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Elgenoflex

Elgenoflex®

FOR SKIN, JOINT AND CONNECTIVE TISSUE HEALTH

  • 1 tablet a day helps maintain joint function
  • Source of BioCell Collagen that assures elasticity and strength of articular surfaces
  • Beneficial for patients with arthritis and musculoskeletal disorders
  • Beneficial for people with a high level of physical exertion
  • Made of natural ingredients in the USA by GMP standards

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WHO NEEDS ELGENOFLEX?

Anyone who has issues with joints, especially if:

  • You are a sport lover - frequent runner, soccer, basketball player, or bicycle rider
  • You are a professional athlete
  • You have osteoarthritis
  • Your profession keeps you on your feet (retail worker, teacher, hairdresser, healthcare employee, etc)
  • You are very physically active throughout the day
  • You often wear high heels

 

WHY ELGENOFLEX?

  • Elgenoflex contains scientifically and clinically proven ingredients.
  • Elgenoflex contains  BioCell Collagen, a multifunctional, patented ingredient, which plays a vital role in helping maintain healthy cartilage, tendons, and ligaments that support joint function.
  • Elgenoflex is made of 100% pure chicken sternum cartilage, and naturally contains Chondroitin Sulfate, hyaluronic acid and cartilage matrix glycoprotein (CMGP), powerful substances that support cartilage health and function as well as assure joint comfort.
  • Elgenoflex helps protect physically active people from pain and damage of muscle tissue, negative consequences for joints, and the increased probability of direct joint injuries.
  • Elgenoflex along with the right diet, weight loss, exercise and pain medications can help reduce moderate to severe pain of patients with osteoarthritis.  
  • Elgenoflex is produced in easy-to-swallow tablets: Just one tablet a day helps joint health!
  • Elgenoflex is manufactured in the USA according to GMP standards from environmentally friendly animal and plant sources, and is a natural product, free of chemical agents.

SERVING SIZE: 1 tablet

SERVINGS PER CONTAINER: 30

Ingredients   

Amount Per Serving

% Daily Value

BioCell Collagen®

(Hydrolyzed Chicken Collagen

Type II)

500 mg

*

Methylsulfonylmethane

400 mg

*

Glucosamine HCl (from shrimp and crab)

300 mg

*

* Daily Value not established.

Other ingredients: microcrystalline cellulose, stearic acid, vegetable stearate, croscarmellose sodium, silicon dioxide, pharmaceutical glaze.

PROPERTIES OF INGREDIENTS

Owing to the presence of three natural ingredients, each of which is an efficient regulator of the functions of the musculoskeletal system, Elgenoflex has a multifaceted influence on the body as a result of synergistic, complimentarily effects   of its components, which are:

  • regenerative
  • anti-inflammatory
  • antioxidant
  • pain relieving

RECOMMENDED USE

  • Chronic inflammatory diseases of the musculoskeletal system such as arthritis (including rheumatoid arthritis), bursitis, and myositis
  • Degenerative and dystrophic diseases of the musculoskeletal system such as osteoarthritis, osteochondrosis, etc.
  • During the recovery period after surgery of the musculoskeletal system and after injuries (fractures, ligament sprains and ruptures, tendon damage)
  • Restoration of the cartilage surfaces of the menisci and intervertebral discs
  • Maintenance of the musculoskeletal function in people with regular physical activity
  • Various diseases of the musculoskeletal system

DIRECTIONS FOR USE

For adults and children over 15, 1 tablet once a day after a meal.  Can be taken daily for up to 6 months.

CONTRAINDICATIONS

Hypersensitivity to one of the components of Elgenoflex.

WARNINGS

  • If pregnant or nursing, consult your healthcare practitioner before taking this product.
  • For patients with diabetes, intake duration needs to be adjusted by a physician.
  • Contains shrimp and crab.

STORAGE AND PACKAGING

Store in a cool, dry place. Keep out of reach of children.

A bottle contains 30 tablets.

WHAT MAKES ELGENOFLEX DIFFERENT FROM OTHER SUPPLEMENTS FOR JOINT HEALTH? 

The vast majority of supplements to support joint, and connective tissue health contain glucosamine and methylsulfonylmethane (MSM), as well as their combinations, which are widely used as supplements in patients with osteoarthritis and musculoskeletal disorders, and their beneficial effects have been documented in multiple clinical trials.

Along with glucosamine and methylsulfonylmethane (MSM) Elgenoflex also contains BioCell Collagen, which is a multifunctional, patented ingredient for joint, and vascular support.

It is a collagen type II hydrolysate derived from chicken sternal articular cartilage, which also contains hyaluronic acid and chondroitin sulfate and makes the supplement more effective for patients with osteoarthritis and musculoskeletal disorders.

 

WHAT IS BIOCELL COLLAGEN? 

BioCell Collagen, the main component of Elgenoflex (approximately 2/3 by weight), produced by BioCell Technology LLC (Newport Beach, CA, USA) is a multifunctional, patented ingredient for joint, skin, and vascular support. BioCell Collagen plays a vital role in helping maintain healthy cartilage, tendons, and ligaments that support joint function; it is also a source of elasticity and strength for articular surfaces. It also helps in maintaining the mobility and flexibility of joints. BioCell Collagen is made from 100% pure enzymatically hydrolyzed chicken sternum cartilage, and naturally contains depolymerized chondroitin sulfate, hyaluronic acid and cartilage matrix glycoprotein (CMGP), powerful substances that support cartilage health and function as well as joint comfort.

 

WHAT IS COLLAGEN TYPE II (TYPE TWO)? 

Collagens are structural proteins found in various connective tissues. Of the 28 known types of collagens, type II is the major collagen found in cartilage.

A substantial number of studies have documented the beneficial effect of supplementation with various forms of collagen. Collagen type II hydrolysates are used most often, both in healthy people and in patients with musculoskeletal disorders. Like other ingested proteins, collagens are hydrolyzed in the digestive tract and cannot be directly incorporated into human tissues. Nevertheless, their ingestion may be beneficial because it may stimulate production of endogenous collagens.The intake of collagens, especially collagen hydrolysates, may facilitate the synthesis of endogenous collagen.

 

ARE COLLAGEN HYDROLYSATES SAFE? 

Collagen hydrolysates are safe for our bodies, which is 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 safe by the US Food and Drug Administration (FDA).

 

IS IT SAFE TO TAKE ELGENOFLEX IF I HAVE ARTHRITIS? 

Elgenoflex is a dietary supplement that contains several ingredients: hydrolyzed type II collagen, which also naturally contains chondroitin sulfate and hyaluronic acid, glucosamine, and methylsulfonylmethane (MSM).

Rheumatoid arthritis is an autoimmune disorder that mainly affects small joints in the hands and feet and results in their inflammation, pain, and eventually deformation. No definitive cure exists for rheumatoid arthritis. An abnormal immune response against the patient’s own collagen type II (cartilage collagen) is thought to play a role in the development of rheumatoid arthritis.

Unlike rheumatoid arthritis, osteoarthritis is not an autoimmune disease. It develops with age when the cartilage on bone ends wears down. Osteoarthritis mainly affects joints that are under continuous stress (most often knee joints); joint injuries and repetitive stress due to work or sports activities increase the risk of osteoarthritis. As in the case of rheumatoid arthritis, no cure exists for osteoarthritis, and in severe cases joint replacement may be needed. Degradation of collagen type II is associated with the progression of osteoarthritis in the knees and hands.

After a pioneering study was published in 1993, a number of studies reported positive effects of chicken type II collagen and its hydrolysates in patients with rheumatoid arthritis. In particular, short collagen fragments (as found in collagen hydrolysates such as BioCell Collagen used in Elgenoflex) reduce joint swelling and tenderness, and improve several other criteria used to assess the disease.

