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Published by Arenus, 2017-12-01 14:22:55

Steadfast Canine Whitepaper

Full product and information details on Steadfast Canine, a patented canine joint and structural support supplement from Arenus.

Keywords: steadfast,steadfast canine,arenus,canine,dog,joint,joint supplement,supplement,soft tissue

WHITEPAPER


TABLE OF CONTENTS

I. Executive Summary����������������������������������������������������������������������������������������������������������������������������������3
II.Background������������������������������������������������������������������������������������������������������������������������������������������������3

a. Chondromodulating Agents������������������������������������������������������������������������������������������������������3-4
b. Natural Eggshell Membrane (NEM®)������������������������������������������������������������������������������������������4
c. Sulfur-Containing Products����������������������������������������������������������������������������������������������������������4
III. STEADFAST® Canine�������������������������������������������������������������������������������������������������������������������������4-5
a. Trace Minerals�����������������������������������������������������������������������������������������������������������������������������5-6
b. Trace Mineral – Antioxidant Support������������������������������������������������������������������������������������������6
c. Sources of Methionine�������������������������������������������������������������������������������������������������������������������6
d. Benefits of NEM®������������������������������������������������������������������������������������������������������������������������ 6-7
IV. Conclusion������������������������������������������������������������������������������������������������������������������������������������������������8
V. References������������������������������������������������������������������������������������������������������������������������������������������ 8-10

Altera International, Ltd.

CONFIDENTIAL

Do not photocopy without the written permission of Altera International, Ltd. For discussion purposes only.
References are for informational purposes. Altera does not necessarily agree with references cited or the

2 conclusions of the researchers.


I. EXECUTIVE SUMMARY 3

Osteoarthritis (OA) is a common affliction having multiple causes and is characterized
by pathologic changes of the synovial or diarthrodial joint. Clinical signs include impaired
joint motion, severe pain, and ultimately disability. The pain and loss of mobility can be
crippling to humans, horses and dogs. Prevalence of OA in dogs has been estimated to
affect as many as 20% of dogs older than 1 year of age [32]. At present, there is no cure
for OA, and supportive therapy, including non-steroidal anti-inflammatory drugs (NSAIDs)
and corticosteroids, is the most common approach taken in the management of this
condition [34]. While the NSAIDs, as a group, are quite effective for relief of symptoms
(pain and swelling), they do not improve the joint structure of cartilage, or slow the
progression of the disease. Of more concern, long-term use of these drugs can cause
gastrointestinal problems, such as ulcers and bleeding, as well as increased risk for
cardiovascular events [7, 12, 51, 56]. As a result, alternative therapies are commonly used
in both human and veterinary medicine.
Joint supplement products may offer advantages over drugs in the treatment and
intervention of OA [4] for a few reasons. Firstly, nutrition is better positioned to provide
long-term rather than short-term health benefits. This is because a nutritional compound
has only limited effects on its biological target and relevant and significant differences are
reached only over time through a buildup effect in which daily benefits add up day after
day. For this reason, and because the time window for intervention is longer in chronic
diseases such as arthritis, OA should benefit from nutrition. Secondly, the mechanisms
of cartilage degradation in OA are multi-factorial and most health supplements usually
contain multiple active compounds that target multiple pathways. Joint supplement
products could provide an alternative to pharmacological interventions whose often
monomodal mode of action may explain their partial lack of clinical efficacy in OA.
Lastly, the attractiveness of using joint supplement products for OA lies in the detriments
that can be prevented from using supplements versus drugs. Long-term pharmacological
NSAIDs are associated with significant adverse events or side effects such as GI upset,
ulcers, and cardiovascular events. Nutraceuticals and functional foods, by regulatory
laws, are required to be devoid of adverse effects and joint supplement products as a
whole have been shown to be safe.

