NATURAL INGREDIENTS FOR BONE

AND JOINT REJUVENATION

How Cyplexinol® Gives Consumers the Results they Want
Society as a whole is getting older. With advances in medicine, people are living longer than ever and the average age is on the rise. Advancing years, however, bring more health
challenges such as bone loss and joint dysfunction. Already, an estimated 1.7 billion people worldwide currently suffer from musculoskeletal disorders, and with our aging population this
number is only going to increase.1

This trend has not gone unnoticed by consumer healthcare companies. Products for bone and joint health rank in the top five types of health supplements purchased in the United
States, the United Kingdom, China, and other countries based on their market shares.2 Likewise, people are increasingly concerned about environmental health and the negative effects
of synthetic drugs and other chemicals. One in four consumers in the United States say they would be persuaded to purchase a supplement that is naturally-derived.3
Cyplexinol®, an all-natural complex of stem cell-activating proteins specifically known as bone morphogenetic proteins (BMPs), and various growth factors, is the perfect ingredient for
consumers’ bone and joint health needs. BMPs are the signals which build bone tissue, renew joint cartilage, and support regeneration in many other parts of the body. Best of all,
Cyplexinol’s® efficacy for increasing bone mineral density and improving joint function has been clinically tested - a trait many health-conscious consumers look for in health
supplements.4,5

THE MARKET FOR BONE AND JOINT HEALTH SUPPLEMENTS

Current market share and projections

Supplements for bone and joint health comprise a considerable portion of the total supplement market. In 2017, sales for bone health supplements totaled $1.96 billion while sales for
joint health supplements came in at $1.90 billion, representing 4.5% and 4.4% of the total sales of health supplements in the United States, respectively. Growth in each sector is
expected to be higher than 3% annually through at least the year 2021.6

Novel ingredients are driving this market growth. Traditional products, such as calcium supplements, have actually seen declining sales over the past decade.6 Part of this trend has to
do with newer research that has emerged. Health-conscious consumers are excited by ingredients that have shown promise clinically, but are increasingly wary of products which have
received unfavorable results.

Who buys bone and joint supplements?

People concerned about healthy aging are the primary consumers of bone and joint supplements. This demographic includes people across various age spectrums. Aging adults who
wish to prevent or slow musculoskeletal degeneration frequently purchase such products, as do younger, active adults wanting to maintain the peak strength and flexibility of their bones
and joints. Both populations are seeking effective ingredients that are backed by scientific evidence. They also desire natural ingredients amidst an increase in environmental concern.6
Musculoskeletal disorders, such as osteoporosis and osteoarthritis, cause more than half the cases of long-term and chronic disability in people over the age of 50. Worldwide, an
estimated 1.7 billion people currently suffer from such disorders, including one out of every two adults in the United States, accounting for hundreds of billions of dollars in medical
expenses.7,8 The average age of the United States and most developed countries is on the rise, and so is the rate of problems affecting bones and joints. Accordingly, the demand for
products to prevent and manage such disorders is expected to increase as well.

Joint function is not just a concern for the elderly. Pain, inflammation, and stiffness in joints along with acute joint injuries affect active young adults, including athletes and fitness
trainees. Joint health is a major part of sports nutrition, and interest in natural products that improve joint strength and flexibility has steadily increased.6

TOP INGREDIENTS TODAY AND TOMORROW

Calcium
• 38% of the bone supplement market in 2017
• Sales have been declining for over a decade
• Supplements help slow bone mineral density loss, but have recently been linked to some health conditions like colorectal polyps

Glucosamine/Chondroitin
• 33% of the joint supplement market and 2% of the bone supplement market in 2017
• Shows some clinical effectiveness in select groups with joint pain
• Sales have declined over the past decade

Collagen
• Strong, elastic protein which is a major component of bone and joint tissue

Vitamin D
• 19% of the bone supplement market in 2017
• Deficiency is common, and can lead to brittle bones and other health disorders
• Sales grew 5.6% from 2016 to 2017

Magnesium
• 14% of the bone supplement market in 2017
• Important component of bone mineral and some enzymes
• Sales grew 8.9% from 2016 to 2017
Hyaluronic acid (hyaluronan)
• A glycosaminoglycan (GAG) which is a component of cartilage
• Acts as a lubricant for joints
• Estimated CAGR of 5.2% from now until at least 20239

Turmeric
• A natural product with potent anti-inflammatory properties
• 7% of the joint supplement market in 2017
• Sales grew 17.1% from 2016 to 2017

Fish oil
• Major source of omega-3 fatty acids
• 7% of the joint supplement market in 2017
• Sales have slowly increased since 2015