Collagen type II hydrolysates are also effective in patients with osteoarthritis, as shown by many clinical trials, including one that used exactly the same collagen type II hydrolysate as that is included in ElgenoflexBioCell Collagen, a patented preparation produced by BioCell Technology LLC (Newport Beach, CA, USA). This trial reported a significant reduction in pain improvement in physical activity and the scores used to assess various parameters of the disease. These effects were noticeable after just five weeks of supplementation.

Methylsulfonylmethane (MSM), which is also included in Elgenoflex, has been suggested by several clinical trials to have beneficial effects in patients with osteoarthritis, such as a reduction in pain and physical function impairment, and an improvement in performing daily activities, although it does not affect joint stiffness.

 

CAN ELGENOFLEX BE BENEFICIAL FOR PATIENTS WITH MUSCULOSKELETAL DISORDERS? 

Although musculoskeletal disorders are not life-threatening, they are the most common cause of disability and considerably affect the quality of life of those who suffer with them. The most common musculoskeletal disorders are osteoarthritis, rheumatoid arthritis, and fibromyalgia. Taking food supplements for musculoskeletal disorders has gained popularity in the last two decades. Collagen hydrolysates, hyaluronic acid, chondroitin sulfate, glucosamine, and methylsulfonylmethane, which are all components of Elgenoflex, are among the substances most widely used for this purpose.

Most clinical trials that investigated the beneficial effects of these substances involved patients with osteoarthritis and rheumatoid arthritis. However, Elgenoflex components can also be useful for prevention of musculoskeletal pain and musculoskeletal conditions, especially in people who are at increased risk because of a high level of physical activity, which puts considerable strain on the musculoskeletal system.

 

HOW LONG SHOULD I TAKE ELGENOFLEX?

The absence of side effects and safety of long-term intake of Elgenoflex ingredients have been confirmed by clinical studies. Therefore, there are no time restrictions on regular intake of Elgenoflex, if consumed at the dosage of 1 tablet a day.

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BENEFITS OF TAKING ELGENOFLEX FOR PATIENTS WITH ARTHRITIS

Elgenoflex contains the following active ingredients: hydrolyzed type II collagen from chicken (which naturally contains chondroitin sulfate and hyaluronic acid), glucosamine, and methylsulfonylmethane (MSM). In this article, the beneficial effects of Elgenoflex components in patients with rheumatoid arthritis and osteoarthritis are considered.

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BENEFITS OF TAKING ELGENOFLEX FOR PATIENTS WITH ARTHRITIS

Elgenoflex contains the following active ingredients: hydrolyzed type II collagen from chicken (which naturally contains chondroitin sulfate and hyaluronic acid), glucosamine, and methylsulfonylmethane (MSM). In this article, the beneficial effects of Elgenoflex components in patients with rheumatoid arthritis and osteoarthritis are considered.

 

Rheumatoid arthritis is an autoimmune disorder that occurs predominantly in women and mainly affects small joints in the hands and feet, resulting in inflammation, pain, and eventually joint deformation [1,2]. No definitive cure exists for rheumatoid arthritis and treatment is aimed mainly at preventing joint damage and alleviating symptoms. Surgery is sometimes used in patients with severely deformed joints. One of the auto antigens thought to play a role in the development of rheumatoid arthritis is cartilage collagen type II [3,4,5,6].

 

Unlike rheumatoid arthritis, osteoarthritis is not an autoimmune disease. It develops with age when the cartilage on bone ends wears down and affects mostly joints that are under continuous stress; joint injuries and repetitive stress on particular joints caused by professional or sports activities increase the risk of osteoarthritis development [2,7]. As in the case of rheumatoid arthritis, no cure exists for osteoarthritis, and in severe cases joint replacement may be needed. Degradation of collagen type II is associated with the progression of knee and hand osteoarthritis [8] and with osteoarthritis flares [11]. Accordingly, a recent study of 3,582 osteoarthritis patients concluded that a fragment of collagen type II is the most informative biochemical marker for prediction of this disease[12]. A partial replacement of collagen II with the “incorrect” collagen I in osteoarthritic joints, especially in the later stages of the disease, has also been reported [13].

 

Collagen hydrolysates

Collagens are structural proteins found in various connective tissues. Collagen type II is the major collagen of the cartilage [14]. A number of studies have documented the beneficial effects of supplementation with collagen type II hydrolysates in patients with rheumatoid arthritis and osteoarthritis.

 

After a pioneering study was published in 1993 in Science [15] , a number of studies have reported positive effects of chicken type II collagen and its hydrolysates in patients with rheumatoid arthritis. An early pilot study found that administration of chicken collagen type II for three months resulted in a reduction in joint swelling and tender joints in 8 out of 10 participants with juvenile rheumatoid arthritis [16]. However, the exact origin of the supplement in this study was not specified, and it was unclear whether the collagen was hydrolyzed. A larger study (36 rheumatoid arthritis patients) found statistically significant improvements in the joint swelling score, Ritchie's index (a measure of joint tenderness), disease activity score, and Health Assessment Questionnaire score in patients given collagen tripeptides for three months in comparison with the placebo group, although no improvement in the subjective condition of the patients was found [17]. However, these responses did not reach statistical significance when more stringent assessment criteria were used.

 

Another pilot study (13 participants) assessed the effects of chicken type II collagen hydrolysate on juvenile rheumatoid arthritis as well as uveitis associated with this condition [18]. The authors found that six participants showed improvement in arthritis and four in uveitis, although the ophthalmic outcomes of two participants worsened. Since this study did not include a placebo group and the number of participants was small, the statistical significance of these results remained uncertain.

 

A much larger phase III clinical trial assessed the effects of a chicken type II collagen hydrolysate in patients with rheumatoid arthritis in comparison with methotrexate, a drug that is approved for treatment of this disease [19]. This multicenter, double-blind, randomized study, which enrolled a total of 503 participants, used administration of 0.1 g of chicken type II collagen hydrolysate daily for 24 weeks. Using several variables to assess the effects of the treatments on the disease, the authors found that the collagen hydrolysate effectively alleviated rheumatoid arthritis symptoms. Some of its effects were slightly weaker than the effects of methotrexate, but collagen hydrolysate also had fewer and milder side effects in comparison with methotrexate. These studies indicate that chicken type II collagen hydrolysate can be used as a supplement for patients with rheumatoid arthritis.

 

At least one study used exactly the same collagen type II hydrolysate as that included in Elgenoflex—BioCell Collagen, a patented preparation produced by BioCell Technology LLC (Newport Beach, CA, USA). This randomized, double-blind, placebo-controlled trial involved 80 patients with osteoarthritis in the knee and/or hip joints [20]. The authors found that ingestion of BioCell Collagen (2 g daily) for 10 weeks resulted in a significant reduction in pain in comparison with the placebo group. Both physical activity and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores were significantly improved in the BioCell Collagen group in comparison with the placebo group after five weeks of supplementation, and this effect persisted until the end of the trial (10 weeks). No difference in tolerability was noted between BioCell Collagen and the placebo [20]. These data suggest that formulations containing BioCell Collagen, such as Elgenoflex, can be expected to be beneficial for patients with osteoarthritis.

 

Another randomized, double-blind, controlled study that enrolled 250 patients with primary osteoarthritis of the knee used a similar collagen type II hydrolysate preparation (10 g daily for three months) [21]. The authors found significant improvement in knee joint comfort, especially in patients with the greatest joint deterioration and those who consumed less meat.

 

A more recent phase IV multicenter trial conducted in Spain involved 108 physically active patients with knee osteoarthritis, who 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. In fact, there is ample evidence for the positive effects of other components of Elgenoflex when they are used as separate supplements or in combinations. Examples of such studies are described below.

 

Glucosamine, hyaluronic acid, and chondroitin sulfate

Glucosamine is a precursor of the polysaccharides glycosaminoglycans, which include hyaluronic acid and chondroitin sulfate. A progressive loss of glycosaminoglycans is observed during the progression of osteoarthritis, and glycosaminoglycan content in cartilage tissue is used to grade the osteoarthritis stages [8].

