Vol. 21, No.
9 September 1999 V 20TH ANNIVERSARY
CE Refereed Peer Review
FOCAL POINT
★Lack of standardization for safety,
efficacy, and truth in labeling of
most nondrug oral compounds
makes the decision-making
process difficult for veterinarians
choosing new products to treat
osteoarthritis (OA).
KEY FACTS
■ Nondrug oral compounds cannot
be sold with the claim that they
treat OA, degenerative joint
disease, or pain.
■ Quality, grade, and quantity
must be carefully assessed when
determining which nondrug oral
compound to use.
■ The various unprocessed
chondroitin sulfate products may
not have equivalent results in the
treatment of OA.
■ Glycosaminoglycans can be
derived only from animal sources
and not from sea algae, gelatin,
or other plant sources.
■ No veterinary studies support
or refute the efficacy of collagen
type II, fatty acids, antioxidants,
amino acids, proteolytic enzymes,
and botanicals in the treatment of
OA.
Oral Chondroprotective
Agents. Part II.
Evaluation of Products*
Veterinary Specialty Services, St. Louis, Missouri
Mark A. Anderson, DVM, MS
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
about a product before deciding to recommend that owners purchase it for their pets.
T
he number of the nondrug oral compounds known as chondroprotective
agents has increased in recent years. However, lack of control by any gov-
ernment agency has led to poor regulation and contributed to veterinari-
ans’ inability to decide which products are safe, effective, and have accurate la-
bels. The lack of product standardization makes comparisons between similar
products difficult if not impossible.
New chondroprotective-agent candidates include such compounds as type II
collagen, fatty acids, antioxidants, amino acids, proteolytic enzymes, and botani-
cals. However, until standardized methods for comparison are devised, none of
these agents should be used as primary treatment of osteoarthritis (OA). Al-
though many of these compounds have shown promise in treating arthritis in
humans, veterinarians should evaluate products based on sound scientific find-
ings and manufacturer reputations. Part I of this two-part series discussed no-
menclature and the types of available chondroprotective agents. This article pro-
vides some parameters for evaluating many new chondroprotective products.
SAFETY, EFFICACY, AND TRUTH IN LABELING
The confusion and occasional misinformation that surround the use of chon-
droprotective agents may be frustrating for veterinarians and clients alike. The
list of compounds proposed as chondroprotective agents is long and expected to
grow. Until chondroprotective agents are held to efficacy and safety standards
similar to those of pharmaceuticals, veterinarians should approach newly pro-
posed products with an open mind combined with healthy skepticism.1–3
Individuals in search of accurate information about chondroprotective agents
are often thwarted by a lack of definite answers. Scientific veterinary information
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
to have a low percentage (18%) of GAG.15 A recent study
using a purified, water-soluble protein fraction of shark
cartilage showed an antiinflammatory effect in laborato-
ry animals.18 However, this documented effect of the
purified form of shark cartilage differs from that associ-
ated with feeding raw cartilage. Other research has
shown shark cartilage to have an antiangiogenic effect.17
Perna mussel has been reported to be a source of
GAG; however, the specific GAGs have never been
identified.16 The analysis of Perna mussel has included
proteins, amino acids, enzymes, carbohydrates, and
fats; glucosamine, CS, and the specific GAGs are not
listed on the label.19 Most research done on Perna mus-
sel has been for the treatment of rheumatoid arthritis
and is dated.16,17,20–22 Because Perna mussel lacks an
identifiable active ingredient and a confirmed mecha-
nism of action, research is limited on Perna mussel as a
treatment of OA.16 In addition, although anecdotal re-
ports exist, there are no good controlled studies that
substantiate Perna mussel as a treatment of OA.
Sea algae and gelatin are also proposed sources of raw
GAG. However, GAGs can be derived only from ani-
mal sources and not from plants or algae.22 The only
known exception is some bacteria (Streptococcus species)
that can produce hyaluronic acid. As a result, it is im-
possible for algae to be a source of any GAG. Gelatin is
mainly a conglomeration of water and soluble proteins.
Based on this fact, GAGs should be either minimal or
not present in gelatin. Veterinary studies have not been
performed to confirm either algae or gelatin as an effec-
tive treatment for OA.
