ArticlePDF AvailableLiterature Review

The Synergistic Interplay between Vitamins D and K for Bone and Cardiovascular Health: A Narrative Review

  • Medical University of Graz & Specialist Clinic for Rehabilitation Bad Gleichenberg, Bad Gleichenberg - AUSTRIA

Abstract and Figures

Vitamins D and K are both fat-soluble vitamins and play a central role in calcium metabolism. Vitamin D promotes the production of vitamin K-dependent proteins, which require vitamin K for carboxylation in order to function properly. The purpose of this review is to summarize available evidence of the synergistic interplay between vitamins D and K on bone and cardiovascular health. Animal and human studies suggest that optimal concentrations of both vitamin D and vitamin K are beneficial for bone and cardiovascular health as supported by genetic, molecular, cellular, and human studies. Most clinical trials studied vitamin D and K supplementation with bone health in postmenopausal women. Few intervention trials studied vitamin D and K supplementation with cardiovascular-related outcomes. These limited studies indicate that joint supplementation might be beneficial for cardiovascular health. Current evidence supports the notion that joint supplementation of vitamins D and K might be more effective than the consumption of either alone for bone and cardiovascular health. As more is discovered about the powerful combination of vitamins D and K, it gives a renewed reason to eat a healthy diet including a variety of foods such as vegetables and fermented dairy for bone and cardiovascular health.
This content is subject to copyright. Terms and conditions apply.
Review Article
The Synergistic Interplay between Vitamins D and K for Bone and
Cardiovascular Health: A Narrative Review
Adriana J. van Ballegooijen,
Stefan Pilz,
Andreas Tomaschitz,
Martin R. Grübler,
and Nicolas Verheyen
Department of Health Sciences, Vrije Universiteit Amsterdam and the Amsterdam Public Health Research Institute,
Amsterdam, Netherlands
Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
Department of Epidemiology and Biostatistics, VU University Medical Center and the Amsterdam Public Health Research Institute,
Amsterdam, Netherlands
Bad Gleichenberg Clinic, Bad Gleichenberg, Austria
Department of Cardiology, Swiss Cardiovascular Center Bern, Bern University Hospital, University of Bern, Bern, Switzerland
Department of Cardiology, Medical University of Graz, Graz, Austria
Correspondence should be addressed to Adriana J. van Ballegooijen;
Received 2 June 2017; Accepted 17 August 2017; Published 12 September 2017
Academic Editor: Constantinos Pantos
Copyright © 2017 Adriana J. van Ballegooijen et al. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work
is properly cited.
Vitamins D and K are both fat-soluble vitamins and play a central role in calcium metabolism. Vitamin D promotes the production
of vitamin K-dependent proteins, which require vitamin K for carboxylation in order to function properly. The purpose of this
review is to summarize available evidence of the synergistic interplay between vitamins D and K on bone and cardiovascular
health. Animal and human studies suggest that optimal concentrations of both vitamin D and vitamin K are benecial for bone
and cardiovascular health as supported by genetic, molecular, cellular, and human studies. Most clinical trials studied vitamin D
and K supplementation with bone health in postmenopausal women. Few intervention trials studied vitamin D and K
supplementation with cardiovascular-related outcomes. These limited studies indicate that joint supplementation might be
benecial for cardiovascular health. Current evidence supports the notion that joint supplementation of vitamins D and K might
be more eective than the consumption of either alone for bone and cardiovascular health. As more is discovered about the
powerful combination of vitamins D and K, it gives a renewed reason to eat a healthy diet including a variety of foods such as
vegetables and fermented dairy for bone and cardiovascular health.
1. Introduction
Worldwide, a large group of people is prescribed to a sup-
plemental regime of both vitamin D and calcium. In
Europe, depending on a country and sex, between 1 and
66% of the adult population use vitamin D supplements
[1, 2]. Over the last decade, large vitamin D supplementa-
tion is promoted to restore 25-hydroxyvitamin D
(25(OH)D) concentrations and is considered to be safe
with doses up to 4000 international units (IU) per day
[3]. However, little is known about potential long-term
high-dose vitamin D supplementation [2, 4].
Vitamin D is a fat-soluble vitamin that can be ingested by
foods such as fatty sh, dairy products, and eggs, but is
mainly synthesized by the human skin when exposed to
sunlight. In the liver, vitamin D is hydroxylated to
25(OH)D, the main circulating vitamin D metabolite that is
measured to assess and classify vitamin D status. Circulating
25(OH)D is further metabolized by the kidney for full biolog-
ical activity into its most active form 1,25-dihydroxyvitamin
D (1,25(OH)D) also known as calcitriol. Calcitriol is also
produced endogenously by extrarenal production through
peripheral 1-α-hydroxylase and has positive eects on
immune function and anticancer activity [57]. Vitamin D
International Journal of Endocrinology
Volume 2017, Article ID 7454376, 12 pages
plays a main role in regulating calcium metabolism by
increasing intestinal calcium absorption [8]. Ample evidence
recommends vitamin D supplementation for the prevention
of falls and fractures [9, 10]; however, evidence suggests
calcium precipitation in the vasculature and other potential
side eects [4, 1114].
Vitamin K is another fat-soluble vitamin that exists in
two forms of vitamin K: vitamin K
(phylloquinone, mainly
found in green leafy vegetables) and vitamin K
none, mainly found in fermented dairy and produced by
lactic acid bacteria in the intestine) [15]. Vitamin K stores
are limited, but they can be recycled to a certain extent
[16]. Vitamin K
is principally transported to the liver, regu-
lating the production of coagulation factors, while vitamin K
is transported to extrahepatic tissues, such as bone and the
vascular wall, regulating the activity of matrix Gla protein
(MGP) and osteocalcin (bone Gla protein)the main
vitamin K-dependent proteins. They require vitamin K for
carboxylation in order to function properly. When circulat-
ing concentrations of vitamin K are insucient, a greater
proportion of MGP and osteocalcin remain uncarboxylated,
which is associated with unfavorable outcomes such as
cardiovascular disease, lower BMD, and osteoporosis [17].
The current recommendation for vitamin K
intake is
70 μg/day for all adults dened by an adequate intake [18].
This amount is solely based on maintaining coagulation
function and might not be enough for optimal carboxylation
of other vitamin K-dependent proteins, which require higher
amounts of vitamin K [19].
The role of vitamin K in cardiovascular health has mainly
been studied in isolation [20]; however, a growing body of
evidence suggests a synergistic eect of vitamin K combined
with vitamin D [2126]. Vitamin D promotes the production
of vitamin K-dependent proteins, as shown in rats by Karl
et al. already in 1985 [27]. These ndings cannot be explained
by our current understanding of the biochemical role of
vitamin K, but suggest that vitamin D may inuence vitamin
K-dependent proteins [28].
The purpose of this narrative review is to summarize
available evidence in the eld of the synergistic interplay
between vitamins D and K on bone and cardiovascular
health. The primary focus is on the general population and
includes observational studies that investigated both vitamin
D and vitamin K status with outcome measures and supple-
mentation studies that administered both vitamins D and K.
2. Interaction of Vitamins D and K for
Bone Health
2.1. Experimental Studies. In experimental models, the explo-
ration of the interaction between vitamins D and K on
bone health is ongoing for decades and a fair amount of
literature is available. Recent understanding suggests that
vitamin D enhances vitamin K-dependent bone protein con-
centrations and induces bone formation in vitro [2931] with
stimulation of osteoblast-specic gene expression [32].
Osteoblast-specic expression of osteocalcin is controlled at
the transcriptional level by 1,25(OH)D through the
1,25(OH)D-responsive element within the promoter of the
osteocalcin gene [32]. The underlying mechanism of mineral-
ization induced by vitamin K in the presence of 1,25(OH)D
was dierent from vitamin K alone [33]. In rats, 1,25(OH)D
receptor binding can undergo gamma-carboxylation in the
presence of vitamin K. This means that 1,25(OH)D receptor
carboxylation can potentially modify the intrinsic biochemi-
cal properties of the nuclear receptors and modulates its bind-
ing to DNA [34].
The eect of 1,25(OH)D and warfarina vitamin K
antagoniston the vitamin K cycle was studied in cultured
osteoblasts [26]. Epoxide reductase, one of the key enzymes
in the vitamin K cycle, was strongly inhibited by warfarin,
whereas it was not aected by 1,25(OH)D, meaning that
the vitamin K metabolic cycle functions normally in human
Human osteoblast cell cultures indicate that glycoxida-
tion interferes with the maturation of osteoblasts; however,
this process may be counterbalanced by adding vitamins D
and K, which reverses the detrimental glycoxidation on sev-
eral bone markers [35]. Therefore, the addition of vitamins
D and K may induce important biochemical changes in bone,
which may exert therapeutic eects on bone metabolic
diseases such as osteoporosis [36].
2.2. Animal Models. A growing body of evidence is also doc-
umenting the interaction between vitamins D and K in ani-
mal models. The eect of vitamin K of bone mineralization
is enhanced by plasma 25(OH)D concentration. Vitamin K
was administered to prevent osteoporosis in ovariecto-
mized rats, but bone loss was only prevented in rats fed
with a diet containing vitamin D or vitamin D supplemen-
tation [37, 38]. These ndings suggest that combined
treatment with vitamins D and K is more eective than
vitamin K alone particularly in the early phase of estrogen
deciency after menopause.
Vitamin K and vitamin D supplementation on calcium
balance was investigated in young rats fed with a normal or
low calcium diet, plus vitamin K and/or vitamin D [39].
Vitamin K supplementation promoted the reduction in
urinary calcium excretion and stimulated intestinal calcium
absorption in rats on a normal calcium diet. Vitamin D
supplementation stimulated intestinal calcium absorption
with prevention of the abnormal elevation of serum PTH
concentrations, prevented hypocalcemia in rats fed with a
low calcium diet, and stimulated intestinal calcium absorp-
tion in rats fed with a normal calcium diet. The stimula-
tion of intestinal calcium absorption was associated with
increased 1,25(OH)D concentrations. An additive eect
of vitamin K and vitamin D on intestinal calcium absorption
was only found in rats fed with a normal calcium diet. This
study shows the dierential eects of vitamin K and vitamin
D supplementation on calcium balance in young rats fed with
a normal or low calcium diet.
2.3. Observational Evidence. Human evidence for the role of
1,25(OH)D in stimulating vitamin K-dependent proteins is
scarce. In hemodialysis patients, vitamin D analog users
had much higher concentrations of bone Gla protein (BGP)
than nonusers indicating that vitamin D administration
2 International Journal of Endocrinology
may play a role in stimulating vitamin K-dependent protein
activity [40]. More research on the stimulating role of vita-
min D on vitamin K-dependent proteins is urgently needed
to study the underlying mechanisms.