 

Hyaluronic acid is necessary for the production of the synovial fluid in the joints and is a component of articular cartilage; its injection directly into the knee joint is widely used in patients with knee osteoarthritis [23]. Although this approach is efficient, its major drawback is the necessity for regular injections. However, several studies suggest that oral hyaluronic acid is also effective. A pilot randomized, double-blind, placebo-controlled trial conducted in the USA enrolled 20 patients with osteoarthritis, who received an extract of chicken combs with high content (~60%) of hyaluronic acid (80 mg daily, corresponding to ~50 mg of hyaluronic acid daily) for eight weeks [24]. The authors found statistically significant improvements in the WOMAC scores both in the hyaluronic acid group and the placebo group, but the improvement in the hyaluronic acid group was significantly higher than that in the placebo group. Similar changes were found in several markers of life quality: whereas both groups showed statistically significant improvements compared to baseline, the improvements in bodily pain and social functioning were greater in the in the hyaluronic acid group than in the placebo group [24].

 

Similar findings were reported by studies conducted in Japan. A randomized, double-blind, placebo-controlled study enrolled 43 patients with knee osteoarthritis, who received a chicken comb extract (equivalent to 60 mg of hyaluronic acid daily) for 16 weeks [25]. In the hyaluronic acid group, the authors found moderate but significant improvements in parameters related to pain and walking function or going up and down stairs, although not in joint flexion or swelling. Although improvements were also observed in the placebo group, they were not statistically significant [25]. The authors also examined the markers of collagen degradation and synthesis and found that the synthesis to degradation ratio was increased in the hyaluronic group [25]. This finding indicates that the presence of hyaluronic acid in collagen type II hydrolysates would have a synergistic positive effect in osteoarthritis patients. A more recent double-blind, placebo-controlled study that enrolled 60 patients who were asked to perform daily physical exercise found that oral administration of hyaluronic acid (0.2 g daily) for one year alleviated the symptoms of knee osteoarthritis, especially in participants younger than 70 years of age [26]. This study also found improvements in the placebo group, however they were less pronounced than in the hyaluronic acid group, with the differences between the two groups reaching statistical significance on the second and fourth months of treatment [26].

 

Similar to hyaluronic acid, chondroitin sulfate is an important component of synovial fluid and cartilage, and is a component of a number of proteoglycans in the extracellular matrix, where it plays a variety of regulatory roles. 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 [27] and references therein). Whereas the US Federal Drug Administration (FDA) considers glucosamine and chondroitin sulfate as food supplements, chondroitin is recognized as an osteoarthritis drug in European countries [28].

 

Chondroitin is one of the most popular supplements used by osteoarthritis patients. The authors of a recent systematic meta-analysis of 43 randomized controlled trials, which lasted between one month and three years and involved a total of 9,110 participants (mainly with knee osteoarthritis, with fewer cases of hip or hand osteoarthritis), concluded that chondroitin significantly reduced the narrowing of minimum joint space [29]. In studies shorter than six months, the authors also found that an index that takes into account pain, function, and disability showed statistically significant improvements in patients taking chondroitin in comparison with those taking a placebo. Curiously, this meta-analysis also found that chondroitin resulted in significantly fewer side effects than placebo [29].

 

Although glucosamine is often used in combination with chondroitin sulfate, it is also effective alone. An example of a study that assessed long-term effects of glucosamine in patients with knee osteoarthritis is a randomized, placebo-controlled clinical trial by Reginster and colleagues conducted in Belgium, Italy, and the UK, which was published in the highly respected British journal The Lancet [30]. This study enrolled 212 patients who were taking either glucosamine sulfate (1.5 g daily) or a placebo for three years. The authors found significant narrowing of the joint space in the placebo group but not in the glucosamine group. The WOMAC scores revealed some worsening of osteoarthritis symptoms in the placebo group but improvement in the glucosamine group [30].

 

Despite a large number of clinical trials, the efficiency of glucosamine and chondroitin sulfate is surrounded by controversy. This can be illustrated by the 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 [31,32], whereas a group from Switzerland concluded that chondroitin has only minimal or no beneficial effects in osteoarthritis patients [33]. Possible causes of the confusion might include the “placebo effect” (improvements seen in groups taking placebo) and the difficulty in quantitatively assessing pain. In this respect, using techniques that allow objective pain measurements may resolve some of these controversies. For example, using functional magnetic resonance imaging (fMRI), Montfort and colleagues [34] found that this technique made it possible to reveal statistically significant improvements in pain in osteoarthritis patients, whereas evaluation of subjective pain by the same patients did not produce clear results. Finally, it should be noted that patients with rheumatoid arthritis do not benefit from glucosamine and chondroitin sulfate supplements [35].

 

Methylsulfonylmethane (MSM), which is also included in Elgenoflex, has been suggested by several clinical trials to have beneficial effects in patients with osteoarthritis. For example, in a randomized, double-blind, placebo-controlled pilot trial, 50 patients with knee osteoarthritis received MSM (6 g daily) or a placebo for 12 weeks [36]. The supplement was reported to result in a statistically significant reduction in pain and physical function impairment (according to WOMAC scores) and in improvement in performing daily activities, although not in WOMAC joint stiffness and total symptoms scores [36]. Another 12-week double-blind, placebo-controlled trial that involved 118 patients with knee osteoarthritis found that MSM reduced pain in comparison with the placebo group [37].

 

A more recent randomized, double-blind, controlled clinical trial enrolled 49 patients with knee osteoarthritis, who received MSM (ca. 7 g daily) or a placebo; the treatment period (12 weeks) was the same as in the two previous studies [38]. The authors found statistically significant improvements in WOMAC physical function and the total score, but not in joint stiffness. Disparate results were obtained for pain when it was assessed using two different approaches [38].

 

Although Usha and Naidu [37] found pain reduction in patients taking MSM, this supplement alone was inferior to glucosamine, and a combination of MSM and glucosamine was more effective than each supplement individually. Similarly, glucosamine and chondroitin sulfate are known to act synergistically [39]. These observations, together with the controversy regarding the effects of glucosamine and chondroitin, suggest that beneficial effects of each of these substances may be relatively small and noticeable only under certain circumstances or in certain groups of patients. Whereas it is far from clear under which circumstances which substances are most effective, formulations that contain combinations of several active ingredients, like Elgenoflex, may hold more promise than formulations containing one or few ingredients.

