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Glucosamine - What's in a name?

5 Jan 2015 8:27 PM -

Glucosamine products are now a common sight on supermarket shelves and in produce stores, with various claims regarding joint health.  For example, Nutriflex: ‘…proven cartilage regenerative ability…’ and Cosequin®: 'stimulates synthesis of synovial fluid and the complete cartliage matrix, including collagen and proteoglycans.’ However, not all products are created equal.  Did you know that whilst glucosamine products are classified in the Agricultural and Veterinary Chemicals Code Regulations 1995 as a veterinary chemical product and thus require registration, the evidence to support the product registration may be 'borrowed' from other research on other products with the glucosamine constituent but complexed with something else?  This is called bioequivalence for  chemicals and phytoequivalence for herbs., which means that the new product is stated to have the same target in terms of efficacy and safety to another research confirmed product.  However, the new product itself has not be researched or trialled.

Glucosamine is an essential component of normal, healthy cartilage and is the first step in glycosaminoglycan biosynthesis.  An unstable form of glucosamine was first prepared in 1898, but it was not until 1969 when German researchers were able to demonstrate application to osteoarthritis symptoms with a stable form derived from crustaceans.  The first placebo-controlled clinical trials investigating glucosamine in osteoarthritis was in the 1980s with a Rotta Pharmaceutical Company (Rottapharm) crystalline glucosamine sulphate product.  A Cochrane review found 56% human random controlled trials exclusively evaluated the crystalline glucosamine sulphate product made by Rottapharm and that this preparation was superior to placebo in the treatment of pain and functional impairment resulting from symptomatic osteoarthritis.  (Theodosakis, 2004) (Oke, Aghazadeh-Habashi, Weese, & Jamal, 2006) (Towheed, et al., 2009)

In vitro research with human osteoarthritic articular cartilage chondrocytes has found glucosamine increases proteoglycans by affecting the synthesis of monomeric proteoglycans capable of assembling into high molecular weight aggregates.  However, numerous pharmacokinetic studies have concluded that a simple ‘building block’ analogy in the synovial joint is unlikely due to low bioavailability following oral ingestion, nasogastric incubation or intravenous administration.  Comparative bioavailability and efficacy studies (human and animal) have found glucosamine sulphate is superior to glucosamine hydrochloride, however the mechanism of action remains unclear.  A possible anti-inflammatory medical action has been proposed by some researchers and others have speculated that the sulphate moiety may mediate the clinical benefit of glucosamine in osteoarthritis.  (Towheed, et al., 2009) (Muelyzer, et al., 2008) (Hoffler, Kaplan, Hamadeh, Grigoriu, & Baron, 2001) (Welch, Potter, Gibbs, & Eller, 2012)

Given the variability in research results, determining an appropriate, clinical therapeutic form, administration and dose is important in order to achieve maximum efficacy in treatment and cost.  A number of studies have reviewed available products both for efficacy in dose and purported label to product content.  Three studies, summarised in Table 1, have found major variances in quality.  Additionally, Oke, Aghazadeh-Habashi, Weese, & Jamal (2006) found significant variation in the recommended daily maintenance dose with only five of the 25 products reviewed suggested by  Laverty, et al., (2005), that being 10g of glucosamine per day  per os for a 500 kg horse.  

Cosequin ®, marketed in Australia by Ceva Animal Health Pty Ltd, is a glucosamine hydrochloride and chondroitin sulphate combination containing 54.5 g of glucosamine per 100g of the product.  The dosages recommended on the label provide significantly different quantities of glucosamine to those recommended by Laverty, et al., (2005), a total of 18 g per day for a 500 kg horse for the first four to six weeks and then 3.6 g per day as a maintenance dose.  A small randomised, double-blind, placebo-controlled trial in 2001with 14 horses by Hanson, et.al., using the Cosequin ® label dosages for an 8 week period reported significant improvements in lameness scores, but no significant improvements in radiographical scores.  Along with the potential bias caused by sponsorship from the manufacturer of the tested product, the design of the trial employed one investigator and the horse owners to do a visual lameness evaluation, including hoof tester examination, as opposed to employing more quantitative assessment and analysis tools.  Another trial in 1997 using Cosequin ® also reported lameness improvements, however the trial lacked a placebo group, there was no randomization or blinding of the examiners, and commercial sponsorship may have added an additional source of bias (Richardson & Loinaz, 2007).

