinical Excellence (NICE) of the UK Department of Health, recognize that glucosamine (1500 mg daily) is effective in mild or modest reduction of pain in some patients. The NHS guidelines also recommend patients who decide to take glucosamine to evaluate their pain before starting the supplement and after three months, to evaluate whether it is beneficial for them [9].

 

Glucosamine and chondroitin sulfate are recognized as osteoarthritis drugs in some European countries [10]. In France, glucosamine and chondroitin sulfate are considered drugs acting over long periods of time and are available as medications; after intense discussions on the effectiveness of glucosamine and chondroitin sulfate as symptomatic drugs for patients with osteoarthritis of the lower extremities, the French National Authority for Health (La Haute Autorité de santé — HAS) decided in 2008 to maintain their status, and medications that contain these substances (except one) continue to be partially reimbursed by the national social security system (Sécurité Sociale) [11]. Similarly, the Association of Rheumatologists of Russia recommends prescribing chondroitin sulfate (500 mg twice daily over long periods of time) for patients with knee osteoarthritis and glucosamine sulfate (1500 mg daily for 4–12 weeks two or three times a year) for patients with knee and hand osteoarthritis [12].

 

The guidelines of the OsteoArthritis Research Society International (OARSI) for the management of hip and knee osteoarthritis [13] recognize the use of glucosamine and/or chondroitin sulfate for symptom relief as well as their possible “structure-modifying effects”. OARSI recommends that glucosamine, chondroitin sulfate, or their combination be taken for an initial period of six months and discontinued if no symptomatic benefit is apparent after this treatment.

 

Similar to the NHS recommendations in the UK, in Denmark physicians starting treatment of a patient with osteoarthritis are advised to consider the use of glucosamine sulfate for a trial period of three months; if there is no improvement in symptoms after this period, NSAIDs are prescribed instead [14].

 

Whereas most guidelines concern the management of knee osteoarthritis, the recommendations of the European League Against Rheumatism (EULAR) on management of hand osteoarthritis note that glucosamine sulfate and chondroitin sulfate “have a symptomatic effect and low toxicity, but effect sizes are small, [and] suitable patients are not well defined” [15].

 

Hyaluronic acid. Hyaluronic acid is necessary for the production of the synovial fluid in the joints and is a component of articular cartilage. Although hyaluronic acid is also widely used for the management of osteoarthritis, the major administration route is by injections into the knee joints (see the OARSI guidelines [13] and a review by Bannuru and colleagues [16]). However, the obvious major drawback of this approach is the necessity for regular injections.

 

Several studies suggest that oral hyaluronic acid is also effective in patients with knee osteoarthritis. A pilot randomized, double-blind, placebo-controlled trial conducted in the USA found that taking ~50 mg of hyaluronic acid daily for eight weeks statistically significantly reduced some WOMAC scores in comparison with the placebo group [17]. Similar findings were reported by studies conducted in Japan. A randomized, double-blind, placebo-controlled study found that taking a chicken comb extract (equivalent to 60 mg of hyaluronic acid daily) but not placebo for 16 weeks resulted in moderate but significant improvements in parameters related to pain and walking function or going up and down the stairs, and also increased the ratio of collagen synthesis to its degradation [18]. A more recent study, which was also double-blind and placebo-controlled, found that oral administration of hyaluronic acid (200 mg daily) for one year alleviated the symptoms of knee osteoarthritis, especially in participants younger than 70 years of age [19].

 

Since the use of oral hyaluronic acid for osteoarthritis management has only relatively recently been supported by clinical studies, to the best of our knowledge no guidelines have so far been issued in this respect by any authorities. However, the above studies indicate that oral intake of hyaluronic acid at doses corresponding to one to four Elgenoflex pills would have beneficial effects at least in patients knee osteoarthritis.

 

Type II collagen hydrolysates

A substantial number of studies have documented the beneficial effects of supplementation with various collagen forms, of which collagen type II hydrolysates are most often used, both in healthy people and in patients with musculoskeletal disorders, mainly knee osteoarthritis [20,21]. For example, in a recent phase IV multicenter trial conducted in Spain physically active patients with knee osteoarthritis received collagen hydrolysate and hyaluronic acid (7 g and 25 mg daily, respectively) for 90 days [22]. The authors reported a gradual highly statistically significant decrease in functional disability, joint stiffness, and pain. As the formulation contained not only collagen hydrolysate, but also hyaluronic acid (similar to Elgenoflex), its strong positive effect may have been due to a combination of the individual effects of its components.

 

Whereas no specific guidelines are available on the use of collagen hydrolysates, they are generally recognized as safe, which has been confirmed by the World Health Organization (WHO) and the European Commission for Health and Consumer Protection; gelatin (denatured collagen from which the hydrolysates are produced) is also recognized as safe by the FDA [23].

 

Methylsulfonylmethane

Although MSM is often included in commercial supplements containing glucosamine and chondroitin sulfate, it is inferior to glucosamine when used alone [24], and no clinical guidelines for its use as a separate supplement are available. However, when used in combination with glucosamine, MSM was reported to be more effective in alleviating pain in osteoarthritis patients than each supplement individually [24]. The FDA recognizes MSM as a “generally recognized as safe” (GRAS) compound [23].

 

Placebo effect

A particularly strong placebo effect is observed in patients with osteoarthritis, especially with respect to alleviation of pain; this effect is usually larger than specific effects of available treatments [25,26,27]. An impressive example of a long-lasting powerful placebo effect was revealed by a two-year GAIT follow-up study in which a subset of GAIT patients continued to receive treatments (or a placebo) for 24 months [28]. None of the treatments, including celecoxib, showed statistically significant differences from the placebo (although celecoxib and glucosamine showed beneficial trends), but the placebo resulted in a graduate decline in the WOMAC score for pain, which plateaued at about 50% of the initial value in 6–7 months and remained at this level until the end of the study (i.e. 2 years) [28].

 

Since the placebo effect is subtracted from the effects of the tested treatments in clinical trials, a strong placebo effect makes it difficult to estimate the effectiveness of treatments used in patients with osteoarthritis, which is exemplified by the outcome of the GAIT trial described above. As pain relief is one of the aims of any osteoarthritis treatment, it has been argued that the placebo effect may be effectively used for the benefits of the patients and should be taken into account when choosing the treatment [25]. If the placebo effect is taken into account, the overall beneficial effect of glucosamine and/or chondroitin sulfate becomes substantial [25].

 

Finally, it is worth noting that the effects of glucosamine and chondroitin sulfate are known to be synergistic when they are used as components of the same supplement [29,30]. Similarly, as mentioned above, methylsulfonylmethane and glucosamine combined in the same supplement alleviate pain in osteoarthritis patients more effectively than each substance used alone [24]. Therefore, supplements containing several active ingredients, such as Elgenoflex, can be expected to be more efficient than those containing one or fewer ingredients.

References

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  3. Bruyere, O. & Reginster, J.Y. Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis. Drugs Aging 24, 573-580 (2007).
  4. Reichenbach, S. et al. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med 146, 580-590 (2007).
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