Dietary Supplement Ingredients for Bone and Joint Health: Come In, K2

There’s more to vitamin K than meets the eye. To start with, let’s call it by its proper name: vitamin K1 (phylloquinone) or K2 (menaquinone). Why? Because K2 deserves recognition all its own-and chances are you aren’t getting enough of it.

Inadequate vitamin K intake could be putting your bones at risk. That claim has even been confirmed by the European Food Safety Authority (Parma, Italy), which in 2009 said a cause-and-effect relationship is clear between vitamin K dietary intake and maintenance of healthy bones.

But which source of K best suits the bones’ needs? A look at recent science suggests it’s K2.

K1 versus K2
K1 is sourced from a variety of plant foods, including green vegetables like spinach and kale. This form of vitamin K is best known for its ability to maintain blood coagulation.

K2 can be produced within our intestines and is available from certain fermented foods, such as curd cheeses, cheeses, and Japanese natto. Thanks to K2’s longer side-chains, the nutrient’s benefits appear more far-reaching, making this form of vitamin K a candidate for better bone health.

K, K2, and Your Bones
Vitamin K’s appeal for building bones relates to its potential to activate a protein called osteocalcin.

“Osteocalcin is a vitamin K–dependent protein,” says Peter Wisler, director of business development for health and nutrition at Danisco BioActives (Paris), supplier of ActivK MK-7 (MK-7 is a form of K2, to be discussed ahead). “Osteocalcin is needed to bind calcium into the bone matrix. However, newly made osteocalcin is inactive and must become fully activated by a process called carboxylation.” The process is activated by vitamin K; without vitamin K, insufficient bone calcium can be expected.

How does osteocalcin affect bone health? Studies conducted in the late 1990s associated higher levels of undercarboxylated (inactive) osteocalcin (ucOC) with greater risks of hip fractures in women.(1,2)

In 2004, a trial on 245 healthy girls concluded that lower circulating levels of ucOC were associated with less bone turnover.(3) (In general, low bone turnover is associated with high bone quality and strength.)

A 2007 study on 223 prepubertal girls found that blood ucOC levels were inversely associated with vitamin D levels and bone mineral content. Greater vitamin K status was also associated with less bone turnover.(4)

And as recently as 2008, a study on 307 healthy children found higher ratios of carboxylated (cOC) to ucOC levels to be associated with greater bone mass.(5) A greater understanding of these mechanisms is encouraging for population groups where bone health is a notable concern, such as postmenopausal women and even children.

“The reason why children are an important target for adequate K2 consumption is because of their developing bone mass,” says Wisler. “We don’t reach our peak bone mass until our late twenties, and once reached, bone resorption is faster than building new bones. Increasing calcium utilization during these very critical years will mean that we get the best use of the available calcium and are taking the best efforts to build a high peak bone mass.”

For all of the science supporting vitamin K and activated osteocalcin, longer side-chains of K2 enable this form of vitamin K to carboxylate osteocalcin at a much higher rate than K1.(6)

Calcium without K2
If K2 is needed to efficiently move calcium to the bones, you may be wondering what happens with a diet high in calcium and low in vitamin K.

One theory is that for those who take lots of calcium for bone management, that calcium may be getting stranded in the blood vessel walls-a serious health risk.

“Over the past two years, several publications and news stories have addressed the issue of misdirected calcium,” says Vladimir Badmaev, MD, PhD, director of scientific affairs at P.L. Thomas (Morristown, NJ), supplier of MenaquinGold MK-7. “The findings show that increased calcium intake to strengthen bones, but without the necessary cofactors vitamin D and K2, may actually increase one’s risk of cardiovascular events.”

Badmaev points to a 2008 study in the British Medical Journal in which 1471 postmenopausal New Zealand women (average age 74 years) were assigned to daily placebo or a 1-g calcium supplement (without cofactors), and followed up with every six months, for five years. The study concluded that patients taking calcium were more than twice as likely to have heart attacks as patients on placebo.(7)

More longstanding support exists in a 2004 study published in the Journal of Nutrition. Using documented dietary eating habits collected from the Netherlands-based Rotterdam Study, researchers assessed dietary K2 intake in 4807 subjects, from 1990 to 2000, and related it to total incidence of heart-disease mortality. (No subjects had a documented history of heart disease.) An inverse relationship was observed between K2 intake and heart-disease mortality.(8)

Making sure calcium is moved out of the blood vessels is an even greater concern for those people who use anticoagulant drugs like warfarin. These drugs end up depleting the body of its vitamin K, creating a greater risk of calcium overload in the arteries.