Some observational studies support the hypothesis that
optimal concentrations of both vitamins D and K support
bone mineralization and lower fracture risk. In a cross-
sectional study among Japanese older men, lower 25(OH)D
and vitamin K
concentrations were concomitantly associ-
ated with BMD, indicating a nonestrogen-dependent path-
way in men [41]. In a case-control study of 184 Norwegian
older adults, the combination of low vitamin K
and low
25(OH)D was synergistically associated with hip fractures:
odds ratio 7.6 (95% CI 2.3, 26.7) [42]. In the NOREPOS
study, another Norwegian population study, similar results
were observed among 1318 older adults [43]. During 8.2-year
follow-up, the combination of both low vitamin D and K
concentrations was associated with a greater hip fracture
risk, hazard ratio 1.41 (95% CI 1.09, 1.82), compared to
the high vitamin D and vitamin K category. No increased
risk was observed in the groups low in 1 vitamin only.
These results indicate that the combination of low concen-
trations of vitamin K
and 25(OH)D is associated with
increased risk of hip fractures.
2.4. Human Intervention Studies. A small study among 15
healthy women indicated that 3 weeks of supplementation
of 20 ml extra virgin olive oil enriched with vitamins D, K,
and B
resulted in lower concentrations of uncarboxylated
osteocalcin [44]. This means that a vitaminized oil can inu-
ence vitamin K-dependent proteins within multiple weeks.
An increasing amount of randomized controlled trials
have demonstrated the combined eects of vitamins D
and K on postmenopausal osteoporosis mostly pursued in
Japan with a study duration between 8 weeks and 3 years
(Table 1). A randomized trial with 4 arms (diet, menaqui-
none-4, cholecalciferol, and menaquinone-4 + cholecalcif-
erol) showed that only the vitamin K plus vitamin D
arm increased BMD [45]. Similar results were found in
another trial with postmenopausal women with osteoporo-
sis 5 years after menopause [46]. After 2 years of follow-up,
the longitudinal changes in BMD were signicant com-
pared with those in the calcium lactate-, vitamin D-, and
vitamin K-only groups (P<0001). A modest synergistic
eect of vitamins D and K was found after 2 years in
healthy older women from nutritionally relevant intakes
of vitamin K
together with supplements of calcium plus
vitamin D
on bone mineral concentration compared to
either vitamin D or K alone or placebo [47]. The comple-
mentary eect of vitamin K
(1 mg/day) and a mineral +
vitamin D supplement (8 μg/day) was most eective in
reducing bone loss at the femoral neck after 3 years
among postmenopausal women versus vitamin D alone
or placebo [48]. The addition of vitamin K to vitamin D
and calcium supplements compared to vitamin D and cal-
cium alone in postmenopausal Korean women increased
BMD and reduced uncarboxylated osteocalcin concentra-
tions after 6 months compared to vitamin D and calcium
alone [49]. In postmenopausal women, 1 year of oral
supplementation with extra virgin olive oil enriched with
vitamins D
, and B
or extra virgin olive oil reduced
uncarboxylated osteocalcin concentrations and increased
the T-score of BMD [50]. These ndings indicate that
combined administration of vitamin D and vitamin K
appears to be useful in increasing BMD in postmenopausal
women. It should be noted that these studies found bene-
cial eects at some but not all BMD sites measured.
Furthermore, treatment with vitamins D and K with
calcium increased BMD in older female patients with
Alzheimers disease and led to the prevention of nonvertebral
fracture odds ratio: 7.5 (95% CI 5.6, 10.1); however, no
placebo capsules were administered, hampering the inter-
pretation of the results [51].
Not all studies observed synergistic eects of vitamin D
and K supplementation. A small study among adults with
Crohns disease in Ireland showed generally no eect of com-
bined vitamin D and K supplementation versus placebo on
bone mass after 1 year, except a modest increase in bone mass
of the total radius [52]. Among healthy women, 1 year of
vitamin D and calcium + vitamin K supplementation either
by phylloquinone or menaquinone-4 supplementation had
no eect on BMD compared to calcium and vitamin D alone
[53]. This study does not support a combined role for vita-
min D + K supplementation in osteoporosis prevention;
however, the relatively short study duration and the inclusion
of healthy women could explain the null nding. It is how-
ever questionable if BMD can be improved in 12 months
since changes in BMD usually require at least 1 year of
follow-up time.
Among healthy older men and women, no dierence
was observed between multivitamin and calcium and
vitamin D compared with the addition of vitamin K on
BMD after 3 years [19]. An additive eect was noticeable
for decreased percentage of uncarboxylated osteocalcin,
which indicates an improved vitamin K status in the
treatment group.
The ECKO trial among postmenopausal women with
osteopenia showed no benecial eect of vitamin D and
calcium +vitamin K supplementation versus vitamin D and
calcium alone after 2 years of follow-up in vitamin D-
sucient women [54]. However, the risk of fracturesa
clinically more meaningful endpointwas lower in the vita-
min D and calcium + vitamin K groups: hazard ratio 0.41 (95
CI 0.1, 1.18) at 2 years and 0.45 (95% CI 0.20, 0.98) after 4
years of follow-up. This result on fracture risk indicates that
bone quality rather than quantity is more important as not
all trials showed synergistic eects of vitamin D and K
supplementation on bone mineral density.
The protective eect of vitamin D with K on
prednisolone-induced loss of BMD in patients with chronic
glomerulonephritis after 8 weeks of treatment was similar
in the vitamin D-only group [55], meaning that the addition
of vitamin K had no synergistic eect. The elevation in serum
calcium concentrations in the vitamin D group was, however,
attenuated in the vitamin D + K group.
Taken together the evidence for combined vitamin D and
K supplementation, the majority of the studies found bene-
cial eects for BMD among postmenopausal women.
3International Journal of Endocrinology
Table 1: Summary of clinical trials of combined vitamin D and K supplementation on bone health.
Author, year Country Participants Treatment Study
duration Outcome Results for the highest versus
the lowest quartiles
Iwamoto et al.,
2000 [46] Japan
women 5 years after
menopause, mean
age 64 years
(i) Calcium (calcium lactate, 2 g/day)
(ii) Vitamin D
0.75 μg/day
(iii) Vitamin K
45 mg/day
(iv) Vitamin D
plus vitamin K
2 years Bone mineral density
% change
Combined vitamins
D and K increased BMD
Ushiroyama et al.,
2002 [45] Japan
N= 126 postmenopausal
women with osteopenia
and osteoporosis,
mean age 53 years
(i) Diet
(ii) Vitamin K
45 mg/day MK-4
(iii) 1-αhydroxylcholecalciferol 1 μg/day
(iv) Vitamin K
2 years Bone mineral density
% change
K + D group increased BMD %
change at 2 years P<0 001
Braam et al.,
2003 [48] Netherlands
N= 155 postmenopausal women
between 50
and 60 years
(i) Placebo
(ii) Mineral + vitamin D (8 μg/day)
(iii) Mineral + vitamin D + vitamin K
3 years Bone loss
Mineral + vitamin D + vitamin K
showed reduced bone loss of
the femoral neck
Yonemura et al.,
2004 [55] Japan
N=60patients with
chronic glomerulonephritis,
mean age 32 years, 53% female
(i) Control
(ii) Vitamin D (alfacalcidol 0.5 mg)
(iii) Vitamin K
MK-4 45 mg/d
(iv) Vitamins D plus K
8 weeks Bone mineral density The preventive eect in groups
K and D + K was similar to D
Sato et al.,
2005 [51] Japan
N= 200 older women with
Alzheimers disease, mean
age 78 years
(i) Placebo
(ii) 45 mg menatetrenone, 1000 IU
ergocalciferol, and 600 mg calcium
2 years Bone mineral density
and fractures
BMD increased in vitamin
D + K group
Odds ratio nonvertebral fractures
7.5 (95% CI 5.6, 10.1)
et al., 2007 [47] UK N= 244 healthy women,
mean age 68 years
(i) Placebo
(ii) 200 mg/d vitamin K
(iii) 400 IU vitamin D
+ 1000 mg calcium
(iv) Vitamins K
and D
plus calcium
2 years Bone mineral content
Combined vitamin K with vitamin
D plus calcium associated with an
increase in bone mineral content
at the ultradistal radius
Booth et al.
2008 [19] US
N= 401 healthy men and
women, mean age 69,
59% female
(i) Multivitamin + 10 μg vitamin
D and 600 mg calcium
(ii) Multivitamin + vitamin D +
calcium + 500 μg vitamin K
3 years Bone mineral density
No dierences in change in BMD
Vitamin D + K group lower
uncarboxylated osteocalcin
Cheung et al.,
2008 [54] Canada
N= 440 postmenopausal
women with osteopenia,
mean age 59 years
(i) 1500 mg calcium + 800 IU vitamin D
(ii) 5 mg of vitamin K
+ calcium and
vitamin D
24 years Bone mineral density No eect on BMD
Binkley et al.,
2009 [53] US N= 381 postmenopausal women,
mean age 62 years
(i) Calcium 315 mg + vitamin D
200 IU
(ii) Phylloquinone 1 mg + calcium and
vitamin D
(iii) MK-4 (45 mg day) + calcium and
vitamin D
1 year Bone mineral density No eect on BMD
Je et al., 2011 [49] South
N=78Korean postmenopausal
women, mean age 68 years
(i) Vitamin D 400 IU + calcium (630 mg)
(ii) Vitamin D + calcium +45 mg of
vitamin K
6 months Bone mineral density BMD increased signicantly in
the vitamin D + K group
4 International Journal of Endocrinology
Table 1: Continued.
Author, year Country Participants Treatment Study
duration Outcome Results for the highest versus
the lowest quartiles
OConnor et al.,
2014 [52] Ireland N=46adults with Crohns
disease, mean age 45 years
(i) Placebo
(ii) Phylloquinone 1 mg, vitamin D 10 μg,
and calcium 500 mg/d
1 year Bone mineral density Small eect on BMD of the
total radius for vitamin D +K group
Mazzanti et al.,
2015 [50] Italy 60 healthy postmenopausal
women, mean age 55 years
(i) Extra virgin olive oil
(ii) Extra virgin olive oil enriched with
vitamins D
, and B
1 year Bone mineral density Vitaminized oil D, K, and B
increased the T-score of BMD
BMD: bone mineral density; MK-4: menaquinone-4.
5International Journal of Endocrinology
3. Interaction between Vitamins D and K for
Cardiovascular Health
Besides bone health, also, the interaction between vitamins
D and K with regard to cardiovascular health receives
growing research interest. MGPthe vascular marker of
vitamin K statusneeds γ-glutamate carboxylation to
inhibit vascular calcication [56]. In an experimental rat
model, warfarin was administered to induce vitamin K
deciency and caused arterial calcication [57], which
was accelerated when given toxic doses of vitamin D and
resulted in premature death.
The Czech MONICA study cross-sectionally observed
that subjects in the highest quartile of dephosphorylated-
uncarboxylated MGP (dp-ucMGP) plus the lowest quartile
of 25(OH)D concentrations had the highest pulse wave
velocity in middle-aged healthy adults [58]. Further, poten-
tial interaction between vitamin K status and polymorphisms
of the vitamin D receptors was investigated. Pulse wave
velocity was higher with the number of G-allele polymor-
phisms and highest in the top quartile of dp-ucMGP for the
GG vitamin D receptor genotype.