II. BACKGROUND

a. Chondromodulating Agents

Of all the OA supplements, more information is known about chondromodulating agents
(e.g., glucosamine and chondroitin sulfate), than any other supplement. These oral joint
supplements (OJSs) are purported to slow or alter the progression of OA. Glucosamine
and chondroitin sulfate are precursors to glycosaminoglycans (GAGs) and GAGs are a
major component of joint cartilage. Supplementation of glucosamine and/or chondroitin
sulfate may help rebuild cartilage [10] and in vitro data supports this claim [11, 22,
40]. Beneficial effects may include a positive effect on cartilage matrix synthesis and
hyaluronan synthesis by synovial membrane as well as an inhibitory effect on catabolic
enzymes in osteoarthritic joints [47]. Despite their widespread use, poor product quality
and poor bioavailability have been identified in glucosamine-containing OJSs [21, 23, 28,
38, 48, 52].
The glucosamine molecule is available commercially in several forms; the most popular
form attached to a sulfate moiety (GS), but it can also be attached to hydrochloric acid
(GHCl) or an acetyl group (N-acetylglucosamine). Many experts feel that the sulfur is just
as important as the glucosamine, and together they work effectively [39, 57]. A recent
review of all human glucosamine studies suggested that the sulfate form was preferred
over the hydrochloride [44]. Note that the sulfur may also be provided by other sulfur-
containing compounds such as methylsulfonylmethane (MSM), S-adenosylmethionine
(SAMe), chondroitin sulfate, sulfur amino acids or a combination of one or more of these
compounds. Trials of SAMe indicated positive results, but adverse effects and high
dropout rates were recorded [25, 30, 36, 49]. Methylsulfonylmethane is a derivative of
dimethyl sulfoxide and has mostly been used in humans as a treatment for allergies to
help reduce inflammation. There is also some evidence for MSM efficacy in humans


for the treatment of OA [41, 70]. Methylsulfonylmethane has high sulfur content, and may help with cartilage
structure.

b. Natural Eggshell Membrane (NEM®)

The strength of the keratin formed in the hoof is determined by the cross-linking of sulphur-containing amino
acids provided by and between cystine (Cys) residues [19]. Methionine is an essential sulfur-containing amino
acid which is critical for the production of cystine. Methionine also acts as an antioxidant to reduce inflammation,
as the sulfur it supplies inactivates free radicals and increases lecithin production, as well as the synthesis of
phosphatidylcholine and other phospholipids required for cartilage, ligament and tendon growth. In addition,
methionine provides sulfur to promote healthy skin and coat. STEADFAST® Equine provides a supplemental
source of methionine as methionine hydroxyl analogue. Methionine hydroxyl analogue differs from dl, methionine
in its chemistry and has been demonstrated to differ in its absorption and utilization within the body. Advantages
of methionine hydroxyl analogue as compared to dl, methionine include more rapid absorption and anti-microbial
activity against certain undesirable species of bacteria and mold.

c. Sulfur-Containing Products

The glucosamine molecule is available commercially in several forms; the most popular form attached to a sulfate
moiety (GS), but it can also be attached to hydrochloric acid (GHCl) or an acetyl group (N-acetylglucosamine).
Many experts feel that the sulfur is just as important as the glucosamine, and together they work effectively
[30, 44]. A recent review of all human glucosamine studies suggested that the sulfate form was preferred over
the hydrochloride [25]. Note that the sulfur (S) may also be provided by other sulfur-containing compounds such
as methylsulfonylmethane (MSM), S-adenosylmethionine (SAMe), chondroitin sulfate, sulfur amino acids or a
combination of one or more of these compounds. Trials of SAMe indicated positive results, but adverse effects
and high dropout rates were recorded [36, 41, 49, 70]. Methylsulfonylmethane is a derivative of dimethyl sulfoxide
and has mostly been used in humans as a treatment for allergies to help reduce inflammation. There is also some
evidence for MSM efficacy in humans for the treatment of OA [35, 67]. Methylsulfonylmethane has high sulfur
content, and may help with cartilage structure.

