Vol. 21, No.
7 July 1999 V 20TH ANNIVERSARY
CE Refereed Peer Review
FOCAL POINT
★Understanding joint physiology
and oral chondroprotective
agents may allow veterinarians
to make an educated decision
regarding the products available
for use in treating osteoarthritis.
KEY FACTS
■ A synovial joint consists of the
synovial membrane, synovial
fluid, subchondral bone,
surrounding supporting
structures, and hyaline
cartilage.
■ Chondroprotective agents alter
cartilage metabolism, decrease
destructive enzymes, and inhibit
the formation of fibrin thrombi in
periarticular tissue.
■ Although research is ongoing,
much information about
chondroprotective products
is anecdotal.
■ Slow-acting, disease-modifying
agents are a subset of
chondroprotective agents
that directly influence cartilage
metabolism and improve joint
function.
Oral Chondroprotective
Agents. Part I.
Common Compounds
Veterinary Specialty Services, St. Louis, Missouri
Mark A. Anderson, DVM, MS
ABSTRACT: Joint structure and physiology may be modulated by some nondrug compounds.
Categorizing these compounds as oral chondroprotective agents; nutraceuticals; or slow-act-
ing, disease-modifying agents has produced confusion. This article provides descriptions and
rationales for the use of some commonly marketed nondrug compounds used to treat os-
teoarthritis. Some form of combination therapy may be best for treating osteoarthritis in vet-
erinary patients.
C
hondroprotective agents enhance cartilage metabolism, decrease break-
down products, and prevent formation of periarticular fibrin thrombi.
Oral chondroprotective agents have been confused with nutraceuticals, a
group of nondrug substances that are constituents of normal body structure and
are intended to improve animal health and well-being. To add to this confusion,
oral chondroprotective agents are poorly regulated and the efficacy of many
available products is uncertain.
Several common oral chondroprotective agents have been described in the lit-
erature,1,2 although in many cases much research is needed to determine their
merit. Part I of this two-part presentation reviews information designed to help
veterinarians make educated decisions about oral chondroprotective products;
Part II will provide criteria for evaluating product safety, efficacy, and purity and
discuss compounds that may impact the marketplace in the future.
SYNOVIAL JOINT STRUCTURE
Synovial joints comprise a complex arrangement of a variety of tissue. A thor-
ough knowledge of joint anatomy and physiology is needed to understand how
chondroprotective agents function; a brief discussion of pertinent tissues fol-
lows.
A synovial joint generally consists of hyaline cartilage, a synovial membrane,
synovial fluid, subchondral bone, and surrounding supporting structures (Figure
1). The majority of chondroprotective agents with slow-acting, disease-modify-
ing ability appear to have an effect in hyaline cartilage. In addition, oral chon-
droprotective agents may have antiinflammatory capabilities and affect the struc-
ture and function of cartilage.
Small Animal/Exotics 20TH ANNIVERSARY Compendium July 1999

Hyaline Cartilage physical therapy or antiin-

Hyaline cartilage is com- flammatory agents (e.g., non-
posed primarily (more than Bone steroidal antiinflammatory
95%) of extracellular matrix drugs [NSAIDs] or cortico-
plus a relatively small num- steroids).1
ber of chondrocytes, which Increased knowledge about
Subchondral
maintain cartilage tissue by joint-tissue biochemistry
bone
secreting collagen and pro- has recently fueled interest
teoglycans that form the ex- in the possibility of modu-
Hyaline Synovial lating the metabolism of
tracellular matrix. The ma-
cartilage fluid joint tissue and actually
trix, in turn, determines the
type of cartilage formed and managing disease processes
provides the environment the more consistently and more
chondrocytes require. The specifically than is possible
relationship between colla- with existing therapies. The
gen and proteoglycan aggre- Joint capsule term chondroprotective agents
gates in the matrix is respon- and synovial has been used to describe
sible for the slippery, resilient membrane compounds that could the-
Bone
nature of hyaline cartilage. oretically function to (1)
The properties of hyaline stimulate the synthetic ca-
cartilage are fundamental to pabilities of chondrocytes
normal cartilage physiology. Figure 1—Cross-section through a normal synovial joint. and synoviocytes, (2) de-
Changes in the matrix, such Hyaline cartilage, synovial fluid, and the synovial membrane crease the action of degrada-
as degradation of proteogly- are the major features. tive enzymes (e.g., metallo-
cans and collagen, may be proteases) in the joint, and
the initiating events in the (3) inhibit fibrin and thrombi
pathogenesis of such joint disease as osteoarthritis.3 formation in periarticular tissue.5 To date, no single
molecule has been able to meet all three criteria (partic-
