Vitamin K: Essential for bone health

Vitamin K: Essential for bone health

 
 

While it has built a strong reputation for its role in blood coagulation, research is showing that vitamin K also plays a critical role in bone health. But the importance of this secondary role is somewhat overshadowed by its primary function to which many associate vitamin K with and nothing else.

A victim of its discovery

I recently caught up with a friend I haven’t seen in a while. When we first met, he mentioned in a shy, softly spoken voice that he was an accountant. As we conversed this time, he told me in a more confident, outspoken voice that he was now, a school teacher. I could feel my mind struggling to comprehend that this was the same person and despite this most recent catch up, I still see him as the shy, timid accountant. Once you get that first impression of someone, it can be difficult trying to associate them with anything else. We do this often as humans, not just in social situations but in gaining knowledge as well. We find a need to label and classify things, usually based on the reports of who first discovered it and what its primary function is.

So like many things in life, essential nutrients often get pigeon-holed for their primary role or what they were first identified for. Vitamin K is one nutrient that has suffered this fate.  Upon its discovery, it was noted to prevent haemorrhaging and bleeding, to which it came to be known as, the coagulation vitamin; or as it was first published in a German journal, Koagulations vitamin (Vitamin K). Thus when you’re literally named after your primary function, it’s difficult for anyone to associate vitamin K with anything but blood coagulation. Recently, research has revealed vitamin K has roles in other areas of the body such as bone health. However it’s hard for many to understand that this role is important, when all they really think about is how it affects the blood.

A closer look

Vitamin K is a co-factor for the enzyme, gammaglutamate carboxylase (GGCX). This enzyme is required for the post-translational modifications of proteins that contain the amino acid residue, glutamic acid (Glu). In the presence of vitamin K and GGCX, these proteins go through a carboxylation process that alters the structure by converting Glu residues into γ-carboxyglutamic acid (Gla) residues (Figure 1). The functional significance of this change is that Gla residues have a strong binding affinity to calcium. Thus in support of the blood clotting pathway, Vitamin K is required for the activation of prothrombin, factors VII, IX and X and proteins C, S and Z. However, other Gla-proteins have been discovered in the body which also rely on vitamin K to function; Osteocalcin, for bone formation and development; MGP (Matrix Gla Protein) for artery calcification inhibition and Gas-6 (Growth Arrest Specific-6) for cell growth regulation.

 Carboxylation of proteins

FIGURE 1: The vitamin K-dependent carboxylation of proteins

Dietary requirements do not consider other roles

As you might expect, the dietary requirements originally set by health authorities (World Health Organization; 65-80µg/d[1]& Institute of Medicine; 90-120µg/d[2]) for adults were designed to prevent the primary clinical deficiency of vitamin K, excessive bleeding. A recent study confirmed that an intake of54-62µg/d should be adequate to prevent this[3]. But in the same study it was revealed that 152-188µg/d is required to prevent secondary (subclinical) deficiencies of vitamin K, bone loss. Hence, current dietary requirements do not protect against secondary deficiency symptoms of vitamin K.

Why subclinical deficiencies exist

The primary target site of ingested vitamin K is the liver. All the hepatic vitamin K requirements (coagulation) are attended to first[4]. If all coagulation demands are met, the excess vitamin K is then transported onto non-hepatic tissues, where it can carry out its secondary functions. This is why underlying subclinical vitamin K deficiencies can exist without affecting coagulation. At minimum, the pharmacokinetics of vitamin K ensures coagulation requirements are met first. Therefore bone loss due to insufficient vitamin K can be a silent process, not always identified. There is also a common misconception or fear that large doses of vitamin K will increase thrombosis risk. However, toxic effects of vitamin K are rare and as the pharmacokinetics reveal, excess vitamin K is transported away from the liver for other functions and does not result in more clotting factor carboxylation[4]. Thus, we can actually tolerate high doses of vitamin K over a long period[4].

