Atherosclerosis 235 (2014) 130e139

Contents lists available at ScienceDirect

Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Review

Vitamin D supplementation and lipid prole: What does the best

available evidence show?
Dimitrios Challoumas*
School of Medicine, Cardiff University, Heath Park Campus, Cardiff CF14 4XW, UK

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 12 March 2014
Received in revised form
10 April 2014
Accepted 13 April 2014
Available online 30 April 2014

Vitamin D supplements have increasingly been used for the treatment and prevention of osteoporosis.
Historically, effects of the vitamin on the cardiovascular (CV) system have been proposed and demonstrated in the literature, including benets on serum lipids. Although observational studies support an
association between increased serum vitamin D levels and a favorable lipid prole, interventional studies
have shown no effects.
This review presents and analyzes all the related randomized controlled trials (RCTs) identied in the
literature from 1987 to present. A systematic literature search was conducted via MEDLINE, Cochrane
Library and EMBASE and, out of 19 relevant RCTs identied, only one reported benets of vitamin D
supplementation on lipid prole parameters, while the rest showed no effects or even adverse outcomes,
which are highlighted by the only meta-analysis in the eld.
Attempts to explain the paradox of benecial ndings of observational studies versus discouraging
results of interventional studies have been made and the most popular suggests that high serum vitamin
D concentrations may not be the cause of good health but its outcome instead, as healthy people are
more likely to stay outdoors longer and have better eating habits.
For denitive answers to be given, large, well-designed RCTs need to be conducted that will take into
account and adjust for dietary consumption as well as serum calcium and parathyroid hormone levels,
both of which have been shown to be associated with the CV system. Until then, recommendations for
vitamin D supplementation should not change.
2014 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Vitamin D
Supplements
25-OH D
Lipids
Triglycerides
LDL
HDL
Effects
Randomized controlled trials

Contents
1.

2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
1.1.
Vitamin D receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
1.2.
Vitamin D2 versus vitamin D3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
1.3.
Vitamin D status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
2.1.
Vitamin D and CV events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
2.2.
Vitamin D and lipid profile e a summary of observational studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
2.3.
Vitamin D and lipid profile e metabolic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
2.4.
Proposed effects of vitamin D on the CV system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Vitamin D and lipid profile e randomized controlled trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
3.1.
Selection of studies and inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
3.2.
Beneficial effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
3.3.
Neutral or adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
3.3.1.
Single-dose or periodical supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
3.3.2.
Daily supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

* Tel.: 44 292087400.
E-mail address: challoumasd@cardiff.ac.uk.
http://dx.doi.org/10.1016/j.atherosclerosis.2014.04.024
0021-9150/ 2014 Elsevier Ireland Ltd. All rights reserved.

D. Challoumas / Atherosclerosis 235 (2014) 130e139

4.
5.
6.

131

Paradox . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Vitamin D, calcium and PTH: which is to blame? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

1. Introduction
Vitamin D has traditionally been associated with bone health
and, together with calcium, is increasingly becoming popular for
the prevention and treatment of osteoporosis. Recently, both calcium and vitamin D have been suggested to exert effects on the
cardiovascular (CV) system, however the existing evidence is highly
controversial. The effects of calcium on the CV system have been
reviewed elsewhere and although ndings of different studies are
conicting, calcium supplements should be prescribed with
caution as signicant adverse CV effects have been reported with
high intake [1].
The determination of the presence and nature of effects of
vitamin D on the CV system is particularly important for a number
of reasons. Firstly, hypovitaminosis D is a global health problem
with detrimental consequences and notably, according to a recent
Workshop Consensus for Vitamin D Nutritional Guidelines,
approximately 50% of the elderly population in North America and
60% in the rest of the world have insufcient levels of vitamin D,
partly due to reduced outdoor activity, global dimming and decreases in the skin synthesis of vitamin D with age [2,3]. Large
proportions of younger populations also have unsatisfactory
vitamin D concentrations. If the correlation between hypovitaminosis D and CV events that were recently reported by epidemiological pooled analysis of prospective studies is true, vitamin D
supplementation will function dually both to neutralize inadequate
vitamin D levels and the direct metabolic consequences and as a
prevention tool of the number one cause of death, CV disease
[2,4,5]. Conversely, should the evidence strongly suggest adverse
effects of the vitamin on the CV system, its use will be restricted
where possible and replaced by safer alternatives.
The present review specically discusses the relationship between vitamin D and serum lipid prole, focusing on evidence
deriving from all RCTs identied in the literature.

