People don’t usually think about their bones, which hold them up and allow for movement, until something breaks, or goes out of alignment (spine). And the skeleton is a busy system, replenishing itself constantly.

Ask anyone what’s good for bones and most will respond, “calcium.” Yes, that is true, but Rome wasn’t built by one person; and a healthy skeleton is not created by just one natural ingredient. The skeleton needs a crew to flourish throughout life.

For brand manufacturers in the natural health arena, R&D never stops, nor should it, as suppliers continue to refine and strengthen what is available for increasingly efficacious products. This activity is bolstered by science and technology, as well as consumer perceptions and expectations.

Critical to Health
According to Mark Thurston, president, AIDP, City of Industry, CA, there is a demographic component that is influencing the bone-support product marketplace. As the idea of brittle bones causing major fractures is fearsome when people think of growing elderly, women should be greatly concerned—80% of those affected by osteoporosis are women. Further, he cited, one in two women and one in four men 50 and older will have an osteoporosis-related fracture in his/her remaining lifetime. Osteoporosis causes more than 1.5 million fractures annually, primarily in hips, vertebrae and wrists.

“Due to the growing aging population, loss of bone mass may be impacting more than 40 million people today,” said Todd Johnson, senior director of marketing, human nutrition and pharma, Balchem/Albion Minerals, Layton, UT. “Because agility and mobility can positively impact quality of life as we age, the desire to remain active, no matter our age, is a big driver for bone health support. Additionally, consumers want to get a jump on prevention and even millennials are looking for ways to help ensure quality of life throughout the years.”

To that end, Eric Anderson, senior vice president of global sales and marketing, NattoPharma USA, Inc., Metuchen, NJ, observed that consumers of all ages actively and habitually educate themselves online, and there is no shortage of information, products or brands available there. “One of the top concerns they are investigating due to increased media attention is bone health,” he said.

As with every category of supplements, consumers are more demanding. According to David O’Leary, commercial manager of Marigot Ltd., Cork, Ireland, “consumers are seeking bone health supplements that are available in multiple delivery systems such as on-the-go/ready-to-drink, capsules, tablets, sachets etc., and they want products that taste good and can be taken at any time during the day.” A growing consideration is the use of renewable/sustainably sourced materials that don’t impact the raw material’s availability long term while at the same time offer proven alternatives to synthetic drug treatment, he added.

With global populations aging, consumer demand for solutions to age-related conditions like bone health, that keep people active for longer has been growing at an impressive rate during recent years, observed Lara Niemann, marketing director, Americas, GELITA, Sioux City, IA. The number of people aged 60 and older is growing faster than any other age group; so a healthy, sturdy skeleton is important if older people are to remain independent. “Experts estimate that, by 2050, hip fractures are expected to increase by 240% in men and 310% in women throughout the world,” she noted.

Low bone mass and osteoporosis are now regarded as serious health threats, according to the International Osteoporosis Foundation, which estimated that by 2020, adults aged 50 and older at risk of osteoporosis could reach as high as 61 million.

Formulation Strategies
“Combining minerals with other ingredients for bone support is one approach formulators are using to help stimulate more interest in the category,” Mr. Johnson said. “Combining more novel ingredients with tried and true minerals is proving to be both highly effective and easier for consumers to embrace.”

Mr. Anderson noted, “Calcium has long been recognized as a core bone-support ingredient, but over the last few years, studies have circulated showing that excessive calcium supplementation can lead to increased cardiovascular risk, which had an effect on calcium sales (i.e., they were observed dipping).”

The human body does not produce calcium so it needs supplementation. “But to make sure that calcium is being directed to the bones where it is needed, and blocked from depositing in arteries and blood vessels, we need vitamin K2,” Mr. Anderson explained. “So, we have seen an increase in bone-support products that feature calcium and vitamins D and now K2.”

Mr. O’Leary agreed, asserting, “Calcium as a standalone offering is no longer sufficient. Growth in awareness and proven efficacy has led to the development of products containing the following actives being promoted for bone health, and the category has thus evolved.” He pointed to magnesium, vitamins D and K2, curcumin, manganese, strontium, omega-3 fatty acids, and the various calcium salt derivatives such as citrates, phosphates, lactates and carbonate as being very useful for bones.

