Cardiovascular calcification and bone: A
comparison of the effects of dietary and
serum vitamin K and its dependent proteins
Rachel Nicoll
1, John McLaren Howard
2and Michael Y Henein
11. Department of Public Health and Clinical Medicine and Heart Centre Umea University, Umea, Sweden
2. Acumen Lab, Tiverton, Devon, UK
Introduction
Vitamin K, formerly thought to be merely a coagulation
inducer, is now exciting considerable interest over its effect
on cardiovascular (CV) calcification and bone. Several studies
have found an association between severe CV calcification and
osteoporosis
1,2and we have previously shown that some of the
nutrients and micronutrients that benefit arteries are generally
also beneficial for bone
3-5. Fat-soluble vitamin K occurs naturally
in two forms: phylloquinone (vitamin K1), found in vegetables,
which is the more commonly ingested, and menaquinone
(vitamin K2), synthesised by fermentation. Despite large
quantities of menaquinones being synthesised in the gut, little
appears to be bioavailable
6, although use of antimicrobials can
cause deficiency
7. Menaquinone may take 14 different forms, of
which MK4 and MK7 are the most studied, with high quantities
of MK7 found in the Japanese food natto, made from fermented
soy. Both forms of vitamin K can function as enzyme cofactors
in the γ-carboxylation of glutamic acid residues to produce the
calcium-binding γ-carboxyglutamate (Gla) proteins, which impact
blood coagulation, CV calcification and bone formation, with the
mechanisms for all three being similar
8,9.
There are 17 vitamin K-dependent proteins discovered so
far
10, of which the principal proteins involved in CV and bone
mineralisation are matrix Gla protein (MGP) and bone Gla protein
(osteocalcin), respectively. Once MGP and osteocalcin (OC)
are γ-carboxylated, the resultant Gla residues give it a calcium
ion-binding property but if the protein is undercarboxylated,
calcium binding can be severely attenuated
8. The total
circulating MGP and OC is the sum of its carboxylated (c) and
undercarboxylated (uc) forms
8, although older assays cannot
distinguish between them
11. This calcium binding property may
determine whether calcium ends up in bone (full carboxylation)
or soft tissue (undercarboxylation) although the study of MGP
carboxylation has now become more complicated by the
parallel assessment of its serine phosphorylation, thought to
promote the cellular release of MGP, so that both γ-carboxylation
and serine phosphorylation can impact CV calcification
12. The
recent discovery of Gla-rich protein (GRP) may additionally be
of relevance since it also has calcium-binding properties and
regulated extracellular calcium metabolism
13; both cGRP and
ucGRP have been found at sites of microcalcification
14. Similarly
the vitamin K-dependent protein Gas-6 affects apoptosis
of VSMCs and bone metabolism, while periostin regulates
angiogenesis
14, although very limited studies have so far been
carried out.
Many patients with CV calcification may also be on warfarin, a
vitamin K antagonist. Warfarin blocks the γ-carboxylation of MGP,
primarily produced by vascular smooth muscle cells (VSMCs)
15and inhibits the effect of 1,25(OH)2D on OC production
from new bone synthesis
16. Warfarin treatment significantly
increased coronary, iliac and femoral artery, and cardiac valve
calcification presence and coronary artery calcification extent
in CV patients
17,18and was associated with increased plasma
ucMGP
19. Recent studies found that only age and duration of
warfarin predicted breast arterial calcification, an effect which
ISSN: 2410-2636 © Barcaray Publishing * Corresponding author. E-mail: [email protected]
Abstract
This review compares the effect of vitamin K on cardiovascular (CV) calcification and bone, which appears to ensure that
hydroxyapatite is kept out of the CV system and is deposited in bone. This is an important finding, since there is currently no
reliable treatment for CV calcification, which is predictive of coronary events and mortality. Of the two forms of vitamin K, vitamin
K2 (menaquinone) may be more effective in the arteries, while vitamin K1 (phylloquinone) is more active in bone. Nevertheless, there
remains considerable uncertainty over the precise functions of the two intermediate proteins matrix Gla protein (MGP), active mainly
in the CV system, and its bone equivalent osteocalcin (OC), which require γ-carboxylation by vitamin K before activation. Although a
diet high in vegetables could deliver adequate phylloquinone, supplementation of menaquinone may be necessary for those at risk
of CV calcification. Several animal studies and one human study have demonstrated that arterial calcification could be reduced with
vitamin K supplementation and there are further trials in progress. Patients on warfarin, a vitamin K antagonist, are particularly prone
to CV calcification but there has been concern that supplementation would either counter warfarin treatment or destabilise INR.
In fact, studies suggest that low dose phylloquinone does not increase coagulation and may improve the stability of anticoagulant
therapy.
Key words:
Arterial calcification; bone calcification; vitamin K, diet
was cumulative and may be irreversible
20, while in chronic kidney
disease (CKD) patients, vitamin K antagonist treatment was the
most important variable explaining variation in dp-ucMGP levels,
which were correlated with the calcification score
21. Furthermore,
in CKD patients followed up after 4 years, those with the CG/
GG genotype of the gene encoding vitamin K epoxide reductase
complex subunit 1 (VKORC1), the enzyme target of warfarin, had
higher baseline CAC scores, increased risk of CAC progression
and four times higher mortality compared with those with the
CC genotype
22. Since warfarin also inhibits the γ-carboxylation
of OC, it was thought that these patients would also have
increased fracture risk and lowered bone mineral density (BMD)
but curiously most studies show no association
23.
CV calcification
The few studies of vitamin K intake generally show no
association of phylloquinone intake and the CAC score, CAC
progression or abdominal aortic calcification (AAC) presence
24-29,
although in postmenopausal women, a higher intake of
MK4 (48.5mcg/d vs 18mcg/d), but not other menaquinones,
was associated with a lower CAC score
24and was inversely
associated with severe AAC (28.8mcg/d vs 25.6mcg/d)
25but
some studies show no association between menaquinone intake
and CAC presence
28. Similarly, a systematic review showed that
there was a significant inverse association between incidence of
CHD and intake of menaquinone, but not phylloquinone
30, while
later studies indicate that phylloquinone intake is significantly
lower in those at high CV risk
31. In CKD patients those with
higher vitamin K intake had a lower risk of all-cause and CVD
mortality
32. Similarly, there was no correlation between serum
phylloquinone concentrations and extreme CAC progression
26or presence of aortic valve calcification (AVC), mitral annulus
calcification (MAC) or thoracic aorta calcification (TAC) in
postmenopausal women after 8.5 years
33, although one study
found that serum phylloquinone was positively associated with
increased CAC presence, serum cholesterol, triglyceride and
ionised calcium concentrations in CKD and non-CKD subjects
34.
The association with triglycerides and cholesterol is possibly
because both forms of vitamin K are transported by
triglyceride-rich lipoproteins, while menaquinone, but not phylloquinone,
may also be transported by low density lipoproteins
8. By
contrast, serum MK4 deficiency predicted aortic calcification,
while MK7 deficiency predicted iliac calcification in CKD
patients but curiously MK5 deficiency appeared protective
against calcification
27. In the only human trial investigating CV
calcification, 500mcg/d phylloquinone supplemented for three
years in older adults showed significantly less CAC progression,
independent of changes in serum MGP
35. Similarly, animal and in
vitro studies also show that phylloquinone and MK4 reduce CV
and renal calcification
36,37, with MK4 proving more effective than
phylloquinone
38.