limited to, blood pressure, serum lipids, CV events, CV death, cardiac work and cardiometabolic syndromes [8].
1.2. Vitamin D2 versus vitamin D3
Although the major source of vitamin D is synthesis in the skin
secondary to ultraviolet (UV) B irradiation, it can also be acquired
through dietary consumption. Vitamin D may exist in the form of
vitamin D2 (ergocalciferol), which derives from the UV irradiation of
ergosterol (found in plants and fungi), or vitamin D3 (cholecalciferol) that is produced after UVB irradiation of 7-dehydrocholesterol
in the skin of animals. Both are thought to be prohormones as they
are biologically inactive and only after a two-step hydroxylation
process in the liver and kidneys do they yield the active hormone
1,25-dihydroxyvitamin D (calcitriol). Synthetic supplements exist in
both D2 and D3 forms and even though both are eventually converted to the biologically active metabolite, recent data suggested a
difference in their efcacy in raising serum 25-OH D, which is the
established marker of vitamin D status [9].
In fact, a large meta-analysis of RCTs indicated that vitamin D3
supplements may be more efcacious in elevating serum 25-OH D
compared to vitamin D2 supplements, as a statistically signicant
difference was reported. The favoring of vitamin D3 was evident
even with small daily doses and less frequent administration as a
bolus at higher dosages [9].
Additionally, a Cochrane meta-analysis investigating the effects
of vitamin D supplementation on all-cause mortality found that
only vitamin D3 supplementation seems to decrease mortality,
while vitamin D2, calcitriol and alfacalcidol had no statistically
signicant effect on mortality [10].
The exact reasons underlying this difference are still unclear,
however these results must be taken seriously into consideration
for the future manufacture and use of vitamin D supplements [9].
1.3. Vitamin D status

1.1. Vitamin D receptor

The vitamin D receptor (VDR) has been historically considered
as the only means by which calcitriol achieves its functions, which
were thought to be exclusively endocrine and related to mineral
metabolism. The VDR initially couples with retinoic X receptor to
form a heterodimer, which subsequently binds to vitamin D
response elements in the promoter regions of target genes. Recent
data, however, has shown that the VDR is expressed in a number of
tissues leading to various effects such as immunomodulation and
enhancement of cellular proliferation and differentiation. Interestingly, vitamin D regulates around 3% of the genome with
numerous effects and functions. Finally, a cytoplasmic form of the
VDR has also been identied that responds rapidly or nongenomically to calcitriol and is thought to be involved in cellular
calcium handling and other processes [6e8].
The identication of VDR expression in endothelial cells,
vascular smooth muscle cells and cardiac myocytes strongly reinforced the presence of a relation linking vitamin D and the CV
system, without, however, implying the nature of this association.
Potential effects have been proposed on factors including, but not

Each individual may be characterized as vitamin D decient,

insufcient or sufcient based on serum 25-OH D levels. The limit
for deciency is set at a value (20 ng/ml) below which PTH levels
become suppressible when challenged with pharmacologic doses
of vitamin D and sufciency is above the value (30 ng/ml) where
PTH levels reach their lowest and intestinal calcium absorption is at
its maximum. Hence deciency is <20 ng/ml, sufciency >30 ng/
ml and insufciency in-between (21e29 ng/ml) [2]. In order for
sufcient levels to be achieved, at least 1000 International Units
(IU) of vitamin D2 or D3 are thought to be required daily in cases
where sun exposure is either absent or inadequate (e.g. winter,
sunscreen use) [2].
2. Evidence
2.1. Vitamin D and CV events
Before discussing the potential CV effects of the vitamin, a
concise section summarizing its reported association with CV
events is worthwhile, as possible links with CV mortality and

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D. Challoumas / Atherosclerosis 235 (2014) 130e139

events may be more important than correlations to CV parameters.