A Dutch prospective cohort indicates that the combina-
tion of low vitamin D <50 mmol/L and low K status 323 m-
mol/L dp-ucMGP was associated with increased systolic and
diastolic blood pressures and incident hypertension after 6
years of follow-up [59]. Up to now, no study investigated
the combination of optimal vitamin D and K status in rela-
tion to coronary artery calcication and cardiovascular
events after long-term follow-up. This would give valuable
insight if vitamins D and K are involved in developing car-
diovascular disease.
So far, two human intervention studies in healthy popu-
lations have investigated the combined eect of vitamins D
and K on vascular function and calcication (Table 2) [60,
61]. In postmenopausal women, after 3 years of supplemen-
tation (1000 μg/d vitamin K
+ 320 IU vitamin D), the vita-
min D + K group maintained vessel wall characteristics of
the carotid artery, whereas the control group and the vitamin
D-only group signicantly worsened over 3 years of follow-
up [60]. However, vitamin K status was not measured as a
marker of compliance to investigate what would have
occurred following supplementation. Further, in a 3-year,
double-blind, randomized controlled trial in older men and
women free of clinical CVD, daily supplemental vitamin K
in amounts achievable by high dietary intake of green, leafy
vegetables (500 μg/day) combined with 600 mg calcium car-
bonate and 10 μg (400 IU) vitamin D did not result in lower
coronary artery calcium progression as assessed by comput-
erized tomograph y compared to the calcium + vitamin D
group. In a subgroup analysis of participants who were
85% adherent to supplementation, there was less coronary
artery calcium progression in the vitamin K + calcium and
vitamin D groups than in the calcium and vitamin D group
alone [61]; however, MGP carboxylation status was not
determined. These data are hypothesis generating, and fur-
ther studies are warranted to clarify the mechanism.
Among overweight type 2 diabetic patients with coronary
heart disease, cosupplementation for 12 weeks of vitamins D
(10 μg) and K (180 μg) and calcium (1000 mg) had benecial
eects on maximum levels of left carotid intima-media thick-
ness and insulin metabolism markers [62]; however, no eect
on right intima-media thickness was found and the results
could be a chance nding. Unfortunately, circulating markers
of vitamin K concentrations and vitamin K-dependent
proteins were not taken into account to get a better mechanis-
tic understanding.
Two trials studied the eect of vitamin D versus vitamin
D + K in nondialyzed CKD patients on vascular calcication
and cardiovascular risk factors for 9 months [63, 64]. In 42
CKD patients, the increase in carotid intima-media thickness
(IMT) was signicantly lower in the K (90 μg menaquinone-
7) + D (10 μg vitamin D) group compared with the D-only
group after 9 months [63]. Another small trial (n=38) from
the same research group did not show dierences between
the D versus D + K groups on cardiovascular risk markers
[64]. These few studies show some potential for the com-
bined eect of vitamins D + K versus D alone on subclinical
CVD risk markers. It should be noted that very few clinical
studies have been conducted in this eld and that vitamin
D + K supplements have been often combined with dierent
micronutrients making it dicult to solely pinpoint the eect
of vitamin D + K. These limited studies indicate that joint
supplementation might benet cardiovascular health.
4. Vitamins D and K with Glucose Metabolism
and Inflammation
Another pathway that might aect CVD risk is via disturbances
in glucose metabolism. Among Iranian vitamin D-decient
women with polycystic ovary syndromea dysmetabolic
disordercosupplementation of calcium (1000 mg) and vita-
mins D (400 IU) and K (180 μg) for 8 weeks improved
markers of insulin metabolism and lipid concentrations com-
pared to placebo [65]. The joint supplementation of vitamins
D and K might improve insulin metabolism through an eect
on upregulation of the insulin receptor genes, the regulation
of insulin secretion from the pancreatic beta-cell, the
enhancement of β-cell proliferation, and suppression of
parathyroid hormone [6669].
Further, another feature in which both vitamins D and
K overlap is on inammation, which is strongly related to
the development of CVD and osteoporosis [70]. In the same
Iranian clinical trial among vitamin D-decient women
with polycystic ovary syndrome, the joint supplementation
of calcium with vitamins D and K had benecial eects
on endocrine and oxidative stress markers, however no
eect on inammatory markers [71].
5. Effects of Long-Term Vitamin D
A large group of people uses both vitamin D and calcium for
the prevention of falls and fractures. Given the fact that
25(OH)D is converted to 1,25(OH)D, vitamin D supplemen-
tation stimulates the production of 1,25(OH)D [72]. This
means that long-term vitamin D supplementation could
promote the production of large amounts of vitamin K-
6 International Journal of Endocrinology
Table 2: Summary of clinical trials of combined vitamin D and K supplementation on cardiovascular health and disease.
Author, year Country Participants Treatment Study
duration Outcome Results for the highest versus
the lowest quartiles
Braam et al.,
2004 [60] Netherlands N= 181 postmenopausal women,
means age 55, 100% female
(i) Placebo
(ii) Minerals + 8 μg vitamin D
(iii) Minerals + 8 μg vitamin D
+ 1 mg vitamin K
3 years Vessel wall
MDK group unchanged, placebo and
minerals + vitamin D decreased
elastic properties
Shea et al.,
2009 [61] US N= 388 healthy men and postmenopausal
women, mean age 66 y, 60% female
(i) Multivitamin + 10 μg vitamin
D and 600 mg calcium
(ii) Multivitamin + vitamin D +
calcium + 500 μg vitamin K
3 years Coronary artery
No dierence between vitamin K
group and control group
Asemi et al.,
2016 [62] Iran
N=66overweight diabetic patients
with coronary heart disease, mean
age 65 y, 47% female
(i) Placebo
(ii) Vitamin D (10 μg), K (180 μg),
and calcium (1000 mg)
12 weeks Carotid IMT
Lower left carotid intima-media
thickness and improved insulin
metabolism markers
Chronic kidney disease patients
et al., 2015 [63],
2016 [64]
Poland N=42nondialyzed CKD patient stages,
mean age 60 y, 35, 45% female
(i) 10 μg cholecalciferol
(ii) 10 μg cholecalciferol +
90 μg MK-7
270 days Carotid IMT Reduced progression IMT, reduced
dp-ucMGP and osteocalcin
IMT: intima-media thickness; dp-ucMGP: dephosphorylated-uncarboxylated matrix Gla protein; MK-7: menaquinone-7.
7International Journal of Endocrinology
dependent proteins, which remain inactive because there is
not enough vitamin K to carboxylate (Figure 1). We propose
a new hypothesis that if vitamin D concentrations are
constantly high, there might not be enough vitamin K for
activation of vitamin K-dependent proteins. Consequently,
excess vitamin D diminishes the ability of vitamin K-
dependent proteins to function properly, to stimulate bone
mineralization, and to inhibit soft tissue calcication.
Further, increasing vitamin D intake through dietary or
supplemental source increases intestinal calcium absorption,
particularly when combined with calcium supplementation,
and promotes hypercalcemia [73]. In this context, a human
trial was performed in older women who received either
1200 mg calcium or 1200 mg calcium and 800 IU vitamin D
per day over a 12-week period [74]. At the end of the 12
weeks, neither group observed a change in calcium concen-
trations, meaning that calcium was either excreted or stored
somewhere. Increased calcium intake by itself may not be
problematic as long as there is a steady state between optimal
vitamin D and vitamin K concentrations. The disbalance
between vitamin D and vitamin K promotes an environment
in which excess calcium will be deposited into our vascular
tissue instead of bone. The migration of calcication into
the vascular tissue is described by the double burden of ath-
erosclerosis and osteoporosis [7577]. Additionally, as vita-
min D increases calcium absorption, it might also promote
hypercalcemia as seen in the Womens Health Initiative,
which found a 24% higher risk of myocardial infarction in
individuals taking calcium and vitamin D supplements and
a greater risk for urinary tract stone occurrence: hazard ratio
1.17 (95% CI 1.02, 1.34) [11, 13, 14]. One prospective study
found that higher 1,25(OH)D concentrations were strongly
associated with the incidence of hypertension, while
25(OH)D was inversely associated with hypertension risk
[78]. Higher 1,25(OH)D was associated with lower urinary
calcium excretion, which could mean that the calcium meant
for bone is stored somewhere else. Unfortunately, vitamin K
status was not measured which would have given valuable
insight into the association between vitamins D and K with
calcium excretion.
6. Calciphylaxis and Vitamin K Antagonist Use
Calciphylaxis is a syndrome of calcication of the blood
vessels, coagulopathy, and skin necrosis. It is seen mostly in
patients with end-stage kidney disease, but can occur in the
absence of kidney failure. Vitamin K antagonist use may con-
tribute to its development [79]. The syndrome may cause a
substantial morbidity and mortality. However, it should be
acknowledged that the term calciphylaxis refers to a hetero-
geneous disorder that is characterized by soft tissue and
vascular necrosis and has a clinical presentation from mild
to severe. The underlying causes of calciphylaxis are not well
understood; however, reported risk factors include female
sex, obesity, elevated calciumphosphate product, warfarin
use, and vitamin D derivatives, for example, calcitriol,
calcium-based binders, or systemic steroids, low blood albu-
min concentrations, and type 2 diabetes [80]. A recent study
among patients with hemodialysis with calciphylaxis versus
hemodialysis showed that cases had higher plasma uncar-
boxylated MGP concentrations than controls, which suggest
a role of MGP in the pathophysiology of calciphylaxis. The
fraction of total MGP that was carboxylated was also lower
in cases than in controls. Vitamin K deciency-mediated
reduction in relative carboxylated MGP concentration may
play a role in the pathogenesis of calciphylaxis [81]. This
could be further mediated by the combined use of vitamin
D derivatives and warfarin. Further, another study indi-
cated that vitamin K antagonist use predisposes to the
development of calciphylaxis in end-stage renal disease
[82]. More evidence on the combined role of vitamin K
antagonist use and vitamin D on bone and cardiovascular
health is urgently needed.
7. Vitamin D and K Supplementation
Based on the current body of evidence, there is not
enough evidence to recommend combined vitamin D
and K supplementation for the prevention and treatment
of osteoporosis. Most trials studied low-dose vitamin D
in isolation (400800 IU daily), which demonstrated only
Vitamin K-dependent proteins
1,25-dihyroxyvitamin D
Optimal vitamin K
Fracture risk
So tissue
Vascular calcication
Figure 1: Simplied overview of potential synergy between vitamins D and K and bone and cardiovascular health. dp-ucMGP:
dephosphorylated-uncarboxylated matrix Gla protein: BMD: bone mineral density. Genetic, molecular, cellular, and human evidence
support that optimal concentrations of both vitamin D and vitamin K are benecial for bone and cardiovascular health. Vitamin K is
needed for the carboxylation of vitamin K-dependent proteins such as osteocalcin and matrix Gla protein, while vitamin D promotes the
production of vitamin K-dependent protein concentrations. These vitamin K-dependent proteins are needed for extrahepatic organs such
as the bone and the vascular system. This will result in bone mineralization and will inhibit soft tissue calcication, which will ultimately
lead to lower risks of fractures and coronary heart disease.