Indeed, Ms. Niemann declared, “Bones need more than just calcium to stay healthy. Collagen, which counts as one of the essential building blocks of human bones, keeps them flexible and elastic. Just like a bridge—if it was made only of concrete, it would collapse. For stability, it needs a steel frame to which the concrete clings. In humans, the concrete corresponds to the calcium, and the steel frame to the collagen to which the calcium adheres.”

The Skeleton ‘Crew’
Creating—or re-creating—bone support formulas that consumers will use regularly is a more exciting prospect than ever due to the quality of ingredients and what science has shown about their efficacy in skeletal preservation. Here are some reliable and loyal members of the “skeleton crew.”

One ingredient was shown to help preserve mass in the entire skeleton. According to Mr. Thurston, a study presented at Experimental Biology 2014 reported the long-term efficacy of AIDP’s KoACT (a proprietary formulation of calcium and collagen) in reducing bone loss in post-menopausal women. In the study, 39 women were randomly assigned to receive either 5 grams of KoACT containing 500 mg of elemental calcium and 200 IU of vitamin D or 500 mg of calcium in the form of calcium carbonate and 200 IU of vitamin D (control). Total Bone Mineral Density (BMD) and BMD of the lumbar spine and hip were evaluated at baseline, six months and 12 months using duel energy X-ray absorptiometry. Blood was collected at baseline, six and 12 months to assess serum biomarkers of bone turnover.

“KoACT prevented the loss of whole body BMD when compared to control,” Mr. Thurston reported. “The KoACT group had reduced levels of tartrate-resistant acid phosphatase (TRAP5B) at six months and higher bone-specific alkaline phosphatase (BAP)/TRAP5B ratio at six months and tended to be higher at 12 months whereas there were no changes in control.”

Another mechanism of action to preserve bone through aging is stimulating collagen metabolism. GELITA’s Fortibone, Ms. Niemann said, is derived from native collagen of bovine or porcine origin. GELITA Bioactive Collagen Peptides (BCP) are a composition of different peptides optimized for specific physiological benefits. “The peptides are derived from a production process of collagen which is determined by hydrolyzation conditions. As a result, GELITA Bioactive Collagen Peptides differ in physiological functionality. They are optimized to maximize stimulation of the human cell types involved in collagen biosynthesis,” she said.

GELITA’s Fortibone works by stimulating osteoblast (collagen production) and reducing the activity of osteoclasts (collagen degradation), therefore, it increases the formation of the extracellular bone matrix, which is the essential framework for calcium mineralization. “Thus, Fortibone supplies the body with the basic components needed for a strong and stable bone structure, supporting overall bone stability and flexibility,” Ms. Niemann said. “In addition, Fortibone regulates the degenerative processes that affect bones by reducing osteoclast-based protease production. These specific Bioactive Collagen Peptides make bones more stable and elastic and help to reduce bone loss or fragility fractures.”

According to Ms. Niemann, a new study (not yet published) showed that Bioactive Collagen Peptides make a significant contribution to promoting bone strength and flexibility—and to counteracting osteoporosis. This randomized, double-blind study included 180 women with reduced bone mass. Over a period of 12 months, the subjects received five grams of Fortibone or a placebo. The change in bone mass was measured in the femoral neck and in the spine. The bone density of the participants who had taken Fortibone improved significantly. The data showed a significant increase in bone mineral density (BMD).

Fortibone is free from fat, sugar/carbohydrates, cholesterol, purines, allergens and additives. It can be used in a wide variety of foods, such as dairy products, functional foods, nutritional supplements and beverages, according to the company.

The term “bone mineralization” is highly reflective of the need for minerals in supplements geared for skeletal support. Mineralization describes the process of helping to create bone matrix through layering of minerals. Normal bone has a content of approximately 50-70% minerals.

An example of a mineral complex that can be used to fortify foods, beverages and supplements is Aquamin, which Mr. O’Leary said is a marine-derived multi-mineral complex that provides bioactive calcium, magnesium and 72 other trace marine minerals. Aquamin is distinguished by the fact that all the minerals come from one source—Lithothamnion seaweed harvested under an exclusive license off the coast of Iceland. The seaweed absorbs trace minerals from its marine habitat; this “coupled with Aquamins’s unique structure, results in a mineral-rich product that is neutral tasting, free of chalky texture and readily accepted by the human body,” he said.

