THEMATIC REVIEW SERIES: VITAMIN K
Vitamin K Status and Vascular Calcification:
Evidence from Observational
and Clinical Studies1,2
M. Kyla Shea3* and Rachel M. Holden4
3Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem NC; and4Department of Medicine, Queen’s University, Kingston, Ontario,
Vascular calcification occurs when calcium accumulates in the intima (associated with atherosclerosis) and/or media layers of the vessel wall.
Coronary artery calcification (CAC) reflects the calcium burden within the intima and media of the coronary arteries. In population-based studies,
CAC independently predicts cardiovascular disease (CVD) and mortality. A preventive role for vitamin K in vascular calcification has been
proposed based on its role in activating matrix Gla protein (MGP), a calcification inhibitor that is expressed in vascular tissue. Although animal and
in vitro data support this role of vitamin K, overall data from human studies are inconsistent. The majority of population-based studies have relied
on vitamin K intake to measure status. Phylloquinone is the primary dietary form of vitamin K and available supplementation trials, albeit limited,
suggest phylloquinone supplementation is relevant to CAC. Yet observational studies have found higher dietary menaquinone, but not
phylloquinone, to be associated with less calcification. Vascular calcification is highly prevalent in certain patient populations, especially in those
with chronic kidney disease (CKD), and it is plausible vitamin K may contribute to reducing vascular calcification in patients at higher risk.
Subclinical vitamin K deficiency has been reported in CKD patients, but studies linking vitamin K status to calcification outcomes in CKD are
needed to clarify whether or not improving vitamin K status is associated with improved vascular health in CKD. This review summarizes the
available evidence of vitamin K and vascular calcification in population-based studies and clinic-based studies, with a specific focus on CKD
patients. Adv. Nutr. 3: 158–165, 2012.
Vascular calcification occurs when vessel and/or valvular tis-
sue becomes mineralized. In the vessel wall, calcium deposi-
tion can occur in the intimal and/or medial layers.
Calcification of the intimal layer isreflective of atherosclerotic
heart disease. Calcium deposition in the intimal layer of the
coronary arteries (known as CAC5) can lead to vascular oc-
clusion. It is detectable in ~30% of adults without clinical
CVD (1–4) and is incrementally predictive of future cardio-
vascular events and overall mortality, independent of tradi-
tional CVD risk factors (5–7). Certain patient groups,
especially those with CKD, are at greater risk for CAC (8–10).
In 2004, it was determined that 11% of the general popu-
lationin the UnitedStateshad CKD, translating into >19mil-
lion affected people (11). CKD is defined as the presence of
kidney damage with or without reduced kidney function
(12). The severity of CKD is determined by a staging process
that is based on an estimated glomerular filtration rate. Mod-
erate to severe CKD (stages 3–5) is represented by an esti-
mated glomerular filtration rate of <60, <30, and <15 mL/
(min$1.73 m2), respectively, and stage 5b encompasses those
(hemodialysis, peritoneal dialysis, or kidney transplant) (12).
At every stage of CKD, the leading cause of mortality is
CVD and patients are more likely to die of a cardiac event
than they are to ever require a form of kidney replacement
therapy (13). CKD patients are particularly prone to medial
calcification (known as Monckeberg’s sclerosis), which leads
to arterial stiffening, elevated systolic pressure, and in-
creased cardiac workload (14,15). Medial calcification is pre-
dictive of cardiovascular and all-cause mortality in CKD
patients, independent of intimal calcification and CVD risk
1Supported by the AHA (09CRP2070013), the Wake Forest University Claude D. Pepper Older
Americans Independence Center (P30-AG21332) (M.K.S.), and the Kidney Foundation of
Canada and the Heart and Stroke Foundation of Ontario (R.M.H.).
2Author disclosures: M. K. Shea and R. M. Holden, no conflicts of interest.