References

  1. Mayo Clinic. Diseases and conditions: Rheumatoid arthritis. http://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/basics/definition/con-20014868 (2014).
  2. World Health Organization. Chronic diseases and health promotion: Chronic rheumatic conditions. http://www.who.int/chp/topics/rheumatic/en/ (2015).
  3. Londei, M. et al. Persistence of collagen type II-specific T-cell clones in the synovial membrane of a patient with rheumatoid arthritis. Proc Natl Acad Sci U S A 86, 636-640 (1989).
  4. Ohnishi, Y. et al. Altered peptide ligands control type II collagen-reactive T cells from rheumatoid arthritis patients. Mod Rheumatol 16, 226-228 (2006).
  5. Rowley, M.J., Nandakumar, K.S. & Holmdahl, R. The role of collagen antibodies in mediating arthritis. Mod Rheumatol 18, 429-441 (2008).
  6. Sekine, T. et al. Type II collagen is a target antigen of clonally expanded T cells in the synovium of patients with rheumatoid arthritis. Ann Rheum Dis 58, 446-450 (1999).
  7. Mayo Clinic. Diseases and conditions: Osteoarthritis. http://www.mayoclinic.org/diseases-conditions/osteoarthritis/basics/definition/con-20014749 (2014).
  8. Poole, A.R. An introduction to the pathophysiology of osteoarthritis. Front Biosci 4, D662-670 (1999).
  9. Rousseau, J.C., Sornay-Rendu, E., Bertholon, C., Garnero, P. & Chapurlat, R. Hand osteoarthritis is associated with increased type II collagen degradation in women: the OFELY study. Osteoarthr Cartilage 21, S71–S72 (2013).
  10. Sharif, M. et al. A 5-yr longitudinal study of type IIA collagen synthesis and total type II collagen degradation in patients with knee osteoarthritis–association with disease progression. Rheumatology (Oxford) 46, 938-943 (2007).
  11. Manicourt, D.H., Bevilacqua, M., Righini, V., Famaey, J.P. & Devogelaer, J.P. Comparative effect of nimesulide and ibuprofen on the urinary levels of collagen type II C-telopeptide degradation products and on the serum levels of hyaluronan and matrix metalloproteinases-3 and -13 in patients with flare-up of osteoarthritis. Drugs R D 6, 261-271 (2005).
  12. Valdes, A.M. et al. Large scale meta-analysis of urinary C-terminal telopeptide, serum cartilage oligomeric protein and matrix metalloprotease degraded type II collagen and their role in prevalence, incidence and progression of osteoarthritis. Osteoarthritis Cartilage 22, 683-689 (2014).
  13. Miosge, N., Hartmann, M., Maelicke, C. & Herken, R. Expression of collagen type I and type II in consecutive stages of human osteoarthritis. Histochem Cell Biol 122, 229-236 (2004).
  14. Kadler, K.E., Baldock, C., Bella, J. & Boot-Handford, R.P. Collagens at a glance. J Cell Sci 120, 1955-1958 (2007).
  15. Trentham, D.E. et al. Effects of oral administration of type II collagen on rheumatoid arthritis. Science 261, 1727-1730 (1993).
  16. Barnett, M.L., Combitchi, D. & Trentham, D.E. A pilot trial of oral type II collagen in the treatment of juvenile rheumatoid arthritis. Arthritis Rheum 39, 623-628 (1996).
  17. Arborelius, M., Jr., Konttinen, Y.T., Nordstrom, D.C. & Solovieva, S.A. Gly-X-Y repeat sequences in the treatment of active rheumatoid arthritis. Rheumatol Int 18, 129-135 (1999).
  18. Thompson, D.J., Barron, K.S., Whitcup, S.M. & Robinson, M.R. The safety and efficacy of chicken type II collagen on uveitis associated with juvenile rheumatoid arthritis. Ocul Immunol Inflamm 10, 83-91 (2002).
  19. Wei, W. et al. A multicenter, double-blind, randomized, controlled phase III clinical trial of chicken type II collagen in rheumatoid arthritis. Arthritis Res Ther 11, R180 (2009).
  20. Schauss, A.G., Stenehjem, J., Park, J., Endres, J.R. & Clewell, A. Effect of the novel low molecular weight hydrolyzed chicken sternal cartilage extract, BioCell Collagen, on improving osteoarthritis-related symptoms: a randomized, double-blind, placebo-controlled trial. J Agric Food Chem 60, 4096-4101 (2012).
  21. Benito-Ruiz, P. et al. A randomized controlled trial on the efficacy and safety of a food ingredient, collagen hydrolysate, for improving joint comfort. Int J Food Sci Nutr 60 Suppl 2, 99-113 (2009).
  22. Llopis-Miró, R., de Miguel-Saenz, J. & Delgado-Velilla, F. [Efficacy and tolerance of an oral hyaluronate and collagen chondroprotector on joint function in active adults suffering from knee osteoarthritis]. Apunts. Medicina de l'Esport 47, 3-8 (2011).
  23. Bannuru, R.R., Vaysbrot, E.E., Sullivan, M.C. & McAlindon, T.E. Relative efficacy of hyaluronic acid in comparison with NSAIDs for knee osteoarthritis: a systematic review and meta-analysis. Semin Arthritis Rheum 43, 593-599 (2014).
  24. Kalman, D.S., Heimer, M., Valdeon, A., Schwartz, H. & Sheldon, E. Effect of a natural extract of chicken combs with a high content of hyaluronic acid (Hyal-Joint) on pain relief and quality of life in subjects with knee osteoarthritis: a pilot randomized double-blind placebo-controlled trial. Nutr J 7, 3 (2008).
  25. Nagaoka, I. et al. Evaluation of the effects of a supplementary diet containing chicken comb extract on symptoms and cartilage metabolism in patients with knee osteoarthritis. Exp Ther Med 1, 817-827 (2010).
  26. Tashiro, T. et al. Oral administration of polymer hyaluronic acid alleviates symptoms of knee osteoarthritis: a double-blind, placebo-controlled study over a 12-month period. ScientificWorldJournal 2012, 167928 (2012).
  27. Iovu, M., Dumais, G. & du Souich, P. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage 16 Suppl 3, S14-18 (2008).
  28. Jordan, K.M. et al. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis62, 1145-1155 (2003).
  29. Singh, J.A., Noorbaloochi, S., MacDonald, R. & Maxwell, L.J. Chondroitin for osteoarthritis. Cochrane Database Syst Rev 1, CD005614 (2015).
  30. Reginster, J.Y. et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 357, 251-256 (2001).
  31. Reginster, J.Y., Heraud, F., Zegels, B. & Bruyere, O. Symptom and structure modifying properties of chondroitin sulfate in osteoarthritis. Mini Rev Med Chem 7, 1051-1061 (2007).
  32. Bruyere, O. & Reginster, J.Y. Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis. Drugs Aging 24, 573-580 (2007).
  33. Reichenbach, S. et al. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med 146, 580-590 (2007).
  34. Monfort, J. et al. Effects of chondroitin sulfate on brain response to painful stimulation in knee osteoarthritis patients: a randomized, double-blind, placebo-controlled clinical trial. Arthr Rheum 65, 2146 (2015).
  35. Matsuno, H. et al. Effects of an oral administration of glucosamine-chondroitin-quercetin glucoside on the synovial fluid properties in patients with osteoarthritis and rheumatoid arthritis. Biosci Biotechnol Biochem 73, 288-292 (2009).
  36. Kim, L.S., Axelrod, L.J., Howard, P., Buratovich, N. & Waters, R.F. Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial. Osteoarthritis Cartilage 14, 286-294 (2006).
  37. Usha, P.R. & Naidu, M.U. Randomised, double-blind, parallel, placebo-controlled study of oral glucosamine, methylsulfonylmethane and their combination in osteoarthritis. Clin Drug Investig 24, 353-363 (2004).
  38. Debbi, E.M. et al. Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the knee: a randomized controlled study. BMC Complement Altern Med 11, 50 (2011).
  39. Bottegoni, C., Muzzarelli, R.A., Giovannini, F., Busilacchi, A. & Gigante, A. Oral chondroprotection with nutraceuticals made of chondroitin sulphate plus glucosamine sulphate in osteoarthritis. Carbohydr Polym 109, 126-138 (2014).

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COLLAGEN TYPE II: THE ADVANTAGE OF ELGENOFLEX

Collagens are structural proteins found in various connective tissues. Of the 28 known types of collagens [1], type II is the major collagen found in cartilage. A molecule of type II collagen consists of three identical polypeptide chains produced by the COL2A1 gene. Another, less abundant cartilage collagen is type XI, each molecule of which combines a type II chain and two chains of another type. Thus, type II chains are necessary to form both type II and type XI collagens.

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COLLAGEN TYPE II: THE ADVANTAGE OF ELGENOFLEX

Collagens are structural proteins found in various connective tissues. Of the 28 known types of collagens [1], type II is the major collagen found in cartilage. A molecule of type II collagen consists of three identical polypeptide chains produced by the COL2A1 gene. Another, less abundant cartilage collagen is type XI, each molecule of which combines a type II chain and two chains of another type. Thus, type II chains are necessary to form both type II and type XI collagens.