Synovial Membrane and Fluid ularly the first two criteria). However, combinations of
The synovial membrane is the inner surface of the compounds have shown potential in meeting most, if
joint capsule. There are two types of synoviocytes in the not all three, characteristics of a chondroprotective
synovial membrane: Type-A cells are macrophage-like agent.6 Many compounds involved in combinations are
and have both secretory and phagocytic capabilities; actually molecules that are endogenous to joint tissue,
type-B cells are fibroblast-like and produce hyaluronan. and others have a similar molecular structure to en-
Both cell types secrete specific cytokines. The synovial dogenous molecules.7,8
membrane does not merely act as a barrier for synovial As mentioned, oral chondroprotective agents are
fluid but is also essential for normal fluid production sometimes confused with nutraceuticals, but the two
and turnover. Synovial fluid functions in joint lubrica- terms are not synonymous. The North American Veteri-
tion, nutrition, and protection and is thus a crucial fac- nary Nutraceutical Association defines a nutraceutical as
tor in joint health. The activity of most chondroprotec- a nondrug substance that is produced in a purified or ex-
tive agents is directed toward the synovial membrane, tracted form and administered orally to provide com-
synovial fluid, and/or hyaline cartilage.4 pounds required for normal body structure and function
with the intent of improving health and well-being.9 Not
CHONDROPROTECTIVE AGENTS all proposed chondroprotective agents are nutraceuticals
Diseases of joint tissue, specifically the hyaline carti- because many do not meet the definition. For instance,
lage and synovial membrane, are major concerns in vet- some purported chondroprotective agents are not in a
erinary medicine. Although seldom life-threatening, purified or extracted form but are raw products.
joint disease can cause significant economic losses for There is increasing interest in chondroprotective
cattle producers and horse owners and may greatly re- agents, but several issues have confounded efforts to
duce the quality of life for many companion animal study these agents.2 First, there may be an abundance
species. Conventional therapy for joint disorders has of anecdotal evidence regarding a certain compound’s
been primarily symptomatic and has included medical efficacy but a lack of published research substantiating
and surgical intervention. Medical therapy can include its biochemistry, pharmacology, efficacy, and safety.10

EXTRACELLULAR MATRIX ■ JOINT DISEASE ■ NUTRACEUTICALS

Compendium July 1999 20TH ANNIVERSARY
This situation is changing rapidly as more basic re-
search is being devoted to the mechanisms of action
and clinical responses to some chondroprotective
agents, especially the combination of glucosamine hy-
drochloride and chondroitin sulfate.1 Second, chon-
droprotective agents are grouped on the basis of pro-
posed effects rather than on molecular structure or
mechanism of action; therefore, chondroprotective
agents are a heterogeneous group of compounds. Sub-
stances that have been considered chondroprotective
agents include glycosaminoglycans (GAGs), amino sug-
ars, structural proteins, enzymes, minerals, preparations
of whole tissue, and semisynthetic compounds.11
To further confound things, some veterinary chon-
droprotective compounds are classified as drugs under
FDA regulations, whereas others are considered food.9 All
injectable agents are classified as drugs because of the route
of administration, although the same or similar substance
given orally may sometimes be considered a food.9
The injectable agents (polysulfated GAGs, hyaluron-
ic acid, and superoxide dismutase) will not be discussed
at length in this article because they have already been
evaluated by the FDA for efficacy and safety and have
clear and concise label information. However, the same
is not true for veterinary nondrug oral agents because
the manufacturing and labeling of these products are
not closely regulated. As a result of poor regulation and
lack of manufacturing standards, inaccurate labeling
and packaging can often occur.12–14 Manufacturers of
these agents cannot legally claim that their products
can treat, prevent, or cure disease.9,15,16
NOMENCLATURE
The term chondroprotective agent is currently used
loosely in veterinary medicine and has been applied to
compounds that have not been proven by consistent re-
search to affect cartilage metabolism. As a result, some
investigators have suggested that chondroprotective agent
be replaced by the term slow-acting, disease-modifying
agent.10 For the purpose of this article, chondroprotective
agent will include the broad scope of all agents that
have been proposed to modify cartilage structure; slow-
acting, disease-modifying agents will represent a subset of
agents that have been documented to slow or reverse
the progression of osteoarthritis.