5Abbreviations used: AAC, abdominal aortic calcification; BAC,breast artery calcification; CAC,
coronary artery calcification; CKD, chronic kidney disease; CVD, cardiovascular disease; ESKD,
end-stage kidney disease; HF, heart failure; PROSPECT, Predictors of Response to Cardiac
Resynchronization Therapy study; VSMC, vascular smooth muscle cell.
*To whom correspondence should be addressed. E-mail: email@example.com.
ã2012 American Society for Nutrition. Adv. Nutr. 3: 158–165, 2012; doi:10.3945/an.111.001644.
factors (16,17). Calcific uremic arteriopathy, also known as
calciphylaxis, is unique to patients with ESKD and classically
manifests as calcification of cutaneous and s.c. arteries with
occlusive intimal proliferation and subsequent fat necrosis
Although the cellular and molecularevents leading to cal-
cium deposition invascular tissue continue to be explored, it
is understood to be a highly regulated process. Animal and
molecular studies have demonstrated that vitamin K is in-
volved in the development and progression of vascular cal-
cification, as mediated by the carboxylation of matrix gla
protein (MGP) (19). MGP, which is synthesized by VSMC,
functions as a calcification inhibitor (20–22). In mice, tar-
geted deletion of the MGP gene results in rapid and com-
plete arterial calcification, resulting in death by 6 wk (23).
For MGP to inhibit soft-tissue calcification, vitamin K is re-
quired as an enzymatic cofactor in the g-carboxylation of
the protein. It has been suggested that a lack of functional
MGP, rather than the amount of total MGP, may increase
risk for vascular calcification (24). This is supported by
the observation that vitamin K antagonism with warfarin,
which antagonizes the vitamin K-dependent carboxylation
of MGP, also leads to rapid arterial calcification in rats
(20). Furthermore, diets high in vitamin K have been shown
to reverse aortic calcification and improve arterial elasticity
inwarfarin-treated rats (22), suggesting that the calcification
in response to warfarin treatment is due to the inhibition of
the vitamin K-dependent g-carboxylation of MGP. In addi-
tion, MGP isolated from atherosclerotic plaque of aging rats
was found to be incompletely carboxylated, thereby inhibit-
ing its ability to function as a calcification inhibitor (25). Al-
though vitamin K’s role in vascular calcification has been
demonstrated in animal and in vitro studies, the evidence
from human studies is less clear. The aim of this review
was to examine the human evidence of vitamin K’s role in
vascular calcification, first in population-based studies and
then in patients with CKD, a group at greater risk for vascu-
lar calcification (26,27).
Current status of knowledge
Population-based studies are studies of free-living, non-
clinic-based participants who were not selected with respect
to the disease of interest, allowing for the study of natural
history of disease incidence and progression. Population-
based studies are more generalizable to the general popula-
tion than clinic-based studies, although participant selection
procedures should be considered (28).
Observational studies. The majority of population-based
studies reporting on the association between vitamin K sta-
tus and vascular calcification have relied onvitamin K intake
as the measure of status (summarized in Table 1). The pri-
mary form of vitamin K in most diets is phylloquinone
(vitamin K1), which is found primarily in green leafy
vegetables and vegetable oils (29). The current RDA for vi-
tamin K in the US are 90 and 120 mg/d for adult women
and men, respectively, based on median intakes according
to NHANES (1988–1994) (30). In a small (n = 113), nested,
case-control study of Dutch community-dwelling postmen-
opausal women, Jie et al. (31) reported that women with ab-
dominal aortic calcification (AAC) reported lower intakes of
phylloquinone (190 6 15 mg/d) compared to women with-
out (244 6 15 mg/d). However, subsequent observational
studies have not supported this finding. Among 4473 men
and women (mean 6 SD age = 67 6 8 y) in the Rotterdam
Study, there wereno significant differences in phylloquinone
intake across categories of AAC severity (32). In 564 healthy
Dutch postmenopausal women participating in the Predic-
tors of Response to Cardiac Resynchronization Therapy