8 International Journal of Endocrinology
modest or null eects on BMD and fracture prevention in
mostly 65 years postmenopausal women [68]. Large
clinical trials of moderatehigh dose (800 IU daily)
vitamin D supplementation (cholecalciferol) are currently
in progress.
The most widely used vitamin K form for supplemen-
tation is vitamin K
and more specically menaquinone-4
and menaquinone-7. Menaquinone-4 is more used in trials
with bone outcomes, while menaquinone-7 is more in
trials with cardiovascular outcomes with dosages between
90360 μg. Menaquinone-7 has a higher bioavailability
and may be of particular importance for extrahepatic
tissue [83]. No cut-ovalue for vitamin K status nor
vitamin K supplementation is available yet. Future studies
are needed to determine whether vitamin D combined
with vitamin K rich foods or vitamin K supplementation
could improve bone and cardiovascular health.
8. Recommendations for Future Research
The recommendations for future research are as follows:
(i) Evaluate the role of vitamin D administration in
vitamin K-dependent proteins in human populations
(ii) Question the possible long-term consequences of
high-dose vitamin D supplementation
(iii) Assess the combined role of vitamin K antagonist
use and vitamin D in bone and cardiovascular
(iv) Investigate the joint supplementation of vitamins D
and K on hard clinical endpoints
9. Conclusion
Taken together, animal and human studies suggest that
optimal concentrations of both vitamin D and vitamin K
are benecial for bone and cardiovascular health as sup-
ported by genetic, molecular, cellular, and some human
studies. However, vitamin D and calcium supplementation
along with vitamin K deciency might also induce long-
term soft tissue calcication and CVD, particularly in
vitamin K antagonist users and other high-risk popula-
tions. At this moment, we should be careful about supple-
menting high-dose vitamin D, unless indicated dierently.
More clinical data about the potential interplay between
vitamin D and vitamin K metabolism is urgently needed
before broader treatment recommendations can be given.
The consumption of a well-balanced diet is key for
population-based primary prevention of chronic diseases.
As more is discovered about the powerful combination of
vitamins D and K, it gives a renewed reason to eat a healthy
diet including a variety of foods such as vegetables and
fermented dairy for bone and cardiovascular health.
Conflicts of Interest
The authors declare that there is no conict of interest
regarding the publication of this paper.
[1] G. Skeie, T. Braaten, A. Hjartaker et al., Use of dietary supple-
ments in the European prospective investigation into cancer
and nutrition calibration study,European Journal of Clinical
Nutrition, vol. 63, Supplement 4, pp. S226S238, 2009.
[2] A. Spiro and J. L. Buttriss, Vitamin D: an overview of vitamin
D status and intake in Europe,Nutrition Bulletin, vol. 39,
pp. 322350, 2014.
[3] EFSA Panel on Dietetic Products, NaA, Scientic opinion on
the tolerable upper intake level of vitamin D,EFSA Journal,
vol. 10, p. 2813, 2012.
[4] A. Zittermann, J. B. Ernst, S. Prokop et al., Eect of vitamin D
on all-cause mortality in heart failure (EVITA): a 3-year ran-
domized clinical trial with 4000 IU vitamin D daily,European
Heart Journal, vol. 38, no. 29, pp. 22792286, 2017.
[5] J. S. Adams, B. Rason, S. Witzel et al., Regulation of the
extrarenal CYP27B1-hydroxylase,The Journal of Steroid
Biochemistry and Molecular Biology, vol. 144, Part A, pp. 22
27, 2014.
[6] A. Dusso, A. Brown, and E. Slatopolsky, Extrarenal produc-
tion of calcitriol,Seminars in Nephrology, vol. 14, pp. 144
155, 1994.
[7] H. S. Cross and E. Kallay, Nutritional regulation of extrarenal
vitamin D hydroxylase expression - potential application in
tumor prevention and therapy,Future Oncology, vol. 1,
pp. 415424, 2005.
[8] J. C. Fleet, The role of vitamin D in the endocrinology
controlling calcium homeostasis,Molecular and Cellular
Endocrinology, vol. 17, pp. 3022130226, 2017.
[9] G. Bjelakovic, L. L. Gluud, D. Nikolova et al., Vitamin D sup-
plementation for prevention of mortality in adults,Cochrane
Database of Systematic Reviews, article CD007470, 2014.
[10] A. Avenell, J. C. Mak, and D. O'Connell, Vitamin D and
vitamin D analogues for preventing fractures in post-
menopausal women and older men,Cochrane Database
of Systematic Reviews, article CD000227, 2014.
[11] M. J. Bolland, A. Grey, A. Avenell, G. D. Gamble, and I. R.
Reid, Calcium supplements with or without vitamin D and
risk of cardiovascular events: reanalysis of the Womens
Health Initiative limited access dataset and meta-analysis,
British Medical Journal, vol. 342, article d2040, 2011.
[12] I. Thiele, J. Linseisen, C. Meisinger et al., Associations
between calcium and vitamin D supplement use as well as their
serum concentrations and subclinical cardiovascular disease
phenotypes,Atherosclerosis, vol. 241, pp. 743751, 2015.
[13] D. Challoumas, A. Stavrou, A. Pericleous, and G. Dimitrakakis,
Eects of combined vitamin Dcalcium supplements on the
cardiovascular system: should we be cautious?,Atherosclerosis,
vol. 238, pp. 388398, 2015.
[14] R. B. Wallace, J. Wactawski-Wende, M. J. O'Sullivan et al.,
Urinary tract stone occurrence in the Womens Health Initia-
tive (WHI) randomized clinical trial of calcium and vitamin D
supplements,The American Journal of Clinical Nutrition,
vol. 94, pp. 270277, 2011.
[15] S. L. Booth and A. RajabiAl, Determinants of vitamin K status
in humans,Vitamins and Hormones, vol. 78, pp. 122, 2008.
[16] M. J. Shearer and P. Newman, Recent trends in the metabo-
lism and cell biology of vitamin K with special reference to
vitamin K cycling and MK-4 biosynthesis,Journal of Lipid
Research, vol. 55, pp. 345362, 2014.
9International Journal of Endocrinology
[17] S. A. Lanham-New, Importance of calcium, vitamin D and
vitamin K for osteoporosis prevention and treatment,The
Proceedings of the Nutrition Society, vol. 67, pp. 163176, 2008.
[18] D. Turck, J. L. Bresson, B. Burlingame et al., EFSA panel on
dietetic products, nutrition and allergies. Dietary reference
values for vitamin K,EFSA Journal, vol. 15, p. 4780, 2017.
[19] S. L. Booth, G. Dallal, M. K. Shea, C. Gundberg, J. W. Peterson,
and B. Dawson-Hughes, Eect of vitamin K supplementation
on bone loss in elderly men and women,The Journal of Clin-
ical Endocrinology and Metabolism, vol. 93, pp. 12171223,
[20] A. J. Ballegooijenvan and J. W. Beulens, The role of vitamin K
status in cardiovascular health: evidence from observational
and clinical studies,Current Nutrition Reports, pp. 19, 2017.
[21] X. Fu, X. D. Wang, H. Mernitz, R. Wallin, M. K. Shea, and
S. L. Booth, 9-cis retinoic acid reduces 1alpha,25-dihydrox-
ycholecalciferol-induced renal calcication by altering
vitamin K-dependent gamma-carboxylation of matrix
gamma-carboxyglutamic acid protein in A/J male mice,
The Journal of Nutrition, vol. 138, pp. 23372341, 2008.
[22] N. C. Arbour, H. M. Darwish, and H. F. DeLuca, Transcrip-
tional control of the osteocalcin gene by 1,25-dihydroxyvita-
min D-2 and its 24-epimer in rat osteosarcoma cells,
Biochimica et Biophysica Acta, vol. 1263, pp. 147153, 1995.
[23] Y. Seyama, M. Horiuch, M. Hayashi, and Y. Kanke, Eect of
vitamin K2 on experimental calcinosis induced by vitamin
D2 in rat soft tissue,International Journal for Vitamin and
Nutrition Research, vol. 66, pp. 3638, 1996.
[24] E. C. Breen, A. J. Wijnenvan, J. B. Lian, G. S. Stein, and J. L.
Stein, In vivo occupancy of the vitamin D responsive element
in the osteocalcin gene supports vitamin D-dependent tran-
scriptional upregulation in intact cells,Proceedings of the
National Academy of Sciences of the United States of America,
vol. 91, pp. 1290212906, 1994.
[25] J. D. Fraser and P. A. Price, Induction of matrix Gla protein
synthesis during prolonged 1,25-dihydroxyvitamin D3 treat-
ment of osteosarcoma cells,Calcied Tissue International,
vol. 46, pp. 270279, 1990.
[26] N. Miyake, K. Hoshi, Y. Sano, K. Kikuchi, K. Tadano, and Y.
Koshihara, 1,25-Dihydroxyvitamin D3 promotes vitamin K2
metabolism in human osteoblasts,Osteoporosis International,
vol. 12, pp. 680687, 2001.
[27] P. I. Karl, D. L. Carnes, and P. A. Friedman, Eects of
1,25-dihydroxycholecalciferol administration on the rat renal
vitamin K-dependent carboxylating system,FEBS Letters,
vol. 192, pp. 243246, 1985.
[28] D. D. Bikle, Vitamin D metabolism, mechanism of action,
and clinical applications,Chemistry & Biology, vol. 21,
pp. 319329, 2014.
[29] Y. Koshihara and K. Hoshi, Vitamin K2 enhances osteocalcin
accumulation in the extracellular matrix of human osteoblasts
in vitro,Journal of Bone and Mineral Research, vol. 12,
pp. 431438, 1997.
[30] P. A. Price and S. A. Baukol, 1,25-Dihydroxyvitamin D3
increases synthesis of the vitamin K-dependent bone protein
by osteosarcoma cells,The Journal of Biological Chemistry,
vol. 255, pp. 1166011663, 1980.
[31] P. A. Price and S. A. Baukol, 1,25-dihydroxyvitamin D3
increases serum levels of the vitamin K-dependent bone pro-
tein,Biochemical and Biophysical Research Communications,
vol. 99, pp. 928935, 1981.
[32] S. A. Kerner, R. A. Scott, and J. W. Pike, Sequence elements in
the human osteocalcin gene confer basal activation and induc-
ible response to hormonal vitamin D3,Proceedings of the
National Academy of Sciences of the United States of America,
vol. 86, pp. 44554459, 1989.
[33] Y. Koshihara, K. Hoshi, H. Ishibashi, and M. Shiraki, Vitamin
K2 promotes 1alpha,25(OH)2 vitamin D3-induced minerali-
zation in human periosteal osteoblasts,Calcied Tissue Inter-
national, vol. 59, pp. 466473, 1996.
[34] I. N. Sergeev and A. W. Norman, Vitamin K-dependent
gamma-carboxylation of the 1,25-dihydroxyvitamin D3 recep-
tor,Biochemical and Biophysical Research Communications,
vol. 189, pp. 15431547, 1992.
[35] R. Sanguineti, F. Monacelli, A. Parodi et al., Vitamins D3
and K2 may partially counterbalance the detrimental eects
of pentosidine in ex vivo human osteoblasts,Journal of
Biological Regulators and Homeostatic Agents, vol. 30,
pp. 713726, 2016.