 

The importance of collagen type II in cartilage is confirmed by a number of skeletal disorders caused by mutations in the COL2A1 gene, such as Kniest dysplasia and Stickler syndrome [2]. The former is characterized by short, deformed bones, enlarged joints, and pain in joints that restricts patients’ movement [3,4]. The latter results in defects in facial bone development and a variety of other symptoms such as arthritis (which develops early in life) and abnormalities in the vertebrae and at the ends of long bones [5,6].

 

A substantial number of studies have documented the beneficial effect of supplementation with various forms of collagen. Collagen type II hydrolysates are used most often, both in healthy people and in patients with musculoskeletal disorders [7]. Like other ingested proteins, collagens are hydrolyzed in the digestive tract and cannot be directly incorporated into human tissues. Nevertheless, their ingestion may be beneficial because it may stimulate production of endogenous collagens. At least two likely mechanisms of this stimulation have been suggested. One is that collagens have specific amino acid composition and their synthesis requires much higher amounts of two particular amino acids, glycine and proline, than the synthesis of other proteins. The intake of collagens, especially collagen hydrolysates, may help increase the availability of these amino acids in the body and thus facilitate the synthesis of endogenous collagen [8].

 

Another possible mechanism may rely on the regulatory role of collagen fragments. The appearance of collagen-derived di- and tri-peptides in the blood has been reported after the ingestion of collagen hydrolysates derived from bovine and chicken collagens [9,10]. Although di- and tri-peptides cannot be directly used as building blocks for the synthesis of new collagen, some lines of evidence suggest that they can act as regulatory molecules to increase the production of collagen type II [11] and hyaluronic acid [12]. Therefore, it seems plausible that similar mechanisms may in part be responsible for the beneficial effects of collagen hydrolysates in vivo, although this remains to be demonstrated. Below we consider several examples of studies that have documented the beneficial effect of collagen type II hydrolysates (including studies conducted in the USA using the same collagen type II hydrolysate as in Elgenoflex) and their components hyaluronic acid and chondroitin sulfate.

 

The main component of Elgenoflex (approximately 2/3 by weight) is BioCell Collagen, produced by BioCell Technology LLC (Newport Beach, CA, USA). It is a collagen type II hydrolysate derived from chicken sternal articular cartilage, which also contains low-molecular-weight glycosaminoglycans (hyaluronic acid and chondroitin sulfate) [13,14]. These two additional components may also have beneficial effects (see below).

 

Сollagen type II hydrolysate for patients with arthritis and individuals with high level of physical activity

A randomized, double-blind, placebo-controlled pilot study enrolled eight healthy, physically active volunteers who experienced muscle and connective tissue strain and damage because of intense exercise [13]. The participants received BioCell Collagen (3 g daily) or a placebo for six weeks and were subjected to a muscle-damaging resistance exercise challenge twice during the week following the supplementation period. The authors found a lower increase in serum markers for muscle tissue damage and enhanced stress resilience (as indicated by better performance at the repeated challenge) in the BioCell Collagen group in comparison with the placebo group [13], although the small size of the groups did not allow evaluation of the statistical significance of the findings.

 

A randomized, double-blind, placebo-controlled trial involved 80 patients with osteoarthritis in the knee and/or hip joints [15]. The authors found that ingestion of BioCell Collagen (2 g daily) for 10 weeks resulted in a significant reduction in pain in comparison with the placebo group. Both the Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores and physical activity were significantly improved in comparison with the placebo group after five weeks of BioCell Collagen supplementation, and this effect persisted until the end of the trial (10 weeks). No difference in tolerability was noted between BioCell Collagen and the placebo [15]. These data suggest that formulations containing BioCell Collagen, such as Elgenoflex, can be expected to be beneficial for patients with osteoarthritis. Studies that used BioCell Collagen did not report any serious side effects.

 

A randomized, double-blind, controlled study that enrolled 250 patients with knee osteoarthritis used a similar collagen type II hydrolysate preparation (10 g daily for three months) [16]. The authors found significant improvement in knee joint comfort, especially in patients with the greatest joint deterioration and those who consumed less meat.

 

An important study was a randomized, placebo-controlled, double-blind, pilot trial conducted by McAlindon and colleagues [17], who used sophisticated imaging technology based on magnetic resonance imaging (MRI) to accurately measure short-term changes in knee hyaline cartilage in osteoarthritis patients taking collagen hydrolysate. The authors found an increase in proteoglycan content in knee cartilage in the collagen group and hydrolysate group, but a decrease in the placebo group, with a statistically significant difference after 24 weeks [17].

 

Collagen type II hydrolysates are also effective in patients with rheumatoid arthritis. For example, a phase III clinical trial (503 participants in total) compared the effects of a chicken type II collagen hydrolysate (0.1 g daily for 24 weeks) with those of methotrexate, an approved rheumatoid arthritis drug [18]. The authors found that the collagen hydrolysate alleviated rheumatoid arthritis symptoms. Although its efficacy was slightly lower than that of methotrexate, it had fewer side effects.

 

Thus, collagen type II hydrolysates have beneficial effects in healthy people with strenuous physical activity as well as patients with osteoarthritis and rheumatoid arthritis.

 

Beneficial effects of hyaluronic acid in patients with osteoarthritis. Hyaluronic acid is necessary for the production of synovial fluid in the joints and is a component of articular cartilage; intra-articular injections are widely used in patients with osteoarthritis [19,20]. Several clinical trials have shown that oral administration of hyaluronic acid may also be effective. The obvious advantages of oral administration are that patients can avoid the discomfort of regular injections and can take the supplements at home, without having to visit a clinic.

 

A pilot randomized, double-blind, placebo-controlled trial conducted in the USA enrolled 40 patients with osteoarthritis, who received an extract of chicken combs with high content (~60%) of hyaluronic acid (80 mg daily, corresponding to ~50 mg of hyaluronic acid daily) for eight weeks [21]. The authors found statistically significant improvements in the WOMAC scores in both the hyaluronic acid group and the placebo group, but the improvement in the hyaluronic acid group was significantly higher than that in the placebo group. Similar changes were found in several markers of life quality: whereas both groups showed statistically significant improvements compared to baseline, the improvements in pain and social functioning were greater in the hyaluronic acid group than in the placebo group [21].

 

Similar results were obtained in a randomized, double-blind, placebo-controlled study that was conducted in Japan and enrolled 43 patients with knee osteoarthritis, who received a chicken comb extract (equivalent to 60 mg of hyaluronic acid daily) for 16 weeks [22]. In the hyaluronic acid group, the authors found moderate but significant improvements in parameters related to pain and walking function or going up and down stairs, although not in joint flexion or swelling. Although improvements were also observed in the placebo group, they were not statistically significant [22]. The authors also examined the markers of collagen degradation and synthesis and found that the synthesis to degradation ratio was increased in the hyaluronic group [22]. This finding indicates that the presence of hyaluronic acid in collagen type II hydrolysates would have a synergistic positive effect in osteoarthritis patients.

 

Chondroitin sulfate for joint health

Chondroitin sulfate is a component of a number of proteoglycans in the extracellular matrix, where it plays a variety of regulatory roles. Similar to hyaluronic acid, chondroitin sulfate is an important component of the synovial fluid and cartilage, and is widely used as a separate supplement in patients with osteoarthritis (see review by Iovu and colleagues [23] and references therein). Despite a large number of clinical trials that used chondroitin sulfate, there has been a continuous controversy over the last decade regarding its efficiency [24]. Possible causes of confusion might include the “placebo effect” (improvements seen in groups taking a placebo) and the difficulty in quantitatively assessing pain. To address the latter issue, Monfort and colleagues have recently used functional magnetic resonance imaging (fMRI) to assess pain in osteoarthritis patients taking chondroitin sulfate or a placebo for four months [25]. In this phase IV, randomized, double-blind trial, the patients taking chondroitin sulfate but not those in the placebo group tended to report reduced subjective pain, but this effect did not reach statistical significance. However, imaging of the pain-processing region of the brain, which is activated when a person perceives pain, demonstrated a statistically significant reduction in pain in the chondroitin sulfate group, which was significantly greater than that in the placebo group [25]. These findings not only confirm the efficacy of chondroitin sulfate but also set a precedent for the use of a technique that may help resolve uncertainties in the efficacy of other supplements that are assumed to alleviate pain. The US Federal Drug Administration (FDA) considers chondroitin sulfate as a food supplement; in European countries, it is recognized as an osteoarthritis drug [26].