study(PROSPECT) study (mean 6 SD age 67 6 5 y old),
the prevalence of CAC did not significantly differ across
quartiles of phylloquinone intake (33). In a separate analysis
of PROSPECT participants that measured breast artery cal-
cification (BAC), phylloquinone intake did not differ signif-
icantly between women with BAC [adjusted mean (95% CI)
= 209 (194–225) mg/d] and women without [adjusted mean
(95% CI) = 211 (206–216) mg/d]. Among U.S. military per-
sonnel, Villines et al. (34) did not find phylloquinone intake
to be associated with presence or severity of CAC. Because
this was a younger cohort (39–45 y old) at low risk for
CVD, the expected extent of CAC would be less than for
other groups, so any association with vitamin K intake
may have been more difficult to detect. In these studies,
self-reported phylloquinone intakes were semiquantitatively
estimated using validated FFQ (35–38). The reported phyl-
loquinone intakes in studies outside the US (31–33,39) were
on average more than double the current U.S. recommenda-
tions [mean 6 SD = 217 6 92 mg/d (33); 211 6 73 mg/d
(39); and 249 6 126 mg/d (32)]. It is plausible that overall
nutrient adequacy may have blunted the ability to detect
an association. However, intakes among U.S. military per-
sonnel were in line with U.S. recommendations and were
also not associated with CAC (mean 6 SD = 115 6 79
mg/d) (34). Self-reported dietary intakes are imprecise and
there are inherent limitations to estimating nutrient intakes
from FFQ (40). Because phylloquinone is found in healthy
foods (green vegetables), self-reported intakes may be sub-
ject to overreporting (41). Phylloquinone intake is a marker
of a heart-healthy diet (42), so it may be difficult to disen-
tangle whether it or generally healthy lifestyle behaviors
are associated with calcification outcomes, even when statis-
tical adjustment is made (43).
Menaquinones (collectively referred to as vitamin K2)
differ structurally from phylloquinone in their side-chain
length and saturation. They are primarily found in meat
and dairy-based foods and fermented soybeans (known as
natto, commonly consumed in Japan). In most diets, mena-
quinones generally contribute less to total dietary vitamin K
intakes than phylloquinone (29,44). Consumption of foods
high in menaquinone tends to vary geographically; they ap-
pear to be more commonly consumed in non-Western diets.
Circulating levels of menaquinone-7, e.g., are reported to be
higher than phylloquinone in Japanese women, indicating a
Vitamin K and vascular calcification in humans159
higher intake of this form of vitamin K in this region (45).
Geleijnse et al. (32) reported a lower odds of severe AAC
among Dutch men and women in the highest tertile of me-
naquinone intake (>32.7 mg/d, included menaquinones-4
through 10) [OR (95%CI) = 0.48 (0.32–0.71)] but no differ-
ence with respect to moderate AAC. In the PROSPECT co-
hort, Dutch women in the highest quartile of menaquinone
intake (mean 6 SD = 48.5 6 9.0 mg/d, energy adjusted) had
a significantly lower prevalence of CAC [prevalence ratio
(95%CI) = 0.80 (0.65–0.98)] (33). However, in the study
of BAC in PROSPECT, menaquinone intake did not signif-
icantly differ betweenwomenwith BAC and womenwithout
[adjusted mean (95% CI) = 29 (27–30) and 29 (28–30) mg/d,
respectively] (39). When interpreting these associations, it is
important to note that the range of menaquinone intake re-
ported in these studies was narrow compared to phylloqui-
none and the differences between tertiles/quartiles was
small [i.e., 10–30 mg/d difference between highest and lowest
groups (32,33)]. It is uncertain if intake differences of this
magnitude would result in considerable differences in vascu-
lar tissue accumulation of menaquinone in humans. Because
menaquinone intake data were derived from FFQ, there are
inherent limitations to these estimates (40). Dietary sources
of menaquinones are not reflective of overall healthy diet
and lifestyle patterns, so menaquinone intake data may not
be prone to overreporting and residual confounding to the
same extent as are phylloquinone intake data. However,
food composition data available for certain menaquinones
are limited and circulating menaquinone concentrations are
usually nondetectable, so validating dietary menaquinone in-
take data is problematic (42).