Vitamin K may also work indirectly through γ-carboxylation of
vitamin K-dependent proteins. Serum MGP was significantly
elevated in postmenopausal women with minor carotid
calcification compared to those without carotid calcification
(104mcg/l vs 80mcg/l); the threshold for serum MGP
appeared to be 87.9mcg/l
39. Healthy subjects had significantly
higher ucMGP compared to CAD, aortic stenosis, CKD and
calciphylaxis patients
40, while those with calcification had
lower concentrations but ucMGP was found colocalised with
calcification, suggesting that deposition of ucMGP at the site
of CV calcification reduces the circulating fraction
40,41. A study
of healthy women found no association between total ucMGP,
dp-ucMGP or dp-cMGP and the CAC score, although when
taking the log of the CAC score it was found to be associated
only with total ucMGP
28. By contrast, in CKD and T2D patients
serum ucMGP levels correlated inversely with CAC and
peripheral arterial calcification scores
42,43although plasma
dp-ucMGP levels were positively correlated with calcification
scores
43and mortality
44, but not with risk of CHD or stroke after
11.5 years
45. Similarly, a large study of asymptomatic subjects
found that higher dp-ucMGP was associated with higher
mortality, including cardiovascular mortality, but lower coronary
event incidence
46, possibly reflecting the protective effect of
coronary calcification by stabilising plaque. Likewise, lower
levels of dp-cMGP were associated with a higher calcification
score and all-cause and CV mortality in CKD
47. Both dp-ucMGP
and dp-cMGP were higher in symptomatic aortic stenosis and
heart failure patients
44and among patients who had suffered a
CV event, those in the highest quartile of ucMGP and
dp-cMGP had a higher risk of all-cause and CV mortality after five
years
48. Although it had been thought that MGP and OC had
their distinct spheres of effect (arteries and bone respectively)
49,
a recent study showed that in older Caucasian men higher
baseline total OC (carboxylation status not assessed) predicted
10 year progression of abdominal aortic calcification and lower
mortality rate
50, while MGP appears also to be implicated in
bone and cartilage formation
51.
In healthy older adults, plasma ucMGP was significantly
higher with lower concentrations of plasma phylloquinone and
supplementation of 500mcg/d phylloquinone for three years
significantly decreased plasma ucMGP, although there was no
association between ucMGP and CAC. Any association between
phylloquinone intake and change in CAC was not analysed
but the authors suggest that phylloquinone impacts CAC
progression independent of changes in serum MGP.
52Short-term
MK7 supplementation dose dependently reduced dp-ucMGP in
both CKD patients and healthy subjects, which was significant
only with the higher dose (360mcg/d vs135mcg/d)
53-55, although
another study found an effect on ucMGP, but not
dp-cMGP, with 135mcg/d
47. None of these studies investigated
CV calcification. Ongoing clinical trials such as VitavasK
(NCT01742273), VitaK-CAC (NCT01002157), VITAKANDOP
(NCT01232647), SAFEK (NCT01533441), and OVWAK VII
(NCT00990158) should provide greater insight into the effect of
vitamin K on CV calcification.
Bone
A 2007 review showed that dietary and serum vitamin K
manifests a positive correlation with BMD and is inversely
associated with fracture risk
8. More recent studies have
generally confirmed these association with respect to
phylloquinone intake, although menaquinone intake appears
to have no association with fracture risk
56. An effective intake
for phylloquinone was found to be >/=116mcg/d
52, with little
benefit to higher amounts. Phylloquinone intake was generally
inversely associated with serum ucOC
57and with the ratio of
serum ucOC/OC levels among elderly Japanese patients
58. In
Japanese men, intake of natto (largely MK7) was also inversely
associated with serum ucOC and positively associated with
BMD but this association became insignificant after adjusting for
ucOC levels
59.
results are mixed with respect to an association between serum
ucOC/OC and BMD
63,64,66, with the ratio being significantly
greater in carriers of the apoE4 phenotype, normally a risk factor
for atherosclerosis
34while lower ucOC was associated with
apoE2 genotype
49. This may be due to the apoE4 phenotype
giving markedly faster hepatic clearance of chylomicrons
and very low density lipoproteins, which lowers circulating
vitamin K relative to the apoE2 phenotype
8. Ethnicity may also
play a role in generating inconsistent results; among Chinese
postmenopausal women, plasma phylloquinone was significantly
higher and plasma ucOC was significantly lower than among
British or Gambian women, while only among British women was
plasma phylloquinone inversely associated with ucOC
49. Among
healthy women, serum phylloquinone and MK7, but not serum
MK4, were generally inversely correlated with ucOC and the
ucOC/OC ratio
67, while there appears to be a gender difference
with respect to the meaning of high plasma OC; in those aged
>/=75, but not younger, higher plasma OC was associated with
reduced CVD risk in men but with increased risk in women
68.
Several recent meta-analyses and reviews of the effects of
vitamin K supplementation show a positive effect on BMD and
indices of bone strength, with reduced fracture incidence in
mainly postmenopausal women; the majority of long-term trials
supplemented MK4 to Japanese
8,69,70. A subsequent study
confirmed the beneficial effect of vitamin K1 supplementation
on BMD in postmenopausal women, with doses of 80mcg/d
phylloquinone proving effective
66. There were, however, mixed
results for MK4, with one trial showing that 45mg/d, together
with vitamin D and calcium, had a beneficial effect on BMD in
Korean postmenopausal women
71, while another showed that
MK4 enhanced the effect of bisphosphonates in Japanese
postmenopausal females
72but a larger study over three years
found no effect on BMD, although BMC and femoral neck
width were increased compared to placebo
73. 180mcg/d MK7
also significantly improved BMD in postmenopausal women
74,
although 360mcg/d MK7 failed to show a difference in bone loss
relative to the placebo group
75but this may have been because
the placebo was olive oil, which also has a beneficial effect on
bone
3.
In addition, a 2009 review and subsequent study showed
that phylloquinone can dose-dependently reduce ucOC in
postmenopausal women, with a consistently effective dose
being 1mg/d, although there were inconsistent results for
total OC
69,76. Phylloquinone can also increase cOC in older
adults
77and lower ucOC/OC
78but results for younger adults
are inconclusive
77,79. Furthermore, 45mg/d MK4 significantly
decreased ucOC in postmenopausal women
71,72,76,80,81, increased
cOC and generally increased total OC
80,81, although 1.5mg/d
may be sufficient to decrease serum ucOC and ucOC/OC while
increasing cOC
82; a dose of 1.5mg/d accords with the amount of
MK4 obtainable from diet, whereas 45mg/d is pharmacological
83.
In the few studies of MK7, 360mcg/d reduced ucOC and
increased cOC in early postmenopausal women
75, although
a lower dose may also be effective in increasing cOC
9,55.
Nevertheless, reduction of serum ucOC is not always
accompanied by improvement in BMD
76.