Gelatin
• Animal-derived collagen
• Sales grew 11.9% from 2016 to 2017

5-Loxin
• Patented joint supplement derived from Boswellia serrata extract
• Still fairly novel but initial studies indicate it is effective in improving joint pain and flexibility in osteoarthritis10,11

INTRODUCING A BREAKTHROUGH IN MUSCULOSKELETAL HEALTH SUPPLEMENTATION: CYPLEXINOL®

Cyplexinol® is the first over-the-counter dietary ingredient to improve bone and joint health by providing the signaling protein molecules required for activating stem cells. It consists of
a complex of bone proteins, with bone morphogenetic proteins (BMPs) and other growth factors bound to and contained within a network of collagen fibers. Derived entirely from
natural sources, it can be taken orally without harmful side effects. Clinical studies support that taking Cyplexinol® daily can improve bone mineral density in people with bone loss, as
well as improving joint comfort and functionality.4,5,12

How Cyplexinol® is made

Cyplexinol® is not manufactured but rather extracted as a multi-protein complex from certified organic, closed-herd bovine bones. ZyCal Bioceuticals uses a proprietary and patented
cold-process to carefully extract this complex while maintaining its biological activity. This biological activity, of activating and transforming mesenchymal stem cells into osteoblasts
and chondrocytes, producing de novo bone and cartilage tissue (a process known as osteoinduction) is unique to Cyplexinol® as the only orally available complex.

Cyplexinol® is taken orally

While the class of proteins in Cyplexinol® is new to the nutritional world, it has been used for decades in orthopedic spine surgeries, where surgeons directly applied the complex to
bone for healing and fusion.13 As a nutritional supplement, this class of proteins, extracted from a certified organic food source, is able to survive stomach acid and digestive enzymes.
This unique feature, which most proteins do not display, is due to the natural folding (tertiary and quaternary protein structures) within the complex.

CYPLEXINOL® ACTIVATES STEM CELLS TO REGENERATE BONES AND JOINTS

Stem cells: agents of regenerative medicine

Stem cell therapy is all the rage these days. Stem cells can grow and divide indefinitely, and provide new cells to replace old or dead cells.14 New methods for addressing a range of
conditions, including joint damage and bone fractures, make use of the power of stem cells to regenerate damaged or degraded tissue. Consumers are increasingly taking advantage of
greater availability of such technologies. For the next several years, the stem cell market is expected to enjoy a 10.04% compound annual growth rate.15
Traditional stem cell therapies are typically long, involve painful injections, are expensive, and many are not approved by the FDA. Cyplexinol® offers an alternative that is significantly
cheaper, less invasive, pain free and orally delivered. Our natural supplement stimulates growth from the body’s own stem cells,16,17 and represents the future of stem cell-based
tissue regeneration.

Bone morphogenetic proteins: signals for structural growth

Bone morphogenetic proteins (BMPs) are produced naturally in the body. They are essential for the growth, development, and remodeling of bones and joints. They start the process of
osteoinduction, the first step in both bone and cartilage synthesis. When they bind to BMP receptors on bone stem cells, they trigger them to grow, divide, and turn into osteoblasts or
chondrocytes, which in turn product new, healthy bone and cartilage tissue.18,19

Bone morphogenetic proteins: Balanced Inflammation Signaling

BMPs not only possess the osteoinductive capabilities described above but are nature’s immune response supporters. BMPs have an immunomodulating effect as they work on IL-1, IL-6
and even IL-8 in the gut.20-22 By modulating these pathways BMPs effect NFKappaBeta and matrix metalloproteases (MMPs), resulting in rapid joint comfort.23
Mechanism of action18,24
• BMPs are released into the bloodstream
• BMPs bind to specific receptors on stem cells (e.g. osteoprogenitor cells)
• The signal is relayed through the cell from the receptor to the nucleus
• Gene expression is changed to drive cell growth, division, and migration, and to produce specialized proteins for tissue synthesis

Osteoprogenitor cells: bone stem cells

The stem cells of the skeletal system are known as osteoprogenitor cells. They are capable of transforming into any of the types of cells that produce skeletal tissue. When they receive
the correct stimulation, they proliferate and differentiate into chondrocytes, which produce cartilage, or osteoblasts, which build stronger, denser bone proteins.25,26

BMPs and degenerative disorders

Osteoporosis: Many different molecules, including several types of BMPs, regulate bone mass. Bone resorption by osteoclasts and bone formation are tightly controlled by the
interactions of these various molecules. Disruptions to these signaling pathways can skew the activities toward more bone resorption and less regeneration.27 However, studies in
animals have demonstrated that supplementing with BMPs can actually restore bone density after it has decreased.16,28

Osteoarthritis: Cartilage regeneration by chondrocytes likewise is controlled by signals from BMPs and other molecules. People with osteoarthritis tend to have lower levels of BMPs in
the synovial tissues (joint membranes) of arthritic joints.29 Some genetic variations in BMP genes have been associated with a higher risk of developing osteoarthritis as well.30