NEW CHONDROPROTECTIVE AGENTS
In addition to the compounds discussed in Part I,
there are a multitude of compounds that are marketed
as being effective in the treatment of OA but have un-
substantiated efficacy. Some of these new chondropro-
tective agents will be discussed. The interaction caused
by combining these new compounds with the previous-
ly mentioned products is unknown. Many of these
compounds are added to numerous formulations that
are sold in the veterinary market but in such small con-
centrations that they appear to have little or no effect in
the treatment of OA.
Type II Collagen
Type II collagen is a molecule endogenous to the car-
tilage matrix that has been investigated as a potential
treatment for OA.23 Hyaline cartilage is primarily com-
posed of type II collagen and, to a lesser extent, types
IX and XI. The random framework of type II collagen
is essential to the normal function of the hyaline carti-
lage matrix. Derangement of the superficial zone of hya-
PERNA MUSSEL ■ HYALINE CARTILAGE ■ VITAMIN E
Small Animal/Exotics
line cartilage has been implicated as the initiating cause,
and reason for progression, of OA.24 More recently, re-
search on collagen as a therapy for joint disease has cen-
tered on oral administration of type II collagen for
treating humans with rheumatoid arthritis.23,25 Two in-
vestigations have identified autoantibodies directed
against type II collagen in dogs with naturally occur-
ring joint disease.26,27 These facts may indicate that au-
toimmunity may be at least a part of the disease pro-
gression in certain humans and animals with joint
disease. The potential for collagen-based therapies to
contribute to the management of joint diseases is novel;
however, more research needs to be performed before
collagen can be recommended for treatment of joint
disease.
Fatty Acids
Omega-3 and omega-6 fatty acids have occasionally
been successful at modulating joint disease in hu-
mans,28 but there are no controlled veterinary studies
that evaluate these compounds in treating joint disease.
These fatty acids are essential for health and have been
used successfully to treat other inflammatory diseases in
veterinary patients (e.g., skin disorders).29 Fatty acids, as
well as other endogenous molecules, are being investi-
gated for their role in modulating rheumatoid arthritis
and OA in humans.28 Current human research uses high
doses (ranging from 2 to 5 g/day) to obtain clinical re-
sults30; it seems questionable that lower amounts added
to a combination product would be of any value in ei-
ther humans or animals. Although fatty acids may be
valuable in managing joint disease in animals, little is
known regarding their specific role. Many fatty acids
have been implicated as antiinflammatory agents in cer-
tain disease conditions (e.g., autoimmune arthritis, skin
disease); however, potential interactions with current
therapies are unknown.28–30 Many questions regarding
this group of compounds and their use in the treatment
of OA remain unanswered.
Antioxidants
Antioxidants (e.g., vitamins E and C, selenium) may
have some effect in decreasing joint disease in humans,
but no veterinary studies have evaluated the efficacy of
any of these compounds. In humans, the dose for vita-
min E is 400 to 800 IU/day for musculoskeletal dis-
ease, with minimal effects being observed; however, vi-
tamin E is oil soluble, and overdose is possible.31 Other
antioxidants, such as selenium, have not shown a sig-
nificant decrease in pain scores in humans with OA, al-
though using selenium to treat rheumatoid arthritis is
promising.32 Vitamin C has been proposed as a treat-
ment for many musculoskeletal diseases because of the
Small Animal/Exotics 20TH ANNIVERSARY
crucial role it plays in collagen synthesis.33,34 However,
because dogs make vitamin C endogenously, the role of
additional vitamin C in the diet has been questioned.
In addition, very high doses of vitamin C would be re-
quired to increase the tissue levels of vitamin C. A dose
of 90 mg/kg was required to clinically improve OA in
dogs,17 but these results have not been repeatable. If
large doses of vitamin C are used, gastrointestinal side
effects may occur.17
Amino Acids and Proteolytic Enzymes
Creatine is an amino acid thought to modify muscu-
loskeletal activity in humans. Creatine’s benefit in the
treatment of OA is questionable; it has been document-
ed that large doses help muscle function in humans.35
The dose used in some veterinary products is extremely
small, making any potential benefit unlikely.
Bromelain is a proteolytic enzyme that reportedly de-
creases acute swelling from sport injuries in humans
when taken in high doses every 4 hours.36,37 However,
to be effective, most proteolytic enzymes must be given
prior to the insult.36,37 Because bromelain appears to be
most effective when given before acute injuries, its use
is unlikely to be beneficial in the treatment of OA.