GLUCOSAMINE HYDROCHLORIDE/CHONDROITIN
SULFATE/MANGANESE ASCORBATE
The most common oral chondroprotective agent in
veterinary medicine (and one of the only agents that
has been studied) is a patented combination of glu-
cosamine hydrochloride, chondroitin sulfate, and man-
ganese ascorbate (Cosequin®; Nutramax Laboratories,
GLYCOSAMINOGLYCANS ■ SLOW-ACTING, DISEASE-MODIFYING AGENT
Small Animal/Exotics
Baltimore, MD). This chondroprotective combination
has been studied in humans with osteoarthritis in the
knee and been proven effective.17,18
Glucosamine Hydrochloride
Glucosamine is an amino sugar—not a GAG, which
has different physical and biochemical properties. A de-
crease in the chondrocytes’ synthesis of glucosamine has
been implicated in the decline in matrix GAGs in early
osteoarthritis.19 Cell culture studies have confirmed that
glucosamine has a stimulatory effect on chondrocytes,
causing them to secrete increased amounts of normal
collagen and proteoglycans.20 Oral availability is excel-
lent when glucosamine is presented in the form of a
salt, such as a sulfate or hydrochloride.21 Glucosamine
sulfate and glucosamine hydrochloride are both effica-
cious when given in a pure form. However, N-acetyl-
glucosamine in cell culture was shown to be less effica-
cious compared with other glucosamine products.22 All
of glucosamine’s functions appear to stimulate metab-
olism in hyaline cartilage, and it has no apparent cata-
bolic effect on the cartilage matrix.23
Chondroitin Sulfate
Chondroitin sulfate, a GAG present in several body
tissues, has been shown to inhibit cartilage breakdown
in vitro and in vivo.24,25 A specific purified formulation
of chondroitin sulfate has been used in research. Two
types of chondroitin sulfate exist. Chondroitin-4-sul-
fate, which is sulfated on the fourth carbon of the N-
acetylgalactosamine residue, is derived primarily from
mammalian tissue. Chondroitin-6-sulfate, which is sul-
fated on the sixth carbon, is derived primarily from
shark cartilage. These two types of chondroitin sulfate
are not the same and may vary greatly in molecular
weight, potentially influencing bioavailability and purity.17
Chondroitin-4-sulfate is the most abundant GAG in
growing mammalian hyaline cartilage. This form of
chondroitin sulfate is structurally important because it
binds to collagen in the cartilage matrix, thereby con-
tributing to the resiliency and water-holding properties
of cartilage. As animals age, chondrocytes secrete de-
creased amounts of chondroitin-4-sulfate and increased
amounts of other GAGs (e.g., keratin sulfate); this
change in the type of GAG in the cartilage matrix has
been implicated in the initiation and progression of de-
generative processes within cartilage. Cell culture stud-
ies have shown that exogenously supplied chondroitin
sulfate competitively inhibits the action of metallopro-
teases in the cartilage matrix,26 decreasing the degrada-
tion of collagen and proteoglycans. In addition, chon-
droitin sulfate was shown to be clinically effective in
decreasing NSAID use in human trials.27–29
Small Animal/Exotics 20TH ANNIVERSARY
Chondroitin sulfate is a large molecule, and oral ab-
sorption has been questioned by some researchers.30
However, administered orally, radiolabeled chondroitin
sulfate is more than 70% absorbed unchanged.31,32 Ex
vivo experiments have shown a significant rise in serum
GAGs after oral administration of high-grade sodium
chondroitin sulfate in dogs.10 Chondroitin sulfate plays
a role in many body tissues and has been investigated
for its effects on the cardiovascular system. Chondroitin
sulfate is released by platelets as a part of normal con-
trol of blood coagulation. There is evidence that dis-
ease- or age-related decreases in endogenous chon-
droitin sulfate levels are involved in the pathologic
formation of occlusive thrombi in the microvascula-
ture. Prevention of thrombi formation in the microvas-