Collectively, studies have shown that Aquamin helps in healthy bone formation, as well as promotes healthy inflammatory response, reduced discomfort and range of motion improvement. For example, one study published in the Journal of the Mechanical Behavior of Biomedical Materials (2015) showed that incorporation of Aquamin enhanced osteogenesis (i.e., production of new bone) and improves the mechanical properties of a collagen-based bone graft substitute. “This study results are in vitro evidence that Aquamin can increase osteogenesis, thus improving bone formation, strength and mineralization,” Mr. O’Leary said.

Another study (Journal of Nutrition, 2014) in post-menopausal women showed that Aquamin positively contributes to bone health as measured by DEXA and bone turnover markers.

Calcium is, undeniably, the monarch of bone mineral supplementation. But not all raw material formats perform the same in the body. For example, Albion’s Mr. Johnson pointed out that supplementing with inorganic sources of minerals can irritate the gastrointestinal tract and also cause mineral interactions, which can suppress rates of absorption. “Albion minerals chelated with amino acids have shown greater bioavailability and utilization in humans. Human studies have indicated less irritation from ingesting minerals as metal amino acid chelates.”

One meta-analysis of 352 human studies investigated the relationship between calcium solubility and absorption, listing seven calcium sources, two of which were Albion calcium citrate malate and calcium bisglycinate chelate. The other calcium sources were three found naturally in foods and two other popular forms, calcium carbonate and calcium citrate. The study authors found that both Albion’s calcium chelates had the highest solubility (Calcified Tissue International, 1990).

Another study compared the bioavailability of calcium after supplementation with four preparations: Albion di-calcium malate, Albion calcium chelate containing 18% calcium, calcium chelate containing 26% calcium, and industry standard calcium carbonate. “Based on the results of this study, di-calcium malate seems to be the most bioavailable compared to the other supplements being investigated with a longer half-life,” Mr. Johnson reported. “The two calcium chelates were the next most bioavailable of the four followed by calcium carbonate.” (The FASEB Journal, 2006)

Albion uses quality starting materials that meet the standards of the U.S. Pharmacopeial Convention (USP) or Food Chemicals Codex (FCC). The minerals are hypoallergenic, vegetarian and vegan friendly, pharmaceutically pure, chemically validated by its patented FT-IR process, GMO-free, BSE free, industry certified ISO and GMP, Kosher and Halal certified.

“Albion pioneered the use of Fast-Fourier Transforming Infrared spectroscopy (FT-IR) for mineral chelates,” said Mr. Johnson. “This technology identifies the bonds between the ligand and mineral to verify the molecular structure of a true chelate. Without this test for quality assurance, manufacturers and consumers have no way of knowing whether a mineral is truly chelated, and therefore useful by the body.”

But there is a downside to calcium; it tends to also have a strong affinity for cardiovascular arteries. Formulas for bone support that key in on calcium and vitamin D should also include vitamin K2 menaquinone-7 (MK-7). If bones are school and cardiovascular arteries are the local teen hangout, K2 essentially prevents calcium from being truant, escorting it to bones where it belongs and ensuring it stays away from where it doesn’t.

“Think of MK-7 as the body’s light switch,” said NattoPharma’s Mr. Anderson. “It activates important proteins in the body, such as osteocalcin and the matrix Gla protein for heart health. By activating these K-dependent proteins, vitamin K2 helps keep calcium in the bones and away from arteries so they don’t harden.”

Results of a three-year study (Osteoporosis International, 2013) of MenaQ7 on 244 healthy women showed statistically significant protection of the vertebrae and hip (femoral neck) against bone loss with a daily dose of 180 mcg of MK-7. The MK-7 supplementation group significantly increased the circulating active osteocalcin, a well established biomarker for bone and vitamin K status. The inactive or undercarboxylated osteocalcin in the MK-7 group decreased by 51% (+/- 21%) as compared to the placebo group (+4% +/- 49%).

After three years of supplementation, maintenance in both bone mineral content and bone mineral density were statistically significant in the supplementation group. Bone strength was also statistically improved, demonstrating therapeutic benefits for the MK-7 group versus the placebo group. This was not only statistically significant, but clinically relevant—ongoing MK-7 supplementation would essentially push the risk of fracture beyond life expectancy.

