Tissue Rejuvenator's Glucosamine Sulfate & Chondroitin Sulfate

By William Misner, Ph.D.

William Misner, Ph.D.
William Misner, Ph.D.
From 1996 until his retirement in 2006, Dr. Bill worked full-time as Director of Research & Development at Hammer Nutrition. Among his many accomplishments, both academically and athletically, he is an AAMA Board Certified Alternative Medicine Practitioner and the author of "What Should I Eat? A Food-Endowed Prescription For Well Being".
Q: What do you say in response to the NEJM study on Glucosamine and Chondroitin. They found that it only beat the placebo for severe joint pain. Does this imply anything for Tissue Rejuvenator since "G" and "C" are the main ingredients? 

The rate of response to glucosamine was 3.9 percentage points higher, the rate of response to chondroitin sulfate was 5.3 percentage points higher, but the rate of response to combined treatment was 6.5 percentage points higher, compared to the rate the rate of response in the celecoxib control group as 10.0 percentage points higher than that in the placebo control group: 

COMMENT: Interesting that patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2% vs. 54.3%). Furthermore, Glucosamine and Chondroitin primarily as building blocks if not available for natural structural synthesis over a 24-week period did produce limited symptom reduction. Osteoarthritic knee pain symptomology is effected body weight, ongoing weight bearing trauma, and the individual CELECOXIB response. CELECOXIB is a known anti-inflammatory, yet it absorbed only 1 part of 10 above placebo, or 3 parts above taking nothing out of a possible symptom-free "10" parts. I can rationalize the same sort of reasoning with protein intake in exercising subjects. Joint compatibility ease of exercise is influenced by muscle mass synthesis following exercise. The athlete who does not consume adequate protein will not grow the muscle required for future exercise event stress demand, while the athlete who consumes enough protein to satiate the muscle mass resynthesis process post exercise will gain more muscle mass, hence better performance results. Other papers listed also contradict the NEJM paper (http://content.nejm.org/cgi/content/short/354/8/795) including the remaining anti-inflammatory natural substances in the Tissue Rejuvenator product, which, in my opinion deserve a careful review. I never conclude a review without consideration of a number of research publications. Whether Glucosamine or Chondroitin Sulfates are considered for their building block potential or anti-inflammatory effects are not conclusive based on one large study that calls 10% "significant" but calls 6.5% "insignificant." It is too close to call "insignificant" in light of so many other studies reporting "significant" results. 

The paper you refer to utilized Glucosamine HCL in a large subject contingent. Tissue Rejuvenator is formulated with Glucosamine Sulfate and 16 other ingredients shown to reduce chronic and some acute inflammatory joint pain. In contradiction, research does argue that glucosamine in dose dependent fashion reduces chronic inflammation in a large majority of human subjects. 

Tissue Rejuvenator compound reduces the rate of trauma-induced inflammation by several different pathways. Besides Glucosamine Sulfate and Chondroitin Sulfate, other ingredients such as Methylsulfonylmethane, Peptidase, Bromelain, Papain, Protease, Amylase, Lipase, Cellulase, Phytase, Boswellia Serrata, Devils Claw, Yucca Root, Curcuma Longa, Quercetin (Saphora Japonica), Undenatured Type II Collagen have been shown to reduce inflammation. You may download PubMedline research on each one to determine its efficacy in reducing joint inflammation. 

I have included the link to the National Library of Medicine below for research engine to access the literature. 

No single study showing an association without corroborating evidence from other research properly concludes findings outside the study population. Science methodology typically requires 20 research papers from an assortment of researchers without biased competing interests. I suggest there is a simple explanation for the role of Glucosamine in reducing chronic inflammatory pain and support the oversimplification with what has survived the peer-review process published from recorded science. 

Kwashiorkor occurs most commonly in areas of famine with protein deprivation occurs, growth failure, loss of muscle mass, generalized swelling (edema), and decreased immunity. An over-simplified explanation is to compare muscle resynthesis following muscle loss, muscle damage or injury recovery on a low protein diet. When activity increases the need for protein increases in order to accommodate the rate of loss and resynthesis repair. Protein synthesis requires from 3-14 days to complete, however glucosamine synthesis required for stimulating production of proteoglycans by chondrocytes can require from 28-180 days to complete. One researcher advises that a 3-year protocol has advantages. Glucosamine availability is to the repair and health of the joints, connective tissue, and joint space fluids what protein is to muscle growth and repair. Exogenous, supplemental glucosamine instructs chondroclasts to cease destroying cartilage and can reactivate chondroblasts to recommence "building" new cartilage. Our body does not revive joint structures as quickly as it does the high vascular tissues, such as muscles and skin areas. When the body has adequate supplies of both glucosamine sulfate and chondroitin sulfate, it will heal itself at the most rapid rate. In the absence of or deficiency of glucosamine sulfate and chondroitin sulfate, the body will not repair activity-induced joint structures, but with provocation and chronic deficiency, the inflammation state will progress. 

