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Vol. 21, No.

9 September 1999 V 20TH ANNIVERSARY

CE Refereed Peer Review

Oral Chondroprotective
FOCAL POINT Agents. Part II.
★Lack of standardization for safety, Evaluation of Products*
efficacy, and truth in labeling of
most nondrug oral compounds
makes the decision-making Veterinary Specialty Services, St. Louis, Missouri
process difficult for veterinarians Mark A. Anderson, DVM, MS
choosing new products to treat
osteoarthritis (OA). ABSTRACT: Many new chondroprotective products are becoming available on the veterinary
market to treat osteoarthritis. Several of the new products on the horizon are discussed. These
products must be used with some caution. Veterinarians should review all of the information
KEY FACTS about a product before deciding to recommend that owners purchase it for their pets.

T
■ Nondrug oral compounds cannot he number of the nondrug oral compounds known as chondroprotective
be sold with the claim that they agents has increased in recent years. However, lack of control by any gov-
treat OA, degenerative joint ernment agency has led to poor regulation and contributed to veterinari-
disease, or pain. ans’ inability to decide which products are safe, effective, and have accurate la-
bels. The lack of product standardization makes comparisons between similar
■ Quality, grade, and quantity products difficult if not impossible.
must be carefully assessed when New chondroprotective-agent candidates include such compounds as type II
determining which nondrug oral collagen, fatty acids, antioxidants, amino acids, proteolytic enzymes, and botani-
compound to use. cals. However, until standardized methods for comparison are devised, none of
these agents should be used as primary treatment of osteoarthritis (OA). Al-
■ The various unprocessed though many of these compounds have shown promise in treating arthritis in
chondroitin sulfate products may humans, veterinarians should evaluate products based on sound scientific find-
not have equivalent results in the ings and manufacturer reputations. Part I of this two-part series discussed no-
treatment of OA. menclature and the types of available chondroprotective agents. This article pro-
vides some parameters for evaluating many new chondroprotective products.
■ Glycosaminoglycans can be
derived only from animal sources SAFETY, EFFICACY, AND TRUTH IN LABELING
and not from sea algae, gelatin, The confusion and occasional misinformation that surround the use of chon-
or other plant sources. droprotective agents may be frustrating for veterinarians and clients alike. The
list of compounds proposed as chondroprotective agents is long and expected to
■ No veterinary studies support grow. Until chondroprotective agents are held to efficacy and safety standards
or refute the efficacy of collagen similar to those of pharmaceuticals, veterinarians should approach newly pro-
type II, fatty acids, antioxidants, posed products with an open mind combined with healthy skepticism.1–3
amino acids, proteolytic enzymes, Individuals in search of accurate information about chondroprotective agents
and botanicals in the treatment of are often thwarted by a lack of definite answers. Scientific veterinary information
OA. on most oral chondroprotective agents is limited.4 In most cases, this lack of accu-
rate information is complicated by legal and economic, rather than purely scien-
*Part I of this two-part presentation appeared in the July 1999 (Vol. 21, No. 7) issue of
Compendium.
Small Animal/Exotics 20TH ANNIVERSARY Compendium September 1999