Again pressing the need for K2 and not just K1, a 2003 study compared the effects of K2 (in the form of MK-4) with K1 in warfarin-treated rats. K2 was utilized more efficiently by the aorta and the heart.(9)

If anticoagulants deplete vitamin K stores, watch out for accelerated bone loss, an outcome observed in several studies.(10, 11)

K2 Deficiency
K2 sources do exist in the Western diet, but the extent to which those sources provide adequate K2 for bone health remains inconclusive and an ongoing discussion.

“Scientists have measured the proteins activated by K2 in individuals on a Western diet and concluded that there is a K2 deficiency among the Western population,” says Herman Zhang, president of Pacific Rainbow International (City of Industry, CA), a supplier of MK-7 K2 and nattokinase.

In 2007, a USDA-funded study sampled various meats (n=128), dairy and eggs (n=24), and fast foods (n=169) common to the U.S. diet, only to find that “no single food item in these categories is a rich dietary source of any one form of vitamin K.”(12)

In 2003, 21 older women participated in an 84-day USDA-funded study in which women were placed on vitamin K–restricted diets for four weeks, followed by gradual reintroduction of vitamin K through K1 supplementation. Researchers determined that, even after supplementation, the K1 available to support carboxylation of osteocalcin was “insufficient.” The researchers speculated that this was because K1 was being used up by the liver to deal with blood coagulation functions.(13)

These findings left researchers to conclude that the current recommended Adequate Intake of vitamin K for older women (90 µg/day) does not support adequate carboxylation of osteocalcin. Is it because all of that vitamin K is coming in the form of K1, not K2?

Vitamin K deficiency isn’t just a part of U.S. culture, as similar reports have surfaced in countries such as Ireland and the Netherlands.(14, 15)

In Japan, one unusually high source of dietary K2 is eaten regularly. That source is natto-a fermented soy product rare to Western kitchens.

So how might natto consumers compare?

Research published in the journal Nutrition sampled serum MK-7 concentrations from women in three different geographic locations: Tokyo (where natto is eaten frequently), Hiroshima (where it is reportedly “seldom” eaten), and Britain. Mean serum MK-7 concentrations were recorded at means of 5.26 ng/mL in Tokyo, 1.22 ng/mL in Hiroshima, and 0.37 ng/mL in Britain.

The researchers further concluded that MK-7 levels were inversely correlated with incidence of hip fracture for the three groups.(16)

Several other studies support the notion that natto consumption increases circulating MK-7 levels and cOC levels, while also strengthening bones.

K2 Forms
K2 is available in two commercial forms: MK-4 and MK-7 (the former having a shorter side-chain).

Laurent Leduc, vice president of health for Frutarom Americas (North Bergen, NJ), a marketer of uniK2 brand MK-7, says that the bioavailability of menaquinones can depend largely upon the length of their side-chains.

“Among the various forms of K2,”  says Leduc, “the length of the side-chain plays an additional role in bioavailability, as menaquinones with medium-length side-chains (e.g., MK-7) are better absorbed compared to those with short (e.g., MK-4) or long (e.g., MK-8 and MK-9) side-chains.”(17, 18)

But much published science exists with MK-4 as the chosen K2 supplementation, and with good results to boot.

The journal Osteoporosis International published a 2007 Netherlands-based study in which 325 postmenopausal women were assigned to placebo or 45 mg of MK-4 daily for three years. Results of this trial identified improved bone mineral content, as well as femural bone health, from MK-4 supplementation.(19)
A year prior, a Cochrane review on K2 utilized available studies of six-month or longer supplementation with MK-4. This K2 source was associated with significant reductions of bone fractures.(20)

Still, it is important to note that MK-7 studies typically rely on dosages in micrograms, compared to MK-4 science that is typically based on higher, milligram dosages.

