Chondroitin Sulfate health benefits

Chondroitin Sulfate

In by Raphikammer

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

uncommon (4).

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

uncertain.

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.

Chondroitin Sulfate

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.

 

PHARMACOLOGY

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

glucosamine.

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

Trial (GAIT).

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

manufacturer.

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

20% (15).

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

with glucosamine.

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

observations.

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

4-sulfate (16).

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).

CLINICAL STUDIES

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

benefit.

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

clinical significance.

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

periods.

SAFETY

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.

 

RECOMMENDATIONS

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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