Although nutritional biomarkers are not susceptible to the
biases inherent to dietary intake questionnaires (46,47), popu-
lation-based studies of vitamin K status biomarkers and vascu-
lar calcification are fairly limited. There is currently no one
biomarker considered to be a robust indicator of vitamin K
to reflect overall status but are highly correlated with TG [due
to it being transported on TG-rich lipoproteins (48)] and fluc-
tuate according to recent intakes (29,49). In a cross-sectional
analysis of older men and women, lower plasma phylloqui-
tential confounders (50). The undercarboxylated fractions of
vitamin K-dependent proteins, which can also be measured
in circulation, are considered functional indicators of vitamin
K status of certain tissues. These measures are elevated when
vitamin K status is low (49,51). Undercarboxylated prothrom-
bin (PIVKA-II) reflects hepatic vitamin K status and changes
according to vitamin K intake (52). However, it is generally
not used as a marker of subclinical vitamin K deficiency in
population-based studies, because changes in PIVKA-II do
not reflect changes in clotting function in generally healthy
adults (52). Undercarboxylated osteocalcin (ucOC) (the pri-
mary vitamin K-dependent protein in bone) has been utilized
asa measure ofvitamin Kstatus of bone inseveralpopulation-
based studies (53–55). Jie et al. (31) found women with AAC
had higher levels of undercarboxylated (free) OC in serum, re-
flective of lower vitamin K status compared towomenwithout
AAC. However, ucOC may not necessarily reflect vitamin K
status in vascular tissue. MGP is the most-studied vitamin
K-dependent protein implicated in the regulation of vascular
calcification. Although assays that measure the total MGP in
circulation (regardless of its carboxylation status) have been
available for some time (56), data are conflicting as to whether
the total circulating MGP poolreflectsatheroscleroticcalcifica-
tion (56–58). Because only the carboxylated form of MGP can
function as a calcification inhibitor, distinguishing the uncar-
boxylated and carboxylated fractions of MGP in circulation
has been suggested, to clarify the role of the functional forms
of MGP in vascular calcification (19). Recently assays that
measure different fractions of MGP in circulation have
been developed, only one of which [the dephosphorylated
Studies of phylloquinone intake
Population-based observational studies of vitamin K intake and vascular calcification1
Participants Design Outcome measureResults
women (60–69 y old)
4807 men and women
(62% female, $55 y old)
807 military personnel
(18% female, 39–45 y)
1689 women (49–70 y old)
AAC Women with AAC had lower
phylloquinone intake (P , 0.05)
No association between
phylloquinone intake and AAC
No association between
phylloquinone intake and CAC
No association between
phylloquinone intake and BAC
No association between
phylloquinone intake and CAC
(33) 560 postmenopausal womenCross-sectional CAC
Studies of menaquinone intake
(32) 4807 men and women
(62% female, $55 y old)
Cross-sectionalAAC Lower odds of AAC in highest
tertile of menaquinone intake
(P-trend , 0.001)
No association between menaquinone
Lower prevalence of CAC in highest
quartile of menaquinone intake
(P-trend = 0.03)
(39) 1689 women (49–70 y old)Cross-sectionalBAC
(33)560 postmenopausal women Cross-sectionalCAC
1AAC, abdominal aortic calcification; BAC, breast artery calcification; CAC, coronary artery calcification.
