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Glucosamine / Chondroitin (Doctors' Edition) PDF Print E-mail
Written by Dr. Edward Zimmer   

Many of our patients present for our counsel on how to reduce arthritic pain. Two of the most commonly recommended natural treatments are for glucosamine (GS) and chondroitin sulfate (CS). My goal in this issue is to expose you to more than the regular “run of the mill” information you get regarding these supplements. Additionally, in our “Topics By Request” section I have been asked to cover the use of natural supplements for sleep assistance.

Glucosamine/chondroitin sulfate Arthritis Intervention Trial (GAIT) study

  • I was amazed to read the January 2006 issue of the Prescriber’s Letter® where the author commented on the NIH’s GAIT (Glucosamine/Chondroitin Arthritis Intervention Trial) study1 by stating, “But the study merely adds to the debate.” and “There’s also still no answer on whether combining glucosamine and chondroitin works any better than either one alone.” I am not sure how anyone who read the specifics of the GAIT study could come to these conclusions. I also find it interesting that this letter describes itself as “...an independent service providing unbiased drug information for subscribers.” Let me disclose to you right up front that Alternative Health Update is written from a biased point of view. However, I will always attempt to outline the reasoning behind my point of view so you can better put my biases into prospective to decide what you will accept as accurate.
chondroitin2
  • Here are the specifics for the GAIT study. 1,258 participants completed this study on knee pain. The WOMAC pain assessment scale was utilized to identify patients as having either mild pain (125-300mm) or severe pain (301-400mm). Patients were double-blinded to either placebo, glucosamine alone (500 mg/tid), chondroitin sulfate alone (400 mg/tid), glucosamine + chondroitin (same doses), or celecoxib 200mg/day. Results were evaluated at weeks 4, 8, 16, and 24.
  • The results after 24 weeks from the study were reported as the percentage of patients receiving at least a 20% improvement in baseline symptoms.
  • I draw your attention to the Severe Pain results. Celecoxib scored 69.4% improvement in WOMAC pain severity while glucosamine + chondroitin scored significantly better at 79.2%. Neither glucosamine nor chondroitin alone showed any statistical benefit. The very clear results of this study were that glucosamine + chondroitin performed better than glucosamine alone, chondroitin alone, AND celecoxib in patients with severe arthritic knee pain after 24 weeks.
  • So, do these results show that glucosamine, chondroitin, or a combination do not work for milder arthritic pain? I think clinical insight can be gained by asking why the combination worked so well for severe pain, but not for mild pain. One answer is that GS and CS simply do not work for this kind of arthritis. Other studies, which will be outlined next, and my clinical experience with real patients have shown benefit even for mild arthritis. Another answer was tendered by the authors of this study, “The lack of response in patients with mild pain may be due to a floor effect, limiting ability to detect response.” It is difficult to dismiss that the use of these agents improves joint health in the long-run. This would explain the change in response from non-significant to significant with GS + CS.
  • Notice the placebo effect in this study. Basically, more than 1/2 of the patients perceived benefit from a “nothing” pill. This extremely high placebo response illustrates just how difficult it is to test arthritic remedies using symptoms alone.

Glucosamine & Chondroitin, Individually

  • A number of studies have shown benefit from oral glucosamine. One multicenter study concluded that 95% of patients taking 1.5 g of glucosamine/day rated their treatment as good or sufficient.2 Two smaller double-blind placebo-controlled studies concluded similar results.3-4 Another double-blind trial tested glucosamine vs. ibuprofen in knee OA.5 Pain scores decreased faster with ibuprofen until week 8. At that time glucosamine was shown to be significantly better. The implication is that glucosamine improves joint health. This hypothesis is supported by other studies.6-8 Unfortunately, most studies showing stimulation of articular cartilage proteoglycan synthesis were done in-vitro using animal samples.8-11
  • Both double-blind, placebo-controlled studies, as well as open studies, have shown benefit in patients with OA including the reduction in NSAID use.12-14 One of those studies concluded, “This study provides evidences that oral CS decreased pain and improved knee function. The inhibitory effect of CS on the radiological progression of the medial femoro-tibial joint space narrowing could suggest further evidence of its structure-modifying properties in knee OA.” 14
  • The GAIT study, was not the only study concluding no symptomatic benefit from using CS alone. A recent study concluded, “While there was no significant symptomatic effect in this study, long-term treatment with CS may retard radiographic progression in patients with OA of the knee.”15 Again, the implication is that a benefit beyond symptom reduction may be gained through the use of CS.

