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Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial

BMJ 2008; 336 doi: (Published 31 January 2008) Cite this as: BMJ 2008;336:262

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The need for vitamin K in calcium supplements

Calcium supplements and myocardial infarction risk

Bolland and colleages reported that intake of supplemental calcium
resulted in improved bone strength but that the increased calcium
consumption was paralleled by an over 2-fold increase of adverse
cardiovascular events (1). Here we wish to put forward that during recent
years it has become clear that two vitamins are involved in the regulation
of calcium metabolism: whereas vitamin D stimulates intestinal uptake of
calcium, vitamin K is required for the synthesis of two regulatory
proteins: osteocalcin in bone and matrix Gla-protein (MGP) in the
vasculature. Vitamin K is required for the biological activity of both
proteins (2). It has been demonstrated that the majority of young healthy
adults not receiving vitamin K supplements are vitamin K-insufficient,
resulting in a substantial fraction (about 30%) of osteocalcin and MGP
being synthesized as inactive proteins. This fraction increases with age
(3). Various research groups have reported an association between poor
vitamin K status and the rate of bone loss and cardiovascular
calcification. MGP is an inhibitor of calcium salt precipitation and it is
the strongest inhibition of soft tissue calcification presently known.

Moreover, it is the only known defence system of the vasculature against
mineralization. This defence system is compromised in non-supplemented
subject since the typical “western” diet contains insufficient vitamin K
to activate all MGP. Under such conditions it is only to be expected that
if the calcium load is increased by administering a calcium supplement,
the risk of vascular calcification will increase. We have recently shown
that aortic calcification, myocardial infarction risk and cardiovascular
mortality are inversely associated with the intake of vitamin K, notably
K2 (4). Moreover, in a 3-year intervention study age-related vascular
stiffening was completely blocked by high vitamin K intake (5). It is to
be expected, therefore, that the increased infarction risk associated with
calcium supplements is counteracted by the concomitant intake of vitamin
K2. We therefore strongly recommend that calcium supplements (which in
most cases also contain vitamin D) will be enriched with a low dose of
vitamin K2. Preliminary data from our lab suggest that a dose between 20
and 200 micrograms per day may be effective in this respect.

1. Bolland MJ, Barber, PA, Doughty RN, Mason B, Horne A, Ames R,
Gamble GD, Grey A, Reid IR. Vascular events in healthy older women
receiving calcium supplementation: randomised controlled trial. Brit Med J
published online 15 Jan 2008.

2. Berkner KL, Runge KW. The physiology of vitamin K nutrititure and
vitamin K-dependent protein function in atherosclerosis. J Thromb
Haemostas 2004; 2: 2118-2132.

3. Schurgers LJ, Teunissen KJF, Hamulyák K, Knapen MHJ, Vik H,
Vermeer C. Vitamin K-containing dietary supplements: comparison of
synthetic vitamin K1 and natto-derived menaquinone-7. Blood 2007; 109:

4. Geleijnse JM, Vermeer C, Grobbee DE, Pols HAP, Schurgers LJ,
Knapen MHJ, van der Meer IM, Hofman A, Witteman JCM. Dietary intake of
vitamin K-2 reduces the risk of cardiac events and aortic atherosclerosis:
The Rotterdam Study. J. Nutr. 2004; 134: 3100-3105.

5. Braam LAJLM, Hoeks APG, Brouns F, Hamulyák K, Gerichhausen MJW,
Vermeer C. Beneficial effects of vitamin K on the elastic properties of
the vessel wall in postmenopausal women: a follow-up study. Thromb
Haemostas 2004; 91: 373-380.

Competing interests:
None declared

Competing interests: No competing interests

01 February 2008
Leon J Schurgers
Senior Scientist
Cees Vermeer
University Maastricht, VitaK BV universiteitssingel 50, 6200 MD Maastricht, the Netherlands