[36] A. Gigante, M. Torcianti, E. Boldrini et al., Vitamin K and D
association stimulates in vitro osteoblast dierentiation of
fracture site derived human mesenchymal stem cells,Journal
of Biological Regulators and Homeostatic Agents, vol. 22,
pp. 3544, 2008.
[37] K. Hara, Y. Akiyama, T. Tomiuga, M. Kobayashi, T.
Nakamura, and T. Tajima, Inuence of vitamin D3 on
inhibitory eect of vitamin K2 on bone loss in ovariecto-
mized rats,Nihon Yakurigaku Zasshi, vol. 104, pp. 101
109, 1994.
[38] S. Matsunaga, H. Ito, and T. Sakou, The eect of vitamin K
and D supplementation on ovariectomy-induced bone loss,
Calcied Tissue International, vol. 65, pp. 285289, 1999.
[39] J. Iwamoto, A. Seki, Y. Sato, H. Matsumoto, T. Tadeda, and J.
K. Yeh, Vitamin K2 promotes bone healing in a rat femoral
osteotomy model with or without glucocorticoid treatment,
Calcied Tissue International, vol. 86, pp. 234241, 2010.
[40] M. Fusaro, S. Giannini, M. Gallieni et al., Calcimimetic and
vitamin D analog use in hemodialyzed patients is associated
with increased levels of vitamin K dependent proteins,Endo-
crine, vol. 51, pp. 333341, 2016.
[41] M. Tamatani, S. Morimoto, M. Nakajima et al., Decreased
circulating levels of vitamin K and 25-hydroxyvitamin D in
osteopenic elderly men,Metabolism, vol. 47, pp. 195199,
[42] A. C. Torbergsen, L. O. Watne, T. B. Wyller et al., Vitamin K1
and 25(OH)D are independently and synergistically associated
with a risk for hip fracture in an elderly population: a case con-
trol study,Clinical Nutrition, vol. 34, pp. 101106, 2015.
[43] T. E. Finnes, C. M. Lofthus, H. E. Meyer et al., A combination
of low serum concentrations of vitamins K1 and D is associ-
ated with increased risk of hip fractures in elderly Norwegians:
a NOREPOS study,Osteoporosis International,vol. 27,
pp. 16451652, 2016.
[44] A. Vignini, L. Nanetti, F. Raaelli et al., Eect of supplemen-
tation with fortied olive oil on biochemical markers of bone
turnover in healthy women,Mediterranean Journal of Nutri-
tion and Metabolism, vol. 1, pp. 117120, 2008.
[45] T. Ushiroyama, A. Ikeda, and M. Ueki, Eect of continuous
combined therapy with vitamin K(2) and vitamin D(3) on
bone mineral density and coagulobrinolysis function in
postmenopausal women,Maturitas, vol. 41, pp. 211221,
10 International Journal of Endocrinology
[46] J. Iwamoto, T. Takeda, and S. Ichimura, Eect of combined
administration of vitamin D3 and vitamin K2 on bone mineral
density of the lumbar spine in postmenopausal women with
osteoporosis,Journal of Orthopaedic Science, vol. 5, pp. 546
551, 2000.
[47] C. Bolton-Smith, M. E. McMurdo, C. R. Paterson et al.,
Two-year randomized controlled trial of vitamin K1 (phyl-
loquinone) and vitamin D3 plus calcium on the bone health
of older women,Journal of Bone and Mineral Research,
vol. 22, pp. 509519, 2007.
[48] L. A. Braam, M. H. Knapen, P. Geusens et al., Vitamin K1
supplementation retards bone loss in postmenopausal women
between 50 and 60 years of age,Calcied Tissue International,
vol. 73, pp. 2126, 2003.
[49] S. H. Je, N. S. Joo, B. H. Choi et al., Vitamin K supplement
along with vitamin D and calcium reduced serum concentra-
tion of undercarboxylated osteocalcin while increasing bone
mineral density in Korean postmenopausal women over
sixty-years-old,Journal of Korean Medical Science, vol. 26,
pp. 10931098, 2011.
[50] L. Mazzanti, M. Battino, L. Nanetti et al., Eect of 1-year die-
tary supplementation with vitaminized olive oil on markers of
bone turnover and oxidative stress in healthy post-menopausal
women,Endocrine, vol. 50, pp. 326334, 2015.
[51] Y. Sato, T. Kanoko, K. Satoh, and J. Iwamoto, Menatetrenone
and vitamin D2 with calcium supplements prevent nonverteb-
ral fracture in elderly women with Alzheimers disease,Bone,
vol. 36, pp. 6168, 2005.
[52] E. M. O'Connor, G. Grealy, J. McCarthy et al., Eect of phyl-
loquinone (vitamin K1) supplementation for 12 months on the
indices of vitamin K status and bone health in adult patients
with Crohns disease,The British Journal of Nutrition,
vol. 112, pp. 11631174, 2014.
[53] N. Binkley, J. Harke, D. Krueger et al., 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, vol. 24, pp. 983991, 2009.
[54] A. M. Cheung, L. Tile, Y. Lee et al., Vitamin K supplementa-
tion in postmenopausal women with osteopenia (ECKO trial):
a randomized controlled trial,PLoS Medicine,vol. 5, article
e196, 2008.
[55] K. Yonemura, H. Fukasawa, Y. Fujigaki, and A. Hishida, Pro-
tective eect of vitamins K2 and D3 on prednisolone-induced
loss of bone mineral density in the lumbar spine,American
Journal of Kidney Diseases, vol. 43, pp. 5360, 2004.
[56] L. J. Schurgers, E. C. Cranenburg, and C. Vermeer, Matrix
Gla-protein: the calcication inhibitor in need of vitamin K,
Thrombosis and Haemostasis, vol. 100, pp. 593603, 2008.
[57] P. A. Price, S. A. Faus, and M. K. Williamson, Warfarin-
induced artery calcication is accelerated by growth and vita-
min D,Arteriosclerosis, Thrombosis, and Vascular Biology,
vol. 20, pp. 317327, 2000.
[58] O. Mayer Jr., J. Seidlerova, P. Wohlfahrt et al., Synergistic
eect of low K and D vitamin status on arterial stiness in a
general population,The Journal of Nutritional Biochemistry,
vol. 46, pp. 8389, 2017.
[59] A. J. Ballegooijenvan, A. Cepelis, M. Visser, I. A. Brouwer, N.
M. Schoorvan, and J. W. Beulens, Joint association of low
vitamin D and vitamin K status with blood pressure and
hypertension,Hypertension, vol. 69, pp. 11651172, 2017.
[60] L. A. Braam, A. P. Hoeks, F. Brouns, K. Hamulyák, M. J.
Gerichhausen, and C. Vermeer, Benecial eects of vita-
mins D and K on the elastic properties of the vessel wall
in postmenopausal women: a follow-up study,Thrombosis
and Haemostasis, vol. 91, pp. 373380, 2004.
[61] M. K. Shea, C. J. O'Donnell, U. Homann et al., Vitamin K
supplementation and progression of coronary artery calcium
in older men and women,The American Journal of Clinical
Nutrition, vol. 89, pp. 17991807, 2009.
[62] Z. Asemi, F. Raygan, F. Bahmani et al., The eects of vitamin
D, K and calcium co-supplementation on carotid intima-
media thickness and metabolic status in overweight type 2
diabetic patients with CHD,The British Journal of Nutrition,
vol. 116, pp. 286293, 2016.
[63] I. Kurnatowska, P. Grzelak, A. Masajtis-Zagajewska et al.,
Eect of vitamin K2 on progression of atherosclerosis and
vascular calcication in nondialyzed patients with chronic
kidney disease stages 3-5,Polskie Archiwum Medycyny
Wewnętrznej, vol. 125, pp. 631640, 2015.
[64] I. Kurnatowska, P. Grzelak, A. Masajtis-Zagajewska et al.,
Plasma desphospho-uncarboxylated matrix Gla protein as a
marker of kidney damage and cardiovascular risk in advanced
stage of chronic kidney disease,Kidney & Blood Pressure
Research, vol. 41, pp. 231239, 2016.
[65] M. Karamali, M. Ashra, M. Razavi et al., The eects of
calcium, vitamins D and K co-supplementation on markers
of insulin metabolism and lipid proles in vitamin D-
decient women with polycystic ovary syndrome,Experi-
mental and Clinical Endocrinology & Diabetes, vol. 125,
pp. 316321, 2017.
[66] B. Maestro, S. Molero, S. Bajo, N. Dávila, and C. Calle, Tran-
scriptional activation of the human insulin receptor gene by
1,25-dihydroxyvitamin D(3),Cell Biochemistry and Function,
vol. 20, pp. 227232, 2002.
[67] I. N. Sergeev and W. B. Rhoten, 1,25-Dihydroxyvitamin D3
evokes oscillations of intracellular calcium in a pancreatic
beta-cell line,Endocrinology, vol. 136, pp. 28522861, 1995.
[68] N. Sakamoto, I. Wakabayashi, and K. Sakamoto, Low vitamin
K intake eects on glucose tolerance in rats,International
Journal for Vitamin and Nutrition Research, vol. 69, pp. 27
31, 1999.
[69] M. Yoshida, P. F. Jacques, J. B. Meigs et al., Eect of vitamin K
supplementation on insulin resistance in older men and
women,Diabetes Care, vol. 31, pp. 20922096, 2008.
[70] G. Crepaldi and S. Maggi, Epidemiologic link between osteo-
porosis and cardiovascular disease,Journal of Endocrinologi-
cal Investigation, vol. 32, pp. 25, 2009.
[71] M. Razavi, M. Jamilian, M. Karamali, F. Bahmani, E.
Aghadavod, and Z. Asemi, The eects of vitamin D-K-
calcium co-supplementation on endocrine, inammation,
and oxidative stress biomarkers in vitamin D-decient
women with polycystic ovary syndrome: a randomized,
double-blind, placebo-controlled trial,Hormone and Meta-
bolic Research, vol. 48, pp. 446451, 2016.
[72] P. Lips, A. Wiersinga, F. C. Ginkelvan et al., The eect of
vitamin D supplementation on vitamin D status and para-
thyroid function in elderly subjects,The Journal of Clinical
Endocrinology and Metabolism, vol. 67, pp. 644650, 1988.
[73] M. Peacock, Calcium metabolism in health and disease,
Clinical Journal of the American Society of Nephrology, vol. 5,
Supplement 1, pp. S23S30, 2010.
11International Journal of Endocrinology
[74] H. A. Bischo, H. B. Stahelin, W. Dick et al., Eects of vitamin
D and calcium supplementation on falls: a randomized con-
trolled trial,Journal of Bone and Mineral Research, vol. 18,
pp. 343351, 2003.
[75] D. Uylden, M. T. Nurmohamed, L. H. Tuylvan, H. G.
Raterman, and W. F. Lems, (Sub)clinical cardiovascular
disease is associated with increased bone loss and fracture
risk; a systematic review of the association between cardio-
vascular disease and osteoporosis,Arthritis Research &
Therapy, vol. 13, article R5, 2011.