The Australian Government Agricultural and Veterinary Chemicals Code Regulations (2014) classifies glucosamine as a veterinary chemical product and as such products are subject to registration, monitoring and auditing to ensure manufacture is in such a way as to comply with their registered particulars, as well as applicable standards.  The APVMA issued manufacturing licenses are subject to compliance with Manufacturing Principles (Australian Government, 2014) and the Australian Code of Good Manufacturing Practice for Veterinary Chemical Products (GMP) (APVMA, 2007).  These regulations require Australian manufacturers to have in place procedures to ensure the quality of the manufactured product.  The Code of GMP ensures consistency in manufacture to the quality standards appropriate for their intended veterinary use.  Manufacturer quality control, required as a part of GMP, includes specifications, sampling and testing of a given product to ensure the appropriate, consistent level of quality prior to release for sale.   The APVMA employs a risk-based approach to compliance and enforcement of regulations pertaining to veterinary chemicals.  Included in this approach is the monitoring of marketed product labels, random testing and sampling of chemical substances and compliance audits.  Therefore, the variances of product quality reported by Oke, et. al., (2006),  Adebowale, et. al., (2000) and Ramey, et.al., (2002) theoretically should not be evident in veterinary chemical products for sale on the Australian market.  However, efficacy may be a significant issue.

Characteristics

(Hanson, et al., 2001)

(Oke, Aghazadeh-Habashi, Weese, & Jamal, 2006)

(Adebowale, Cox, Zhongming Liang, & Eddington, 2000)

(Ramey, Eddington, Thonar, & Lee, 2002)

Methods

Randomised

Double-blind

Placebo-controlled

Reverse-phase HPLC using precolumn derivatisation with 1-naphthyl isothiocyanate and ultraviolet detection

UV-HPLC

Glucosamine analysed using precolumn dervatisation with ultraviolet HPLC

Blinded lab testing (outsourced)

Population

14 horse with navicular syndrome

23 x commercial equine OSJs

14 products containing either glucosamine hydrochloride or sulphate

11 products containing glucosamine, chondroitin sulfate or  both

Intervention

N=8 16.5 g of Cosequin  BD in the feed.

t=8 weeks

Glucosamine free base (GFB) calculated as:

Samples & standards - the mean of three assays per product sample

Product label conversion –

1 g glucosamine hydrochloride or potassium salt = 0.83g GFB

1 g N-acetyle glucosamine = 1 g GFB

1 g glucosamine sulphate = 0.6 g GFB

Single quantitative measure

Average measured amount (of 3 samples) of each product sample

Comparison

N=6 Placebo

Control samples:

            glucosamine hydrochloride

            ascorbic acid

            Flx+ and Corta-Flx+ (rice-based nutraceuticals)

Sample product compared to product label

%Label claim = Measured amount (mg)/Labelled amount (mg) x 100

Outcomes

Significant improvement in lameness scores and clinical condition.

No significant differences in radiographic scores.

Actual vs Product label:

Range: 0 – 221.2%

Mean: 99.0%

Median: 106/5%

9/23 had less than  product label

4/23 had < 30% corresponding product label

Dose: average 6302.2mg, median 5000mg; range 1800–12000mg per os /day

Significant differences between analysis amount and product label

Range: 25% - > 115%

6/6 products containing  glucosamine: averaged measured amount ≠ product label;

Range: 63.6% - 112.2%

$ glucosamine range:

$0.11 / kg - $0.79 /kg

Shortfalls

Commercial sponsorship may have added an additional source of bias.