Glucosamine sulfate is required by the body to regenerate or reform joints and tendons. We require a minimum amount of glucosamine sulfate to preserves the structural integrity of the joints (1-2 grams per day) in order to eliminate the pain from damaged joints or repair damaged joints. Glucosamine sulfate is an essential component of the connective tissue matrix of ligaments, cartilage, and tendons. Everyone's body makes glucosamine, but they do not synthesize it as fast as we may damage these structures. Both glucosamine sulfate and Chondroitin sulfate are precursor moieties (like building blocks) the body synthesizes naturally to generate connective tissue, cartilage, and synovial joint space fluid. Glucosamine sulfate is 64.6% glucosamine, presenting 90-98% oral bioavailability orally-ingested absorption rate. 

The majority of positive reporting clinical studies used glucosamine sulfate. The sulfate in the glucosamine sulfate molecule contributes to the therapeutic effects of this form. It has a short half-life and probably does not inhibit the elastase enzyme (which the chondroitin sulfate form DOES). 

Drovanti reported in 1980:
 "Eighty inpatients with established osteoarthritis received either 1,500 mg of glucosamine sulfate or placebo daily, in three divided oral doses, for 30 days. Articular pain, joint tenderness and swelling, and restriction of active and passive movements were scored at one week intervals, as were possible side reactions. Hematologic analysis, urine analysis, and occult blood in feces were recorded before and after treatment. Samples of articular cartilage from two patients of each group and from one healthy subject were submitted to scanning electron microscopy after the end of treatment. All symptoms decreased in both groups. The patients treated with glucosamine sulfate experienced a reduction in overall symptoms that was almost twice as large (730 vs. 41%) twice as fast (time to reduce symptoms by 50%: 20 days vs. 36 days) as those who received placebo. The improvement of autonomous mobility was relatively less, compared to improvement in the other symptoms, for patients with placebo; with glucosamine sulfate, on the contrary, the improvement was as great and as fast as that of the other symptoms. A direct action of glucosamine sulfate on the cartilage is hypothesized. This hypothesis is supported by the findings of electron microscopy. The patients who had placebo showed a typical picture of established osteoarthritis. Those who had glucosamine sulfate showed a picture more similar to healthy cartilage. The authors concluded that glucosamine sulfate tends to rebuild the damaged cartilage, thus restoring articular function in most chronic osteoarthritis patients."

Lopes et al. (1982) reported:
 "A double-blind trial was carried out in 40 out-patients with unilateral osteoarthrosis of the knee to compare the efficacy and tolerance of oral treatment with 1.5 g glucosamine sulphate or 1.2 g ibuprofen daily over a period of 8 weeks. Pain scores decreased faster during the first 2 weeks in the ibuprofen than in the glucosamine treatment group. Although the rate of decrease was slower, the reduction in pain scores was continued throughout the trial period in patients an glucosamine and the difference between the two groups turned significantly in favour of glucosamine at Week 8. No significant differences were observed in swelling or any of the other parameters monitored. Tolerance was satisfactory with both treatments, with only minor complaints being reported by 2 patients on glucosamine compared with 5 patients on ibuprofen."

Kelly's (1998) research reported that:
 "Glucosamine sulfate stimulates the regeneration of cartilage after experimentally induced damage."

Dr. Murray summarily stated (1994):
 "Glucosamine sulfate may promote the incorporation of sulfur into cartilage."

Professor Bohmen's (1984) research reported:
 "Athletes with damaged knee cartilage who received 1,500 mg of glucosamine sulfate per day for 40 days, followed by 750 mg of glucosamine sulfate per day for a further 100 days experienced either a complete cure of the injury or were able to resume training."

Chondroitin sulfate is the substrate precursor for optimal joint space fluid levels. Chondroitin sulfate inhibits collagenase (an enzyme that degrades the body's collagen). Chondroitin sulfate (CS-C form) inhibits the activity of elastase against collagen deterioration in the joint. Length of dose and dose potency are factors. Chondroitin sulfates are some of the most common glycosaminoglycans in the human body. They are mostly bound to collagen and serve as constituents of the fundamental substance of connective tissue. 

Morreale et al. (1996) reported that using natural metabolites from chrondroitin sulfate may require longer use than the paper referenced: 

"The objective of this study was to assess the clinical efficacy of chondroitin sulfate (CS) in comparison with the nonsteroidal antiinflammatory drug (NSAID) diclofenac sodium (DS) in a medium/longterm clinical study in patients with knee osteoarthritis (OA). This was a randomized, multicenter, double blind, double dummy study. 146 patients with knee OA were recruited into 2 groups. During the first month, patients in the NSAID group were treated with 3 x 50 mg DS tablets/day and 3 x 400 mg placebo (for CS) sachets; from Month 2 to Month 3, patients were given placebo sachets alone. In the CS group, patients were treated with 3 x 50 mg placebo (for diclofenac) tablets/day and 3 x 400 mg CS sachets/day during the first month; from Month 2 to Month 3, these patients received only CS sachets. Both groups were treated with 3 x 400 mg placebo sachets from Month 4 to Month 6. Clinical efficacy was evaluated by assessing the Lequesne Index, spontaneous pain (using the Huskisson visual analog scale), pain on load (using a 4 point ordinal scale), and paracetamol consumption. Patients treated with the NSAID showed prompt and plain reduction of clinical symptoms, which, however, reappeared after the end of treatment; in the CS group, the therapeutic response appeared later in time but lasted for up to 3 months after the end of treatment. CS seems to have slow but gradually increasing clinical activity in OA; these benefits last for a long period after the end of treatment." 