In overview, despite the existence of a few studies that report
neutral ndings, the protective properties of vitamin D in terms of
CV events and all-cause mortality are evident in the literature [10e
15].
A prospective cohort study found no association between dietary or serum vitamin D and CV disease, which included coronary
heart disease and cerebrovascular accidents [11]. Conversely, after
prospectively following Framingham Offspring Study participants,
Wang et al. reported a graded increase in CV disease with
decreasing serum 25-OH D levels, while vitamin D deciency was
found to be associated with increased incidence of myocardial
infarction and mortality in a population of older adults [12,13]. The
Honolulu Heart Program, nally, is in support of the protective CV
effects of vitamin D as low dietary vitamin D consumption
appeared to be an independent risk factor for 34-year incidence of
all stroke and thromboembolic stroke in JapaneseeAmerican men
[14].
All-cause mortality (including CV mortality) may be higher with
vitamin D deciency according to a Norwegian study, however the
association was statistically signicant in non-smokers only [15]. A
review conducted by the Cochrane Collaboration reported protective effects of vitamin D supplementation (only in the form of
vitamin D3) in terms of all-cause mortality mainly in elderly females who are predominantly in institutions and dependent care
and nally, another meta-analysis of RCTs found that intake of ordinary doses of vitamin D supplements seems to be associated with
lower total mortality rates [10,16].
2.2. Vitamin D and lipid prole e a summary of observational
studies
Historically, researchers have found that individuals with high
serum vitamin D levels have a more favorable lipid prole
compared to vitamin D-insufcient or decient people [17e21].
A Norwegian study aiming to examine whether the increased
mortality associated with low serum 25-OH D concentrations is
related to serum lipids found positive results. The study consisted
of a cross-sectional (n 10,105) and a longitudinal study
(n 2159). In the former, signicant increases were noted in total
cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL), as well as signicant reductions in serum triglycerides and LDL/HDL with decreasing serum 25-OH D levels.
Smokers in the highest serum 25-OH D quartile had 18.5% lower
serum triglyceride levels compared to those in the lowest quartile.
The longitudinal study (14 years duration) revealed an inverse
association between serum triglyceride and serum 25-OH D levels.
The ndings of both components of this study contribute to
explain the increased mortality in populations with low serum 25OH D concentrations [19].
Ponda et al. selected 108,711 patients who had repeated
serum 25-OH D and lipid testing 4e26 weeks apart from 4.06
million laboratory test results. With increasing serum 25-OH D
levels, pronounced differences were observed in lipid proles:
decreases in total cholesterol, LDL and triglycerides and an increase in HDL. However, the outcomes of the interventional part
of the same study are in contrast to the results of these observational data [20].
Following their cross-sectional study, the same group performed a retrospective cohort study which revealed that, despite
the association between low serum vitamin D concentrations and
unfavorable lipid prole, replenishing vitamin D to correct the
deciency may not necessarily improve lipid concentrations. This
longitudinal part of the study included 2 subgroups: 6260 patients
(repletion group) with initial serum 25-OH D concentrations