160 Shea and Holden
uncarboxylated MGP, (dp)ucMGP] appears to reflect vita-
min K status (59). This was confirmed by a post hoc analysis
of archived blood samples from avitamin K supplementation
study, which found (dp)ucMGP was inversely correlated with
plasma phylloquinone, positively correlated with ucOC, and
was reduced following 3 y of phylloquinone supplementation
(500 mg/d) in community-dwelling older adults. However,
(dp)ucMGP was not associated with CAC in this cohort,
cross-sectionally or longitudinally (51). The associations of
other circulating forms of MGP [dephosphorylated carboxyl-
ated MGP ((dp)cMGP) and total ucMGP (regardless of phos-
been reported in population-based studies. The biochemistry
and physiology of MGP continues to be explored and the rela-
be clarified by ongoing longitudinal analyses of vitamin K bio-
markers in larger population-based cohorts.
Intervention studies. There are currently 2 reported inter-
vention trials of vitamin K on cardiovascular outcomes,
only one of which directly measured vascular calcification.
In a 3-y, double-blinded, randomized controlled trial, 500
mg/d of phylloquinone supplementation was associated
with reduced CAC progression in 388 older men and
women free of clinical CVD. Although the effect of supple-
mentation was not significant in intent-to-treat analysis,
men and womenwith preexisting CAC who received phyllo-
quinone supplementation had 6% less CAC progression
compared to the controls over 3 y, which was significant
(60). In a 3-y follow-up analysis of patients treated with stat-
ins, those who had a myocardial infarction had 25% more
CAC progression compared to myocardial infarction-free
participants (61), so the clinical relevance of the observed ef-
fect of vitamin K remains to be clarified. Because calcifica-
tion progresses more rapidly in persons with preexisting
CAC (62,63) and in vitro studies show increased MGP ex-
pression in calcified VSMC (64,65), it is plausible that vita-
min K may affect CAC progression more than it does disease
onset. In an earlier, double-blind, randomized supplementa-
tion trial in 108 postmenopausal women, those who were
randomized to receive a supplement containing 1000 mg/d
phylloquinone in addition to minerals and 320 IU cholecal-
ciferol had better carotid artery distensibility, compliance,
and elasticity after 3 y compared to women who received
the mineral supplement alone or the mineral supplement
with cholecalciferol (66). Although no direct measures of
calcification were included in this study, the authors spec-
ulated their findings may be due in part to vitamin K’s po-
tential role in reducing calcium deposition in the vessel
Vascular calcification is highly prevalent in certain patient
populations, especially in those with CKD. Although studies
in this area are still limited, there is growing interest in a po-
tential role for vitamin K in modifying the progression of
calcification in patients with CKD, because vascular calcifi-
cation is common in this patient group.
According to estimates from the Chronic Renal Insuffi-
ciency Cohort Study, >60% of CKD patients have detectable
CAC, the severityof which increases as CKD progresses (67).
In one cross-sectional study, >30% of patients with stage 3–
5 CKD already had severe CAC (>400 Agatson units) despite
the absence of a cardiac history (68). Accelerated calcifica-
tion in patients with CKD relates in part to the mineral
bone disorder that is observed in these patients and is char-
acterized by abnormalities in phosphorus homeostasis. The
regulation of phosphate is primarily mediated by renal ex-
cretion in healthy participants; in CKD, a positive phosphate
balance occurs and multiple studies have linked abnormal
phosphorus levels with severity and progression of calcifica-
tion (69,70–72). Excess phosphate uptake into VSMC via a
sodium-phosphate cotransporter is thought to be a key ini-
tiating event in the process of vascular calcification (73,74).
Elevated intracellular and extracellular phosphate stimulates
expression of proteins involved in bone formation [e.g.,
Cbfa-1, BMP-2, and -4, and OC] and downregulates the ex-
pression of VSMC contractile proteins (75,76).
Observational studies of CKD patients
A numberof studies have determined the vitamin K status of
individuals with CKD; however, studies linking vitamin K
status to clinical outcomes or surrogate measures of calcifi-
cation are lacking. Dietary vitamin Kintake may be compro-
mised in patients with CKD for at least 2 reasons. First, the
renal diet is restricted with respect to potassium-rich foods
that otherwise may be a good source of vitamin K, and sec-
ondly, this population has a high frequency of anorexia and
gastrointestinal symptoms that result in a compromised
overall energy intake (77). Usual dietary vitamin K intake
was assessed in a cohort of patients with stage 3–5 CKD
by a FFQ validated for vitamin K intake in the general pop-
ulation (78,79). The mean phylloquinone intake was 130 6
103 mg/d, with higher intakes largely reflected by overall en-
ergy intake and better clinical nutritional status (78).