 

Finally, it should be noted that collagen hydrolysates 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 US Food and Drug Administration (FDA) [8].

References

  1. Kadler, K.E., Baldock, C., Bella, J. & Boot-Handford, R.P. Collagens at a glance. J Cell Sci 120, 1955-1958 (2007).
  2. Winterpacht, A. et al. Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2A1) defect. Nat Genet 3, 323-326 (1993).
  3. Gilbert-Barnes, E., Langer, L.O., Jr., Opitz, J.M., Laxova, R. & Sotelo-Arila, C. Kniest dysplasia: radiologic, histopathological, and scanning electron microscopic findings. Am J Med Genet 63, 34-45 (1996).
  4. Spranger, J., Winterpacht, A. & Zabel, B. Kniest dysplasia: Dr. W. Kniest, his patient, the molecular defect. Am J Med Genet 69, 79-84 (1997).
  5. Nowak, C.B. Genetics and hearing loss: a review of Stickler syndrome. J Commun Disord 31, 437-453; 453-434 (1998).
  6. Liberfarb, R.M. et al. The Stickler syndrome: genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1. Genet Med 5, 21-27 (2003).
  7. Van Vijven, J.P. et al. Symptomatic and chondroprotective treatment with collagen derivatives in osteoarthritis: a systematic review. Osteoarthritis Cartilage 20, 809-821 (2012).
  8. Sibila, S., Godfrey, M., Brewer, S., Budh-Raja, A. & Genovese, L. An overview of the beneficial effects of hydrolysed collagen as a nutraceutical on skin properties: scientific background and clinical studies. Open Nutraceuticals J 8, 29-42 (2015).
  9. Iwai, K. et al. Identification of food-derived collagen peptides in human blood after oral ingestion of gelatin hydrolysates. J Agric Food Chem 53, 6531-6536 (2005).
  10. Sugihara, F., Inoue, N., Kuwamori, M. & Taniguchi, M. Quantification of hydroxyprolyl-glycine (Hyp-Gly) in human blood after ingestion of collagen hydrolysate. J Biosci Bioeng 113, 202-203 (2012).
  11. Oesser, S. & Seifert, J. Stimulation of type II collagen biosynthesis and secretion in bovine chondrocytes cultured with degraded collagen. Cell Tissue Res 311, 393-399 (2003).
  12. Ohara, H., Iida, H., Ito, K., Takeuchi, Y. & Nomura, Y. Effects of Pro-Hyp, a collagen hydrolysate-derived peptide, on hyaluronic acid synthesis using in vitro cultured synovium cells and oral ingestion of collagen hydrolysates in a guinea pig model of osteoarthritis. Biosci Biotechnol Biochem 74, 2096-2099 (2010).
  13. Lopez, H.L., Habowski, S.M., Sandrock, J., A., K. & Ziegenfuss, J.Y. Effects of BioCell Collagen on connective tissue protection and functional recovery from exercise in healthy adults: a pilot study. Int J Radiat Oncol Biol Phys 11(Suppl 1), P48 (2014).
  14. Schwartz, S.R. & Park, J. Ingestion of BioCell Collagen, a novel hydrolyzed chicken sternal cartilage extract; enhanced blood microcirculation and reduced facial aging signs. Clin Interv Aging 7, 267-273 (2012).
  15. Schauss, A.G., Stenehjem, J., Park, J., Endres, J.R. & Clewell, A. Effect of the novel low molecular weight hydrolyzed chicken sternal cartilage extract, BioCell Collagen, on improving osteoarthritis-related symptoms: a randomized, double-blind, placebo-controlled trial. J Agric Food Chem 60, 4096-4101 (2012).
  16. Benito-Ruiz, P. et al. A randomized controlled trial on the efficacy and safety of a food ingredient, collagen hydrolysate, for improving joint comfort. Int J Food Sci Nutr 60 Suppl 2, 99-113 (2009).
  17. McAlindon, T.E. et al. Change in knee osteoarthritis cartilage detected by delayed gadolinium enhanced magnetic resonance imaging following treatment with collagen hydrolysate: a pilot randomized controlled trial. Osteoarthritis Cartilage 19, 399-405 (2011).
  18. Wei, W. et al. A multicenter, double-blind, randomized, controlled phase III clinical trial of chicken type II collagen in rheumatoid arthritis. Arthritis Res Ther 11, R180 (2009).
  19. Anderson, I. The properties of hyaluronan and its role in wound healing. Prof Nurse 17, 232-235 (2001).
  20. Bannuru, R.R., Vaysbrot, E.E., Sullivan, M.C. & McAlindon, T.E. Relative efficacy of hyaluronic acid in comparison with NSAIDs for knee osteoarthritis: a systematic review and meta-analysis. Semin Arthritis Rheum 43, 593-599 (2014).
  21. Kalman, D.S., Heimer, M., Valdeon, A., Schwartz, H. & Sheldon, E. Effect of a natural extract of chicken combs with a high content of hyaluronic acid (Hyal-Joint) on pain relief and quality of life in subjects with knee osteoarthritis: a pilot randomized double-blind placebo-controlled trial. Nutr J 7, 3 (2008).
  22. Nagaoka, I. et al. Evaluation of the effects of a supplementary diet containing chicken comb extract on symptoms and cartilage metabolism in patients with knee osteoarthritis. Exp Ther Med 1, 817-827 (2010).
  23. Iovu, M., Dumais, G. & du Souich, P. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage 16 Suppl 3, S14-18 (2008).
  24. Zheng, C., Wei, J. & Lei, G. Is chondroitin sulfate plus glucosamine superior to placebo in the treatment of knee osteoarthritis? Ann Rheum Dis 74, e37 (2015).
  25. Monfort, J. et al. Effects of chondroitin sulfate on brain response to painful stimulation in knee osteoarthritis patients: a randomized, double-blind, placebo-controlled clinical trial. Arthr Rheum 65, 2146 (2015).
  26. Jordan, K.M. et al. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis62, 1145-1155 (2003).

[endmore]

[more]

BENEFITS OF TAKING ELGENOFLEX FOR THE PREVENTION OF MUSCULOSKELETAL DISORDERS AND SUPPORT OF THE MUSCULOSKELETAL SYSTEM IN PEOPLE WITH A HIGH LEVEL OF PHYSICAL EXERTION

Although musculoskeletal disorders are not life-threatening, they are the most common cause of morbidity and disability, and considerably affect the quality of life of affected patients [1,2]. The most common musculoskeletal disorders are osteoarthritis, rheumatoid arthritis, and fibromyalgia. Taking food supplements for musculoskeletal disorders has gained popularity in the last two decades. Collagen hydrolysates, hyaluronic acid, chondroitin sulfate, glucosamine, and methylsulfonylmethane, which are all components of Elgenoflex, are among the substances most widely used for this purpose. Most clinical trials that investigated the beneficial effects of these substances involved patients with osteoarthritis and rheumatoid arthritis covered in a separate article. This article considers the evidence for the positive effects of Elgenoflex components for the prevention of musculoskeletal pain and musculoskeletal conditions, especially in people who are at increased risk because of a high level of physical activity, which puts considerable strain on the musculoskeletal system.