Interactions within bone health

Similar to the story of vitamin K; calcium and vitamin D have been pigeon-holed as the two main nutrients associated with bone health. But vitamin K plays a very important role in bone health as well, via the carboxylation of osteocalcin. This process alters the structure of osteocalcin to reveal three Gla residues with strong affinity to calcium[4]. Sufficient vitamin K means adequate amounts of carboxylatedosteocalcin are present in bone tissue to bind to calcium and place it in the strong hydroxyapatite structure. This process (and therefore vitamin K) is an essential part of bone development, formation and metabolism. Inadequate vitamin K levels for bone health can be identified when the ratio of undercarboxylated to carboxylatedosteocalcin is high and is reflected in a low bone mass density or hydroxyapatite binding capacity.

Why other nutrients in bone health benefit from it

A recent review of clinical studies has revealed calcium supplementation on its own has minimal effect on improving bone density and is linked to an increase risk of cardiovascular problems (myocardial infarction and stroke)[5]. This highlights the importance of calcium homeostasis in bone health. Vitamin D is an integral part of this process however; vitamin K has also demonstrated a crucial role in calcium homeostasis which would limit the cardiovascular problems observed in taking calcium only supplements. Vitamin K assists in the carboxylation of the matrix gla protein (MGP) which is found in the heart, kidneys, bone and lungs (Figure 2). Its role is to correctly distribute calcium and inhibit arterial calcification, which is a major factor in cardiovascular problems[6]. Undercarboxylated levels of MGP are linked to an increased risk of cardiovascular diseases[6]. In addition, vitamin D aids the synthesis of undercarboxylatedosteocalcin (Figure 2). Therefore the levels of vitamin K must be sufficient to match the levels of vitamin D and calcium that are ingested; otherwise it can lead to high levels of undercarboxylated proteins that disrupt homeostasis and function.

 : Interactions of vitamin K with calcium and vitamin D

FIGURE 2: Interactions of vitamin K with calcium and vitamin D

Clinical evidence in bone health

A cross-sectional study revealed thatpoor vitamin K status is a concern during childhood[7]. In a group of healthy children (n = 86, mean age: 10 years), the ratio of undercarboxylatedosteocalcin to carboxylatedosteocalcin was considerably high and indicative of a very low vitamin K status. Children displayed vitamin K deficiencies for bone metabolism throughout the various growth stages[7]. Other studies have shown a higher vitamin K status in children is associated with a higher total body bone mineral content[8, 9].

In pregnant and lactating women, supplementation with vitamin K prior to delivery has shown to improve hydroxyapatite binding capacity in mother and baby than that of placebo[10, 11]. It was also able to increase levels within breast milk and infants.

Most of the clinical studies investigating vitamin K in bone health have been in postmenopausal women. Several studies have already confirmed that a low vitamin K status is associated with an increased risk of hip fractures and a lower bone mass density in this population[12-14]. A randomized double-blind placebo-controlled trial observed the addition of vitamin K to a bone health supplement (calcium, magnesium and vitamin D) in 181 healthy postmenopausal women[15]. Results showed that the inclusion of vitamin K significantly reduced the decline of bone mineral density and lowered the potential risk of fractures greater than the supplement without vitamin K. In a similar study, the addition of vitamin K increased bone mineral density, whereas the supplement without vitamin K (calcium and vitamin D) still produced a decline in bone mineral density[16].

Conclusion

While it may be difficult to associate with bone health, the role of vitamin K in calcium homeostasis, bone metabolism and formation is critical and deserves more recognition in this area. Subclinical deficiencies of vitamin K affecting bone loss may be more common than we realize and clinical evidence, although still in its early stages, has been positive for vitamin K.