There is also an interaction between vitamin K and vitamin D,
and Vitamin D may also be important for normal γ-carboxylation
of osteocalcin
84. When vitamin D status is assessed as well
as vitamin K, plasma 25(OH)D, phylloquinone and MK7
concentrations correlated with each other in elderly males
85. In
vitamin D deficiency 45mg/d MK4 can raise serum 1,25(OH)2D
86and where 1,25(OH)2D is elevated MK4 can inhibit its induction
of osteoclast formation
87. Serum 1,25(OH)2D also correlates
with serum OC in osteoporotic females
88and Vitamin D
supplementation can increase serum OC in postmenopausal
women
89and regulate its osteoblastic induction
16, transcription
and translation
83, although there are mixed results in correlating
serum ucOC concentration with 25(OH)D among elderly
females
62,65. Menaquinone enhances this 1,25(OH)2D-induced
OC mRNA production but could not substitute for 1,25(OH)2D in
OC mRNA expression
16. A comparison study of postmenopausal
osteoporotic Chinese women showed no significant difference in
BMD increase between 45mg/d MK4 and vitamin D; interestingly
vitamin D also decreased ucOC, although the decrease was
greater in the MK4 group
90. Where vitamin D is supplemented
with either phylloquinone or MK4, most studies show generally
improved results compared with either vitamin alone
8,91, although
some found no additional benefit to bone parameters or the
carboxylation of OC
92. Furthermore, MK4 improved bone mass
to a greater extent in those with higher serum 25(OH)D
93. The
synergistic effect of combined vitamins K and D on bone loss
is also reflected in animal studies
8,94but possibly only if calcium
intake is optimal
95. Other nutrient interactions include high dose
alpha-tocopherol, which can antagonise vitamin K and reduce
tissue levels
96and fat, but not in hydrogenated form, which can
enhance the bioavailability of menaquinone
97. Zinc can also
enhance the effect of MK7 in increasing bone calcium content in
vitro
98, while combined supplementation had a synergistic effect
on bone in female rats
99.
Mechanisms of effect of vitamin K
MGP appears to act to prevent hydroxyapatite deposition by,
variously, binding calcium ions, binding to and inhibiting bone
morphogenetic proteins (particularly BMP-2, known to trigger
the transformation of VSMCs to osteoblast-like cells), altering
cell differentiation, binding to extracellular matrix components
and regulating apoptosis
100. Arterial calcified lesions contain
elevated concentrations of ucMGP, together with unbound
BMP-2, while BMP-2 binds to the Gla-containing region of cMGP
in the presence of ionised calcium, suggesting further that it
is the binding of BMP-2 which inhibits arterial calcification
101.
OC acts in a similar manner by adhering to hydroxyapatite and
influencing bone remodelling but its main function has been
suggested as a regulator of bone maturation and turnover,
rather than a marker of bone formation
8,83. Neither can bind to
hydroxyapatite unless carboxylated, since undercarboxylated
proteins have a poor affinity for calcium
102.
levels of the other; phylloquinone can be converted into MK4
in the body via removal of the isoprenoid side-chain while MK4
increases serum phylloquinone concentrations
105.
A number of bone studies have shown a synergistic effect
of vitamins D and K
8. OC synthesis by 1,25(OH)2D occurs
through a vitamin D response element in the promoter region
of the OC gene, while the increase in γ-glutamyl carboxylase
activity and mRNA in osteoblasts is promoted by 1,25(OH)2D
106.
MK4, but not phylloquinone, also enhanced the 1,25(OH)2D–
induced mineralisation of osteoblasts and osteocalcin mRNA
production
16and inhibited vitamin D- or PGE2-induced calcium
release from mouse bone, which appears to be independent
of its γ-carboxylation activity since warfarin did not affect the
result
103. It is not known whether this synergistic effect is equally
applicable in arteries, although vitamin D is known to be involved
in the regulation of MGP gene expression
107; Fraser et al have
shown that the MGP promotor contains a vitamin D response
element that is responsible for a 2-3 fold enhancement of MGP
expression after vitamin D binding
108.
Discussion
This review has shown that the γ-carboxylation of the vitamin
K-dependent proteins MGP and its bone equivalent, OC,
generally ensures that hydroxyapatite is kept out of the
arteries and is retained in bone, irrespective of the extent of
hydroxyapatite present
8. Nevertheless, not all forms of vitamin K
are equally effective. In the arteries, menaquinone consistently
appears to be the active form and is also associated with
reduced CHD. Dietary and serum phylloquinone can often
have little effect, although a deficiency appears to be a risk
factor for CV disease but this may be because phylloquinone,
deriving mainly from vegetables, is also an indicator of a
generally healthier diet, while some beneficial effects of MK7
from natto may in fact be due to the isoflavones from the
soyabeans
83. Phylloquinone appears to be much more effective
than menaquinone in observational studies of bone, although
Japanese clinical trials of MK4 also show positive results.
Vermeer et al suggest that the success of these pharmacological
doses of MK4 (45mg/d is greatly in excess of the dose needed
to normalise γ-carboxylation of vitamin K-dependent proteins)
demonstrate that there is an additional mechanism of action,
such as the anti-inflammatory action of vitamin K metabolites
demonstrated in vitro
109. Nevertheless, vitamin K intake
from a normal healthy diet is insufficient to maintain OC, and
possibly MGP, in its fully carboxylated form, which can require
up to 1,000mcg/d phylloquinone, suggesting that possibly full
carboxylation is not necessary, particularly in view of the studies
showing that ucOC is protective
110.
The fact that not all studies show a direct association with
arteries and bone may be because vitamin K can act through
the carboxylation of MGP and OC respectively and also the
phosphorylation of MGP. Studies fairly uniformly show that
both phylloquinone and menaquinone lower plasma ucMPG
or dp-ucMGP, yet some results of the effect of MGP are
counter-intuitive, with higher ucMGP being protective against
calcification. Results are clearer in patient, as opposed to
healthy populations, where ucMGP correlated inversely with
calcification presence and extent and dp-ucMGP concentrations
correlated positively and dp-cMGP correlated inversely with
calcification, yet both dp-ucMGP and dp-cMGP were elevated
in those who had suffered heart failure or a CV event or were at
risk of five-year mortality. It has been suggested that ucMGP
may be a marker for CV calcification, whereas dp-ucMGP
might be a predictor of CV disease events and mortality
10. The
contradictions may also indicate that absolute values of uc and
cMGP are unhelpful and that a ratio of ucMGP/cMGP would be
more informative. Similarly in bone studies, serum phylloquinone
and MK7 generally correlated with ucOC and the ucOC/OC
ratio, although the relationship between serum ucOC/OC and
BMD seems uncertain, possibly because vitamin K may alter OC
production
110, suggesting again that a ratio of ucOC/cOC may be
more helpful.
Research into the association of the various fractions of MGP
with CV calcification is still relatively new and these somewhat
confused and contradictory results indicate that the exact
mechanisms are not yet fully understood. Furthermore, bone
studies have shown that the apoE genotype and ethnicity may
have a bearing on results but these have not been tested in
CV studies. Additionally, there is a marked interaction between
vitamin K and vitamin D, with one study showing little difference
in effect between high dose MK4 and vitamin D on BMD and
improved results when both were supplemented together.