tific, reasons. For nondrug does not determine whether


oral compounds, the FDA the product was properly
does not legally allow claims manufactured. Practitioners
to be made regarding the should choose products for
treatment of arthritis, degen- which research was con-
erative joint disease, or pain. ducted on the brand prod-
Products should be suspect- uct and not the raw com-
ed if such claims are made pound; assumptions that
on any label or literature.3 the brand product and raw
Purity can also vary among compound have met similar
nondrug products. A recent specifications are question-
study found the content of able.10 For instance, manu-
oral superoxide dismutase facturers may only supply
(SOD) to be no higher than Figure 1—Nondrug oral products should be validated by in- references for the raw com-
5% of the label claim made dependent laboratory analysis. pound and not for their prod-
by six different manufactur- uct. Published studies may
ers.5 The low concentration evaluate a compound in pure
of SOD may have been the result of the source not be- form, whereas the product may not use this same pure
ing purified to the labeled amounts or the SOD being compound. Finally, the study must be critically evaluat-
destroyed in the manufacturing process or storage. An- ed (e.g., information published on the treatment of
other study showed that 70% of products analyzed for rheumatoid arthritis may not pertain to the treatment
glucosamine and chondroitin sulfate (CS) did not meet of OA).
label claims.6 Even when a product does contain the
stated amount, quality and grade of the labeled com- GLYCOSAMINOGLYCAN SOURCES
pound may not be specified. For example, glucosamine The efficacy of purified CS for treating OA has been
and CS are available in a variety of grades of raw prod- well documented7,8,10–14; thus, certain whole animal tis-
uct. The studies that have evaluated the safety and effi- sues have been promoted to be beneficial primarily be-
cacy of these two compounds used pharmaceutic-grade cause they are sources of glycosaminoglycan (GAG) or
material7,8; products using lower-grade material may mucopolysaccharide and thus of CS. Because purified
not achieve similar results. CS is expensive, alternative sources have been assumed
When evaluating nondrug oral products, veterinari- to be effective simply because GAG is present. Howev-
ans must base their selection decisions on their knowl- er, that a product is a source of GAG does not ensure
edge of the compound’s safety and efficacy and the the quality or milligram strength of CS. CS is often
manufacturer’s reputation. One standard by which vet- bound to aggrecan and is poorly available.
erinarians can evaluate a manufacturer is whether the Sources of GAG proposed to have effects similar to
product has been subjected to independent laboratory those of CS include cartilage powders of shark, chick-
analysis (Figure 1) and clinical trials and has been made en, or bovine origin; sea cucumber; and Perna mussel.
using good manufacturing practices.9 No study has proven these possible alternative sources
Veterinarians should also study labels to ensure the of CS to be effective in treating OA. Theoretically,
exact amounts of active ingredient are listed and the la- some alternative sources based on whole animal tissues
bels are easy to understand. Labels that are not easy to could be beneficial if high enough doses are given, but
read can often be deceptive if not examined closely.1,2 the absorption may still be poor. These products often
Products that combine metric and apothecary systems provide a nonuniform and unstandardized mixture of
should be questioned because calculating dosages be- proteins, fats, carbohydrates, and minerals with un-
comes difficult. In many instances, the milligram known and/or unpredictable effects. In addition, many
strength may be listed but the sum of the listed ingredi- GAG-source products contain absolutely no glucosa-
ents is heavier than the final product. All products mine.6,15
should contain a specific dose. If a dose is not provided, Cartilage powders have been studied in wound heal-
it becomes difficult to determine how much to use ing,16 but no controlled studies on OA have been per-
when treating patients. formed in either human or veterinary medicine. There
Veterinarians should also request a copy of the analy- have been a few anecdotal reports showing that purified
sis of the finished product—not the raw material— or raw shark cartilage administered at high doses is effi-
from the manufacturer because a raw product analysis cacious in dogs,17 but shark cartilage has been reported

