Osteoarthritis is the most common arthropathy worldwide
and a significant cause of morbidity and disability, especially in the elderly Both biomechanical forces and biochemical processes are important in its pathogenesis, which is characterized by progressive deterioration of articular cartilage causing debilitating pain
and loss of normal joint motion. Standard therapies can alleviate the symptoms of OA to some extent but have no ability to prevent disease progression. A number of alternative
substances, collectively referred to as nutraceuticals,
have been touted in the lay press as being beneficial for OA, with particular interest focused on glucosamine and chondroitin sulfate (2,3). Chondroitin sulfate is a key component of normal
cartilage that is substantially reduced in the cartilage of individuals with OA. This observation stimulated interest in its potential role as a therapeutic agent, and continuing investigations have now identified a number of apparent biologic actions. No consensus exists, however, as to its clinical efficacy or utility.
While it has gained a measure of acceptance in Europe, physicians in the United States appear to be less convinced by the available clinical data.
Nonetheless, the interest of the general population has been piqued, and owing to its universal availability as an over-the-counter supplement, present use of chondroitin
sulfate, either with or without standard OA therapy, is not
STRUCTURE, BIOCHEMISTRY, AND PHYSIOLOGY
Chondroitin sulfate is classified as a glycosaminoglycan
(GAG) and is present abundantly in articular cartilage as
well as in many other tissues, including bone, tendon, intervertebral
disk, aorta, cornea, and skin. It is composed of
alternating N-acetylgalactosamine and D-glucuronic acid
residues, which form a long, unbranched chain. While the
length of the chain is variable, it seldom exceeds 200 to 250
disaccharide units. Sulfation occurs at the 4 or 6 position of
theN-acetylgalactosamine residue to produce chondroitin
4-sulfate (chondroitin sulfate A) and chondroitin 6-sulfate
(chondroitin sulfate C), respectively, whereas the substitution
of L-iduronic acid for D-glucuronic acid produces
dermatan sulfate, formerly known as chondroitin sulfate
The significance of the sulfation position is not fully
understood but appears to be associated with tissue age
and location. Sulfation at the 4 position is seen more frequently
in deeper, immature cartilage, while older, thinner
cartilage is primarily sulfated at the 6 position (5). Additionally,
abnormalities in sulfation appear to be present in
OA cartilage (6), although their physiologic significance is
The chondroitin sulfates comprise one of three primary
divisions of GAGs, heparins and keratan sulfates being
the other two. GAGs are synthesized intracellularly by
chondrocytes, synoviocytes, fibroblasts, and osteoblasts.
Following synthesis, multiple GAGs attach to a protein
core within the Golgi apparatus to form a proteoglycan,
which is subsequently secreted into the extracellular matrix
(7). The factors that promote and regulate proteoglycan
biosynthesis are complex, and it has been estimated
that more than 10,000 enzymatic steps may be required (8).
The predominant proteoglycan in human articular
cartilage is aggrecan, which contains both chondroitin sulfate
and keratan sulfate side chains. Together, these side
chains account for 80% to 90% of the mass of aggrecan.
Chondroitin sulfate predominates over keratan sulfate,
with more than 100 chondroitin sulfate side chains being
present on a single aggrecan molecule. While there is some
variability in the core protein, the physical and chemical
properties of proteoglycans are largely attributable to the
chondroitin sulfate side chains. One important feature of
the proteoglycans is a marked negative electrical charge,
which is created by the ionized sulfate groups within the
GAG side chains.
Articular cartilage consists of collagen fibers surrounded
by a matrix containing aggregates of aggrecan
and hyaluronate. Within the matrix, 100 to 200 aggrecan
molecules bind to a single hyaluronate strand to form a
supramolecular structure large enough to be seen by electron
microscopy. The tensile strength of articular cartilage
is the result of a network of collagen fibers, while the
aggrecan–hyaluronate aggregates, which are rich in chondroitin
sulfate chains, provide resiliency. Under normal
circumstances, water is electrically attracted to cartilage
by the negatively charged GAG residues and becomes entrapped
within the aggregates. When a deforming force
(such as occurs with weight bearing) is applied to the cartilage
surface, minimal deformity occurs under normal
conditions because the movement of water within cartilage
is resisted by (i) its electrical affinity to the GAG
residues, and (ii) the physical obstruction created by the
bulky aggrecan–hyaluronate aggregates.