[76] S. K. Seo, B. H. Yun, E. B. Noe, J. W. Suh, Y. S. Choi, and
B. S. Lee, Decreased bone mineral density is associated with
coronary atherosclerosis in healthy postmenopausal women,
Obstetrics & Gynecology Science, vol. 58, pp. 144149, 2015.
[77] R. Zhou, H. Zhou, M. Cui et al., Association between aortic
calcication and the risk of osteoporosis in a Chinese cohort:
the Chongqing osteoporosis study,Calcied Tissue Interna-
tional, vol. 93, pp. 419425, 2013.
[78] A. J. Ballegooijenvan, R. T. Gansevoort, H. J. Lambers-
Heerspink et al., Plasma 1,25-dihydroxyvitamin D and
the risk of developing hypertension: the prevention of renal
and vascular end-stage disease study,Hypertension,
vol. 66, pp. 563570, 2015.
[79] T. Coates, G. S. Kirkland, R. B. Dymock et al., Cutaneous
necrosis from calcic uremic arteriolopathy,American
Journal of Kidney Diseases, vol. 32, pp. 384391, 1998.
[80] G. Arseculeratne, A. T. Evans, and S. M. Morley, Calciphy-
laxisa topical overview,Journal of the European Academy
of Dermatology and Venereology, vol. 20, pp. 493502, 2006.
[81] S. U. Nigwekar, D. B. Bloch, R. M. Nazarian et al., Vitamin K-
dependent carboxylation of matrix Gla protein inuences the
risk of calciphylaxis,Journal of the American Society of
Nephrology, vol. 28, no. 6, pp. 17171722, 2017.
[82] P. A. Galloway, R. El-Damanawi, V. Bardsley et al., Vitamin K
antagonists predispose to calciphylaxis in patients with end-
stage renal disease,Nephron, vol. 129, pp. 197201, 2015.
[83] T. Sato, L. J. Schurgers, and K. Uenishi, Comparison of
menaquinone-4 and menaquinone-7 bioavailability in healthy
women,Nutrition Journal, vol. 11, p. 93, 2012.
12 International Journal of Endocrinology
... Although severe vitamin D deficiency leading to rickets in infants and children is well-established, the association of BMD with vitamin D in young adults was inconclusive [22,23]. The synergistic interplay of multiple vitamin deficiencies for bone has been shown [24,25]. Therefore, it is worthy to examine the associations between BMD and multiple circulating nutrients' status, i.e., vitamin C, vitamin D, folic acid, and vitamin B12. ...
... Adult subjects aged 20-49 years were enrolled and divided into two age groups: young (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) and early middle-aged (36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49) [55]. Body mass index (BMI) was calculated as the weight in kilograms divided by the square of height in meters (kg/m 2 ). ...
... Men had a higher rate of nutrient deficiency in at least one nutrient. The synergistic effects between suboptimal plasma vitamin C and other nutrient deficiencies may have aggravating effects on bone health [20,25]. Further studies are needed to confirm the findings and clarify the complex associations between deficiencies of vitamin C/other nutrients and BMD. ...
Full-text available
Background: This study was conducted to evaluate associations between bone mineral density (BMD) and four selected circulating nutrients, particularly vitamin C, among adults aged 20-49 years. Methods: In this retrospective cross-sectional study, the lumbar spine BMD of 866 men and 589 women were measured by dual-energy X-ray absorptiometry and divided into tertiles, respectively. Logistic regressions were used to identify the predictors of low BMD by comparing subjects with the highest BMD to those with the lowest. Results: Multivariate logistic regressions identified suboptimal plasma vitamin C (adjusted odds ratio (AOR) 1.64, 95% confidence interval (CI) 1.16, 2.31), suboptimal serum vitamin B12 (AOR 2.05, 95% CI 1.02, 4.12), and low BMI (BMI < 23) (AOR 1.68, 95% CI 1.12, 2.53) as independent predictors for low BMD in men. In women, low BMI was the only independent predictor for low BMD. Plasma vitamin C, categorized as suboptimal (≤8.8 mg/L) and sufficient (>8.8 mg/L), was positively significantly correlated with the lumbar spine BMD in men, but there was no association in women. Conclusions: Plasma vitamin C, categorized as suboptimal and sufficient, was positively associated with the lumbar spine BMD in young and early middle-aged men. A well-designed cohort study is needed to confirm the findings.
... It has been found that insufficient amount of vitamin K in the body reduced the affinity of Calcium to bone matrix as calcium levels are significantly controlled by Vitamin D. A therapy including intake of combination of Vitamin k2 and Vitamin D3 can elevate BMD and lower serum UcOC. (Van Ballegooijen et al., 2017) [76][77] . In study it was clearly shown that taking Vitamin D+ K can significantly lower baseline eGFR (22.4 ±10.1 ml/min/1.73m2 ...
... The BMD after 6 months treatment of postmenopausal women significantly in increased from 0.01 ± 0.03 g/cm 2 vs -0.008 ± 0.04 g/cm 2 as shown in Table 3. A proved that by intake of 1000 μg/day vitamin K1 + 320 IU vitamin D in combination can improve cardiovascular health cardiovascular health maintaining the characteristic of wall of vessels in cartid artery along with balancing CAC and lowering carotid intima-media thickness (CCA-IMT) in the heart as compared to the patients taking alone vitamin D. (Van Ballegooijen et al. 2017) [76][77] . The mechanism behind Vitamin K and Vitamin D interaction can be studied in the figure, where it is shown that Vitamin D Binding Receptors undergo gamma Carboxylation which further results in altering the biochemical properties and increasing Osteocalcin which maintains the bone health as shown in Fig 2. The interaction has also been seen to play important role in glycoxidation can be counterbalanced by adding Vitamin D + Vitamin K which can enhance the maturation of Osteoblastic cells. ...
Full-text available
Vitamin D is a fat-soluble vitamin which is mainly required to maintain calcium and phosphorus levels in the body. Although many animal and plant-based sources are known now, still the main source of Vitamin D is sunlight. Vitamin D is present in two forms Vitamin D2 and Vitamin D3 in the body and their absorption and metabolism in the body are found to be slightly different. Vitamin D is also seen to be in synergic relation with many elements which can enhance the bioavailability of Vitamin D and help in improving bone density, cardiovascular health, osteoporosis and overall it maintains adaptable & innate immunity of the body but in contrast, many factors are responsible for hindering the bioavailability of Vitamin D such as antagonistic minerals, skin pigments, drugs, processing of food etc. Different technologies and processes have been developed to enhance the bioavailability of Vitamin D such as UV radiating the food which can enhance the vitamin D content in the food products just like in humans when UV radiation falls on foods products like mushrooms in the range of 290-330 nm the outer layer produces 7-dehydrocholesterol as it is the precursor of Vitamin and nano-encapsulation improves the solubility of Vitamin D and provides acidic, thermal and enzymatic stability.
... Disorders of calcium metabolism, for example, due to metabolic or nutritional vitamins D, A, and K imbalances might cause soft tissue calcification (41,42). Here, serum levels of phosphate, calcium, vitamins D and K, and parathormone are essential to rule out metabolic reasons for pathologic calcification and to examine feed composition and adjust it if necessary (41,42). ...
... Disorders of calcium metabolism, for example, due to metabolic or nutritional vitamins D, A, and K imbalances might cause soft tissue calcification (41,42). Here, serum levels of phosphate, calcium, vitamins D and K, and parathormone are essential to rule out metabolic reasons for pathologic calcification and to examine feed composition and adjust it if necessary (41,42). As hypervitaminosis D and other calcium disorders are systemic diseases, very often other organ systems are additionally affected by metastatic mineralization: cardiac muscle and vascular wall calcification leads to the cardiovascular failure, renal tubular calcification leads to kidney failure (43,44). ...
Full-text available
A male 10-year-old captive red kangaroo (Macropus rufus) was presented with a chronic progressive pelvic limb lameness and reluctance to jump. The general examination revealed a palpable induration of the lumbar epaxial muscles. Magnetic resonance imaging performed under general anesthesia revealed bilateral almost symmetric, well-circumscribed mass lesions in superficial erector spinae muscles. The lesions had irregular to multilobulated appearance with hyper-, hypo-, and isointense areas in T2- and T1-weighted (w) sequences without contrast enhancement. On computed tomography, a peripheral rim of mineralization was apparent. Histopathological analysis of a muscle biopsy showed osseous trabeculae with rare clusters of chondrocytes indicating metaplasia of muscle tissue to bone. No indications of inflammation or malignancy were visible. The clinical, histopathological, and imaging workup of this case was consistent with myositis ossificans circumscripta. This disorder is particularly well-known among human professional athletes such as basketball players, where excessive, chronic-repetitive force or blunt trauma causes microtrauma to the musculature. Metaplasia of muscle tissue due to abnormal regeneration processes causes heterotopic ossification. The kangaroo's clinical signs improved with cyto-reductive surgery, cage rest, weight reduction, and meloxicam without further relapse.
... Vitamin D promotes the synthesis of VKDPs, which play an imperative role in cardiovascular health. A review by van Ballegooijen et al. [162] concluded that the appropriate concentrations of vitamin D and K supplemented together will be beneficial for reducing the risk of CVD, but a simultaneous intake of calcium can be harmful as it may likely contribute to soft tissue calcification and CVD. A prospective cohort study investigated the relation between vitamin D and K serum level markers and cardiovascular health markers such as LV systolic function and cardiac structure. ...
Full-text available
Cardiovascular disease (CVD), a broad-spectrum term comprising coronary artery disease, stroke, hypertension, and heart failure, presents as one of the most significant strains on global healthcare systems. Coronary artery disease, caused by atherosclerosis, has various modifiable risk factors such as dietary changes and exercise. Since these risk factors are found to be linked to oxidative stress and inflammations, the dietary supplementation with vitamins’ role in treating and preventing the diseases has been of much debate. With various vitamins having anti-inflammatory and antioxidative properties, studies have explored their correlation with cardiovascular health. Therefore, this narrative review explores and evaluates the benefits and risks of all vitamin supplementations in patients with CVDandprovides future recommendations.
... VKDPs are a group of proteins that need vitamin K to conduct carboxylation, including the coagulation factors II, VII, IX, and X, and the anti-coagulation proteins C, S, and Z. Vitamin K and VKDPs were also associated with age-related diseases, such as cardiovascular disease, osteoarthritis, dementia, cognitive impairment, mobility problems and weakness (59). Further, VK and VD played a synergistic role in bone and cardiovascular health (60). Glycoprotein Afm is the fourth member of the albumin gene family. ...