[endshort]

BENEFITS OF TAKING ELGENOFLEX FOR THE PREVENTION OF MUSCULOSKELETAL DISORDERS AND SUPPORT OF THE MUSCULOSKELETAL SYSTEM IN PEOPLE WITH HIGH LEVEL OF PHYSICAL EXERTION

Although musculoskeletal disorders are not life-threatening, they are the most common cause of morbidity and disability, and considerably affect the quality of life of affected patients [1,2]. The most common musculoskeletal disorders are osteoarthritis, rheumatoid arthritis, and fibromyalgia. Taking food supplements for musculoskeletal disorders has gained popularity in the last two decades. Collagen hydrolysates, hyaluronic acid, chondroitin sulfate, glucosamine, and methylsulfonylmethane, which are all components of Elgenoflex, are among the substances most widely used for this purpose. Most clinical trials that investigated the beneficial effects of these substances involved patients with osteoarthritis and rheumatoid arthritis covered in a separate article. This article considers the evidence for the positive effects of Elgenoflex components for the prevention of musculoskeletal pain and musculoskeletal conditions, especially in people who are at increased risk because of a high level of physical activity, which puts considerable strain on the musculoskeletal system.

 

A study conducted at Penn State University examined the effect of supplementation with a collagen type II hydrolysate on activity-related joint pain in 147 healthy athletes [3]. The participants were taking either collagen hydrolysate (10 g daily) or a placebo for 24 weeks; joint pain was assessed by the participants in five different situations (like walking or lifting weight) and also by a physician. The authors found a statistically significant reduction in all six pain parameters in the supplement group in comparison with the placebo group, with a reduction in knee joint pain being the most significant.

 

Another study that reported the ability of collagen hydrolysates to alleviate pain was conducted in Wisconsin (USA) and involved 20 patients with fibromyalgia; 12 of them also had pain in the temporomandibular joint [4]. The patients were taking a supplement that contained collagen type II hydrolysate (the dose was not specified) and an aloe extract for a total of 90 days. The authors reported a significant reduction in pain (by 25% on average) in comparison with the baseline, as well as improvement in other fibromyalgia symptoms, such as fatigue and chronic headache [4].

 

A more recent study used exactly the same chicken collagen type II hydrolysate as that included in Elgenoflex—BioCell Collagen, a patented preparation produced by BioCell Technology LLC (Newport Beach, CA, USA). This randomized, double-blind, placebo-controlled pilot study enrolled eight healthy, physically active volunteers who experienced muscle and connective tissue strain and damage because of intense exercise [5]. The participants received BioCell Collagen (3 g daily) or a placebo for six weeks and were subjected to muscle-damaging resistance exercise challenges twice during the week following the supplementation period. The authors found a lower increase in serum markers for muscle tissue damage and enhanced stress resilience (as indicated by better performance at the repeated challenge) in the BioCell Collagen group in comparison with the placebo group [5], although the small size of the groups did not allow evaluation of the statistical significance of the findings.

 

Whereas moderate physical activity confers extensively documented health benefits, vigorous physical activity may not only cause pain and damage muscle tissue, but also have negative consequences for joints. In addition to increasing the probability of direct joint injuries, these activities, especially some sports such as soccer, increase the risk of osteoarthritis [6,7]. Some professional activities, such as farming, are also known to increase the risk of osteoarthritis [8]. Several studies suggest that dietary supplements containing the same ingredients as Elgenoflex, either individually or in combination, are able not only to alleviate pain but also to reduce degradation of collagen type II, which is a major and indispensable component of articular cartilage [9], and thus prevent or delay the development of osteoarthritis.

 

Two studies conducted in Japan by the same group used an extract of chicken combs (a source of hyaluronic acid) in athletes. In one study, 46 members of a university soccer team received the extract or a placebo for 12 weeks [10]. Out of three kinds of pain (at rest, on pressing, and on moving) in four joints (ankle, knee, hip and shoulder), pain on moving in the ankle was found to be the strongest and was thus chosen as a benchmark for the effect of the extract. The authors found a significant reduction in the scores for pain in the ankle of the dominant foot, but not the other foot, at four and 12 weeks of supplementation in the extract group in comparison with the placebo group [10]. The same authors had previously found increased levels of the markers of collagen type II degradation and synthesis in athletes in comparison with non-athletes [11]; in a follow-up study, they examined the effect of the chicken comb extract on the turnover collagen type II in 29 soccer players [12]. The authors found a significant reduction in the levels of a collagen type II degradation marker (as well as a marker of bone degradation) after 12 weeks of supplementation [12]. These data confirmed the results of an earlier study, which enrolled 43 patients with knee osteoarthritis, who received a chicken comb extract (equivalent to 60 mg of hyaluronic acid daily) for 16 weeks [13]. In this study, the authors also examined the markers of collagen degradation and synthesis and found that the synthesis to degradation ratio was increased in the hyaluronic acid group in comparison with the placebo group [13]. Since playing soccer is known to increase the risk of knee osteoarthritis [7], these findings indicate that supplements containing hyaluronic acid (including Elgenoflex) may be useful for prevention of this disease.

 

Similarly, Yoshimura and colleagues found that administration of glucosamine (1.5 or 3 g daily) to soccer players for three months reduced the levels of the marker of collagen type II degradation without affecting the marker of collagen type II synthesis [11]. The effect of glucosamine was short-lived and disappeared soon after supplementation was stopped. Similar results were observed in a more recent study that enrolled bicycle riders: the same doses of glucosamine reduced collagen type II degradation in a dose-dependent manner but did not affect its synthesis [14]. Thus, glucosamine supplementation may have chondroprotective effects in athletes.

 

A recent systematic review of 13 randomized controlled trials that lasted for at least one year was aimed at identifying substances effective in preserving articular cartilage and delaying the development of knee osteoarthritis [15]. The authors examined available data for 12 treatments, which included glucosamine and chondroitin sulfate (other components of Elgenoflex, i.e. collagen type II hydrolysates, oral hyaluronic acid, and methylsulfonylmethane were not assessed). This study found that glucosamine and chondroitin sulfate were the only effective treatments to delay or prevent osteoarthritis progression.

 

It should be noted that in this case the effects of glucosamine and chondroitin sulfate were analyzed separately, whereas their effects are known to be synergistic when they are used as components of the same supplement [16,17]. Likewise, a combination of methylsulfonylmethane and glucosamine was reported to be more effective in alleviating pain in osteoarthritis patients than each supplement individually [18]. Thus, supplements that contain several active ingredients, such as Elgenoflex, can be expected to be most efficient in alleviating pain and delaying the development of musculoskeletal disorders than supplements that contain only one or fewer ingredients. Even though in some of the above studies the intake doses of active compounds were higher than the amounts included in Elgenoflex, the lower doses could be expected to be offset by the presence of as many as five active ingredients.