In OA, deterioration of articular cartilage is associated
with a loss of proteoglycan, with a consequent change
in water content and decrease in resilience. The pathogenetic
events producing these changes remain uncertain
but may result from changes in proteoglycan catabolism
involving matrix metalloproteinases, serine proteases,
glycosidases, and chondroitin uses secreted from chondrocytes
and other connective tissue cells (9). Experimental
models of OA suggest that synthesis of aggrecan increases
early in the degenerative process in an apparent attempt
at cartilage repair. The chondroitin sulfate side chains synthesized
in this setting, however, are longer and more
antigenic, suggesting that important GAG constitutional
and/or conformational changes may be involved in the
pathogenesis of OA (9). One such change appears to involve
the terminal sulfation of chondroitin (10). Further
study of the mechanisms that produce changes in theGAG
synthesis may yet yield a site for therapeutic intervention
that might have disease-modifying potential.
The pharmacologic properties of exogenously administered
chondroitin sulfate have been examined in a number
of animal models and in humans with doses ranging from
60 mg/kg to 2 g/kg.Various routes of administration have
been utilized in these studies, including oral, intraperitoneal,
subcutaneous, and intravenous (11). In general,
chondroitin sulfate appears to be well tolerated, and no
significant adverse events have been reported with any
route of administration. Determinations of oral bioavailability
have yielded estimates of 5% to 15%, with blood
levels reported to peak between 2 and 28 hours (12,13)
following administration. No significant difference was
observed between divided and single day dosing, while
sustained dosing yielded serumlevels only slightly higher
than those seen following a single dose (12). The elimination
half-life has been estimated at six hours. With a radiolabeled
preparation of chondroitin sulfate administered
orally to rats, more than 70% of the radioactivity was absorbed
and subsequently identified in either the tissues
or the urine. Radioactivity was found in every tissue examined
at 24 hours, with levels variably diminished at
48 hours except in joint cartilage, the eye, the brain, and
adipose tissue, where levels were increased (12). There
are very limited data for chondroitin sulfate pharmacokinetics
when it is administered in conjunction with
The variability in pharmacokinetic derivations reported
to date is considerable and appears to be principally
due to methodological differences and limitations.
Early studies that utilized radioactive forms of chondroitin
sulfate (tritiated) in animals were complicated by
the production of tritiated water, which introduced error
into concentration determinations, while assays utilizing
high-performance liquid chromatography (HPLC)
methodology were unable to detect low concentrations of
chondroitin sulfate. More recent work in humans is similarly
problematic due to assay insensitivity, failure to account
for endogenous chondroitin sulfate levels, and/or
the use of diluents for anticoagulation. Newer technologies
now permit the reliable quantitation of GAG at lower
levels (14), and a pharmacokinetic study incorporating
these techniques is being contemplated in conjunction
with the Glucosamine/Chondroitin Arthritis Intervention
CHONDROITIN SULFATE PREPARATIONS
Chondroitin sulfate is produced by several manufacturers
and is readily available worldwide. It is derived by
extraction from bovine, porcine, or shark cartilage. Various
methods of extraction exist, but the specifics of each
process are the proprietary information of the manufacturer.