It has become evident that a high prevalence of subclin-
ical vitamin K deficiency exists in hemodialysis and perito-
neal dialysis patients and in individuals with earlier stages
of CKD (78,80–82). The percentages of participants that
meet the criteria for subclinical vitamin K deficiency based
on very low circulating concentrations of phylloquinone
are: CKD (6%), hemodialysis (29%), and peritoneal dialysis
(24%) (78,80,81). Individuals with CKD consistently dem-
onstrate marked elevations in serum TG and low levels of
HDL-cholesterol (83). In all cohort studies of CKD patients,
higher levels of phylloquinone strongly and independently
associate with higher levels of TG, which may confound
any association between circulating phylloquinone and
CKD-related health outcomes in this particular group. Be-
tween 60 and 90% of patients with CKD fulfill criteria for
subclinical vitamin K deficiency on the basis of circulating
ucOC (78,81). However, the spectrum of mineral and bone
disorders and potential for accumulation of OC fragments
Vitamin K and vascular calcification in humans 161
in individuals with low kidney function may render it a less
useful measure of vitamin K status in this population. The
strongest predictors of elevated percent ucOC are parame-
ters related to the CKD-mineral bone disorder (higher phos-
phorus and parathyroid hormone levels) (80). In contrast to
healthy populations, PIVKA-II may therefore be a superior
markerof vitamin K deficiency in the CKD population given
that it is not affected by kidney function. Ninety-four per-
cent of CKD patients had PIVKA-II levels > 2 g/L, consistent
with dietary deficiency (78). No study has yet linked abnor-
malities in these particular biomarkers of vitamin K status
with any measure of calcification in CKD.
Warfarin use could be considered a surrogate for im-
paired vitamin K status, because warfarin antagonizes the vi-
tamin K epoxide reductase enzyme, thereby limiting the
carboxylation of vitamin K-dependent proteins. The fre-
quency of warfarin use reported by single-center and popu-
lation-based studies in ESKD patients approaches 20% in
North America (84,85). Despite the frequency of warfarin
prescription, there are few studies that have evaluated the
adverse consequences of its use in patients with CKD. One
study has demonstrated that long-term warfarin exposure
was independently associated with greater severity of aortic
valve calcification in dialysis patients (86) and anecdotal ev-
idence has linked warfarin use to the pathogenesis of calcific
uremic arteriopathy in patients with ESKD (18). Calciphy-
laxis is associated with exceedingly high morbidity and mor-
tality in dialysis patients (87).
Analyses of (dp)ucMGP in case-control studies have re-
ported it to be higher among patients with diseases charac-
terized by vascular calcification, including CKD (59), and
(dp)ucMGP was found to be positively associated with aor-
tic calcium score in 107 patients with CKD (88). Conversely,
Schleiper et al. (89) reported that the circulating (dp)cMGP
and (dp)ucMGP were both lower in patients with ESKD
compared to controls, but neither measure correlated with
vascular calcification in the ESKD patients. An alternate
monoclonal-antibody ELISA that measures total-ucMGP
(whether or not it is phosphorylated) is also available (59),
and this measure of total ucMGP was reported to be in-
versely associated with CAC in a small sample of hemodial-
ysis patients (n = 40) (90). Plasma (dp)cMGP and the total
ucMGP (measured using this monoclonal assay) do not re-
spond to changes in vitamin K status (59,89); therefore, it is
difficult to extrapolate the reported associations between
these measures and calcification to vitamin K status. At
this point, the clinical utility of circulating MGP measures
in CKD patients remains uncertain and may be clarified us-
ing larger cohorts of CKD patients who are well character-
ized for vascular calcification and related outcomes.