Full-text available
The problem of aging is mainly the increase of age-related diseases, and elderly patients have longer hospitalization and worse prognosis. Poorer nutritional status and immunosenescence may be predisposing and severe factors. The mechanism of the high incidence of diseases and poor prognosis behind aging is complex. Finding suitable aging models is of great significance to find strategies to prevent aging related events. In this study, the relationship between thyrotoxicosis and aging was investigated in mice. The results of routine blood tests and flow cytometry showed that immunosenescence occurred in thyrotoxicosis mice, which was characterized by a significant decrease in neutrophils, lymphocytes, CD4+/CD8+ and CD4+IFN-γ+ lymphocytes. Biochemical examination results showed that there were hypocholesterolemia, hypolipoproteinemia, and hyperlipidemia in thyrotoxicosis mice. Serum proteomics analysis showed that the downregulation of complement and coagulation proteins was another manifestation of declined immunity. Moreover, proteomics analysis showed that many downregulated proteins were related to homeostasis, mainly transport proteins. Their downregulation led to the disturbance of osmotic pressure, ion homeostasis, vitamin utilization, lipid transport, hyaluronic acid processing, and pH maintenance. Serum metabolomics analysis provided more detailed evidence of homeostasis disturbance, especially lipid metabolism disorder, including the downregulation of cholesterol, vitamin D, bile acids, docosanoids, and the upregulation of glucocorticoids, triglycerides, sphingolipids, and free fatty acids. The upregulated lipid metabolites were related to lipotoxicity, which might be one cause of immunosenescence and many aging related syndromes. This study provides evidence for the aging model of thyrotoxicosis mice, which can be used for exploring anti-aging drugs and strategies.
... It has become evident that there is a close interaction and joint association between these two vitamins and vascular outcomes [93,94]. Vitamin D promotes the production of MGP and other VKDPs, whereas vitamin K and D work together to maintain calcium homeostasis in bones and circulation [93,95]. Although maintaining optimal levels of vitamin D is highly important for the function of vitamin K, this issue has been repeatedly overlooked or neglected in several interventional studies examining the effect of vitamin K in CKD/ESKD patients. ...
Full-text available
Chronic Kidney Disease (CKD) patients are at high risk of presenting with arterial calcification or stiffness, which confers increased cardiovascular mortality and morbidity. In recent years, it has become evident that VC is an active process regulated by various molecules that may act as inhibitors of vessel mineralization. Matrix Gla Protein (MGP), one the most powerful naturally occurring inhibitors of arterial calcification, requires vitamin K as a co-factor in order to undergo post-translational γ-carboxylation and phosphrorylation and become biologically active. The inactive form of MGP (dephosphorylated, uncarboxylated dp-ucMGP) reflects vitamin K deficiency and has been repeatedly associated with surrogate markers of VC, stiffness, and cardiovascular outcomes in CKD populations. As CKD is a state of progressive vitamin K depletion and VC, research has focused on clinical trials aiming to investigate the possible beneficial effects of vitamin K in CKD and dialysis patients. In this study, we aim to review the current evidence regarding vitamin K supplementation in uremic patients.
... It has been found that calcium and phosphate ions in the extra-hepatic tissues form calcium phosphate that sometimes sticks to fatty deposits present on the walls of blood vessels causing vascular calcification and proneness to CVDs. Vitamin K deficiency or high calcium/vitamin D ratio is the cause of vascular calcification [42]. ...
Full-text available
Vitamin K has recently gained importance as a potential therapeutic agent beyond blood coagulation. Vitamin K2 is found to be a superior nutrient supplement than K1. K1 is mainly obtained from leafy vegetables, whereas K2 is sourced from fermented products and gut microbiota. However, in contrast to other fat-soluble vitamins, body does not accumulate vitamin K and depends on K cycle for its effective use. Vitamin K2 regulates body calcium metabolism. An insufficient vitamin K2 dose increases the risk of osteoporosis, bone fractures, and cardiovascular diseases. Despite a lot of available literature and also approval by safety regulatory bodies, including Food and Drug Administratio (FDA), its awareness among healthcare professionals and general public is still poor. This understudied nutrient has gained a lot of attention in the market because of its multifaceted role in disease management. Aggressive competition within key sellers is one of the critical factors, which expeditiously upsurge the market growth of vitamin K. The rapid increase in patent applications during the last decade reflects its worldwide recognition as an emerging nutraceutical and hence its future market potential.
The person who is pregnant or preparing for pregnancy in the setting of chronic pain is likely to have an especially keen interest in management approaches beyond the usual biomedical model, which tends to focus on symptom management without addressing root causes. Providers and patients also have heightened concerns about the limited efficacy and adverse effects of pharmaceutical management of pain before and during pregnancy. Research increasingly supports an association between diet and chronic pain. Improvements in nutrition will not only facilitate the management of chronic pain but also greatly enhance childbearing outcomes. Persons approaching pregnancy usually have a heightened motivation to make health-enhancing behavioral changes. Chronic pain conditions in the person who is pregnant or preparing for pregnancy present a valuable opportunity to identify and treat underlying causes to enhance long-term health and well-being for the individual and their offspring, impacting the health of the next generation.This chapter utilizes a functional medicine framework in describing the role of diet and nutritional supplements that are safe and beneficial in those living with chronic pain who are preparing for pregnancy or pregnant. Functional medicine provides a framework for understanding and addressing the complex and interrelated factors that create optimal health. Utilizing a systems biology approach, functional medicine recognizes and addresses eight core systems that can be imbalanced (e.g., defense and repair systems, energy production, biotransformation and elimination, transport, communication, structural integrity, and assimilation). Functional medicine focuses on evaluating these systems and finding within them the root cause(s) for illness relying on nutrition, supplements, and lifestyle measures to address and resolve those underlying drivers of imbalance. This chapter will support the healthcare provider to develop an evidence-based plan utilizing diet therapy, functional foods, and nutraceuticals to effectively improve symptoms, quality of life, and comorbidities in people living with chronic pain while simultaneously optimizing fertility and pregnancy outcomes.KeywordsChronic painMicrobiomePregnancyDietNutritionDiet inflammatory indexFunctional medicineFunctional foodsOmega-3Vitamin D
Full-text available
Pengetahun tentang Gizi mutlak diperlukan dan bermanfaat terhadap pemilihan makanan sehari-hari, agar semua zat gizi yang dibutuhkan oleh fungsi normal tubuh dapat terpenuhi. Selain itu dengan mempelajari ilmu gizi bermanfaat pula untuk mengetahui status gizi masyarakat serta upaya penanggulangan masalah gizi yang terjadi di masyarakat/populasi penduduk Buku ini diharapkan dapat dijadikan referensi/sumber rujukan dalam upaya pemenuhan gizi bagi tubuh, yang tertuang dalam beberapa bab berikut ini: Bab 1 Konsep Dasar Ilmu Kesehatan Masyarakat Bab 2 Gizi dan Ruang Lingkupnya Bab 3 Gizi, Pencernaan dan Alat Pencernaan Bab 4 Makanan, Zat Makanan, dan Fungsinya bagi Tubuh Bab 5 Karbohidrat dan Metabolismenya Bab 6 Protein dan Metabolismenya Bab 7 Vitamin dan Metabolismenya Bab 8 Mineral dan Metabolismenya
Full-text available
In the male reproductive tract, the epididymis is an essential organ for sperm maturation, in which sperm cells acquire mobility and the ability to fertilize oocytes while being stored in a protective microenvironment. Epididymal function involves a specialized luminal microenvironment established by the epithelial cells of epididymal mucosa. Low-calcium concentration is a unique feature of this epididymal luminal microenvironment, its relevance and regulation are, however, incompletely understood. In the rat epididymis, the vitamin D-related calcium-dependent TRPV6-TMEM16A channel-coupler has been shown to be involved in fluid transport, and, in a spatially complementary manner, vitamin K2-related γ-glutamyl carboxylase (GGCX)-dependent carboxylation of matrix Gla protein (MGP) plays an essential role in promoting calcium-dependent protein aggregation. An SNP in the human GGCX gene has been associated with asthenozoospermia. In addition, bioinformatic analysis also suggests the involvement of a vitamin B6-axis in calcium-dependent MGP-mediated protein aggregation. These findings suggest that vitamins interact with calcium homeostasis in the epididymis to ensure proper sperm maturation and male fertility. This review article discusses the regulation mechanisms of calcium homeostasis in the epididymis, and the potential role of vitamin interactions on epididymal calcium homeostasis, especially the role of matrix calcium in the epididymal lumen as a cofactor for the carboxylated MGP-mediated scavenging function.
Full-text available
Purpose of Review Vitamin K is a fat-soluble vitamin required for the activation of several vitamin K-dependent proteins to confer functioning. A growing body of evidence supports that vitamin K has beneficial effects on bone and cardiovascular health. This review summarizes key evidence on vitamin K status as measured by circulating measures and cardiovascular outcomes. Recent Findings Overall, observational studies indicate that low vitamin K status as measured by high dephosphorylated uncarboxylated matrix gla protein concentrations plays a potential role in cardiovascular disease development, particularly in high-risk and chronic kidney disease populations. Very few vitamin K intervention trials have been conducted with cardiovascular-related outcomes. A couple of intervention trials studied the effect of the combination of vitamin D + K supplementation, which might have synergistic effects compared to vitamin K supplementation alone. Summary Assessing vitamin K status in prospective studies and well-designed randomized trials would provide important insight whether vitamin K is causally related to vascular calcification and cardiovascular disease.
Full-text available
Aims: Circulating 25-hydroxyvitamin D (25OHD) levels <75 nmol/L are associated with a nonlinear increase in mortality risk. Such 25OHD levels are common in heart failure (HF). We therefore examined whether oral vitamin D supplementation reduces mortality in patients with advanced HF. Methods and results: Four hundred HF patients with 25OHD levels <75 nmol/L were randomized to receive 4000 IU vitamin D daily or matching placebo for 3 years. Primary endpoint was all-cause mortality. Key secondary outcome measures included hospitalization, resuscitation, mechanical circulatory support (MCS) implant, high urgent listing for heart transplantation, heart transplantation, and hypercalcaemia. Initial 25OHD levels were on average <40 nmol/L, remained around 40 nmol/L in patients assigned to placebo and plateaued around 100 nmol/L in patients assigned to vitamin D. Mortality was not different in patients receiving vitamin D (19.6%; n = 39) or placebo (17.9%; n = 36) with a hazard ratio (HR) of 1.09 [95% confidence interval (CI): 0.69-1.71; P = 0.726]. The need for MCS implant was however greater in patients assigned to vitamin D (15.4%, n = 28) vs. placebo [9.0%, n = 15; HR: 1.96 (95% CI: 1.04-3.66); P = 0.031]. Other secondary clinical endpoints were similar between groups. The incidence of hypercalcaemia was 6.2% (n = 10) and 3.1% (n = 5) in patients receiving vitamin D or placebo (P = 0.192). Conclusion: A daily vitamin D dose of 4000 IU did not reduce mortality in patients with advanced HF but was associated with a greater need for MCS implants. Data indicate caution regarding long-term supplementation with moderately high vitamin D doses. Trial registration information: Idenitfier: NCT01326650.