Most processes start with some form of enzymatic
digestion followed by a variable number of washings, incubations,
and elutions. In contrast to the procedure with
prescription medications, the production process is not
strictly regulated, and variations in quality and potency
can occur from batch to batch and from manufacturer to
In a study conducted to identify a high-quality
chondroitin sulfate dosage form for use in a clinical
trial, three different sources of purified chondroitin sulfate
were evaluated in a blinded fashion. While each
sample exhibited similar disaccharide and GAG content
overall, chondroitin sulfate potency varied by 15% to
In the United States, chondroitin sulfate is classified
as a nutritional supplement and is widely available without
a prescription in pharmacies and health and natural
food stores. Not infrequently, it is manufactured in combination
PUTATIVE MECHANISMS OF ACTION
A number of possible mechanisms of action for chondroitin
sulfate in the treatment ofOAhave been suggested
from pilot studies in animals and humans. Additional investigations
are needed to confirm and extend these preliminary
a. Inhibition of matrix proteases and elastases. Articular
cartilage is catabolized by proteinases and elastases
that are elaborated from chondrocytes and leukocytes,
146 Miller and Clegg
respectively. In both in vitro and in vivo studies with
rodents, a modest decrease in elastase activity was seen
following chondroitin sulfate administration. A similar
chondroitin sulfate effect on neutral proteases has
also been observed. The mechanism of this apparent
inhibitory effect of chondroitin sulfate may be ionic
disruption at the catalytic site of the enzyme. Chondroitin
6-sulfate may be more potent than chondroitin
b. Stimulation of proteoglycan production. Several studies
have shown that proteoglycan synthesis in vitro increases
when chondroitin sulfate is added to cultures
of chondrocytes and synoviocytes (17–19). The mechanism
by which this occurs is unknown, but increased
RNA synthesis has been observed, as well as TNF-
inhibition and IL-1 antagonism.
c. Viscosupplementation. An increase in synovial fluid viscosity
has been reported following the administration
of oral chondroitin sulfate to rabbits, rats, and horses
(17,20,21). A more viscous synovial fluid may interfere
physically with cartilage matrix catabolism, but
the mechanism by which chondroitin sulfate might increase
the viscosity of synovial fluid is uncertain.
d. Anti-inflammatory action. Chondroitin sulfate has been
reported to decrease leukocyte chemotaxis, phagocytosis,
and lysosomal enzyme release in vitro. When
administered orally to rodents, it appeared to decrease
granuloma formation in response to sponge implants
as well as attenuate the inflammatory response in adjuvant
arthritis and carrageenan-induced pleurisy (22).
Interest in chondroitin sulfate as a therapeutic agent is
longstanding and has primarily focused on the treatment
of OA. Much of the available clinical data come
from trials conducted in Europe, where it is now classified
as a “symptomatic slow-acting drug in osteoarthritis”
(SYSADOA) (23). Some have suggested that it
may also have chondroprotective properties and thereby
have properties of a “disease-modifying anti osteoarthritis
drug” (DMOAD). Among physicians in the United States,
however, there is considerable skepticism, and its role in
the treatment of OA, if any, remains very controversial.
Most of the clinical experience with chondroitin sulfate
has been in knee OA, which is an important patient
subset due to its prevalence and resulting disability. Radiographic
evidence of knee OA is present in approximately
one-third of people older than 65 years, although not all
have symptoms. Epidemiologic studies suggest that knee
OA increases in frequency with each decade of life and affects
women more often. Obesity, prior trauma, and repetitive
occupational knee bending have also been identified
as risk factors. The functional consequences of knee OA
are considerable, as it produces disability as often as heart
and chronic obstructive pulmonary disease (24).
The initial management of OA includes patient education,
weight reduction, aerobic exercise, and physical
therapy, and these should always be pursued before pharmacologic
intervention is considered. Weight reduction
and strengthening exercises may be of particular benefit
in knee OA. Acetaminophen and nonsteroidal antiinflammatory
drugs (NSAIDs) are the agents most often
prescribed when nonpharmacologic measures prove
insufficient. Local intervention with intra-articular corticosteroid
injections and viscosupplementation may be of
benefit in some patients.
Most rheumatologists would agree that present therapies
for OA are suboptimal for the majority of patients.
This was readily apparent in a representative two-year
clinical trial comparing an NSAID and acetaminophen in
knee OA, in which a majority of participants in both treatment
groups withdrew prior to study completion because
of toxicity or lack of efficacy. Given the shortcomings of
standard therapy, it is not surprising that more than onethird
of patients report that they have experimented with
alternative and complementary treatments (25).
Nutraceuticals are produced and distributed in the
United States under the authority of the Dietary Supplement
Health and Education Act (DSHEA), which was enacted
in 1994 as an amendment to the existing Federal
Food, Drug, and Cosmetic Act. The provisions of DSHEA
broaden the definition of dietary supplements and have
removed the more stringent premarket safety evaluations
that had been required previously. The act stipulates that
the labels of dietary supplements list ingredients and nutritional
information and permits manufacturers to describe
the supplement’s effect on the “structure or function”
of the body and the “well-being” that might be
achieved through its use. However, representations regarding
the use of the supplement to diagnose, prevent,
treat, or cure a specific disease are expressly prohibited.