PURITY ■ FINISHED-PRODUCT ANALYSIS ■ CHONDROITIN SULFATE


Compendium September 1999 20TH ANNIVERSARY Small Animal/Exotics

to have a low percentage (18%) of GAG.15 A recent study line cartilage has been implicated as the initiating cause,
using a purified, water-soluble protein fraction of shark and reason for progression, of OA.24 More recently, re-
cartilage showed an antiinflammatory effect in laborato- search on collagen as a therapy for joint disease has cen-
ry animals.18 However, this documented effect of the tered on oral administration of type II collagen for
purified form of shark cartilage differs from that associ- treating humans with rheumatoid arthritis.23,25 Two in-
ated with feeding raw cartilage. Other research has vestigations have identified autoantibodies directed
shown shark cartilage to have an antiangiogenic effect.17 against type II collagen in dogs with naturally occur-
Perna mussel has been reported to be a source of ring joint disease.26,27 These facts may indicate that au-
GAG; however, the specific GAGs have never been toimmunity may be at least a part of the disease pro-
identified.16 The analysis of Perna mussel has included gression in certain humans and animals with joint
proteins, amino acids, enzymes, carbohydrates, and disease. The potential for collagen-based therapies to
fats; glucosamine, CS, and the specific GAGs are not contribute to the management of joint diseases is novel;
listed on the label.19 Most research done on Perna mus- however, more research needs to be performed before
sel has been for the treatment of rheumatoid arthritis collagen can be recommended for treatment of joint
and is dated.16,17,20–22 Because Perna mussel lacks an disease.
identifiable active ingredient and a confirmed mecha-
nism of action, research is limited on Perna mussel as a Fatty Acids
treatment of OA.16 In addition, although anecdotal re- Omega-3 and omega-6 fatty acids have occasionally
ports exist, there are no good controlled studies that been successful at modulating joint disease in hu-
substantiate Perna mussel as a treatment of OA. mans,28 but there are no controlled veterinary studies
Sea algae and gelatin are also proposed sources of raw that evaluate these compounds in treating joint disease.
GAG. However, GAGs can be derived only from ani- These fatty acids are essential for health and have been
mal sources and not from plants or algae.22 The only used successfully to treat other inflammatory diseases in
known exception is some bacteria (Streptococcus species) veterinary patients (e.g., skin disorders).29 Fatty acids, as
that can produce hyaluronic acid. As a result, it is im- well as other endogenous molecules, are being investi-
possible for algae to be a source of any GAG. Gelatin is gated for their role in modulating rheumatoid arthritis
mainly a conglomeration of water and soluble proteins. and OA in humans.28 Current human research uses high
Based on this fact, GAGs should be either minimal or doses (ranging from 2 to 5 g/day) to obtain clinical re-
not present in gelatin. Veterinary studies have not been sults30; it seems questionable that lower amounts added
performed to confirm either algae or gelatin as an effec- to a combination product would be of any value in ei-
tive treatment for OA. ther humans or animals. Although fatty acids may be
valuable in managing joint disease in animals, little is
NEW CHONDROPROTECTIVE AGENTS known regarding their specific role. Many fatty acids
In addition to the compounds discussed in Part I, have been implicated as antiinflammatory agents in cer-
there are a multitude of compounds that are marketed tain disease conditions (e.g., autoimmune arthritis, skin
as being effective in the treatment of OA but have un- disease); however, potential interactions with current
substantiated efficacy. Some of these new chondropro- therapies are unknown.28–30 Many questions regarding
tective agents will be discussed. The interaction caused this group of compounds and their use in the treatment
by combining these new compounds with the previous- of OA remain unanswered.
ly mentioned products is unknown. Many of these
compounds are added to numerous formulations that Antioxidants
are sold in the veterinary market but in such small con- Antioxidants (e.g., vitamins E and C, selenium) may
centrations that they appear to have little or no effect in have some effect in decreasing joint disease in humans,
the treatment of OA. but no veterinary studies have evaluated the efficacy of
any of these compounds. In humans, the dose for vita-
Type II Collagen min E is 400 to 800 IU/day for musculoskeletal dis-
Type II collagen is a molecule endogenous to the car- ease, with minimal effects being observed; however, vi-
tilage matrix that has been investigated as a potential tamin E is oil soluble, and overdose is possible.31 Other
treatment for OA.23 Hyaline cartilage is primarily com- antioxidants, such as selenium, have not shown a sig-
posed of type II collagen and, to a lesser extent, types nificant decrease in pain scores in humans with OA, al-
IX and XI. The random framework of type II collagen though using selenium to treat rheumatoid arthritis is
is essential to the normal function of the hyaline carti- promising.32 Vitamin C has been proposed as a treat-
lage matrix. Derangement of the superficial zone of hya- ment for many musculoskeletal diseases because of the

PERNA MUSSEL ■ HYALINE CARTILAGE ■ VITAMIN E


Small Animal/Exotics 20TH ANNIVERSARY Compendium September 1999

crucial role it plays in collagen synthesis.33,34 However, and composition of the marketed product may not be
because dogs make vitamin C endogenously, the role of the same as those that were proven effective in the re-
additional vitamin C in the diet has been questioned. search. In addition, calculating the amount of com-
In addition, very high doses of vitamin C would be re- pound to administer may be difficult because most
quired to increase the tissue levels of vitamin C. A dose compounds are unstandardized.1 As more is learned
of 90 mg/kg was required to clinically improve OA in about the mechanism of action of these botanicals,
dogs,17 but these results have not been repeatable. If plant-derived compounds can be expected to become
large doses of vitamin C are used, gastrointestinal side increasingly important as therapeutic agents.
effects may occur.17
ACKNOWLEDGMENT
Amino Acids and Proteolytic Enzymes The author thanks all of the manufacturers that provid-
Creatine is an amino acid thought to modify muscu- ed information for this paper.
loskeletal activity in humans. Creatine’s benefit in the
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27. Niebauer GW, Wolf B, Bashey RI, et al: Antibodies to ca- Dr. Anderson is affiliated with Veterinary Specialty Ser-
nine collagen types I and II in dogs with spontaneous cranial vices, St. Louis, Missouri, and is a Diplomate of the Amer-
cruciate ligament rupture and osteoarthritis. Arthritis Rheu- ican College of Veterinary Surgeons.
matol 30:319–327, 1987.