The Problems With Glucosamine & Chondroitin

  • There are a couple of considerations you must make when you decide whether to suggest the use of GS or CS. The first deals with the form of glucosamine to suggest (glucosamine sulfate vs. glucosamine HCL) and the second deals with concerns over product quality.
  • Most published studies have used the glucosamine sulfate form. The GAIT study used the glucosamine HCL form. Is there a difference that you should be concerned with clinically?
  • A little background may help you to form an opinion. In 1971, Karzel and Domenjoz16 compared glucosamine HCL to glucosamine sulfate. They stated, “glucosamine HCL seems to possess a somewhat stronger effect than glucosamine sulfate. This, however, is only true for a comparison on the basis of absolute concentrations. If the results are calculated with reference to the molecular weights of the compounds no difference is demonstrable.” Essentially, glucosamine HCL has more glucosamine by weight than does glucosamine sulfate. Thus, HCL was only better because it contained more glucosamine.
  • In the early 1980’s, Rotta Research Laboratory (Italy) had the patent on glucosamine sulfate and began publishing studies using, of course, the sulfate form. Interestingly, in 1978 a group from Rotta had published a study proving the effects of glucosamine HCL on both GAG synthesis and cartilage protein synthesis.17 After obtaining the patent Rotta was directly involved or supported dozens of studies showing benefit using oral glucosamine sulfate. This led many to believe and repeat that the sulfate form was preferable. There are NO credible studies showing superiority of the sulfate over the HCL form.
  • The question of quality is always an issue when it comes to the use of supplements. This is unfortunately true when it comes to glucosamine and chondroitin sulfate.
  • There is a chondroitin sulfate formulation approved as a drug in Europe, with evidenced efficacy and safety demonstrated by clinical trials in OA patients. This formulation is manufactured by the Spanish company Bioiberica (distributed by NutraMax in the US). There has been a call to enforce bioequivalence of generic chondroitins to this gold standard product.18 This is the small molecular weight chondroitin that was used in the GAIT study.
  • An eye-opening study published in the Spring 2000 issue of JANA outlined how serious the quality problem is with chondroitin.19 Quoting directly from the study: (I did not have permission to reproduce Figure 3)

    • "Figure 3 (not shown) presents the percent label claim and adjusted retail price of chondroitin sulfate in 32 chondroitin sulfate containing products purchased from pharmacies and health food stores during the period of September 1998 through November 1999 and analyzed by the titration method.” and “Twenty-six out of 32 products were found to contain less than 90% of the chondroitin sulfate stated on the label with 17 products containing less than 40% of label claim. Only five out of 32 products contained the labeled amount of chondroitin sulfate in the product. This would suggest that in many cases 84% of brands that were tested are inferior products.”

  • The most important finding of this study was that NONE of the products tested that were below $1.00/1200 mg chondroitin sulfate even had 10% of label claim. The implication is to stay away from any cheap chondroitin supplement. The problem is that the high quality 95% pure, smaller molecular weight chondroitin from Bioiberica is very expensive when compared to the cheaper products. But if those products contain 1/10 of the claimed chondroitin, then multiplying their price by 10 makes them the more expensive choice.

Putting It All Together/Recommendations For Your Patients

  • Almost NO products contain only chondroitin sulfate. Your choices are either to recommend glucosamine by itself or in combination with chondroitin. (1,500 –2,000 mg glucosamine/day and 1,200 mg chondroitin/day)
  • The studies showing benefit from taking glucosamine alone for symptom reduction are inconsistent, at worst, but tend to lean towards a benefit from taking glucosamine. The true benefit may be in the prevention of disease progression through the stimulation of proteoglycan synthesis. The form of glucosamine can be either HCL or Sulfate.
  • There is now strong support for recommending the combination of chondroitin sulfate with glucosamine both for symptom reduction in the long-run and for the prevention of disease progression. If cost is not the issue, suggest the combination.
  • For patients with financial restraints recommend starting with a bottle of chondroitin + glucosamine and then alternate with the next bottle being only glucosamine. I have had success using this approach.
  • You should inform your patients that taking cheap store-bought brands are more than likely a waste of their time and money as the quality and quantity of both chondroitin and glucosamine have to come into serious question. A rule of thumb will be that high quality chondroitin mixed with glucosamine will cost them at least $30/month (not per bottle). Anything less expensive will be a gamble.