III. STEADFAST® CANINE

STEADFAST® Canine is a unique and comprehensive supplement for total joint health for dogs. It is formulated
with the components necessary to support the development, health and maintenance of bones, joints, and
other connective tissues such as ligaments and tendons. STEADFAST® Canine provides a natural source of
supportive nutrients for healthy joint function from Natural Eggshell Membrane (NEM®), including glucosamine,
chondroitin, and hyaluronic acid. In addition, STEADFAST® Canine utilizes an advanced complex (TêlaFIRM®)
that contains organic sources of zinc, copper and manganese which have improved bioavailability over standard
trace mineral formulations [68]. Moreover, TêlaFIRM® also provides an organic selenium (Se) source shown to
have high bioavailability and tissue retention [72]. Providing trace nutrients in these highly bioavailable forms
is important since most commercial feeds and supplements utilize forms shown to be less stable through the
gastrointestinal (GI) tract and potentially more susceptible to antagonisms [5, 37]. The decreased stability and
bioavailability may result in inadequate levels of micro nutrients to meet the metabolic requirements of dogs. In
addition, STEADFAST® Canine provides methionine (as methionine hydroxyl analogue), calcium (Ca), phosphorus
(P), vitamin C and vitamin D, all which play important roles in the production and maintenance of healthy bone and
cartilage (see appendix I). STEADFAST® Canine supplies these key health supplement components in a palatable
tablet form.
Bone and cartilage are constantly broken down and reformed in response to the mineral needs of the body and the
physical wear and tear of weight bearing [3]. This is a continuous process in adults, and it involves both dissolution
of old bone and cartilage and the synthesis of new bone and cartilage. This turnover is a normal part of bone
maintenance [3] but tends to be increased in older animals. When the breakdown of bone by osteoclasts exceeds
the formation of new bone by osteoblasts, bone mineral density decreases. Thus, to maintain healthy bones,
the signals for bone breakdown must not exceed the capacity for new bone formation. In addition, the substrate
requirements for bone formation must be satisfied and presented in a form readily used by bone cells. Similarly,
cartilage turnover is the normal process of cartilage matrix dissolution and reformation by chondrocytes. Cartilage
turnover becomes even greater in arthritic joints and, as with bone, the precursors for synthesis of new cartilage
by chondrocytes are required to keep the joint from deteriorating. STEADFAST® Canine is formulated to address
maintenance and health of the total structural system of the body, including joints and bones.
STEADFAST® Canine contains critical substrates and vitamin cofactors required for the synthesis of new bone:
calcium, vitamin D3 and vitamin C. STEADFAST® Canine also contains the precursors necessary for new cartilage

4 synthesis including glucosamine, chondroitin, and hyaluronic acid. These are provided by Natural Eggshell


Membrane (NEM®), which also enhances calcium transport in human intestinal epithelial
cells in vitro [14]. In addition, STEADFAST® Canine ensures that the trace minerals
required for bone and cartilage formation, zinc (Zn), copper (Cu), and manganese (Mn),
are present in a form (TêlaFIRM®) that ensures maximum bioavailability and absorption
regardless of antagonists that might be present in the diet. The availability of the minerals
[68] in TêlaFIRM® is greater than can be achieved with inorganic mineral forms such as
sulfate or oxide salts [68]. Inorganic forms have been shown to be less stable through
the GI tract and potentially more susceptible to mineral antagonisms [5, 37]. Providing
trace nutrients in this highly bioavailable form is important since most supplements
contain inorganic forms of micro minerals. Decreased stability and bioavailability of
inorganic trace minerals may result in inadequate levels of micronutrients to meet the
ever-present metabolic requirements for new bone and cartilage synthesis.