References

  1. (WHO), World Health Organization (2004) ‘Vitamin and mineral requirements in human nutrition.’ WHO & Food and Agriculture Organization of the United Nations.
  2. Food & Nutrition Board, Institute of Medicine (2000) ‘Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vandium and Zinc.’ National Academy Press.
  3. Tsugawa, N., K. Uenishi, H. Ishida, T. Minekami, A. Doi, S. Koike, T. Takase, M. Kamao, Y. Mimura, and T. Okano, (2012) ‘A novel method based on curvature analysis for estimating the dietary vitamin K requirement in adolescents.’ Clin Nutr. 31(2): p. 255-60.
  4. Vermeer, C., (2012) ‘Vitamin K: the effect on health beyond coagulation – an overview.’ Food Nutr Res. 56.
  5. Bolland, M.J., A. Avenell, J.A. Baron, A. Grey, G.S. MacLennan, G.D. Gamble, and I.R. Reid, (2010) ‘Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis.’ BMJ. 341: p. c3691.
  6. Schurgers, L.J., (2013) ‘Vitamin K: key vitamin in controlling vascular calcification in chronic kidney disease.’ Kidney Int. 83(5): p. 782-4.
  7. van Summeren, M., L. Braam, F. Noirt, W. Kuis, and C. Vermeer, (2007) ‘Pronounced elevation of undercarboxylated osteocalcin in healthy children.’ Pediatr Res. 61(3): p. 366-70.
  8. O’Connor, E., C. Molgaard, K.F. Michaelsen, J. Jakobsen, C.J. Lamberg-Allardt, and K.D. Cashman, (2007) ‘Serum percentage undercarboxylated osteocalcin, a sensitive measure of vitamin K status, and its relationship to bone health indices in Danish girls.’ Br J Nutr. 97(4): p. 661-6.
  9. van Summeren, M.J., S.C. van Coeverden, L.J. Schurgers, L.A. Braam, F. Noirt, C.S. Uiterwaal, W. Kuis, and C. Vermeer, (2008) ‘Vitamin K status is associated with childhood bone mineral content.’ Br J Nutr. 100(4): p. 852-8.
  10. Greer, F.R., S.P. Marshall, A.L. Foley, and J.W. Suttie, (1997) ‘Improving the vitamin K status of breastfeeding infants with maternal vitamin K supplements.’ Pediatrics. 99(1): p. 88-92.
  11. Thijssen, H.H., M.J. Drittij, C. Vermeer, and E. Schoffelen, (2002) ‘Menaquinone-4 in breast milk is derived from dietary phylloquinone.’ Br J Nutr. 87(3): p. 219-26.
  12. Booth, S.L., K.E. Broe, D.R. Gagnon, K.L. Tucker, M.T. Hannan, R.R. McLean, B. Dawson-Hughes, P.W. Wilson, L.A. Cupples, and D.P. Kiel, (2003) ‘Vitamin K intake and bone mineral density in women and men.’ Am J Clin Nutr. 77(2): p. 512-6.
  13. Booth, S.L., K.E. Broe, J.W. Peterson, D.M. Cheng, B. Dawson-Hughes, C.M. Gundberg, L.A. Cupples, P.W. Wilson, and D.P. Kiel, (2004)
    Associations between vitamin K biochemical measures and bone mineral density in men and women.’ J Clin Endocrinol Metab. 89(10): p. 4904-9.
  14. Feskanich, D., P. Weber, W.C. Willett, H. Rockett, S.L. Booth, and G.A. Colditz, (1999) ‘Vitamin K intake and hip fractures in women: a prospective study.’ Am J Clin Nutr. 69(1): p. 74-9.
  15. Braam, L.A., M.H. Knapen, P. Geusens, F. Brouns, K. Hamulyak, M.J. Gerichhausen, and C. Vermeer, (2003) ‘Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age.’ Calcif Tissue Int. 73(1): p. 21-6.
  16. Je, S.H., N.S. Joo, B.H. Choi, K.M. Kim, B.T. Kim, S.B. Park, D.Y. Cho, K.N. Kim, and D.J. Lee, (2011) ‘Vitamin K supplement along with vitamin D and calcium reduced serum concentration of undercarboxylated osteocalcin while increasing bone mineral density in Korean postmenopausal women over sixty-years-old.’ J Korean Med Sci. 26(8): p. 1093-8.