Animal studies suggest that calcium intake should be adequate
for optimal effect. The combination appears to have different
effects to either vitamin independently, which suggests that
the effect of vitamin K would be enhanced if vitamin D levels
were adequate
8. The other vitamin K-dependent proteins such
as GRP, periostin and Gas-6 may also play a role in regulating
arterial and skeletal calcification and could account for the lack
of clear results in studies of MGP and OC
111. Genetics suggest
that the extent of calcification and its effects is also determined
by the VKORC1 genotype, which is only rarely taken into
account in CV disease studies, while the relevance of the serine
phosphorylation status of MGP is largely undetermined; neither
of these has been considered in bone.
Concern has been expressed that supplementing vitamin K
would either counter warfarin treatment or destabilise INR,
causing patients to need anticoagulants. Because carboxylation
of the coagulation Gla proteins in the liver is the most essential
use of vitamin K, while the Gla proteins in the extrahepatic
tissues are non-essential, the vitamin K transport system
ensures preferential distribution of dietary vitamin K to the liver
and only when these coagulation proteins are fully carboxylated
does vitamin K move to extra-hepatic tissue
10, suggesting that
the body operates a triage system for vitamin K. In osteoporosis
patients given MK4 supplementation, haemostatic parameters
remained stable despite high plasma MK4
112, indicating that
additional vitamin K intake will not increase coagulation,
provided the coagulation Gla proteins are fully carboxylated.
There also appears to be a marked difference in dose/response
between the different forms of vitamin K. MK7 supplementation
as low as 10–20mcg/d may rapidly destabilise therapeutic
anticoagulant control, whereas in patients taking warfarin,
100mcg/d vitamin K improved the stability of anticoagulant
therapy
113,114, while the threshold phylloquinone dose for causing
lowered INR was 150mcg/d, although circulating ucOC did not
decrease until a dose of 300mcg/d
115. Furthermore, there are
now oral anticoagulants such as ximelagatran, which do not
affect vitamin K metabolism and could be used when there is a
need for vitamin K supplementation for artery or bone health
8.
Conclusion
the γ-carboxylation of MGP, vitamin K also has anti-inflammatory
and other properties. When considering bone, most studies
show that phylloqinone is associated with increased BMD
and reduced fracture risk, likely through lowered serum ucOC.
Supplementation of phylloquinone, MK4 and MK7 improves
BMD and indices of bone strength and reduces fracture risk.
Nevertheless, there remain many uncertainties over the precise
role of the various forms of MGP and OC. Some of this may be
explained by genetic polymorphisms and the role of the
recently-discovered vitamin K-dependent proteins GRP, periostin and
Gas-6 in the regulation of arterial and skeletal calcification, as
well as an interaction between vitamin K and vitamin D; vitamin
K supplementation is more effective if vitamin D and calcium
levels are adequate.
Statement of ethical publishing
This paper complies with the ethical requirements for publishing
in a biomedical journal
116.
Conflict of interest statement:
None of the authors has any conflict of interest to declare or has
received any remuneration for this article.
Address for correspondence:
Michael Henein MD PhD FESC FACC FRCP
Professor of Cardiology
Department of Public Health and Clinical Medicine and Heart
Centre, Umea University
Sweden
E-mail: [email protected]
References:
1. Hak AE, Pols HA, van Hemert AM, Hofman A, Witteman JC. Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study. Arterioscler Thromb Vasc Biol 2000;20:1926–31 doi: 10.1161/01.ATV.20.8.1926
2. Kiel DP, Kauppila LI, Cupples LA, Hannan MT, O’Donnell CJ, Wilson PW. Bone loss and the progression of abdominal aortic calcification over a 25 year period: the Framingham Heart Study. Calcif Tissue Int 2001;68:271–6 DOI: 10.1007/s00223-001-0005-6
3. Nicoll R, McLaren Howard J, Henein M. Cardiovascular and renal calcification and bone: A comparison of the effects of dietary fatty acids. International Cardiovascular Forum. 2014; 3: 127-131 DOI: 10.17987/icfj. v1i3.37
4. Nicoll R, McLaren Howard J, Henein M. Ectopic calcification and bone: A comparison of the effects of dietary carbohydrates, sugars and protein. International Cardiovascular Forum. 2014; 4: 175-179 DOI: 10.17987/icfj. v1i4.46
5. Nicoll R, McLaren Howard J, Henein M. Cardiovascular calcification and bone: A comparison of the effects of dietary and serum calcium, phosphorus, magnesium and vitamin D. International Cardiovascular Forum 2014; 5: 209-218 DOI: 10.17987/icfj.v1i5.60
6. Shearer MJ. ‘The roles of vitamins D and K in bone health and osteoporosis prevention’. Proc Nutr Soc. 1997; 56(3): 915-37
7. Conly J, Stein K. Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials. Clin Invest Med 1994;17:531–9
8. Pearson DA. Bone health and osteoporosis: the role of vitamin K and potential antagonism by anticoagulants. Nutr Clin Pract. 2007 Oct;22(5):517-44 doi: 10.1177/0115426507022005517
9. Theuwissen E, Cranenburg EC, Knapen MH, Magdeleynes EJ, Teunissen KJ, Schurgers LJ et al. ‘Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status but had no effect on thrombin generation in healthy subjects’. Br J Nutr. 2012; 31: 1-6 Doi10.1017/ S0007114511007185
10. Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr. 2012 Mar 1;3(2):166-73
11. Vassalle C, Iervasi G. New insights for matrix Gla protein, vascular calcification and cardiovascular risk and outcome. Atherosclerosis. 2014; 235: 236-238 doi: 10.1016/j.atherosclerosis.2014.04.037
12. Cranenburg EC, Koos R, Schurgers LJ, Magdeleyns EJ, Schoonbrood TH, Landewe RB et al. ‘Characterisation and potential diagnostic value