a. Trace Minerals

Increased trace mineral bioavailability can translate into numerous benefits to the animal,
including improvements in bone and tissue development and integrity, enhanced immune
function and better performance. One example of this is tibial dyschondroplasia (TD),
a common developmental defect in fast growing birds, but similar to osteochondrosis
in dogs [53]. In this condition, the cartilage model at the epiphysial plate fails to ossify,
resulting in plugs of cartilage in place of true bone. Bones are therefore weak, and can
result in bone breaks when the birds are heavy. Rath and colleagues have demonstrated
that tibias exhibiting TD have normal collagen content, but reduced amounts of sulfated
glycosaminoglycans and MMP activity when compared to normal tibias [54]. These
findings suggest supplementation with manganese (Mn) and zinc (Zn) may alleviate
TD. In a separate paper, this group also showed that the extent of collagen crosslinking
in tibia correlated with bone breaking strength [20]. These results imply an important
role for copper. A recent trial at a major U.S. turkey producer evaluated the impact of
organic trace minerals (OTM) supplementation on leg development and bone strength
[63]. Turkeys were fed diets with standard inorganic trace minerals (ITM) levels, or diets
additionally supplemented with a blend of TêlaFIRM® organic trace minerals (copper,
manganese and zinc). For the first 10 weeks, the supplementation from TêlaFIRM®
provided 20 ppm zinc and mananese, and 10 ppm copper. After 10 weeks, the
supplemented levels were reduced. Adding TêlaFIRM® to the diet significantly (P<0.05)
reduced the incidence of tibial dyschondroplasia, synovitis, and footpad lesions (Figure
1). Interestingly, synovitis positively correlated with lameness. These structural and
tissue improvements make sense, given that these minerals play fundamental roles in
collagen and keratin synthesis and cross-linking, bone development, and in immune
development and response [71]. Furthermore, it is our belief that these beneficial effects
of TêlaFIRM® on bone structure and integrity in poultry would also be beneficial for bone
and joint health in horses, dogs, and other species where bioavailable zinc, copper, and
manganese may be limiting in the diet. Most pet food rations should be adequate in zinc.
However, zinc bioavailability is decreased by a number of factors (phytate, fiber, high
dietary levels of calcium, phosphorus, copper and iron (Fe). The antagonistic effects of
calcium are greatest when phytate is also present, resulting in the formation of a highly
insoluble complex of calcium, phytate and zinc. Many commercial pet foods contain
calcium concentrations that are 1.5-2 times NRC recommendations for calcium.

5


A study in puppies [27] showed even a 25% increase in calcium above the NRC requirement significantly reduced
zinc bioavailability by 35%. Signs of zinc deficiency have been reported to occur in dogs fed cereal-based dry
foods (e.g., grains may contain significant concentrations of phytate), even when the zinc content of the food
exceeded NRC minimum requirements [44]. High fiber-containing pet food diets (e.g., used in weight loss diets)
often result in poor hair coat which may be a result of fiber binding or reducing zinc and/or copper uptake in the
digestive tract. Deficiencies of both zinc and copper have been shown to adversely affect hair coat integrity and
color.

b. Trace Mineral – Antioxidant Support

Several components of STEADFAST® Canine play roles in the total antioxidant system of the body. Reactive
oxygen is a byproduct of the normal, in fact essential electron transport chain, but must be enzymatically
converted to water in order to minimize oxidative damage to DNA and other oxygen sensitive molecules such
as phospholipids. Zinc and copper are essential cofactors for the superoxide dismutase system, one of the
antioxidant enzymes [66]. In addition, the TêlaFIRM® in STEADFAST® Canine also provides an organic selenium
(Se) source shown to have higher bioavailability and tissue retention than inorganic forms [68]. Antioxidant
selenoenzymes such as glutathione peroxidase and thioredoxin reductase detoxify reactive oxygen species
released during the process of cellular energy production [65]. Glutathione peroxidase protects both intra- and
extra-cellular lipid membranes against oxidative damage. The manganese (Mn) in TêlaFIRM® also has antioxidant
activity through activation of manganese superoxide dismutase (Mn SOD) and the removal of free radicals,
particularly those generated during high energy production in gastrointestinal and liver cell mitochondria [1].
Reactive oxygen species are also released during inflammation, and antioxidants are essential for optimal wound
healing following inflammatory stress, including that in bones and joints. In addition, selenium plays a role in the
regulation of osteoclast activity, the cells responsible for bone resorption [43].