culature may be beneficial to the synovial membrane
and subchondral bone.33,34 This effect on the microvas-
culature along with inhibition of metalloproteases via
the modulation of interleukin-3 meet part of the defi-
nition of a chondroprotective agent not met by glu-
cosamine alone.17
Manganese Ascorbate
Manganese ascorbate is an essential trace element
that affects the growth and development of several con-
nective tissues. Manganese ascorbate is an essential co-
factor in the synthesis of GAGs and, when added to
glucosamine, efficient GAG production is stimulated.35
In addition, manganese deficiency is a limiting factor in
the synthesis of cartilage and synovial fluid.36 An an-
tioxidant effect has been proposed for manganese ascor-
bate as well. As a salt (e.g., ascorbate), manganese ascor-
bate is well absorbed from the digestive tract. No toxic
side effects have been reported.37
Clinical Effects and Efficacy
Neither glucosamine, chondroitin sulfate, nor man-
ganese ascorbate alone satisfies all three criteria of a
proposed chondroprotective agent. However, the con-
current use of glucosamine and chondroitin sulfate
combines the anabolic effects of the former with the
anticatabolic effects of the latter, resulting in a net in-
crease in the amount of healthy cartilage and normal
synovial fluid.17,22,38 The differing mechanisms of action
of glucosamine and chondroitin sulfate provide a syner-
gistic rather than an additive effect because both agents
are endogenous to chondrocytes.17,23 In addition, chon-
droitin sulfate possesses extracellular properties not
found in glucosamine.17,23 The possible synergistic ef-
fect was documented in radiolabeled cartilage cell cul-
ture studies using serum of dogs given glucosamine hy-
drochloride, chondroitin sulfate, and manganese
ascorbate in capsule form for 1 month.39
THROMBI FORMATION ■ CRANIAL CRUCIATE DISEASE ■ METHIONINE
Compendium July 1999
This combination has been used in veterinary medi-
cine for the past 5 years, primarily to treat degenerative
joint disease. Although clinical data are limited, prelim-
inary results show the formulation to be safe and possi-
bly efficacious. 2,40,41 Although a mild and clinically
insignificant decrease in platelet numbers was docu-
mented,42 no clinical evidence of bleeding has been
documented to my knowledge. The lethal dose has
been assessed to be higher than 5 g/kg in rats; however,
no histologic lesions have been identified at extreme
dosages.43
A disease-modifying effect in dogs with cranial cruci-
ate disease was recently identified.44 In this model, the
severity of degenerative joint disease was reduced and
the stifle joints returned to a more normal physiologic
state in treated dogs compared with untreated dogs.44
The same disease-modifying effect was reported in a
meniscectomized rabbit model in which a significant
decrease in moderate to severe osteoarthritic changes in
the stifle was identified.45 In another study, dogs pre-
treated with the combination of glucosamine hydro-
chloride, chondroitin sulfate, and manganese ascorbate
followed by induced synovitis showed decreased in-
flammation and reduced lameness.46
Finally, perceived safety and efficacy were confirmed in
a survey of more than 3000 small animal practitioners,
who reported that the combination improved mobility,
alleviated pain, and improved attitude in small animal
patients.47 The most common adverse side effect was gas-
trointestinal upset, which occurred in 2% of patients.47
This combination of compounds is also reportedly safe
and efficacious in horses and cats48–50 and may be effec-
tive in treating immune-mediated arthritis in rats.51
S-ADENOSYLMETHIONINE
S-adenosylmethionine (SAMe) is synthesized from
methionine and is involved in several biologic reac-
tions. Large doses of methionine are toxic and thus
cannot be given to increase endogenous levels of SAMe.