Full-text available
Low vitamin D and K status are both associated with an increased cardiovascular risk. New evidence from experimental studies on bone health suggest an interaction between vitamin D and K; however, a joint association with vascular health outcomes is largely unknown. To prospectively investigate whether the combination of low vitamin D and K status is associated with higher systolic and diastolic blood pressure in 402 participants and with incident hypertension in 231 participants free of hypertension at baseline. We used data from a subsample of the Longitudinal Aging Study Amsterdam, a population-based cohort of Dutch participants aged 55 to 65 years. Vitamin D and K status were assessed by 25-hydroxyvitamin D and dp-ucMGP (dephosphorylated uncarboxylated matrix gla protein) concentrations (high dp-ucMGP is indicative for low vitamin K status) in stored samples from 2002 to 2003. Vitamin D and K status were categorized into 25-hydroxyvitamin D <50/≥50 mmol/L and median dp-ucMGP <323/≥323 pmol/L. During a median follow-up of 6.4 years, 62% of the participants (n=143) developed hypertension. The combination of low vitamin D and K status was associated with increased systolic 4.8 mm Hg (95% confidence interval, 0.1-9.5) and diastolic 3.1 mm Hg (95% confidence interval, 0.5-5.7) blood pressure compared with high vitamin D and K status (P for interaction =0.013 for systolic blood pressure and 0.068 for diastolic blood pressure). A similar trend was seen for incident hypertension: hazard ratio=1.62 (95% confidence interval, 0.96-2.73) for the low vitamin D and K group. The combination of low vitamin D and K status was associated with increased blood pressure and a trend for greater hypertension risk.
Osteocalcin (OC) is a bone Gla protein synthesized by osteoblasts which have a high affinity for calcium. To adequately carboxylate OC to form carboxylated OC (cOC), the osteoblasts require sufficient vitamin K. If vitamin K is deficient, under-carboxylated OC (ucOC) is produced. The ratio between ucOC and cOC (UCR) as well as the levels of circulating ucOC are used as indicators of the vitamin K status of bone. The aim of the present study was to compare the vitamin K status of bone by measuring the plasma levels of ucOC and UCR in healthy adult women before and after 3 weeks of oral supplementation with 20 ml/day Petrini Plus extra virgin olive oil. Petrini Plus is an organic olive oil enriched with vitamins D3, K1 and B6. Enrolled in the study were 15 healthy female volunteers (aged 25-40 years). Plasma levels of ucOC and cOC were measured by ELISA. ucOC was found to be reduced and UCR was reduced by 44% after Petrini Plus olive oil supplementation. Petrini Plus extra virgin olive oil might therefore be useful for bone protection as it was able to counteract bone loss in healthy volunteers.
Both vitamins K and D are nutrients with pleiotropic functions in human tissues. The metabolic role of these vitamins overlaps considerably in calcium homeostasis. We analyzed their potential synergetic effect on arterial stiffness. In a cross-sectional study, we analyzed aortic pulse wave velocity (aPWV) in 1023 subjects from the Czech post-MONICA study. Desphospho-uncarboxylated matrix γ-carboxyglutamate protein (dp-ucMGP), a biomarker of vitamin K status, was measured by sandwich ELISA, and 25-hydroxyvitamin D3 (25-OH-D3) by a commercial immunochemical assay. In a subsample of 431 subjects without chronic disease or pharmacotherapy, we detected rs2228570 polymorphism for the vitamin D receptor. After adjustment for confounders, aPWV was independently associated with both factors: dp-ucMGP [β-coefficient(SEM) = 13.91(4.87); P=.004] and 25-OH-D3 [0.624(0.28); P=.027]. In a further analysis, we divided subjects according to dp-ucMGP and 25-OH-D3 quartiles, resulting in 16 subgroups. The highest aPWV had subjects in the top quartile of dp-ucMGP plus bottom quartile of 25-OH-D3 (i.e. in those with insufficient status of both vitamin K and vitamin D), while the lowest aPVW had subjects in the bottom quartile of dp-ucMGP plus top quartile of 25-OH-D3 [9.8 (SD2.6) versus 6.6 (SD1.6) m/s; P<.0001]. When we compared these extreme groups of vitamin K and D status, the adjusted odds ratio for aPWV≥9.3 m/secwas 6.83 (95%CI:1.95–20.9). The aPWV was also significantly higher among subjects bearing the GG genotype of rs2228570, but only in those with a concomitantly poor vitamin K status. In conclusion, we confirmed substantial interaction of insufficient K and D vitamin status in terms of increased aortic stiffness.
Background Data on the effects of calcium, vitamins D and K co-supplementation on markers of insulin metabolism and lipid profiles among vitamin D-deficient women with polycystic ovary syndrome (PCOS) are scarce. Objective This study was done to determine the effects of calcium, vitamins D and K co-supplementation on markers of insulin metabolism and lipid profiles in vitamin D-deficient women with PCOS. Methods This randomized double-blind, placebo-controlled trial was conducted among 55 vitamin D-deficient women diagnosed with PCOS aged 18–40 years old. Subjects were randomly assigned into 2 groups to intake either 500 mg calcium, 200 IU vitamin D and 90 µg vitamin K supplements (n=28) or placebo (n=27) twice a day for 8 weeks. Results After the 8-week intervention, compared with the placebo, joint calcium, vitamins D and K supplementation resulted in significant decreases in serum insulin concentrations (−1.9±3.5 vs. +1.8±6.6 µIU/mL, P=0.01), homeostasis model of assessment-estimated insulin resistance (−0.4±0.7 vs. +0.4±1.4, P=0.01), homeostasis model of assessment-estimated b cell function (−7.9±14.7 vs. +7.0±30.3, P=0.02) and a significant increase in quantitative insulin sensitivity check index (+0.01±0.01 vs. −0.008±0.03, P=0.01). In addition, significant decreases in serum triglycerides (−23.4±71.3 vs. +9.9±39.5 mg/dL, P=0.03) and VLDL-cholesterol levels (−4.7±14.3 vs. +2.0±7.9 mg/dL, P=0.03) was observed following supplementation with combined calcium, vitamins D and K compared with the placebo. Conclusion Overall, calcium, vitamins D and K co-supplementation for 8 weeks among vitamin D-deficient women with PCOS had beneficial effects on markers of insulin metabolism, serum triglycerides and VLDL-cholesterol levels.
Vitamin D and its' metabolites are a crucial part of the endocrine system that controls whole body calcium homeostasis. The goal of this hormonal control is to regulate serum calcium levels so that they are maintained within a very narrow range. To achieve this goal, regulatory events occur in coordination at multiple tissues, e.g. the intestine, kidney, bone, and parathyroid gland. Production of the vitamin D endocrine hormone, 1,25 dihydroxyvitamin D (1,25(OH)2 D) is regulated by habitual dietary calcium intake and physiologic states like growth, aging, and the menopause. The molecular actions of 1,25(OH)2 D on calcium regulating target tissues are mediated predominantly by transcription controlled by the vitamin D receptor. The primary role for 1,25(OH)2 D during growth is to increase intestinal calcium absorption so that sufficient calcium is available for bone mineralization. However, vitamin D also has specific actions on kidney and bone.
Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification. The ability of MGP to inhibit calcification requires the activity of a vitamin K-dependent enzyme, which mediates MGP carboxylation. We investigated how MGP carboxylation influences the risk of calciphylaxis in adult patients receiving dialysis and examined the effects of vitamin K deficiency on MGP carboxylation. Our study included 20 patients receiving hemodialysis with calciphylaxis (cases) and 20 patients receiving hemodialysis without calciphylaxis (controls) matched for age, sex, race, and warfarin use. Cases had higher plasma levels of uncarboxylated MGP (ucMGP) and carboxylated MGP (cMGP) than controls. However, the fraction of total MGP that was carboxylated (relative cMGP concentration = cMGP/[cMGP + uncarboxylated MGP]) was lower in cases than in controls (0.58±0.02 versus 0.69±0.03, respectively; P=0.003). In patients not taking warfarin, cases had a similarly lower relative cMGP concentration. Each 0.1 unit reduction in relative cMGP concentration associated with a more than two-fold increase in calciphylaxis risk. Vitamin K deficiency associated with lower relative cMGP concentration in multivariable adjusted analyses (β=-8.99; P=0.04). In conclusion, vitamin K deficiency-mediated reduction in relative cMGP concentration may have a role in the pathogenesis of calciphylaxis. Whether vitamin K supplementation can prevent and/or treat calciphylaxis requires further study.
Osteoporosis is a metabolic multifaceted disorder, characterized by insufficient bone strength. It has been recently shown that advanced glycation end products (AGEs) play a role in senile osteoporosis, through bone cell impairment and altered biomechanical properties. Pentosidine (PENT), a wellcharacterized AGE, is also considered a biomarker of bone fracture. Adequate responses to various hormones, such as 1,25-dihydroxyvitamin D3, are prerequisites for optimal osteoblasts functioning. Vitamin K2 is known to enhance in vitro and in vitro vitamin D-induced bone formation. The aim of the study was to assess the effects of Vitamins D3 and K2 and PENT on in vitro osteoblast activity, to convey a possible translational clinical message. Ex vivo human osteoblasts cultured, for 3 weeks, with vitamin D3 and vitamin K2 were exposed to PENT, a well-known advanced glycoxidation end product for the last 72 hours. Experiments with PENT alone were also carried out. Gene expression of specific markers of bone osteoblast maturation [alkaline phosphatase, ALP; collagen I, COL I?1; and osteocalcin (bone-Gla-protein) BGP] was measured, together with the receptor activator of nuclear factor kappa-B ligand/osteoproteregin (RANKL/OPG) ratio to assess bone remodeling. Expression of RAGE, a well-characterized receptor of AGEs, was also assessed. PENT+vitamins slightly inhibited ALP secretion while not affecting gene expression, indicating hampered osteoblast functional activity. PENT+vitamins up-regulated collagen gene expression, while protein secretion was unchanged. Intracellular collagen levels were partially decreased, and a significant reduction in BGP gene expression and intracellular protein concentration were both reported after PENT exposure. The RANKL/OPG ratio was increased, favouring bone reabsorption. RAGE gene expression significantly decreased. These results were confirmed by a lower mineralization rate. We provided in vitro evidence that glycoxidation might interfere with the maturation of osteoblasts, leading to morphological modifications, cellular malfunctioning, and inhibition of the calcification process. However, these processes may be all partially counterbalanced by vitamins D3 and K2. Therefore, detrimental AGE accumulation in bone might be attenuated and/or reversed by the presence or supplementation of vitamins D3 and K2.
The steroid hormone 1 alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] can elicit biological responses via a nongenomic pathway that involves rapid opening of the plasma membrane Ca2+ channels. There is also evidence that 1,25-(OH)2D3 influences insulin secretion in the pancreatic beta-cell, which is primarily mediated by a rapid rise in the concentration of intracellular free Ca2+ ([Ca2+]i). We employed fluorescent digital ratiometric video imaging at the single cell level to study the effects of 1,25-(OH)2D3 on [Ca2+]i in a pancreatic beta-cell line, RINr1046-38. In RIN cells equilibrated at a steady state glucose concentration (5.5 mM), 1,25-(OH)2D3 (2-20 nM) rapidly, within 5-10 sec, increased [Ca2+]i and evoked sinusoidal [Ca2+]i oscillations with a frequency of 1.87 +/- 0.13 min-1 and an amplitude of 236 +/- 3 nM (from the initial basal level of 110 +/- 2 nM). The [Ca2+]i oscillations were acutely dependent on extracellular Ca2+, but not on extracellular glucose. Further, we investigated the mechanisms o...