Mr. Anderson added that the MK-7 used in these studies was MenaQ7, “So the health benefits that have been identified have been shown specifically using MenaQ7, making it a clinically validated ingredient. MenaQ7 is available as a natural, soy-free (derived from chickpeas) ingredient as well as a nature-identical synthetic. We have patents both granted and pending, and approved structure-function claims for bone and heart that our partners can use on their products.”

For those consumers not keen on ingesting nutraceuticals in pill form, NattoPharma tested its MenaQ7 in yogurt, an increasingly popular food, especially for women. Two studies were published in 2015 and 2016 showing that MenaQ7 was effectively delivered in yogurt products (first a yogurt-fortified drink; second in an enriched yogurt), showing improved K status. “These studies are significant because they show MenaQ7 can be utilized in alternative formats, making it even more accessible for the population, especially children,” Mr. Anderson said (Journal of Nutritional Science, 2015) (European Journal of Clinical Nutrition, 2016).

Increasing osteoclast formation via a complex biochemical pathway is the mechanism of action of ParActin (a patented extract of Andrographis paniculata) from HP Ingredients, Bradenton, FL. According to CEO Annie Eng, ParActin has been shown to support healthy bone function. In research published in the International Journal of Molecular Sciences in 2015, a group of mice whose skeletons mimic postmenopausal osteoarthritis were treated with Andrographolide (AP). The ParActin group showed significant increase in bone mass, trabecular thickness and number, and a decrease in trabecular separation compared to control mice.

“NF-kB activation is essential for Receptor Activator for NF-kB ligand (RANKL)-induced osteoclast formation,” she said. “Andrographolide found in ParActin—a natural NF-kB inhibitor—significantly decreased osteoclast formation in the bone marrow via suppression of RANKL that are responsible for making osteoclasts.”

An in vitro study published in the European Journal of Pharmacology in 2009, found Andrographolide in ParActin inhibits nuclear factors of activated T cells (NFAT) activity, which regulates the expression of osteoclast genes and is linked to bone erosion. In another unpublished study, Andrographolide induced osteoblast mineralization via COX-2 expression, showing a mineralizing effect on bones with the increase of calcium deposits, suggesting ParActin may have other supplemental effects for osteoarthritis.

Overall, a growing number of adults are, or will become, at risk for bone fracture stemming from increasingly porous bones. Effective dietary supplements (and potentially companion foods and beverages) for bone support can help pre-empt the natural effects of aging. 

---

Formulating with Stability

Manufacturers must consider advanced technologies to ensure stability of their bone health products.
 
By Dan Murray
Vice President of Business Development, Xsto Solutions
 
A challenge to formulating an effective bone health product involves the tenuous stability of ingredients. The most widely used ingredients for bone health were traditionally calcium and vitamin D, and more recently vitamin K2 MK7 and magnesium.
 
Vitamin D increases the intestinal uptake of calcium into the bloodstream and vitamin K2 helps facilitate the calcium from blood to the bone (matrix). 
 
Vitamins in general, and fat-soluble vitamins in particular, are inherently sensitive to degradation. Challenges can be physical or chemical in nature and advancements in technology have created improved product forms with enhanced stability.
 
Avoiding excessive heat is essential for ensuring vitamin stability. Suppliers and manufacturers have comprehensive procedures in place to reduce or eliminate heat exposure. For vitamin K2, avoiding exposure to light is also important. Using opaque or dark containers is considered a “best practice” to address the light sensitivity of K2. These are the two most common physical challenges for vitamin mixes.
 
With the increasing awareness of the importance of K2 for good bone health, along with calcium and vitamin D, a new theory has developed concerning physical stress on K2. As a long-chain molecule, some scientists believe the rough edges of calcium (and magnesium) may be sheering the K2 molecule during mixing. If true, this could result in a significant loss of vitamin K2 activity.
 
To combat physical challenges in the past, vitamin manufacturers developed beadlet and cross-linked beadlet technology. This involves adding a very thin but highly protective coating to the raw vitamin for an improved product form. Beadlet technology has been used with great success in fat-soluble vitamins such as A and D and is now being used for K2. The starch matrix beadlet protects the vitamin from sheering as well as heat, moisture and even chemical challenges such as oxidation. Calcium and magnesium are considered “aggressive minerals” instigating oxidation, a significant threat to long-term stability of vitamin-mineral mixes.
 
More advanced technologies are on the horizon but manufacturers need immediate solutions, such as beadlet product forms, to ensure stability in their bone health products.