of circulating Gla protein (MGP) species’. Thromb Haemost. 2010; 104(4): 811-22 doi: 10.1160/TH09-11-0786
13. El Asmar MS, Naoum JJ, Arbid EJ. Vitamin K dependent proteins and the role of vitamin K2 in the modulation of vascular calcification: a review. Oman Med J 2014; 29(3): 172-177 doi: 10.5001/omj.2014.44. 14. Viegas CS, Herfs M, Rafael MS, Enriquez JL, Teixeira A, Luís IM, van ‘t
Hoofd CM, João A, Maria VL, Cavaco S, Ferreira A, Serra M, Theuwissen E, Vermeer C, Simes DC. Gla-Rich Protein Is a Potential New Vitamin K Target in Cancer: Evidences for a Direct GRP-Mineral Interaction. Biomed Res Int. 2014;2014:340216. doi: 10.1155/2014/340216
15. Palaniswamy C, Aronow WS, Sekhri A, Adapa S, Ahn C, Singh T, Malhotra B, Lerner R. Warfarin Use and Prevalence of Coronary Artery Calcification Assessed by Multislice Computed Tomography. Am J Ther. 2012 Jul 19. [Epub ahead of print] doi: 10.1097/MJT.0b013e318249a1c6
16. Koshihara Y, Hoshi K. ‘Vitamin K2 enhances osteocalcin accumulation in the extracellular matrix of human osteoblasts in vitro’. J Bone Miner Res. 1997; 12(3): 431-8 DOI: 10.1359/jbmr.1997.12.3.431
17. Schurgers LJ, Joosen IA, Laufer EM, Chatrou ML, Herfs M, Winkens MH, Westenfeld R, Veulemans V, Krueger T, Shanahan CM, Jahnen-Dechent W, Biessen E, Narula J, Vermeer C, Hofstra L, Reutelingsperger CP. Vitamin K-antagonists accelerate atherosclerotic calcification and induce a vulnerable plaque phenotype. PLoS One. 2012;7(8):e43229 doi: 10.1371/ journal.pone.0043229
18. Fusaro M, Tripepi G, Noale M, Plebani M, Zaninotto M, Piccoli A, Naso A, Miozzo D, Giannini S, Avolio M, Foschi A, Rizzo MA, Gallieni M, Curr Vasc Pharmacol. 2015;13(2):248-58 DOI: 10.2174/15701611113119990146 19. Koos R, Krueger T, Westenfeld R, Kühl HP, Brandenburg V, Mahnken
AH, Stanzel S, Vermeer C, Cranenburg EC, Floege J, Kelm M, Schurgers LJ. Relation of circulating Matrix Gla-Protein and anticoagulation status in patients with aortic valve calcification. Thromb Haemost. 2009 Apr;101(4):706-13 doi 10.1160/TH08-09-0611
20. Tantisattamo E, Han KH O’Neill WC. Increased Vascular Calcification in Patients Receiving Warfarin. Arterioscler Thromb Vasc Biol. 2014 Oct 16. [Epub ahead of print] doi: 10.1161/ATVBAHA.114.304392
21. Delanaye P, Krzesinski JM, Warling X, Moonen M, Smelten N, Médart L, Pottel H, Cavalier E. Dephosphorylated-uncarboxylated Matrix Gla protein concentration is predictive of vitamin K status and is correlated with vascular calcification in a cohort of hemodialysis patients. BMC Nephrol. 2014 Sep 4;15:145 doi: 10.1186/1471-2369-15-145
22. Holden RM, Booth SL, Tuttle A, James PD, Morton AR, Hopman WM, Nolan RL, Garland JS. Sequence variation in vitamin k epoxide reductase gene is associated with survival and progressive coronary calcification in chronic kidney disease. Arterioscler Thromb Vasc Biol. 2014 Jul;34(7):1591-6 doi: 10.1161/ATVBAHA.114.303211
23. Rejnmark L, Vestergaard P, Mosekilde L. ‘Fracture risk in users of oral anticoagulants: a nationwide case-control study’. Int J Cardiol. 2007; 118(3): 338-44 DOI: doi 10.1016/j.ijcard.2006.07.022
24. Beulens JW, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JC, Grobbee DE, van der Schouw YT. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009 Apr;203(2):489-93 DOI: 10.1016/j. atherosclerosis.2008.07.010
25. Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, Hofman A, Witteman JC. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004 Nov;134(11):3100-5
26. Shea MK, Booth SL, Miller ME, Burke GL, Chen H, Cushman M, Tracy RP, Kritchevsky SB. Association between circulating vitamin K1 and coronary calcium progression in community-dwelling adults: the Multi-Ethnic Study of Atherosclerosis. Am J Clin Nutr. 2013 Jul;98(1):197-208 doi: 10.3945/ ajcn.112.056101
27. Fusaro M, Noale M, Viola V, Galli F, Tripepi G, Vajente N, Plebani M, Zaninotto M, Guglielmi G, Miotto D, Dalle Carbonare L, D’Angelo A, Naso A, Grimaldi C, Miozzo D, Giannini S, Gallieni M; VItamin K Italian (VIKI) Dialysis Study Investigators. Vitamin K, vertebral fractures, vascular calcifications, and mortality: VItamin K Italian (VIKI) dialysis study. J Bone Miner Res. 2012 Nov;27(11):2271-8 doi: 10.1002/jbmr.1677.
28. Dalmeijer GW, van der Schouw YT, Vermeer C, Magdeleyns EJ, Schurgers LJ, Circulating matrix Gla protein is associated with coronary artery calcification and vitamin K status in healthy women. J Nutr Biochem. 2013 Apr;24(4):624-8 doi: 10.1016/j.jnutbio.2012.02.012
29. Jie KS, Bots ML, Vermeer C, Witteman JC, Grobbee DE. Vitamin K intake and osteocalcin levels in women with and without aortic atherosclerosis: a population-based study. Atherosclerosis. 1995 Jul;116(1):117-23 DOI: 10.1016/0021-9150(95)05537-7
30 Rees K, Guraewal S, Wong YL, Majanbu DL, Mavrodaris A, Stranges S, Kandala NB, Clarke A, Franco OH. Is vitamin K consumption associated with cardio-metabolic disorders? A systematic review. Maturitas. 2010 Oct;67(2):121-8 doi: 10.1016/j.maturitas.2010.05.006
32. Cheung CL, Sahni S, Cheung BM, Sing CW, Wong IC. Vitamin K intake and mortality in people with chronic kidney disease from NHANES III. Clin Nutr. 2014 Apr 2. pii: S0261-5614(14)00086-7 doi: 10.1016/j. clnu.2014.03.011
33. Dalmeijer GW, van der Schouw YT, Booth SL, de Jong PA, Beulens JW. Phylloquinone concentrations and the risk of vascular calcification in healthy women. Arterioscler Thromb Vasc Biol. 2014 Jul;34(7):1587-90 doi: 10.1161/ATVBAHA.114.303853
34 Pilkey RM, Morton AR, Boffa MB, Noordhof C, Day AG, Su Y, Miller LM, Koschinsky ML, Booth SL. Subclinical vitamin K deficiency in hemodialysis patients. Am J Kidney Dis. 2007 Mar;49(3):432-9 DOI: 10.1053/j.ajkd.2006.11.041
35 Shea MK, O’Donnell CJ, Hoffmann U, Dallal GE, Dawson-Hughes B, Ordovas JM, Price PA, Williamson MK, Booth SL. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr. 2009 Jun;89(6):1799-807 doi: 10.3945/ ajcn.2008.27338.