Legislation passed by the U.S. Congress in 1991
and 1993 (P.L. 102–170 and P.L. 103–43, respectively)
established an office within the National Institutes of
Health “to facilitate the study and evaluation of complementary
and alternative medical practices and to disseminate
the resulting information to the public.” This
Office of Alternative Medicine became the forerunner of
the present National Center for Complementary and Alternative
Medicine (NCCAM), which was formally instituted
in February 1999. With a present budget of more
than $125.5 million, the stated mission of NCCAM is to
“explore complementary and alternative healing practices
in the context of rigorous science.” One of the first clinical
trials to be sponsored by NCCAM was GAIT, a Phase III
evaluation of the efficacy and safety of glucosamine and
chondroitin sulfate in knee OA.
Much of the clinical experience and study data with
chondroitin sulfate suffers from poor study design, possible
sponsor bias, inadequate concealment, and lack of
intention-to-treat principles. More recent studies have
sought to address these issues with larger trials that
are more rigorously designed. Under the sponsorship of
NCCAM, GAIT was a multicenter, randomized, doubleblind,
and placebo-controlled trial designed to evaluate
the tolerability and efficacy of glucosamine and chondroitin
sulfate in the treatment of knee OA (26). The study
assigned 1583 patients to five treatment arms that consisted
of glucosamine alone, chondroitin sulfate alone, a
combination of glucosamine and chondroitin sulfate, celecoxib,
and placebo. This trial was a two-part study designed
to compare the efficacy of glucosamine and chondroitin
sulfate alone and in combination with that of an
active comparator (celecoxib) and placebo in alleviating
Chondroitin Sulfate 147
the pain of knee OA over 24 weeks. An ancillary study
on a subset of GAIT patients was developed to determine
whether radiographic benefit was evident after 24 months
of agent exposure.
Overall, GAIT results revealed no difference in response
to chondroitin sulfate alone or in combination with
glucosamine. However, in the subgroup of patients with
moderate-to-severe pain, there was a significantly higher
rate of response with combined therapy. In addition, a
statistically significant improvement in joint effusion was
noted in the chondroitin sulfate group among the secondary
outcome measures. Hochberg et al. (27) conducted
a post hoc analysis of the GAIT data that specifically addressed
the effects of chondroitin sulfate on joint swelling,
and concluded that the patients with earlier disease based
on symptoms and radiographic stage were most likely to
Two meta-analyses published in 2007 evaluated the
recent data for the use of chondroitin sulfate for pain relief
in OA (28,29). The first meta-analysis assessed randomized
controlled trial (RCT) data on several medications
used for short-term pain control inOAincluding NSAIDs,
opioid analgesics, paracetamol, intra-articular steroids,
glucosamine, and chondroitin sulfate (28). Data on chondroitin
sulfate was limited to six RCTs (362 patients) and
demonstrated a small effect on pain relief at four weeks
that was statistically significant. Interestingly, a secondary
outcome measure of pain relief at three months after the
start of treatment showed a slight improvement in pain relief
between weeks 4 to 12. This outcome differed from all
other therapeutic interventions that showed no change or
a decrease in pain relief from week 4 to 12. However, five
of the six studies were sponsored by pharmaceutical companies,
and the remaining trial did not show improvement
in pain relief at 12 weeks. Overall, none of the available
medications evaluated in this meta-analysis met criteria
for a clinically relevant change in the primary outcome.
The second meta-analysis evaluated the use of chondroitin
sulfate for pain in OA of the knee or hip as the
primary objective (29) Joint space narrowing effects were
analyzed as a secondary objective. Though a statistically
significant effect size for pain relief was reported using the
20 trials (3846 patients) included in the analysis, this effect
size approached zero when only the three larger trials
with adequate concealment and intent-to-treat data were
included in the analysis (1553 patients). Five studies reported
data on joint space narrowing, and upon analysis
showed a significantly lower rate of joint space loss with
chondroitin sulfate over placebo. Though the effect size
was statistically significant, it was small and of unclear
The first meta-analysis concluded that chondroitin
sulfate was likely beneficial in alleviating the symptoms of
knee OA to some degree but felt that the magnitude of the
clinical effect was most likely less than that reported (28).