Botanicals
Botanicals that have been proposed as potentially
chondroprotective include the yucca (several species of
the Agavaceae family), boswellia (Boswellia serrata), and
tumeric (Curcuma longa) plants. Substances derived
from these plants have been used for years to treat a va-
riety of human ailments. However, no veterinary stud-
ies have documented or refuted the use of these botani-
cals in the treatment of OA. Many of these plants or
herbs appear to have some unknown antiinflammatory
effect but do not meet any of the criteria for the defini-
tion of a chondroprotective agent.
Although it is entirely reasonable that plant-derived
agents may be beneficial in treating OA, research is re-
quired to standardize the plant extracts, determine the
pharmacologic principles and mechanism of activity,
and document the proposed effects. Because not all
plant-derived substances are harmless or beneficial, these
substances should meet the same standardization rigors
as do pharmaceuticals before any conclusions regarding
safety or efficacy can be made.1,3 Even if the substances
are found to be safe and effective, interactions with oth-
er compounds must be considered before using them in
a combined therapy. Currently, the labeling of herbal
products is often vague, incorrect, and misleading, and
thus purity and dosing must be questioned.
Even when a botanical has been shown to have an
antiinflammatory effect for a given condition, the dose
CREATINE ■ BROMELAIN ■ PLANT-DERIVED COMPOUNDS
Compendium September 1999
and composition of the marketed product may not be
the same as those that were proven effective in the re-
search. In addition, calculating the amount of com-
pound to administer may be difficult because most
compounds are unstandardized.1 As more is learned
about the mechanism of action of these botanicals,
plant-derived compounds can be expected to become
increasingly important as therapeutic agents.
ACKNOWLEDGMENT
The author thanks all of the manufacturers that provid-
ed information for this paper.
REFERENCES
1. Boothe DM: Nutraceuticals in veterinary medicine. Part I.
Definitions and regulations. Compend Contin Educ Pract Vet
19(11):1248–1255, 1997.
2. Boothe DM: Nutraceuticals in veterinary medicine. Part II.
Safety and efficacy. Compend Contin Educ Pract Vet 20(1):
15–21, 1998.
3. Dzanis DA: Nutraceuticals: Food or drug? Proc TNAVC:
430–433, 1998.
4. Plumbs M: Cartilage supplements help treat arthritis.
Michael Plumb’s Horse J 4:3–11, 1997.
5. Beale BS: Evaluation of active enzyme in six oral superoxide
dismutase products. Proc Vet Orthop Soc:65, 1998.
6. Deal C, Moskowitz RW: Nutraceuticals as therapeutic
agents in osteoarthritis: The role of glucosamine, chondroi-
tin sulfate and collagen hydrolysate. Rheum Dis Clin North
Am 25:379–395, 1999.
7. Hulse DS: Treatment methods for pain in the osteoarthritic
patient. Vet Clin North Am Small Anim Pract 28:361, 1998.
8. McNamara PS, Johnston SA, Todhunter RJ: Disease-modi-
fying osteoarthritic agents. Vet Clin North Am Small Anim
Pract 27:863–867, 1997.
9. Boothe DM: Pharmacology: Nutraceuticals: The good, the
bad, and the ugly. Proc AAHA:292–295, 1998.
10. Das A: The biochemistry of cartilage and osteoarthritis treat-
ment options. Orthoped Special Ed 5:1–4, 1999.
11. Bourgeois P, Chales G, Dehais J, et al: Efficacy and tolera-
bility of chondroitin sulfate 1200 mg/day vs. chondroitin
sulfate 3 × 400 mg/day vs. placebo. Osteoarthr Cartilage
6:25–30, 1998.
12. Busci L, Poor G: Efficacy and tolerability of oral chondroitin
sulfate as a symptomatic slow-acting drug for osteoarthritis
in the treatment of knee osteoarthritis. Osteoarthr Cartilage
6:31–36, 1998.
13. Verbruggen G, Goemaere S, Veys EM: Chondroitin sulfate:
Structure/disease modifying antiosteoarthritis drug in the
treatment of finger joint osteoarthritis. Osteoarthr Cartilage
6:37–38, 1998.
14. Uebelhart D, Thonar EJ, Delmas PD, et al: Effects of oral
chondroitin sulfate on the progression of knee osteoarthritis:
A pilot study. Osteoarthr Cartilage 6:39–46, 1998.
15. Coughlan A: Is there a role for oral glucosamine and chon-
droitin sulphate supplements in managing the osteoarthritic
patient?, in Coughlan A (ed): Coughlan Orthopedics. Cheshire,
England, Neston, 1997, pp 24–28.