36 Schurgers LJ, Spronk HM, Soute BA, Schiffers PM, DeMey JG, Vermeer C. ‘Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats’. Blood. 2007; 109(7): 2823-31 DOI: 10.1182/ blood-2006-07-035345
37 McCabe KM, Booth SL, Fu X, Shobeiri N, Pang JJ, Adams MA, Holden RM. Dietary vitamin K and therapeutic warfarin alter the susceptibility to vascular calcification in experimental chronic kidney disease. Kidney Int. 2013 May;83(5):835-44 doi: 10.1038/ki.2012.477
38 Spronk HM, Soute BA, Schurgers LJ, Thijssen HH, De Mey JG, Vermeer C. Tissue-specific utilization of menaquinone-4 results in the prevention of arterial calcification in warfarin-treated rats. J Vasc Res. 2003 Nov-Dec;40(6):531-7 DOI:10.1159/000075344
39 Silaghi CN, Fodor D, Craciun AM. ‘Circulating matrix Gla protein: a potential tool to identify minor carotid stenosis with calcification in a risk population’. Clin Chem Lab Med. 2013; 55(1): 1115-23 DOI: 10.1515/ cclm-2012-0329
40 Cranenburg EC, Vermeer C, Koos R, Boumans ML, Hackeng TM, Bouwman FG, Kwaijtaal M, Brandenburg VM, Ketteler M, Schurgers LJ. The circulating inactive form of matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification. J Vasc Res. 2008; 45(5): 427-36 doi: 10.1159/000124863
41 Schurgers LJ, Teunissen KJ, Knapen MH, Kwaijtaal M, van Diest R, Appels A, Reutelingsperger CP, Cleutjens JP, Vermeer C. Novel conformation-specific antibodies against matrix γ-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification. Arterioscler Thromb Vasc Biol. 2005 Aug;25(8):1629-33 doi: 10.1161/01. ATV.0000173313.46222.43
42 Cranenburg EC, Brandenburg VM, Vermeer C, Stenger M, Mühlenbruch G, Mahnken AH, Gladziwa U, Ketteler M, Schurgers LJ. Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients. Thromb Haemost. 2009 Feb;101(2):359-66 doi. org/10.1160/TH08-04-0241
43 Liabeuf S, Olivier B, Vemeer C, Theuwissen E, Magdeleyns E, Aubert CE, Brazier M, Mentaverri R, Hartemann A, Massy ZA. Vascular calcification in patients with type 2 diabetes: the involvement of matrix Gla protein. Cardiovasc Diabetol. 2014 Apr 24;13(1):85 doi: 10.1186/1475-2840-13-85. 44 Ueland T, Gullestad L, Dahl CP, Aukrust P, Aakhus S, Solberg OG, Vermeer
C, Schurgers LJ. Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis. J Intern Med. 2010 Nov;268(5):483-92 doi: 10.1111/j.1365-2796.2010.02264.x
45 Dalmeijer GW, van der Schouw YT, Magdeleyns EJ, Vermeer C, Verschuren WM, Boer JM, Beulens JW. Circulating desphospho-uncarboxylated matrix γ-carboxyglutamate protein and the risk of coronary heart disease and stroke. J Thromb Haemost. 2014 May 15. [Epub ahead of print] doi: 10.1111/jth.12609
46 Schlieper G, Westenfeld R, Krüger T, Cranenburg EC, Magdeleyns EJ, Brandenburg VM, Djuric Z, Damjanovic T, Ketteler M, Vermeer C, Dimkovic N, Floege J, Schurgers LJ. Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD. J Am Soc Nephrol. 2011 Feb;22(2):387-95 doi: 10.1681/ASN.2010040339.
47 Ueland T, Dahl CP, Gullestad L, Aakhus S, Broch K, Skårdal R, Vermeer C, Aukrust P, Schurgers LJ. Circulating levels of non-phosphorylated undercarboxylated matrix Gla protein are associated with disease severity in patients with chronic heart failure. Clin Sci (Lond). 2011 Aug;121(3):119-27 doi: 10.1042/CS20100589.
48 Liu YP, Gu YM, Thijs L, Knapen MH, Salvi E, Citterio L, Petit T, Carpini SD, Zhang Z, Jacobs L, Jin Y, Barlassina C, Manunta P, Kuznetsova T, Verhamme P, Struijker-Boudier HA, Cusi D, Vermeer C, Staessen JA. Inactive Matrix Gla Protein Is Causally Related to Adverse Health Outcomes: A Mendelian Randomization Study in a Flemish Population. Hypertension. 2014 Nov 24. [Epub ahead of print]
49 Cancela ML, Laizé V, Conceição N. Matrix Gla protein and osteocalcin: from gene duplication to neofunctionalization. Arch Biochem Biophys. 2014 Nov 1;561:56-63 doi: 10.1161/HYPERTENSIONAHA.114.04494. 50 Confavreux CB, Szulc P, Casey R et al. Higher serum osteocalcin is
associated with lower abdominal aortic calcification progression and
longer 10-year survival in elderly men of the MINOS cohort. J Clin Endocrinol Metab 2013; 98: 1084–1092 doi: 10.1210/jc.2012-3426 51 Willems BA, Vermeer C, Reutelingsperger CP, Schurgers LJ. The realm
of vitamin K dependent proteins: shifting from coagulation toward calcification. Mol Nutr Food Res 2014; 58:1620–1635 doi: 10.1002/ mnfr.201300743
52. Shea MK, O’Donnell CJ, Vermeer C, Magdeleyns EJ, Crosier MD, Gundberg CM, Ordovas JM, Kritchevsky SB, Booth SL. Circulating uncarboxylated matrix gla protein is associated with vitamin K nutritional status, but not coronary artery calcium, in older adults. J Nutr. 2011 Aug;141(8):1529-34 doi: 10.3945/jn.111.139634
53. Westenfeld R, Krueger T, Schlieper G, Cranenburg EC, Magdeleyns EJ, Heidenreich S, Holzmann S, Vermeer C, Jahnen-Dechent W, Ketteler M, Floege J, Schurgers LJ. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. Am J Kidney Dis. 2012 Feb;59(2):186-95 doi: 10.1053/j. ajkd.2011.10.041.
54. Caluwé R, Vandecasteele S, Van Vlem B, Vermeer C, De Vriese AS. Vitamin K2 supplementation in haemodialysis patients: a randomized dose-finding study. Nephrol Dial Transplant. 2013 Nov 26. [Epub ahead of print] doi: 10.1093/ndt/gft464
55. Dalmeijer GW, van der Schouw YT, Magdeleyns E, Ahmed N, Vermeer C, Beulens JW. The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein. Atherosclerosis. 2012 Dec;225(2):397-402 doi: 10.1016/j.atherosclerosis.2012.09.019
56. Apalset EM, Gjesdal CG, Eide GE, Tell GS. Intake of vitamin K1 and K2 and risk of hip fractures: The Hordaland Health Study. Bone. 2011 Nov;49(5):990-5 doi: 10.1016/j.bone.2011.07.035
57. Booth SL, O’Brien-Morse ME, Dallal GE, Davidson KW, Gundberg CM. ‘Response of vitamin K status to different intakes and sources of phylloquinone-rich foods: comparison of younger and older adults’. Am J Clin Nutr. 1999; 70(3): 368-77
58. Kuwabara A, Fujii M, Kawai N, Tozawa K, Kido S, Tanaka K. Bone is more susceptible to vitamin K deficiency than liver in the institutionalized elderly. Asia Pac J Clin Nutr. 2011;20(1):50-5
59. Fujita Y, Iki M, Tamaki J, Kouda K, Yura A, Kadowaki E, Sato Y, Moon JS, Tomioka K, Okamoto N, Kurumatani N. Association between vitamin K intake from fermented soybeans, natto, and bone mineral density in elderly Japanese men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study. Osteoporos Int. 2012 Feb;23(2):705-14 doi: 10.1007/ s00198-011-1594-1
60. Liu G, Peacock M. Age-related changes in serum undercarboxylated osteocalcin and its relationships with bone density, bone quality, and hip fracture. Calcif Tissue Int. 1998 Apr;62(4):286-9
61. Vergnaud P, Garnero P, Meunier PJ, Breart G, Kamihagi K, Delmas PD. ‘Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS Study’. J Clin Endocrinol Metab. 1997; 82(3): 719-24 DOI: 10.1210/jcem.82.3.3805 62. Arunakul M, Niempoog S, Arunakul P, Bunyaratavej N. Level of
undercarboxylated osteocalcin in hip fracture Thai female patients. J Med Assoc Thai. 2009 Sep;92 Suppl5:S7-11
63. Szulc P, Chapuy MC, Meunier PJ, Delmas PD. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture: a three year follow-up study. Bone. 1996 May;18(5):487-8 DOI: 10.1016/8756-3282(96)00037-3 64. Emaus N, Nguyen ND, Almaas B, Berntsen GK, Center JR, Christensen M, Gjesdal CG, Grimsgaard AS, Nguyen TV, Salomonsen L, Eisman JA, Fønnebø VM. Serum level of under-carboxylated osteocalcin and bone mineral density in early menopausal Norwegian women. Eur J Nutr. 2013 Feb;52(1):49-55 doi: 10.1007/s00394-011-0285-1
65. Soontrapa S, Soontrapa S, Bunyaratavej N. Serum concentration of undercarboxylated osteocalcin and the risk of osteoporosis in thai elderly women. J Med Assoc Thai. 2005 Oct;88 Suppl 5:S29-32
66. Schaafsma A, Muskiet FA, Storm H, Hofstede GJ, Pakan I, Van der Veer E. Vitamin D(3) and vitamin K(1) supplementation of Dutch postmenopausal women with normal and low bone mineral densities: effects on serum 25-hydroxyvitamin D and carboxylated osteocalcin. Eur J Clin Nutr. 2000 Aug;54(8):626-31
67. Tsugawa N, Shiraki M, Suhara Y, Kamao M, Tanaka K, Okano T. Vitamin K status of healthy Japanese women: age-related vitamin K requirement for γ-carboxylation of osteocalcin. Am J Clin Nutr. 2006 Feb;83(2):380-6 68. Holvik K, van Schoor N, Eekhoff EM, Den Heijer M, Deeg DJ, Lips P, De
Jongh R. Plasma osteocalcin levels as a predictor for cardiovascular disease in older men and women: A population-based cohort study. Eur J Endocrinol. 2014 May 6. [Epub ahead of print] doi: 10.1530/EJE-13-1044 69. Iwamoto J, Sato Y, Takeda T, Matsumoto H. High-dose vitamin K
supplementation reduces fracture incidence in postmenopausal women: a review of the literature. Nutr Res. 2009 Apr;29(4):221-8 doi: 10.1016/j. nutres.2009.03.012.