Topics By Request: Natural Sleep Aides

  • Many patients present with complaints of insomnia. There are a number of natural products that can be recommended to help with this condition. This section will cover two of the most common and I believe to be the two most effective: Melatonin and Valerian root (valeriana officinalis)
  • Melatonin is synthesized mostly by the pineal gland and the gut by the following chemical pathway:

    • Tryptophan → 5-Hydroxytryptophan (5-HTP) → Serotonin → N-acetylserotonin → Melatonin

  • Supporting this pathway with supplementation of 5-HTP may be of benefit, as anti-depressants are commonly prescribed for insomnia.
  • Supplemental melatonin was shown in studies to help with falling asleep when taken about 30-60 minutes before the desired sleep time. 20,21 The most common dose found to be effective was 3-5 mg.
  • Valerian root contains pungent essential oils that appear to provide its sedative activity. Valerian interacts with neurotransmitters such as GABA and also inhibits the enzyme-induced breakdown of GABA in the brain, with concomitant sedation.22
  • A number of placebo-controlled studies have been done investigating valerian and treatment of insomnia.23-24 These studies show that between 400 mg to 600 mg of valerian were effective compared to placebo. The beneficial effect increased after one week of taking the herb. Valerian root was studied against oxazepam in a double-blind study for six weeks.25 Valerian (600 mg/daily) was found to be equal to oxazepam (10 mg/daily) on sleep quality, measured by the Sleep Questionnaire, CGIS, and Global Assessment of Efficacy.
  • Thus, you can recommend taking 5 mg of melatonin about 30-60 minutes prior to bedtime and/or 400-600 mg of valerian root at the same time. The melatonin seems to have a quicker reaction time as the benefits of taking valerian may not be realized for one week. A word of caution about valerian root: I call it “stinky” root. The essential oils are very pungent and smell like “dirty socks”. I warn all of my patients about this lest they will think something is wrong when they open the bottle. I tell them to swallow quickly.
  • Drug interactions & Cautions using Melatonin: Melatonin is metabolized primarily by CYP1A2. Therefore, drugs that inhibit CYP1A2 can increase serum melatonin. These include fluvoxamine, cimetadine, ciprofloxacin, erythromycin, & tricyclic antidepressants. NSAID’s, such as ibuprofen and naproxen, can suppress endogenous melatonin production. Melatonin may potentiate the effects of coumadin (warfarin). Melatonin has immune boosting effects and I would not suggest its use with autoimmune patients or with cancers such as leukemia or lymphomas.
  • Drug interactions & Cautions using Valerian: Avoid concurrent use with barbiturates. Allergic reactions are very rare.

  • You can contact Dr. Zimmer with any questions, requests, or responses via email or at 317-813-1998 / toll free 1-888-813-1998.