“Over decades, MK-4 has been studied and found to be essential for bone and cardiovascular health,” notes Cecilia McCollum, president of MK-4 ingredient supplier Blue California (Rancho Santa Margarita, CA). “As a matter of fact, if you review the information submitted to EFSA for approval of K2 as a food ingredient, most of the clinical data in the dossier and evaluated by EFSA is done on MK-4.”

K2 Quality Control
What kind of K2 you’re really getting should be of concern to anyone buying the ingredient. Unfortunately, there’s a high degree of confusion surrounding K2 standards, as there isn’t a universal standard.

Improper levels of MK-7, and not distinguishing between MK-4 and MK-7, are potential hazards for customers in the current K2 market. With K2 gaining in popularity, quality control will remain a critical topic.

Choosing the right testing method is a good start says Frank Jaksch, CEO and cofounder of Chromadex (Irvine, CA), an analytical methods provider for dietary ingredients. Jaksch says that HPLC is needed over UV testing.

“You can use a test method and say, ‘Well, we used UV spectrophotometry to prove that this product contains anthocyanins,’ but UV spectrophotometry isn’t specific enough to prove that they are anthocyanins,” says Jaksch. “It just proves that there’s some sort of a pigment there. That’s how [melamine-tainted milk] happened. Melamine was added to protein because it was able to cheat the nonspecific test that was out there.”

The goal, Jaksch says, is “to use test methods specific enough that they can’t be cheated.”

Chromadex most recently partnered with Kappa Bioscience AS (Oslo, Norway) to provide quality-control and analytical- testing methods for the company’s K2 ingredient, K2VITAL.

K2 Future
As K2 science continues to climb, its relevance in traditional bone-health markets will only increase.

Picture yogurts, milks, and other products touting K2 alongside vitamin D and calcium.

Gwen Kent is vice president of U.S. sales for Natto Pharma (Lysaker, Norway), manufacturer of MenaQ7 brand MK-7, which is supplied in the United States by NBTY Inc. (Ronkonkoma, NY). Her company recently secured EU patents for two heart-health claims, and she believes the market will soon embrace K2 fully.

“There is good indication that it will soon be just as important to have K2 in your product as calcium,” says Kent. “If K2 can get the calcification out of arteries, then it should be in every product.”

References:
1. L Schurgers et al., “Vitamin K–containing dietary supplements: comparison of synthetic vitamin K₁ and natto-derived menaquinone-7,” Blood, vol. 109, no. 8 (April 2007): 3279–3283.

2. P Szulc et al., “Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture: A three year follow-up study,” Bone, vol. 18, no. 5 (May 1996): 487–488.

3. P Vergnaud et al., “Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS Study,” Clinical Endocrinology & Metabolism, vol. 82, no. 3 (March 1997): 719–724.

4. H Kalkwarf et al., “Vitamin K, bone turnover, and bone mass in girls,” American Journal of Clinical Nutrition, vol. 80, no. 4 (October 2004): 1075–1080.

5. E O’Connor et al., “Serum percentage undercarboxylated osteocalcin, a sensitive measure of vitamin K status, and its relationship to bone health indices in Danish girls,” British Journal of Nutrition, vol. 97, no. 4 (April 2007): 661–666.

6. M van Summeren et al., “Vitamin K status is associated with childhood bone mineral content,” British Journal of Nutrition, vol. 100, no. 4 (October 2008): 852–858.

7. M Bolland et al., “Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial,” British Medical Journal, published online January 15, 2008.

8. J Geleijnse et al., “Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study,” Journal of Nutrition, vol. 134, no. 11 (November 2004): 3100–3105.

9. L Schurgers et al., “Regression of Warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats,” Blood, vol. 109, no. 7 (April 2007) 2823–2831.

10. H Spronk et al., “Tissue-specific utilization of menaquinone-4 results in the prevention of arterial calcification in Warfarin-treated rats,” Journal of Vascular Research, vol. 40, no. 6 (November–December 2003) 531–537.