70. Fang Y, Hu C, Tao X, Wan Y, Tao F. Effect of vitamin K on bone mineral density: a meta-analysis of randomized controlled trials. J Bone Miner Metab. 2012 Jan;30(1):60-8 doi: 10.1007/s00774-011-0287-3 71. Je SH, Joo NS, Choi BH, Kim KM, Kim BT, Park SB, Cho DY, Kim
increasing bone mineral density in Korean postmenopausal women over sixty-years-old. J Korean Med Sci. 2011 Aug;26(8):1093-8 doi: 10.3346/ jkms.2011.26.8.1093
72. Hirao M, Hashimoto J, Ando W, Ono T, Yoshikawa H. Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K2 in postmenopausal women. J Bone Miner Metab. 2008;26(3):260-4 doi: 10.1007/s00774-007-0823-3
73. Knapen MH, Schurgers LJ, Vermeer C. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. 2007 Jul;18(7):963-72 DOI 10.1007/s00198-007-0337-9
74. Knapen MH, Drummen NE, Smit E, Vermeer C, Theuwissen E. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013 Sep;24(9):2499-507 doi: 10.1007/s00198-013-2325-6.
75. Emaus N, Gjesdal CG, Almås B, Christensen M, Grimsgaard AS, Berntsen GK, Salomonsen L, Fønnebø V. Vitamin K2 supplementation does not influence bone loss in early menopausal women: a randomised double-blind placebo-controlled trial. Osteoporos Int. 2010 Oct; 21(10):1731-40 doi: 10.1007/s00198-009-1126-4
76. Binkley NC, Harke J, Krueger DC, Engelke JA, Vallarta-Ast N, Gemar D, Chappell RJ, Suttie JW. ‘Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density or geometry in healthy postmenopausal North American women’. J Bone Miner Res. 2009; 24(6): 983-91 doi: 10.1359/jbmr.081254
77. Knapen MH, Hamulyák K, Vermeer C. The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Intern Med. 1989 Dec 15;111(12):1001-5 doi:10.7326/0003-4819-111-12-1001
78. Booth SL, Dallal G, Shea MK, Gundberg C, Peterson JW, Dawson-Hughes B. Effect of vitamin K supplementation on bone loss in elderly men and women. J Clin Endocrinol Metab. 2008 Apr;93(4):1217-23 doi: 10.1210/ jc.2007-2490
79. Volpe SL, Leung MM, Giordano H. Vitamin K supplementation does not significantly impact bone mineral density and biochemical markers of bone in pre- and perimenopausal women. Nutr Res. 2008 Sep;28(9):577-82 doi: 10.1016/j.nutres.2008.06.006
80. Ozuru R, Sugimoto T, Yamaguchi T, Chihara K. Time-dependent effects of vitamin K2 (menatetrenone) on bone metabolism in postmenopausal women. Endocr J. 2002 Jun;49(3):363-70
81. Shiraki M, Itabashi A. ‘Short-term menatetrenone therapy increases γ-carboxylation of osteocalcin with a moderate increase of bone turnover in postmenopausal osteoporosis: a randomised prospective study’. J Bone Miner Metab. 2009; 27(3): 333-40 doi: 10.1007/s00774-008-0034-6 82. Koitaya N, Sekiguchi M, Tousen Y, Nishide Y, Morita A, Yamauchi J,
Gando Y, Miyachi M, Aoki M, Komatsu M, Watanabe F, Morishita K, Ishimi Y. Low-dose vitamin K2 (MK-4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women. J Bone Miner Metab. 2014 Mar;32(2):142-50. doi: 10.1007/s00774-013-0472-7
83. Shea MK, Booth SL. Update on the role of vitamin K in skeletal health. Nutr Rev, 2008; 66(10): 549-557 doi: 10.1111/j.1753-4887.2008.00106.x. 84. Szulc P, Chapuy MC, Meunier PJ, Delmas PD. ‘Serum undercarboxylated
osteocalcin is a marker of the risk of hip fracture in elderly women’. J Clin Invest. 1993; 91(4): 1769-74 doi:10.1172/JCI116387
85. Tamatani M, Morimoto S, Nakajima M, Fukuo K, Onishi T, Kitano S et al. ‘Decreased circulating levels of vitamin K and 25-hydroxyvitamin D in osteopenic elderly men’. Metabolism. 1998; 47(2): 195-9 1997; DOI: 10.1016/S0026-0495(98)90220-7
86. Sato Y, Honda Y, Kaji M, Asoh T, Hosokawa K, Kondo I, Satoh K. Amelioration of osteoporosis by menatetrenone in elderly female Parkinson’s disease patients with vitamin D deficiency. Bone. 2002 Jul;31(1):114-8 DOI: 10.1016/S8756-3282(02)00783-4
87. Hiruma Y, Nakahama K, Fujita H, Morita I. ‘Vitamin K2 and geranylgeraniol, its side chain component, inhibited osteoclast formation in a different manner’. Biochem Biophys Res Commun. 2004; 314(1): 24-30 doi:10.1016/j.bbrc.2003.12.051
88. Hartwell D, Riis BJ, Christiansen C. Comparison of vitamin D metabolism in early healthy and late osteoporotic postmenopausal women. Calcif Tissue Int. 1990 Dec;47(6):332-7. DOI 10.1007/BF02555883 89. Martini LA, Booth SL, Saltzman E, do Rosário Dias de Oliveira
Latorre M, Wood RJ. Dietary phylloquinone depletion and repletion in postmenopausal women: effects on bone and mineral metabolism. Osteoporos Int. 2006;17(6):929-35 DOI 10.1007/s00198-006-0086-1 90. Jiang Y, Zhang ZL, Zhang ZL, Zhu HM, Wu YY, Cheng Q, Wu FL, Xing
XP, Liu JL, Yu W, Meng XW. Menatetrenone versus alfacalcidol in the treatment of Chinese postmenopausal women with osteoporosis: a multicenter, randomized, double-blinded, double-dummy, positive drug-controlled clinical trial. Clin Interv Aging. 2014;9:121-7 doi: 10.2147/CIA. S54107
91. Bolton-Smith C, McMurdo ME, Paterson CR, Mole PA, Harvey JM, Fenton ST et al. ‘Two-year randomised controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of