REFERENCES

  1. Clegg D, Reda D, Harris C, Klein M. The efficacy of glucosamine and chondroitin sulfate in patients with painful knee osteoarthritis: the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT). 622, ACR Conference, November 14, 2005.
  2. Tapadinhas MJ, Rivera IC, Binamini AA. Oral glucosamine sulphate in the management of arthrosis: report on a multi-centre open investigation in Portugal. Pharmatherapeutica 1982;3(3):157-68.
  3. Fava M, Alpert J, Nierenberg AA, et al. A Double-blind, randomized trial of St. John’s wort, fluoxetine, and placebo in major depressive disorder. J Clin Psychopharmacol. 2005 Oct;25(5):441-7.
  4. Pujalte JM, Liavorce EP, Ylescupidez FR. Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthrosis. Curr Med Res Opin 1980;7(2):110-14.
  5. Lopes Vaz A. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthritis of the knee in out-patients. Curr Med Res Opin 1982;8(3):145-9.
  6. Drovanti A, Bignamini AA, Rovati AL. Therapeutic activity of oral glucosamine sulfate in osteoarthritis: a placebo-controlled double-blind investigation. Clin Ther 1980;3(4):260-72.
  7. McCarty MF. Glucosamine may retard atherogenesis by promoting endothelial production of heparan sulphate proteoglycans. Med. Hypothesis 1997 Mar;48(3):245-51.
  8. Bassleer C, Rovati L, Franchimont P. Stimulation of proteoglycan production by glucosamine sulfate in chondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthritis Cartilage 1998 Nov;6(6):427-34.
  9. Chan PS, Caron JP, Orth MW. Effect of glucosamine and chondroitin sulfate on regulation of gene expression of proteolytic enzymes and their inhibitors in interleukin-1-challenged bovine articular cartilage explants. Am J Vet Res. 2005 Nov;66(11):1870-6.
  10. Terry DE, Rees-Milton K, Smith P, et al. N-acylation of glucosamine modulates chondrocyte growth, proteoglycan synthesis, and gene expression. J Rheumatol. 2005 Sep;32(9):1775-86.
  11. Tiraloche G, Girard C, Chouinard L, Sampalis J, et al. Effect of oral glucosamine on cartilage degradation in a rabbit model of osteoarthritis. Arthitis Rheum. 2005 Nov;52(11):3680.
  12. Leeb BF, Petera P, Nuemann K. Results of a mulicenter study of chondroitin sulfate use in arthrosis of the finger, knee, and hip joints. Wien Med Wochenschr 1996;146(24):609-614.
  13. Morreale P. Manopulo R, Galati M, et al. Comparison of the anti-inflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. J Rheumatol 1996;23(8):1385-91.
  14. Uebelhart D, Malaise M, Marcolongo R, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage. 2004 Apr;12(4):269-76.
  15. Michel BA, Stucki G, Frey D, et al. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized, controlled trial. Arthritis Rheum. 2005 Mar;52(3):779-86.
  16. Karzel K, Domenjoz R. Effects of hexosamine derivatives and uronic acid derivatives on glycosaminoglycan metabolism of fibroblast cultures. Pharmacology 1971; 5:337-345.
  17. Vidal Y, Plana RR, Bizzarri D, Vovati AL. Articular cartilage pharmacology: 1. In vitro studies on glucosamine and non steroidal anti-inflammatory drugs. Pharmacol Res Com 1978;10(6)557-569.
  18. Verges J, Castaneda-Hernandez G. On the bioavailability of oral chondroitin sulfate formulations: proposed criteria for bioequivalence studies. Proc West Pharmacol Soc. 2004;47:50-3.
  19. Adebowale A, Cox D, Liang Z, Eddington N. Analysis of glucosamine and chondroitin sulfate content in marketed products and the caco-2 permeability of chondroitin sulfate raw materials. JANA 2000 Vol.3, No. 1 Spring.
  20. Zhadanova IV, Wurtman RJ, Lynch HJ, et al. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther 1995;57:552-8.
  21. Hughes RJ, Sack RL, Lewy AJ. The role of melatonin and circadian phase in age-related sleep maintenance insomnia: assessment in a clinical trial of melatonin replacement. Sleep 1998;21:52-68.
  22. Riedel E, Hansel R, Ehrke G. Inhibition of gamma-aminobutyric acid catabolism by valerenic acid derivatives. Planta Med 1982;46:219-220.
  23. Donath F, Quispe S, Diefenback K, et al. Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. Phamacopsychiatry 2000;33:47-53.
  24. Poyares DR, Guilleminault C, Ohayon MM, Tufik S. Can valerian improve sleep of insomniacs after benzodiazepine withdrawal? Prog Neuropsychopharmacol Biol Psychiatry 2002;26:539-545.
  25. Zeigler G, Plock M, et al. Efficacy and tolerability of valerian extract LI 156 compared with oxazepam in the treatment of non-organic insomnia-a randomized, double-blind, comparative clinical study. Eur J Med Res 2002;7:480-486.
 
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