Ronca (1998) research reported:
 "The pharmacokinetics of chondroitin sulfate were investigated in rats and in healthy volunteers using chondroitin sulfate tritiated at the reducing end and chondroitin sulfate labeled with 131I or 99mTc respectively. A rapid absorption of orally administered chondroitin sulfate is observed in rats and in humans when the drug is dissolved in water. Lower and delayed absorption is observed when chondroitin sulfate is administered in gastroresistant capsules. The absolute bio-availability is 15 and 12% for rats and humans respectively. The chondroitin sulfate shows a tropism for cartilagineous tissues in rats and for knee tissues in humans as demonstrated by scintigraphic analysis with 99mTc-CS. Monomers, oligo and polysaccharides produced by enzymatic hydrolysis of chondroitin sulfate appear in the blood and tissues together with native chondroitin sulfate. The effects of partially depolymerized (m.m. 3 to 15 kD) and desulfated fractions on human leukocytes were investigated. Chondroitin sulfate and its fractions inhibit the directional chemotaxis induced by zymosan-activated serum, are able to decrease the phagocytosis and the release of lysozyme induced by zymosan and to protect the plasma membrane from oxygen reactive species. In rats the oral administration of chondroitin sulfate significantly decreases granuloma formation due to sponge implants and cell migration and lysosomal enzyme release in carrageenan pleurisy. Compared with nonsteroidal anti-inflammatory drugs (indomethacin, ibuprofen), chondroitin sulfate appears to be more effective on cellular events of inflammation than on edema formation. It is noteworthy that chondroitin sulfate is devoid of dangerous effects on the stomach, platelets and kidneys. In synovial fluid of patients requiring joint aspiration, treated orally for 10 days with chondroitin sulfate (800 mg per day) the hyaluronate concentration and the intrinsic viscosity significantly increased, while collagenolytic activity, phospholipase A2 and N-acetylglucosaminidase decreased. These results give an insight into the mechanism of the anti-inflammatory and chondroprotective actions demonstrated by this drug in a number of clinical trials in patients with osteoarthritis."

I suggest further research of the other metabolites in TR (Methylsulfonylmethane, Peptidase, Bromelain, Papain, Protease, Amylase, Lipase, Cellulase, Phytase, Boswellia Serrata, Devils Claw, Yucca Root, Curcuma Longa, Quercetin (Saphora Japonica), Undenatured Type II Collagen). Each of these substances are well-research and shown to reduce inflammation without side effects, enhancing the joint space building blocks donor health activity. 


Qiu, G. X., et al. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforschung. 48:469-474, 1998. 

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. 

Drovanti, A., et al. Therapeutic activity of oral glucosamine sulfate in osteoarthritis: A placebo-controlled double-blind investigation. Clin Ther. 3:260-272, 1980. 

Lopes, V. A. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthrosis of the knee in outpatients. Curr Med Res Opin. 8(3):145-149, 1982. 

Kelly, G. S. The role of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease. Alternative Medicine Review. 3(1):27-39, 1998. 

Murray, M. T. Glucosamine sulfate: effective osteoarthritis treatment. Amer J Nat Med. 1994:September 10-14. 

Bohmen, D., et al. (editors). Treatment of chondropathia patellae in young athletes with glucosamine sulfate. Current Topics in Sports Medicine. Urban and Schwarzenberg, Vienna. 1984. 

Morreale, P., et al. Comparison of the anti-inflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. J Rheumatol. 23(8):1385-1391, 1996. 

Ronca et al. Anti-inflammatory activity of chondroitin sulfate. Osteoarthritis Cartilage. 6(Supplement A):14-21, 1998. 

Bucci, L., Glycosaminoglycan supplements as therapeutic agents. Nutrition Report. 14(1):8, 1996. 

Crolle, G., et al. Glucosamine sulfate for the management of arthrosis: A controlled clinical investigation. Curr Med Res Opinion. 7(2):104-109, 1980. 

D'Ambrosio, E. Glucosamine sulfate: A controlled clinical investigation in osteoarthrosis. Pharmatherapeutica. 2:504-508, 1991. 

Muller-Fassbender, H.,et al. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage. 2:61-69, 1994. 

Noack, W., et al. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage. 2:51-59, 1994. 

Pujalte, J. M., et al. Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthritis. Curr Med Res Opin. 7:104-109, 1980. 

Reginster, J. Y. et al. Glucosamine sulfate significantly reduces progression of knee osteoarthritis over 3 years: a large, randomized, placebo-controlled, double-blind, prospective trial. Arthritis & Rheumatism. September 1999. 

Rovalti, L. C., et al. A large, randomized, placebo controlled, double-blind study of glucosamine sulfate vs piroxicam and vs their association on the kinetics of the symptomatic effect in knee osteoarthritis. Osteoarthritis Cartilage. 2(Supplement 1):56, 1994.