Medical Evidence
Evidence For Synergistic Effect Of Glucosamine
And Chondroitin Sulfates In Joint Health
Background: Chondroprotective
agents have been defined as a compound that can accomplish the
following six objectives in joint tissues (Ghosh, P., M. Smith,
C. Wells. Second-line agents in osteoarthritis, Chapter 15 in
Second-Line Agents in the Treatment of Rheumatic Diseases, J.S.
Dixon, D.E. Furst, Eds., Marcel Dekker, New York, 1992, pp.363-427):
1. Enhance chondrocyte macromolecular synthesis (glycosaminoglycans,
proteoglycans, collagens, proteins, RNA, DNA) 2. Enhance synthesis
of hyaluron In synthesis by synoviocytes 3. Inhibit enzymes that
degrade cartilage macromolecules 4. Mobilize thrombi, fibrin,
lipids, cholesterol deposits in synovial spaces and blood vessels
surrounding joints (subchondral vessels) 5. Reduce joint pain
6. Reduce synovitis
At present, no known drug is able to accomplish all of these
objectives. Macromolecules endogenous to cartilage and their semisynthetic
or synthetic mimics have been shown to accomplish some, but not
all, of these objectives. Because the roles and functions of endogenous
macromolecules (or their mimics) are integral to cartilage metabolism,
they alone appear able from a pharmacological perspective to exhibit
multiple objectives. However, at present, no single macromolecule
can accomplish all of the stated objectives. Combinations of anti-inflammatory
or analgesic drugs with macromolecules have exhibited many of
the objectives, but still not all. Part of the problem with drug-nutrient
combinations is the adverse side effects generated by drugs, which
reduces therapeutic benefits. Thus, a new approach to combine
compounds with both overlapping and complimentary functions without
adverse side effects is needed.
Such a combination may exist by combining glucosamine salts and
chondroitin sulfates.
Glucosamine is the predominant amino sugar utilized by connective
tissues for synthesis of glycosaminoglycans and proteoglycans.
Chondroitin sulfates are the major glycosaminoglycan species in
cartilage, and consist of repeating disaccharide units of N-acetylgalactosamine
and glucuronate. Both of these connective tissue components have
been purified to homogeneity, and are available for use as oral
or injectable agents.
Glucosamine synthesis by chondrocytes appears to be the key,
rate-limiting step for synthesis of cartilage matrix. Glucosamine
itself constitutes half of hyaluronan, keratan sulfates, heparan
sulfates, and heparin Glucosamine is easily converted into galactosamine
by epimerases, and thus, constitutes half of chondroitin sulfates
and dermatan sulfates. In addition, almost every protein, including
collagen, is glycosylated with either glucosamine itself or a
derivative amino sugar. Thus, glucosamine is probably the key
single compound necessary for cartilage matrix synthesis. Glucosamine
has exhibited four of the six stated objectives. Evidence has
shown that exogenous glucosamine salts significantly enhance chondrocyte
synthesis of glycosaminoglycans, collagen, and DNA. Glucosamine
has been hypothesized to enhance synthesis of synovial fluid hyaluronan.
Although animal studies found that glucosamine did not possess
analgesic properties, it did exhibit anti-inflammatory effects
against animal models of inflammatory arthritis at high but safe
doses. In addition, the numerous human studies of glucosamine
used for osteoarthritis all exhibited reductions in pain and joint
inflammation (synovitis markers). Thus, glucosamine has exhibited
Chondroprotective abilities for objectives 1, 2, 5, & 6.
Chondroitin sulfates have also exhibited enhancement of chondrocyte
macromolecule synthesis in cultures. Chondroitin sulfates have
exhibited inhibition of degradative enzymes in cartilage. This
appears to be more than fortuitous, since a major target of degradation
in cartilage is the proteoglycans, and hyaluronan in synovial
fluid. Chondroitin sulfates, by virtue of their chain lengths,
competitively inhibit degradative enzymes. Chondroitin sulfates
have been shown repeatedly to mobilize plaque and thrombi in-numerous
studies. Oral administration had little effect on thrombi, but
cholesterol-clearing effects were still evident. In human clinical
studies, administration of chondroitin sulfates was associated
with reduction of joint pain and improved joint mobility. Reduction
in incidence of joint arthritis with associated synovitis in mice
was achieved by oral chondroitin sulfates.
Chondroitin sulfates have exhibited five of the six stated objectives
for chondroprotection. The degree of effect was less than for
drugs, but the long-term safety profile of chondroitin sulfate
meant that higher doses could be taken longer than drugs to achieve
similar objectives. Thus, chondroitin sulfates exhibited chondroprotective
abilities for objectives 1, 3, 4, 5, & 6.
Neither glucosamine or chondroitin sulfates exhibited all six
stated objectives of a chondroprotective agent by themselves.
However, combining the two agents has the potential to meet all
six of the objectives. Overlapping roles include objectives 1,
5, & 6. It appears that objectives 5 & 6 are accomplished by fulfilling
objectives 1 4. In other words, except at high doses, there are
no apparent direct anti-inflammatory or analgesic effects on cartilage.
Thus, the combination of glucosamine and chondroitin sulfates
can accomplish the first four objectives, but neither can accomplish
all four alone.
Glucosamine and chondroitin sulfates appear to stimulate chondrocyte
macromolecular synthesis by different mechanisms. Glucosamine
is a direct precursor as well as a stimulatory agent for chondrocyte
glycosaminoglycan synthesis. Chondroitin sulfates appeared to
stimulate glycosaminoglycan and proteoglycan synthesis by extracellular
mechanisms as well as intracellular mechanisms, which is different
from glucosamine effects. Thus, for the chondroprotective objective
with overlap, differing mechanisms of action have been identified.
Synergism, rather than additive effects, are expected, since
both agents are endogenous to chondrocytes, and chondroitin sulfates
possess extracellular properties not found with glucosamine. Clinical
trials indicate that glucosamine alone has been successful in
treatment of osteoarthritis. Chondroitin sulfates tested in clinical
trials have shown somewhat less success, but still significant
success. Both agents have been listed as slow acting agents for
osteoarthritis. Synergism would be expected to exhibit as a reduction
in healing time compared to each individual agent. Preliminary
studies have indicated accelerated results compared to the time
course of healing in published studies (Nutramax Laboratories,
unpublished data). Therefore, clinical experiences have fit the
concept of a synergistic effect between glucosamine and chondroitin
sulfates.
Conclusions: Conclusions
of this review and their approximately 90 references have been
listed extensively in the Glycosaminoglycans chapter of Nutrition
Applied to Injury Rehabilitation and Sports Medicine, CRC Press,
Boca Raton, 1994, pp. 177-203. Reference citations are available
upon written request.
Source: Nutramax Laboratories,
Inc., Baltimore, MD
Dr. Theo’s Comments: This
analysis is several years old and does not even include some of
the newest information on glucosamine and chondroitin. Nevertheless,
this is a convincing academic argument for the rationale in using
glucosamine and chondroitin (in combination) for the treatment
of osteoarthritis