16. Bucci L: Glycosaminoglycans, in Bucci L (ed): Nutrition Ap-
plied to Injury Rehabilitation and Sports Medicine. Boca Ra-
Compendium September 1999 20TH ANNIVERSARY
ton, FL, CRC Press, 1995, pp 177–203.
17. Belfield WO: Complementary and alternative veterinary
medicine, in Schoen AM, Wynn SG (eds): Complementary
and Alternative Veterinary Medicine. Philadelphia, Mosby,
1998, pp 113–129.
18. Fontenele JB, Araujo GB, de Alencar JW, et al: The anal-
gesic and anti-inflammatory effects of shark cartilage are due
to a peptide molecule and nitric acid (NO) system depen-
dent. Biol Pharm Bull 20:1151–1154, 1997.
19. Glycoflex brochure, Code V-7-0794-R. Essex Junction, VT,
Vetri-Science Laboratories.
20. Miller TE, Dodd J, Ormrod DJ, et al: Anti-inflammatory
activity of glycogen extracted from Perna canaliculus (NZ
green-lipped mussel). Agents Actions 38:C139–C142, 1993.
21. Larkin JG, Capell HA, Sturrock RD: Seatone in rheumatoid
arthritis: A six-month placebo-controlled study. Ann Rheu-
matic Dis 44:199–201, 1985.
22. Champe PC, Harvey RA: Glycosaminoglycans, in Champe
PC, Harvey RA (eds): Lippincott’s Illustrated Review of Bio-
chemistry. Philadelphia, JB Lippincott, 1994, pp 147–162.
23. Trentham DE, Dynesius-Trentham RA, Orav EJ, et al: Ef-
fects of oral administration of type II collagen on rheuma-
toid arthritis. Science 261:1727–1730, 1993.
24. Johnson S: Osteoarthritis: Joint anatomy, physiology and
pathobiology. Vet Clin North Am Small Anim Pract 27:699–
723, 1997.
25. Barnett ML, Combitchi D, Trentham DE: A pilot trial of
oral type II collagen in the treatment of juvenile rheumatoid
arthritis. Arthritis Rheumatol 39:623–628, 1996.
26. Bari SM, Carter SD, Bell SC, et al: Anti-type II collagen an-
tibody in naturally occurring canine joint diseases. Br J
Rheumatol 28:480–486, 1989.
27. Niebauer GW, Wolf B, Bashey RI, et al: Antibodies to ca-
nine collagen types I and II in dogs with spontaneous cranial
cruciate ligament rupture and osteoarthritis. Arthritis Rheu-
matol 30:319–327, 1987.
Small Animal/Exotics
28. Zurier B: Essential fatty acids and inflammation. Ann Rheu-
matic Dis 50:745–746, 1991.
29. Ackerman L: Dermatologic uses of fatty acids in dogs and
cats. Vet Med 90:1149–1155, 1995.
30. Bucci L: Fats: Fatty acids and lipids, in Bucci L (ed): Nutri-
tion Applied to Injury Rehabilitation and Sports Medicine.
Boca Raton, FL, CRC Press, 1995, pp 53–58.
31. Bucci L: Ultratrace minerals, in Bucci L (ed): Nutrition Ap-
plied to Injury Rehabilitation and Sports Medicine. Boca Ra-
ton, FL, CRC Press, 1995, pp 162–166.
32. Heinle K, Adam A, Gradl M, et al: Selenium concentration
in erythrocytes of patients with rheumatoid arthritis. Med
Klin 92:29–31, 1997.
33. Peterkofsky B, Palka J, Wilson L, et al: Elevated activity of
low molecular weight insulin-like growth factor binding pro-
teins in sera of vitamin C deficient and fasted guinea pigs.
Endocrinology 128:1769–1779, 1991.
34. Bucci L: Normal cellular components: Proteins, nucleic
acids and antioxidant enzymes, in Bucci L (ed): Nutrition
Applied to Injury Rehabilitation and Sports Medicine. Boca
Raton, FL, CRC Press, 1995, pp 167–176.
35. Bosco C, Tihanyi J, Pucspk J, et al: Effect of oral creatine
supplementation on jumping and running performance. Int
J Sports Med 18:369–372, 1997.
36. Craig RP: The quantitative evaluation of the use of oral pro-
teolytic enzymes in the treatment of sprained ankles. Injury
6:313–316, 1975.
37. Trickett P: Proteolytic enzymes in the treatment of athletic
injuries. Appl Ther 6:647, 1964.
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.