Methodologically sound, allocation concealment not included, careful control for confounding not evident (e.g. assumptions on bioavailability and dose-response) and little missing data (error rates and uncertainty of analytical procedure not discussed)

Different UV-HPLC procedure to Oke et al., (2006)

 

 

Table 1: PICO Summary of Glucosamine Products Reviews

 

 


References:

Adebowale, A. O., Cox, D. S., Zhongming Liang, M. S., & Eddington, N. D. (2000). Analysis of Glucosamine and Chondroitin Sulfate Content in Marketed Products and the Caco-2 Permeability of Chondroitin Sulfate Raw Materials. Journal of American Nutraceutical Association, 3(1), 37-44.

APVMA. (2007, Mar 29). Australian Code of Good Manufacturing Practice for Veterinary Chemical Products. Retrieved Dec 17, 2014, from APVMA: http://apvma.gov.au/sites/default/files/docs/gmp_code_vet_0.pdf

Australian Govenment. (2014, Aug 26). Agricultural and Veterinary Chemicals Code Regulations 1995. Retrieved Dec 15, 2014, from ComLaw: http://www.comlaw.gov.au/Details/F2014C01004/Html/Text#_Toc396750618

Australian Government. (2014, Jun 25). Agricultural and Veterinary Chemicals Code (Manufacturing Principles) Determination 2014. Retrieved Dec 15, 2014, from ComLaw: http://www.comlaw.gov.au/Details/F2014L00859

Hanson, R. R., Brawner, W. R., Blaik, M. A., Hammad, T. A., Kincaid, S. A., & Pugh, D. G. (2001). Oral treatment with a nutraceutical (Cosequin) for ameliorating signs of navicular syndrome in horses. Veterinary Therapyq, 2(2), 148-159.

Hoffler, L. J., Kaplan, L. N., Hamadeh, M. J., Grigoriu, A. C., & Baron, M. (2001, Jul). Sulfate Could Mediate the Therapeutic Effect of Glucosamine Sulfate. Metabolism, 50(7), 767-770.

Laverty, S., Sandy, J. D., Celeste, C., Vachon, P., Marier, J., & Plaas, A. H. (2005). Synovial fluid levels and serum pharmacokinetics in a large animal model following treatment with oral glucosamine at clinically relevant doses. Arthritis & Rheumatism, 52(1), 181-191.

Muelyzer, M., Vachon, P., Beaudry, F., Vinardell, T., Richard, H., Beauchamp, G., & Laverty, S. (2008). Comparison of pharmacokinetics of glucosamine and synovial fluid levels following administration of glucosamine sulphate or glucosamine hydrochloride. Osteoarthritis and Cartilage, 16, 973-979.

Not Given, Z. (2014, Dec 19). COSEQUIN® Equine Powder Quality Control. (S. M. Johnson, Interviewer) Parkes, NSW, Australia.

Oke, S., Aghazadeh-Habashi, A., Weese, J. S., & Jamal, F. (2006). Evaluation of glucosamine levels in commercial equine oral supplements for joints. Equine Veterinary Journal, 38(1), 93-95.

Ramey, D. W., Eddington, N., Thonar, E., & Lee, M. (2002). An analysis of glucosamine and chondroitin sulfate content in oral joint supplement products. Journal of Equine Veterinary Science, 22(3), 125-127.

Richardson, D. W., & Loinaz, R. (2007). An evidence-based approach to selected joint therapies in horses. Veterinary Clinics Equine Practice, 23, 443-460.

Theodosakis, J. (2004). The Arthritis Cure: The Medical Miracle That Can Halt, Reverse, And May Even Cure Osteoarthritis. St Martins Press.

Towheed, T., Maxwell, L., Anastassiades, T. P., Shea, B., Houpt, J. B., Welch, V., . . . Wells, G. A. (2009). Glucosamine therapy for treating osteoarthritis (Review). The Cochrane Collaboration, 1-49. Retrieved from http://onlinelibrary.wiley.com.ezproxy.csu.edu.au/doi/10.1002/14651858.CD002946.pub2/pdf/standard

Welch, C. A., Potter, G. D., Gibbs, P. G., & Eller, E. M. (2012). Plasma Concentration of Glucosamine and Chondroitin Sulfate in Horses after an Oral Dose. Journal of Equine Veterinary Science, 32(1), 60–64.