older women’. J Bone Miner Res. 2007; 22(4): 509-19 DOI: 10.1359/ jbmr.070116
92. Takahashi M, Naitou K, Ohishi T, Kushida K, Miura M. Effect of vitamin K and/or D on undercarboxylated and intact osteocalcin in osteoporotic patients with vertebral or hip fractures. Clin Endocrinol (Oxf). 2001 Feb;54(2):219-24 DOI: 10.1046/j.1365-2265.2001.01212.x
93. Orimo H, Shiraki M, Fujita T, Onomura T, Inoue T, Kushida K. Clinical evaluation of menatetrenone in the treatment of involutional osteoporosis: a double-blind multi-center comparative study with 1a-hydroxy-vitamin D3. J Bone Miner Res. 1992; 7 (Suppl 1): S122
94. El Khassawna T, Böcker W, Govindarajan P, Schliefke N, Hürter B, Kampschulte M, Schlewitz G, Alt V, Lips KS, Faulenbach M, Möllmann H, Zahner D, Dürselen L, Ignatius A, Bauer N, Wenisch S, Langheinrich AC, Schnettler R, Heiss C. Effects of multi-deficiencies-diet on bone parameters of peripheral bone in ovariectomized mature rat. PLoS One. 2013 Aug 16;8(8):e71665 doi: 10.1371/journal.pone.0071665
95. Iwamoto J, Yeh JK, Takeda T, Sato Y. ‘Comparative effects of vitamin K and vitamin D supplementation on calcium balance in young rats fed normal or low calcium diets’. J Nutr Sci Vitaminol (Tokyo). 2005; 51(4): 211-5
96. Booth SL, Golly I, Sacheck JM, Roubenoff R, Dallal GE, Hamada K, Blumberg JB. ‘Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status’. Am J Clin Nutr. 2004; 80(1): 143-8 97. Uematsu T, Nagashima S, Niwa M, Kohno K, Sassa T, Ishii M, Tomono Y, Yamato C, Kanamaru M. Effect of dietary fat content on oral bioavailability of menatetrenone in humans. J Pharm Sci. 1996 Sep;85(9):1012-6 DOI: 10.1021/js9600641
98. Ehara Y, Takahashi H, Hanahisa Y, Yamaguchi M. Effect of vitamin K2 (menaquinone-7) on bone metabolism in the femoral-metaphyseal tissues of normal and skeletal-unloaded rats: enhancement with zinc. Res Exp Med. 1996; 196: 171-178 DOI 10.1007/BF02576839
99. Ma ZJ, Igarashi A, Yamakawa K, M, Yamaguchi M. J Health Sci, 2001; 47: 40-45
100. Proudfoot D, Shanahan CM. Molecular mechanisms mediating vascular calcification: role of matrix Gla protein. Nephrology (Carlton). 2006 Oct;11(5):455-61 DOI: 10.1111/j.1440-1797.2006.00660.x
101. Wallin R, Schurgers L, Wajih N. ‘Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification’. Thromb Res. 2008; 122(3): 411-7 doi: 10.1016/j.thromres.2007.12.005
102. Vermeer C, Knapen MHJ, Schurgers LJ. ‘Vitamin K and metabolic bone disease’. J Clin Pathol. 1998; 51: 424-426
103. Hara K, Akiyama Y, Nakamura T, Murota S, Morita I. ‘The inhibitory effect of vitamin K2 (menatetrenone) on bone resorption may be related to its side chain’. Bone. 1995; 16(2): 179-84 DOI: 10.1016/8756-3282(94)00027-W
104. Yamaguchi M, Uchiyama S, Tsukamoto Y. ‘Inhibitory effect of
menaquinone-7 (vitamin K2) on the bone-resorbing factors-induced bone resorption in elderly female rat femoral tissues in vitro’. Mol Cell Biochem. 2003; 245(1-2): 115-20 DOI 10.1023/A:1022818111655
105] Al Rajabi A, Booth SL, Peterson JW et al. Deuterium-labeled phylloquinone has tissue-specific conversion to menaquinone-4 among Fischer 344 male rats. J Nutr 2012; 142: 841–845 doi: 10.3945/ jn.111.155804
106] Miyake N, Hoshi K, Sano Y, Kikuchi K, Tadano K, Koshihara Y. 1,25-Dihydroxyvitamin D3 promotes vitamin K2 metabolism in human osteoblasts. Osteoporos Int. 2001;12:680–687 DOI 10.1007/ s001980170068
107. Braam LA, Hoeks AP, Brouns F, Hamulyák K, Gerichhausen MJ, Vermeer C. Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Thromb Haemost. 2004 Feb;91(2):373-80 doi: 10.1160/TH03-07-0423 108. Fraser JD, Price PA. Induction of matrix Gla protein synthesis during
prolonged 1,25- dihydroxyvitamin D3 treatment of osteosarcoma cells. Calcif Tissue Int 1990; 46: 270-9 DOI 10.1007/BF02555007
109. Vermeer K, Shearer MJ, Zittermann A, Bolton-Smith C, Szulc P, Hodges S et al. Beyond deficiency: Potential benefits of increased intakes of vitamin K for bone and vascular health. Eur J Nutr. 2004; 43: 325-335 DOI 10.1007/s00394-004-0480-4
110. Gundberg CM, Lian JB, Booth SL. Vitamin K-dependent carboxylation of osteocalcin: friend or foe? Am Soc Nutr. 2012; 3: 149-157 doi: 10.3945/ an.112.001834
111. Booth SL. Roles for vitamin K beyond coagulation. Annu Rev Nutr. 2009; 29: 89-110 doi: 10.1146/annurev-nutr-080508-141217.
112. Asakura H, Myou S, Ontachi Y, Mizutani T, Kato M, Saito M, Morishita E, Yamazaki M, Nakao S. Vitamin K administration to elderly patients with osteoporosis induces no hemostatic activation, even in those with suspected vitamin K deficiency. Osteoporos Int. 2001 Dec;12(12):996-1000 DOI 10.1007/s001980170007
114. Shearer MJ, Newman P. Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis. J Lipid Res 2014; 55:345–362 doi: 10.1194/jlr.R045559 115. Schurgers LJ, Shearer MJ, Hamulyák K, Stöcklin E, Vermeer C. Effect
of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in healthy subjects. Blood. 2004 Nov 1;104(9):2682-9 doi 10.1182/blood-2004-04-1525