11. P Pastoureau et al., “Osteopenia and bone-remodeling abnormalities in warfarin-treated lambs,” Journal of Bone and Mineral Research, vol. 8, no. 12 (December 1993): 1417–1426.

12. BF Gage, “Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2,” Archives of Internal Medicine, vol. 166, no. 2 (January 2006): 241–246.

13. S Elder et al., “Vitamin K contents of meat, dairy, and fast food in the U.S. diet,” Journal of Agricultural and Food Chemistry, vol. 54, no. 2 (January 2006): 463–467.

14. S Booth et al., “Dietary phylloquinone depletion and repletion in older women,” Journal of Nutrition, vol. 133, no. 8 (August 2003): 2565–2569.

15. A Collins et al., “Phylloquinone (vitamin K₁) intakes and serum undercarboxylated osteocalcin levels in Irish postmenopausal women,” British Journal of Nutrition, vol. 95, no. 5 (May 2006):  982–988.

16. EC Cranenburg et al., “Vitamin K: the coagulation vitamin that became omnipotent,” Thrombosis and Haemostasis, vol. 98, no. 1 (July 2007): 120–125.

17. M Kaneki et al., “Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2:possible implications for hip-fracture risk,” Nutrition, vol. 17, no. 4 (April 2001): 315–321.

18. L Schurgers, “Studies on the role of vitamin K1 and k2 in bone metabolism and cardiovascular disease,” Unigraphic (2002), Universiteit Maastricht, pp 3–26, 141–147.

19. L Schurgers et al., “Determination of phylloquinone and menaquinones in food: effect of food matrix on circulating vitamin K concentrations,” Haemostasis, vol. 30, no. 6 (November–December 2000): 298–307.

20. M Knapen et al., “Vitamin K₂ supplementation improves hip bone geometry and bone strength indices in postmenopausal women,” Osteoporosis International, vol. 18, no. 7 (July 2007): 963–972.

21. S Cockayne et al.,“Vitamin K and the Prevention of Fractures,” Archives of Internal Medicine, vol. 166, no. 12 (June 2006): 1256–1261.  

SIDEBAR: Bone/Joint BreakthroughsClear Calcium: Calcium doesn’t have to be cloudy, anymore. Innophos (Cranbury, NJ) has launched VersaCAL Clear, a new calcium phosphate suited for clear beverages. The company received an excellence award for the ingredient at Health Ingredients Europe in Frankfurt, Germany, last fall.

Turmeric: Turmeric (Curcuma longa) made its case for joint health last year. Several studies examined the effects of turmeric or its active compound curcumin on osteoarthritis patients. One study published in the Italian journal Panminerva Medica saw supplementation with a soy curcumin and soy phosphatidyl choline ingredient (Meriva) result in 58% decreases in overall pain and stiffness.(S-1)

Collagen: BioCell Technology (Irvine, CA) has released the results of its largest-ever human clinical trial on BioCell Collagen II. The type II collagen demonstrated efficacy and safe long-term use in 80 patients with osteoarthritis symptoms. The company has also released a water-soluble topical cosmetic format of its collagen ingredient.

Soy Isoflavones: Bone up with genistein, a soy isoflavone with research mounting on its potential for bone-health support. DSM Nutritional Products (Parsippany, NJ) recently announced the results of a six-month trial of 58 postmenopausal women on a calcium placebo or geniVida, the company’s bone-health blend of genistein, omega-3, vitamin D3, and vitamin K1. The genistein supplement provided up to 3.4% increase in bone-mineral content, compared to calcium placebo, which actually resulted in bone loss for women.(S-2)

References:
S-1. G Belcaro et al., “Product-evaluation registry of Meriva, a curcumin-phosphatidylcholine complex, for the complementary management of osteoarthritis,” Panminerva Medica, vol. 52, 2 Supplement 1 (June 2010): 55–62.

S-2. I Kunz et al., “Effect of combination of genistein, polyunsaturated fatty acids (n-3 PUFAs) and vitamins K1 and D3 on bone mineral density (BMD) in postmenopausal women,” Osteoporosis International, vol. 21, Supplement 1 (May 2010): S25–S388, P494.