Vitamin K in Bone Health

Phylloquinone (vitamin K1) is in foods of plant origin, especially leafy greens and soybean, canola, and olive oil. Menaquinone (vitamin K2) includes multiple forms found in cow’s liver, some meats, and products of bacterial fermentation such as cheese, natto, and miso. Little is known about the contribution of menaquinones to vitamin K status and while initially thought that 50 percent of the daily requirement for vitamin K was provided by intestinal flora, there is insufficient evidence to support this (Booth, 2003).

The different vitamin K entities have tissue-specific distribution. Liver, the main storage site, contains longchain menaquinones (MK-7 through MK-13) and a minor amount of phylloquinone. In plasma and bone, the major forms are phylloquinone followed by short-chain menaquinones MK-4 through MK-8.

The only known biochemical role for vitamin K is as a cofactor in carboxylation of specific glutamate residues in certain proteins. Finding vitamin K-dependent proteins in the skeleton lead to the hypothesis that vitamin K has a role in bone (Booth, 2003). Furthermore, α–carboxyglutamyl residues in these proteins provide mineral binding properties. There are at least three vitamin K-dependent proteins in bone and cartilage; osteocalcin, matrix gla protein, and protein S. Osteocalcin, the best understood of the three, is synthesized by osteoblasts during bone matrix formation. Its hydroxyapatite-binding capacity is associated with α-carboxylation of glutamate residues 17, 21 and 24; carboxylation of residue 17 is required for the conformation that allows binding of osteocalcin to hydroxyapatite.

Percent undercarboxylated Osteocalcin (ucOC) is a marker of vitamin K status. However, an inverse relation exists between serum 25(OH)vitamin D and ucOC. Thus, controlling vitamin D status is important when assessing the impact of vitamin K on bone health (Booth, 2003). Until recently, supporting evidence of a role for vitamin K in age-related bone loss was largely based on associations between dietary intakes or biological markers of vitamin K status and bone mineral density (BMD) or hip fracture. Randomized controlled trials (RCT) attempt to determine whether vitamin K1 has a role in the prevention or treatment of osteoporosis.

This article summarizes four key RCTs of vitamin K1 with dose ranging from 200 ug to 5000 ug per day (1-4). Three trials studied postmenopausal women while the fourth studied older women and men; these studies controlled vitamin D and calcium intakes (previous Vitamin K1 trials have not always done so). Furthermore, subjects started with comparable vitamin K status in all studies and vitamin D status in three of the studies. All studies followed BMD; unfortunately only one also monitored fracture incidence.

Giving vitamin K1 at 200 ug and 5000 ug per day appeared to have a positive effect on bone (1,2). Subjects treated with 200 ug showed a continuous significant increase in BMD over 6 months at the ultradistal radius. Fracture incidence was lower with a 5000 ug vitamin K1 treatment despite no effect on bone density. Vitamin K’s effect may have been on bone microarchitecture. However, since very few subjects had fractures, the observed difference in fracture rate may have occurred by chance. In a third study (3) where vitamin D status was not assessed, 1000 ug of vitamin K1 had no effect on BMD. Finally in a fourth study (4), 500 ug vitamin K1 had no effect on BMD. Larger trials including a range of K1 doses. with fracture as an endpoint and side effect monitoring, are needed.

Implications for Counselling Patients:

In my work at the Osteoporosis Program I am seeing an increasing number of patients taking calcium supplements including vitamin K with marketers stressing its importance in bone health. The typical dose of 50 ug/tablet is so paltry that I feel obliged to explain that a serving of leafy green vegetables provides 200 – 300 ug vitamin K along with many other nutrients and health benefits. I clarify how little their supplements provide in relation to the levels being tested in RCTs.

I also see patients taking anticoagulants who have the misconception that they should avoid all leafy greens because their vitamin K content will interfere with anticoagulation. I recommend to them the need for reasonable consistency in intake of leafy greens from day
to day rather than avoidance.

REFERENCES

Binkley N, Harke J, Krueger D, Engelke J, Vallarta-Ast N, Gemar D, Checovich M, Chappell R, Suttie J. (2009). Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density or geometry in healthy postmenopausal North American women. Journal of Bone and Mineral Research. 24:983-991.

Bolton-Smith C, McMurdo M, Paterson C,Mole P, Harvey J, Fenton S, Prynne C, Mishra G, Shearer M. (2007). Two-year randomized controlled trial of vitamin K1(phylloquinone) and vitamin D3 plus calcium on the bone health of older women. Journal of Bone and Mineral Research. 4: 509-19.

Booth S L. (2003). Dietary vitamin K and skeletal health. In: Nutritional aspects of bone health., The Royal Society of Chemistry: Cambridge, UK.

Booth SL, Dallal G, Shea MK, Gundberg C, Peterson JW, Dawson- Hughes B. (2008). Effect of vtamin K supplementation on bone loss in elderly men and women. Journal of Clinical Endocrinology and Metabolism. 93: 1217-1233.

Cheung A, Tile L, Lee Y, Tomlinson G, Hawker G, Scher J, Hu H, Vieth R, Thompson L, Jamal S, Josse R. (2008). Vitamin K supplementation in postmenopausal women with osteopenia (ECKO Trial): A randomized controlled trial. Public Library of Science Medicine. 5(10): 1461-1471.

Contact

Debbie Reid, MSc, RD
BC Women's Hospital and Health Centre
Vancouver, BC
E: dreid@cw.bc.ca