c. Sources of Methionine

The advanced micronutrient complex (TêlaFIRM®) in STEADFAST® Canine provides these trace minerals in
an organic form that also contains a source of methionine, an essential methyl group donor for the synthesis
of biomolecules such as the organic matrix of bones and joints. Sulfur amino acids, including methionine, act
as antioxidants to reduce inflammation, as the sulfur it supplies inactivates free radicals and provides cysteine
for glutathione synthesis, the most abundant endogenous antioxidant [49]. In addition, methionine provides
sulfur which is an important part of the chemical structure of cartilage [57]. STEADFAST® Canine provides a
supplemental source of methionine as methionine hydroxy analogue. Methionine hydroxy analogue differs from
DL-methionine in its chemistry and has been demonstrated to differ in its absorption and utilization within the body
[19]. Each daily serving of STEADFAST® Canine provides approximately 33% of the Recommended Allowance of
methionine (Met) for the dog. This intake approximates 281 mg/d Met for the small breed and 650 mg/d for the
large breed dog.

d. Benefits of NEM®

STEADFAST® Canine is unique in that it not only provides a complete source of the essential ingredients
necessary to support the growth and maintenance of strong bones, it also maintains and promotes healthy joints.
NEM® in STEADFAST® Canine provides glucosamine, chondroitin and hyaluronic acid, critical for the production
of larger glycosaminoglycans (GAGs), the biologically-produced building blocks of cartilage, connective tissue and
lubricating joint fluids [19]. In addition, another component of STEADFAST® Canine, manganese, is an essential
cofactor for the enzymatic synthesis of the large GAGs in cartilage from these building blocks. Manganese
promotes the formation of normal cartilage and bone through the activation of enzymes needed for synthesis of
the chondroitin sulfate side chains of proteoglycan molecules [33]. Aggrecan, one of the largest GAGs in cartilage,
provides much of the compressive resilience of the hyaline cartilage of joints. The hydrated glycoproteins act
as pillows that absorb the shock of repetitive weight bearing stress and thus protect the bone from mechanical
damage [24]. Thus, manganese is essential in the synthesis of new cartilage required by cartilage turnover. Each
daily serving of STEADFAST® Canine provides approximately 50% of the Recommended Allowance for zinc,
manganese, copper and selenium for the dog. Daily intakes for the small and large breed dog are: zinc, 8 and 18,
manganese, 0.6 and 1.4, copper, 0.8 and 1.8, and selenium, 0.05 and 0.11 mg/d, respectively.
Glucosamine is the main component of GAGs and is required for the production of chondroitin sulfate, the primary
GAG found in joint cartilage and connective tissue, as well as hyaluronic acid, a natural joint lubricant. Chondroitin
sulfate not only serves in a synthetic capacity, but acts to inhibit enzymes that destroy cartilage, as well.
Glucosamine, chondroitin sulfate and hyaluronic acid supplementation has been reported to relieve symptoms
of joint inflammation and arthritis [16]. However, determination of the dosage of each component necessary for
optimal efficacy is unclear. STEADFAST® Canine provides all three key components of joint health in a natural

6 biologic ratio from a single source, NEM®. NEM® is a single source supplement containing a unique matrix of all-