Therefore, SAMe must be supplemented by either in-
jection or oral administration. The high reactivity of
SAMe makes the compound unstable, but the synthesis
of stable salts has enabled SAMe to be administered
and researched.52
In human clinical trials, SAMe was shown to be ef-
fective in treating symptoms associated with osteo-
arthritis via a potent antiinflammatory action similar to
that of most NSAIDs.53,54 SAMe was also shown to
directly affect chondrocytes by increasing proteoglycan
synthesis and protecting cartilage in several in vivo
studies.55–57 The chondroprotective effects of SAMe
partially result from the compound’s capability as a
methyl donor and ability to transsulfate the GAG.52
Compendium July 1999 20TH ANNIVERSARY Small Animal/Exotics

Oral pharmacokinetics have been studied in dogs. Plas-
ma levels have been documented; however, absorption
was better when dogs were fasted overnight before ad-
ministration.52 The recommended dose in humans is
600 mg/day for the first 2 weeks, followed by 400
mg/day. Clinical response was present at 1 month and
was still present after 2 years of treatment.58 Veterinary
studies need to be completed before recommendations
can be made regarding the use of SAMe in animals.
SUPEROXIDE DISMUTASE
Superoxide dismutase (SOD) is the enzyme that con-
verts superoxide formed in phagocytes during the respi-
ratory burst into hydrogen peroxide.57 Hydrogen perox-
ide is potentially harmful, and it is neutralized in the
body by catalase or glutathione peroxidase. SOD has a
potent modifying effect on the inflammatory process
that, unlike the effect of corticosteroids, does not delay
healing or produce any observable side effects.59 SOD is
extracted from bovine liver cells. Oral SOD has been
advocated by some manufacturers but has not been
shown to be absorbable. 60 As a result, only the in-
jectable formulation, which has been thoroughly stud-
ied in mice,60 appears to be effective.61
Oral SOD recently has become more popular in vet-
erinary medicine because of the increasing knowledge of
its mechanism of action. Previous information indicated
that SOD is beneficial in treating acute injury. New re-
search, however, has shown a profound effect in the
treatment of chronic osteoarthritis.62,63 SOD’s effect on
chronic osteoarthritis appears to be related to decreasing
the amount of superoxide that would react with nitric
acid to produce peroxynitrite. Peroxynitrite is a long-last-
ing free radical that can
ENDIU
cause injury to DNA and
MP intracellular proteins, re-
M’
degenerative joint disease is difficult to treat because its
severity varies; thus it becomes rational to combine
agents to achieve a quick and more complete response.
Many practitioners will begin a course of treatment
with an injectable agent, such as SOD or a polysulfated
GAG, because these agents have rapid antiinflammato-
ry action. For a sustained treatment, an oral combina-
tion of glucosamine hydrochloride, chondroitin sulfate,
and manganese ascorbate could be used.40 Another option
would be to use an NSAID for immediate relief fol-
lowed by a long-term oral chondroprotective combina-
tion; however, it seems more synergistic to use chon-
droprotective combinations with differing mechanisms.9
The haphazard combination of numerous agents
should only be used with caution unless a well-recog-
nized synergism exists.12 There is often little scientific
evidence that mixing unstandardized plant products,
whole animal tissue, minerals, and vitamins will work
and thus should not be recommended. A true thera-
peutic agent, regardless of origin, should be given seri-
ous consideration.12,15 However, the benefits of any
chondroprotective agent must be weighed against its
risk. It must be emphasized that neither risk nor bene-
fits have been established for many of the cartilage-
sparing agents.15
ACKNOWLEDGMENT
The author thanks all of the manufacturers that pro-
vided information for this paper.
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CO

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About the Author
Dr. Anderson is affiliated with Veterinary Specialty Ser-
vices, St. Louis, Missouri, and is a Diplomate of the Amer-
ican College of Veterinary Surgeons.