Cyplexinol® for Bone Health

Current therapies for bone loss have several disadvantages:
• Bisphosphonates: Pharmaceutical drugs which inhibit natural bone resorption. These can cause harmful complications such as brittle bones and osteonecrosis of the jaw.31,32
• Calcium and mineral supplements: While still an important part of a healthy diet, minerals only affect the final stage of bone regeneration. Mineralization cannot happen when there is
a lack of protein matrix to bind to.33,34

Cyplexinol® addresses bone and joint health issues at the root of the problem by boosting the first step of bone synthesis. Several case studies have reported that daily supplementa-
tion with Cyplexinol® can reverse bone mineral density loss and improve DEXA scores, with impact seen as quickly as eight months. Additionally, no complications have been reported
from taking Cyplexinol®.5,35

Cyplexinol® for Joint Health

Cyplexinol® makes perfect sense as a natural solution for joint health. In recent medical findings synovial levels of some BMPs are reduced or missing in people with arthritic joints29.
Several clinical trials have investigated the effects of Cyplexinol® supplementation on joint health including subjects with osteoarthritic joints, showing promising results.

In clinical trials, subjects reported the following with daily supplementation of Cyplexinol®, in as fast as 7 days:4,36,37
• Reduced joint pain frequency
• Reduced joint stiffness
• Improved joint flexibility
• Improved overall quality of life in people with osteoarthritis
• No side effects

2-BETA COXATENE: THE OSTEOINDUCTIVE ACTIVITY OF CYPLEXINOL® WITH GREATER IMMUNE SIGNALING SUPPORT

Products that support healthy inflammation signaling and balance have been a major health trend in recent years. Consumers have increasingly looked to these products to help improve
joint function. It is estimated that the global immune support market will be worth $106.1 billion by the year 2020. And the biologics segment is projected to be one of the most
lucrative, as health concerns about long-term use of NSAIDs and corticosteroids have been raised.38

2-Beta Coxatene consists of low-dose, concentrated Cyplexinol® blended with a 65% concentrate of Boswellia serrata, a plant known for its potent anti-inflammatory effects. This
combination makes it a superior option for encouraging balanced immune signaling and has an osteoinductive effective.

Antioxidant and anti-inflammatory properties of Boswellia serrata

Boswellia serrata is a fragrant plant that grows in the Indian subcontinent. It has been used for centuries to manage osteoarthritis and other inflammatory disorders as a part of Ayurvedic
medicine. Extract from its resin contains a number of biologically-active compounds. Some of these can lower inflammatory signaling, and reduce the production of harmful reactive
oxygen species (ROS).39,40

2-Beta Coxatene for optimal healthy joint management

Boswellia serrata extract works on inflammation signaling pathways supporting healthy inflammation balance. Cyplexinol® provides the signaling proteins that stimulate stem cells
needed to generate and support healthy joint tissue; all while supporting healthy inflammation signaling pathways, including IL-1, IL-6 and IL-8. With these double effects, 2-Beta
Coxatene is an ideal platform ingredient for joint health, as well as GI health. In a clinical research trial, subjects supplementing with 2-Beta Coxatene for three months reported a
two-times greater reduction in joint pain and greater joint flexibility than those taking glucosamine and chondroitin.41
NATURAL SUPPORT FOR BONE AND JOINT HEALTH

Cyplexinol®
• The only osteoinductive natural ingredient
• Supports bone tissue growth
• Supports greater bone mineral density
• Supports joint tissue formation
• Improves joint function

2-Beta Coxatene
• Provides a multiple pathway approach to balance inflammation signaling for rapid joint comfort
• Supports healthy cartilage tissue – is osteoinductive
• Supports bone tissue growth – is osteoinductive
• Supports healthy GI mucosal tissue

OPPORTUNITIES FOR CYPLEXINOL® IN HEALTH SUPPLEMENTS

Forging a new direction in musculoskeletal health management

Most of the supplements for bone and joint health currently on the market provide building blocks for bone and collagen construction. This can help to a degree, but only to the extent
that the cellular machinery for building these tissues is fully active and functional. What happens if it is not?
By activating stem cells and their natural healing abilities, Cyplexinol® addresses bone and joint degeneration at the root of the problem. Stimulating the body’s own stem cells to build
new tissue combines the benefits of stem cell technology with the convenience of oral supplementation.

Versatility for any formulation

As a stable protein complex, Cyplexinol® can be combined into a diverse array of delivery types, including:
• Capsules
• Tablets
• Gummies/chews
• Powders
• Others

The flexible utility of Cyplexinol® makes it easy to include in any supplement formulation.
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