natural nutrients including glucosamine, chondroitin sulfate, and hyaluronic acid in the
appropriate biologic ratio. Clinical studies with NEM® have demonstrated a significant
reduction in pain and improved range of motion in the joints of patients suffering
from arthritis and a variety of joint and connective tissue injuries [35, 41]. Dogs that
demonstrated suboptimal joint function were fed NEM® over a six-week clinical study
and showed rapid improvement in pain and joint function [58]. Daily supplementation
with STEADFAST® Canine provides 100 mg/d of NEM® for the small breed and 230 mg/d
of NEM® for the large breed dog.
Degenerative osteoarthritis involves some degree of inflammation, thus nutritional
compounds that modify inflammation should be beneficial. Arachidonic or omega-6 (n-6)
fatty acids, when metabolized produce prostaglandins, leukotrienes and thromboxanes
of the 2 and 4 series. Many drugs used to treat OA inhibit conversion of arachidonic acid
to these eicosanoids [10]. Omega-6 derived eicosanoids have predominantly vasoactive
and proinflammatory effects whereas metabolism of omega-3 (n3) fatty acids produce
eicosanoids of the 3 and 5 series, which are less vasoactive and less proinflammatory.
Several studies in humans with OA demonstrate a beneficial response to n3 fatty acids
[17,61,62] whereas other studies yielded no effect [69]. A study involving 18 dogs
compared the effects of varying n6:n3 fatty acid ratio on experimentally induced stifle
arthritis [6]. Diets ranged from n6:n3 fatty acid ratios of 28:1(high n6), 8.7:1 (typical or
control diet) to 0.7:1 (high n3). Diets were fed for 21 months. Initially, the dogs were
started on their assigned diet 3 months before surgical transaction of the left cranial
cruciate ligament, continued until surgical repair 6 months later, and maintained for
an additional 12 months after repair. Consumption of the high n3 diet was associated
with lower serum concentrations of cholesterol, triglycerides, and phospholipids; lower
synovial concentrations of prostaglandin E2; better ground reaction forces (in other
words, dogs were able to put more weight on arthritic limb(s)); and fewer radiographic
changes of OA. Synovial membrane fatty acid composition mirrored the fatty acid
composition of the diets.
The efficacy of vitamin C in humans with OA has been difficult to determine because
of contradictory results. Epidemiological studies suggest a reduction in risk of OA
progression for both the middle and highest tertile of vitamin C intake and an inverse
association between vitamin C intake and cartilage loss [46]. Lame horses showed
improvement (9 of 10 animals) with vitamin C supplementation [26]. In vitro, vitamin
C increased protein and proteoglycan synthesis [13, 15] by articular chondrocytes and
increased type I and II collagen and aggrecan [59]. Vitamin E. Although 3 out of 5
randomized clinical trials concluded that vitamin E decreased pain in OA patients, the
two longest, largest, and best evidenced based trials failed to detect any symptomatic
or structural effects of vitamin E in knee OA [8, 9, 42, 60, 73]. Ascorbic acid (vitamin
C) is an important cofactor for collagen synthesis [29] and bone cell proliferation [74].
Ascorbic acid is required for the hydroxylation of proline and lysine to hydroxyproline
and hydroxylysine, the structural backbones of collagen [29]. In addition, ascorbic acid
stimulates bone cell growth and strength by increasing chondrocyte production [74],
osteoblast differentiation, and bone mineralization by increased alkaline phosphatase
activity [18]. Ascorbic acid is also a strong antioxidant that may be involved in improving
both cardiac and immune system health [31]. Ascorbic acid is supplied by STEADFAST®
Canine at a rate of 33 and 76 mg/day for the small and large breed dog, respectively.
Although epidemiological evidence suggests a role of vitamin D in OA, no randomized
clinical trials have evaluated vitamin D efficacy in OA patients. The Framingham study
[45], an example of the epidemiological data, found a 3-fold increase in risk of OA
progression for patients in the middle and lowest tertiles of serum levels of 25-vit
D. Low serum levels of vitamin D also predicted loss of joint space and bone spur
growth. Vitamin D (calciferol) is one of the most important biological regulators of
calcium metabolism and as such, is critical for normal bone growth and development.
The biologically active form of vitamin D, vitamin D3, facilitates the absorption of
calcium and phosphorus from the intestine and utilization of these minerals for bone
formation. Vitamin D3 is required for the control of calcium reabsorption, absorption and
mobilization/accretion from bones [50]. The vitamin D3 in STEADFAST® Canine provides
approximately 60% of the recommended allowance for the small and large breed dog.
Daily intakes for vitamin D equate to 72 and 170 mg/day for the small and large breed
dog, respectively.

7


IV. CONCLUSION

Daily supplementation with STEADFAST® Canine supplies critical components necessary for supporting the
growth and health of all structural components (i.e. bones and cartilage) in addition to providing anti-inflammatory
activity for improved joint health in mature dogs.

V. REFERENCES

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