The second meta-analysis determined that data from the
larger, more rigorous trials suggested that symptomatic
benefit from chondroitin sulfate was modest to nonexistent
(29). Few trials addressing the effect of chondroitin
sulfate on joint space narrowing were available for the latter
analysis, and though a small effect was detected, the
authors concluded that it was of uncertain clinical relevance
and more study was necessary (29).
The ancillary radiographic report from GAIT published
by Sawitzke et al. (30) assessed 572 patients with
knee OA followed for two years for radiographic progression
. These patients had been randomized to receive
glucosamine 500 mg three times daily, chondroitin sulfate
400 mg three times daily, the combination of both supplements,
celecoxib 200 mg daily, or placebo as part of the
original GAIT study and were followed over 24 months
with the primary outcome measure of mean change in
joint space width (JSW) using metatarophalyngeal semiflexed
radiography (31). No statistically significant difference
in the loss of JSW in any of the treatment groups was
found compared to placebo, but the study was limited by
the smaller sample size and smaller than expected loss in
JSW. Interestingly, loss of JSW was greater in the combination
group compared to those taking either glucosamine
or chondroitin sulfate alone, leading the authors to raise
the possibility of interference with combined use.
The recently published results of the Study on Osteoarthritis
Progression Prevention assessed the effects of
chondroitins 4 and 6 sulfate on radiographic progression
as well as symptomatic relief in knee OA over a two-year
period (32). This study randomized 622 patients to receive
800 mg of chondroitin sulfate or placebo daily for
two years. Loss in minimum JSW was the primary outcome,
and symptomatic relief was a secondary outcome.
A significant reduction in JSW loss was observed in the
chondroitin sulfate group. This group also showed faster
improvement in pain over the first nine months, but no significant
difference was observed between the two groups
thereafter or at the end of the two years.
It is important to recognize that OA trials designed
to evaluate radiographic progression, may not be appropriate
for detecting the symptomatic benefits of an intervention.
Additionally, interventions that result in slowing
of radiographic progression may not relieve symptoms,
or symptom relief may not correlate with improvements
in radiographic progression. Because OA is generally a
slowly progressive disease, modification of the disease by
an intervention such as chondroitin sulfate may not be evident
for many years. Though some trials may report statistically
significant changes in radiographic progression,
the clinical importance of these changes remains uncertain
and may become apparent with longer observational
Information regarding the safety of chondroitin sulfate
as a single agent, or in combination with other agents,
suggests that adverse effects associated with chondroitin
sulfate use are both minor and infrequent. In the randomized,
controlled trials summarized above, the frequency of
adverse effects reported in the chondroitin sulfate treatment
arms was no greater than that with placebo arms.
The side effects reported most often with chondroitin sulfate
were epigastric distress, diarrhea, and constipation.
Additionally, rashes, edema, alopecia, and extrasystoles
have been reported, though infrequently.
An additional safety concern is the potential for
transmission of bovine spongiform encephalopathy (BSE,
or mad cow disease) from infected beef products. Despite
148 Miller and Clegg
stringent safeguards put in place by the U.S. Department
of Agriculture that banned the import of beef products
from any at-risk country, a case was reported in an American
herd. Those who elect to take chondroitin sulfate
should be familiar with the animal source from which it
has been extracted and, if bovine, assure themselves that
it has come from a disease-free herd.
Considerable published medical literature is available
suggesting that chondroitin sulfate is well tolerated and
safe. Though it may be of benefit in alleviating the symptoms
of OA in select patients, data demonstrating clinically
relevant improvements in OA symptoms with chondroitin
sulfate are sparse. This should be considered in the
overall context that none of the currently available drugs
for treatment of OA have shown dramatic improvements
in pain relief. There are recent data suggesting that chondroitin
sulfate may have effects on radiographic progression,
but only studies of several year duration and sufficient
scientific rigor will be able to determine the clinical
significance of these findings. In light of the large number
of studies documenting the favorable safety profile of
chondroitin sulfate, patientswhoreport benefit and would
like to continue taking it can be assured that adverse
effects are unlikely.
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