References

  1. Bergman, S. Public health perspective–how to improve the musculoskeletal health of the population. Best Pract Res Clin Rheumatol 21, 191-204 (2007).
  2. Vitetta, L., Cicuttini, F. & Sali, A. Alternative therapies for musculoskeletal conditions. Best Pract Res Clin Rheumatol 22, 499-522 (2008).
  3. Clark, K.L. et al. 24-Week study on the use of collagen hydrolysate as a dietary supplement in athletes with activity-related joint pain. Curr Med Res Opin 24, 1485-1496 (2008).
  4. Olson, G.B., Savage, S. & Olson, J. The effects of collagen hydrolysat on symptoms of chronic fibromyalgia and temporomandibular joint pain. Cranio 18, 135-141 (2000).
  5. Lopez, H.L., Habowski, S.M., Sandrock, J., A., K. & Ziegenfuss, J.Y. Effects of BioCell Collagen on connective tissue protection and functional recovery from exercise in healthy adults: a pilot study. Int J Radiat Oncol Biol Phys 11(Suppl 1), P48 (2014).
  6. Buckwalter, J.A. & Lane, N.E. Athletics and osteoarthritis. Am J Sports Med 25, 873-881 (1997).
  7. Lequesne, M.G., Dang, N. & Lane, N.E. Sport practice and osteoarthritis of the limbs. Osteoarthritis Cartilage 5, 75-86 (1997).
  8. Mayo Clinic. Diseases and conditions: Osteoarthritis. http://www.mayoclinic.org/diseases-conditions/osteoarthritis/basics/definition/con-20014749 (2014).
  9. Kadler, K.E., Baldock, C., Bella, J. & Boot-Handford, R.P. Collagens at a glance. J Cell Sci 120, 1955-1958 (2007).
  10. Yoshimura, M. et al. Effect of a chicken comb extract-containing supplement on subclinical joint pain in collegiate soccer players. Exp Ther Med 3, 457-462 (2012).
  11. Yoshimura, M. et al. Evaluation of the effect of glucosamine administration on biomarkers for cartilage and bone metabolism in soccer players. Int J Mol Med 24, 487-494 (2009).
  12. Yoshimura, M. et al. Evaluation of the effect of a chicken comb extract-containing supplement on cartilage and bone metabolism in athletes. Exp Ther Med 4, 577-580 (2012).
  13. Nagaoka, I. et al. Evaluation of the effects of a supplementary diet containing chicken comb extract on symptoms and cartilage metabolism in patients with knee osteoarthritis. Exp Ther Med 1, 817-827 (2010).
  14. Momomura, R. et al. Evaluation of the effect of glucosamine administration on biomarkers of cartilage and bone metabolism in bicycle racers. Mol Med Rep 7, 742-746 (2013).
  15. Gallagher, B. et al. Chondroprotection and the prevention of osteoarthritis progression of the knee: a systematic review of treatment agents. Am J Sports Med 43, 734-744 (2015).
  16. Bottegoni, C., Muzzarelli, R.A., Giovannini, F., Busilacchi, A. & Gigante, A. Oral chondroprotection with nutraceuticals made of chondroitin sulphate plus glucosamine sulphate in osteoarthritis. Carbohydr Polym 109, 126-138 (2014).
  17. Hungerford, D., Navarro, R. & Hammad, T. Use of nutraceuticals in the management of osteoarthritis. J American Nutraceutical Ass3, 23-27 (2000).
  18. Usha, P.R. & Naidu, M.U. Randomised, double-blind, parallel, placebo-controlled study of oral glucosamine, methylsulfonylmethane and their combination in osteoarthritis. Clin Drug Investig 24, 353-363 (2004).

[endmore]

[more]

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.

[endshort]

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

  1. Iovu, M., Dumais, G. & du Souich, P. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage 16 Suppl 3, S14-18 (2008).
  2. Reginster, J.Y., Heraud, F., Zegels, B. & Bruyere, O. Symptom and structure modifying properties of chondroitin sulfate in osteoarthritis. Mini Rev Med Chem 7, 1051-1061 (2007).
  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).
  5. Medicine, N. The NIH Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT). J Pain Palliative Care Pharmacother 22, 39-43 (2008).
  6. Hochberg, M.C. & Clegg, D.O. Potential effects of chondroitin sulfate on joint swelling: a GAIT report. Osteoarthritis Cartilage 16 Suppl 3, S22-24 (2008).
  7. National Center for Complementary and Integrative Health. https://nccih.nih.gov/research/results/gait/qa.htm (2008).
  8. Food and Drug Administration. Glucosamine and chondroitin sulfate: scientific evaluation. http://www.fda.gov/ohrms/dockets/ac/04/briefing/4045b1_05-conclusions.htm.
  9. UK National Health Service. http://www.gwh.nhs.uk/media/151160/10-3ts_glucoasamine_guidance_-_oct2010_-_final.pdf (2010).
  10. Jordan, K.M. et al. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Annals Rheum Diseases 62, 1145-1155 (2003).
  11. Maheu, E. Savoir prescrire un anti-arthrosique d’action lente. Meeting Proceedings: "Avancées thérapeutiques" (Therapeutic Advances) October 8, 2010 [in French] (2010).
  12. Association of Rheumatologists of Russia. Federal recommendations on the diagnosis and treatment of osteoarthritis. http://www.rheumatolog.ru/sites/default/files/Pdf/clinrec/osteoartrit.docx [in Russian] (2013).
  13. Zhang, W. et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 16, 137-162 (2008).
  14. Barten, D.J. et al. Treatment of hip/knee osteoarthritis in Dutch general practice and physical therapy practice: an observational study. BMC Family Practice 16, 75 (2015).
  15. Zhang, W. et al. EULAR evidence based recommendations for the management of hand osteoarthritis: report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Annals Rheum Diseases 66, 377-388 (2007).
  16. Bannuru, R.R., Vaysbrot, E.E., Sullivan, M.C. & McAlindon, T.E. Relative efficacy of hyaluronic acid in comparison with NSAIDs for knee osteoarthritis: a systematic review and meta-analysis. Semin Arthritis Rheum 43, 593-599 (2014).
  17. Kalman, D.S., Heimer, M., Valdeon, A., Schwartz, H. & Sheldon, E. Effect of a natural extract of chicken combs with a high content of hyaluronic acid (Hyal-Joint) on pain relief and quality of life in subjects with knee osteoarthritis: a pilot randomized double-blind placebo-controlled trial. Nutr J 7, 3 (2008).
  18. Nagaoka, I. et al. Evaluation of the effects of a supplementary diet containing chicken comb extract on symptoms and cartilage metabolism in patients with knee osteoarthritis. Exp Ther Med 1, 817-827 (2010).
  19. Tashiro, T. et al. Oral administration of polymer hyaluronic acid alleviates symptoms of knee osteoarthritis: a double-blind, placebo-controlled study over a 12-month period. Scientific World J 2012, 167928 (2012).
  20. Bello, A.E. & Oesser, S. Collagen hydrolysate for the treatment of osteoarthritis and other joint disorders: a review of the literature. Curr Med Research Opin 22, 2221-2232 (2006).
  21. Van Vijven, J.P. et al. Symptomatic and chondroprotective treatment with collagen derivatives in osteoarthritis: a systematic review. Osteoarthritis Cartilage 20, 809-821 (2012).
  22. Llopis-Miró, R., de Miguel-Saenz, J. & Delgado-Velilla, F. [Efficacy and tolerance of an oral hyaluronate and collagen chondroprotector on joint function in active adults suffering from knee osteoarthritis]. Apunts. Medicina de l'Esport 47, 3-8 [in Spanish with summary in English] (2011).
  23. Sibila, S., Godfrey, M., Brewer, S., Budh-Raja, A. & Genovese, L. An overview of the beneficial effects of hydrolysed collagen as a nutraceutical on skin properties: scientific background and clinical studies. Open Nutraceuticals J 8, 29-42 (2015).
  24. Usha, P.R. & Naidu, M.U. Randomised, double-blind, parallel, placebo-controlled study of oral glucosamine, methylsulfonylmethane and their combination in osteoarthritis. Clin Drug Investig 24, 353-363 (2004).
  25. de Campos, G.C. Placebo effect in osteoarthritis: Why not use it to our advantage? World J Orthopedics 6, 416-420 (2015).
  26. Gregory, P.J. The recommendations for glucosamine do not tell the whole story: comment on the article by Hochberg et al. Arthritis Care Res 65, 326-327 (2013).
  27. Zhang, W., Robertson, J., Jones, A.C., Dieppe, P.A. & Doherty, M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Annals Rheum Diseases 67, 1716-1723 (2008).
  28. Sawitzke, A.D. et al. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Annals Rheum Diseases 69, 1459-1464 (2010).
  29. Bottegoni, C., Muzzarelli, R.A., Giovannini, F., Busilacchi, A. & Gigante, A. Oral chondroprotection with nutraceuticals made of chondroitin sulphate plus glucosamine sulphate in osteoarthritis. Carbohydr Polym 109, 126-138 (2014).
  30. Hungerford, D., Navarro, R. & Hammad, T. Use of nutraceuticals in the management of osteoarthritis. J American Nutraceutical Ass3, 23-27 (2000).

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