There are currently no intervention trials evaluating vitamin
Kin the prevention of vascularcalcification in CKD patients.
Therefore, the role of vitamin K in CKD patients remains be
clarified by futurerandomized controlled trials targeting this
high-risk patient population.
Other patient populations
Warfarin is commonly used to manage chronic cardiovascu-
lar conditions, such as atrial fibrillation, venous thrombo-
embolism, and valvular stenosis (91). It stands to reason
that warfarin users represent a group who may be at greater
risk for vascular calcification. Several case-comparison anal-
yses [one of which contained over 1100 participants (92)]
reported greater valvularcalcification inwarfarin users com-
pared to nonusers (92–94). However, a small cross-sectional
study of 70 warfarin patients (mean age = 68 y) attending an
anticoagulation clinic found no association between warfa-
rin treatment duration and CAC (95). It is has been sug-
gested that although the valvular calcification and CAC
processes overlap, the 2 may not be exactly the same (96),
so the 2 outcomes may differ with respect to warfarin treat-
ment. This would be clarified by examining the association
between warfarin treatment duration with vascular and val-
vular calcification together in larger longitudinal studies.
Patients with diabetes (type 1 and 2), hypercholesterole-
mia, and cardiac valve disease are also at higher risk for vas-
cular calcification (96,97). In the limited available studies of
these patients, vitamin K status primarily has been estimated
using the newly developed (dp)ucMGP assay. (dp)ucMGP
was found to be elevated (indicative of lower vitamin K sta-
tus) in patients with aortic stenosis compared to healthy
controls but was not significantlycorrelated with stenosis se-
verity (98). In a separate analysis, the same authors found
(dp)ucMGP to be elevated in patients with chronic HF com-
pared to healthy controls, positively associated with HF se-
verity, and markedly higher in patients who died of HF
progression over 2.9 y compared to survivors. Because this
study’s sample size was modest (n = 179, and 12 deaths
due to HF progression) and vascular calcification was not di-
rectly quantified, it is uncertain if the HF outcomes were re-
lated to calcification or not (99). Parker et al. (100) reported
higher totalucMGP was associated with higherodds ofmitral
annular calcification in diabetics and lower odds of mitral an-
nular calcification in persons without diabetes. Because the
total-ucMGP measure used in this study does not reflect vita-
min K status (59), therelevance ofvitamin Ktothesefindings
is uncertain. Overall, vitamin K’s role in vascular calcification
in these patients has not been well studied. Assessing vitamin
K status using multiple biomarkers in observational longitu-
dinal studies and well-designed randomized trials in these pa-
tients would provide important insight into whether vitamin
K also has a role in vascular calcification in clinic-based pop-
ulations in addition to CKD.
Overall, the available observational population-based evi-
dence, based on dietary intake measures, suggests menaqui-
none intake may be more likely to protect against vascular
calcification than phylloquinone intake. Yet currently, the
only intervention studies have examined the effect of
phylloquinone and provide evidence that phylloquinone
supplementation is relevant to vascular calcification (60,66).
However, confirmatory studies are needed. Furthermore,
162 Shea and Holden
because there are no published intervention studies of me-
naquinone with a measure of vascular calcification as an
outcome, any differential effect of phylloquinone compared
to menaquinone will be clarified by future trials designed to
compare the effects of the different vitamin K forms on vas-
cular calcification. Within the patient populations, individ-
uals with CKD represent a rapidly growing segment at
increased risk for vitamin K deficiency. There are currently
no clinical practice guidelines that recommend routine vita-
min K supplementation for individuals with CKD outside of
patients exposed to long-term oral antibiotics (101). Future
trials should specifically address this at-risk group. In addi-
tion to CKD, vascular calcification is a characteristic of other
chronic health conditions (96), in which the role of vitamin
K merits exploration.
Both authors have read and approved the final manuscript.
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