<20 ng/ml and immediate subsequent 25-OH D levels >30 ng/ml,

and 2332 patients (control group), whose both initial and immediate subsequent serum 25-OH D was <20 ng/ml. Between the
initial and the nal visits, total cholesterol decreased more in the
control than the repletion group, while HDL signicantly rose when
serum 25-OH D increased. No signicant differences were observed
in either LDL or triglyceride concentrations between the two
groups [20]. A very important strength of this study is that the
authors proved that the rise in serum 25-OH D levels observed in
the repletion group was secondary to dietary supplementation and
not skin synthesis. They did this by comparing the increases in
vitamin D2 levels, the source of which is supplementation, between
initial and nal visits and showed that it increased 22.2 ng/ml of the
total 25-OH D increase of 27.3 ng/ml in the repletion level, whereas
in the control group, it increased 0.6 ng/ml of the total 0.9 ng/ml of
serum 25-OH D increase [20].
This inverse association between serum vitamin D and lipid
levels is also evident in children and adolescents. A large metaanalysis by Kelishadi et al. that included 17 cross-sectional
studies (n 25,394) describes weak but signicant benecial associations between serum vitamin D levels and all the important
constituents of the lipid prole: triglycerides (r 0.135), total
cholesterol (r 0.086), LDL (r 0.025) and HDL (r 0.156) [21].
2.3. Vitamin D and lipid prole e metabolic studies
A signicant number of metabolic studies have been conducted
in an attempt to give answers to the ndings of observational
studies and reveal latent associations between vitamin D and
serum lipids.
It has been proposed that the VDR determines cholesterol levels
through regulating bile acid synthesis from cholesterol at a genetic
level [22]. Firstly, two studies in mouse and human hepatoma cells
in 2006 showed that the VDR blocked the expression of farnesoid X
receptor (FXR) which normally acts indirectly to decrease the
expression of the Cyp7a1 gene that codes for CYP7A1, the ratelimiting enzyme in bile acid synthesis, hence resulting in an
elevation of cholesterol levels [23,24].
Specically, Jiang and colleagues found that vitamin D downregulates Cyp7a1 expression through actions on the Liver X Receptor (LXR) alpha, which normally induces the expression of
Cyp7a1 in mice [23]. However, this does not apply to humans as the
CYP7A1 promoter lacks an LXR-binding site. In the second study,
Honjo et al. showed that vitamin D inhibits the chenodeoxycholic
acid-dependent transactivation through the VDR. Reverse transcription PCR conrmed the effect of vitamin D on the expression of
the SHP gene, which normally acts to inhibit the expression of
Cyp7a1, and the specic interaction between FXR and VDR was
identied with the in vitro pull-down assay using chimeric FXR or
VDR fused to glutathione-S-transferase [24].
In contrast to the above ndings is the recent study by Chow
et al. [25]. The authors report reduction in both liver and serum
cholesterol due to activation of Cyp7a1, which appears to be secondary to SHP repression [25]. Similarly, Schmidt et al. demonstrated that mice with knocked out VDR receptors had elevated
Cyp7a1 expression secondary to decreased SHP [26]. A subsequent
injection of calcitriol increased Fgf15 RNA in the intestine which
inhibited Cyp7a1 RNA. This is in contrast with the results of Chow
et al., as calcitriol administration in their study increased Cyp7a1
RNA. The latter authors conclude that there may be a dosedependent effect between the VDR and Cyp7a1 expression as
their calcitriol dose was lower than that used by Schmidt et al.
[22,25].
Finally, Wang and colleagues seem to disagree with the above
ndings. After comparing wild-type mice to VDR-knocked out (KO)

D. Challoumas / Atherosclerosis 235 (2014) 130e139

mice in terms of lipid parameters, they concluded that food, gender

and genetic background factors have effects on the metabolism of
cholesterol, while the role of the VDR seems to be minimal
although it seems to regulate some of the genes involved in the
pathway [27].
The proposed genetic pathway linking vitamin D to the metabolism of cholesterol is illustrated in Fig. 1.
Additionally, with regards to vitamin D effects on other CV parameters, in a recent study, Schmidt et al. demonstrated enhanced
vascular calcication in LDL-receptor-KO mice which were fed a
diet low in vitamin D compared to those that received adequate
vitamin D in their diets. The calcication was accompanied by a
transdifferentiation of vascular cells to osteoblast-like cells and, in
fact, subsequently feeding the mice that received low vitamin D
with normal diets containing sufcient vitamin D actually reversed
the calcication [28].
VDR-null mice, furthermore, have been observed to develop
high renin hypertension, cardiac hypertrophy and increased
thrombogenicity [29], while evidence from another study suggests that macrophage VDR signaling inhibits atherosclerosis in
mice, partly by suppressing the local renineangiotensin system
[30].
It has also been demonstrated that calcitriol administration may
inhibit renin transcription in a mouse model as well as morphological and functional changes in rat cardiomyocytes [31,32]. Lastly,
paricalcitol was found to halt left ventricular hypertrophy in uremic
rats and suppress myocardial brosis in mice with pressure overload [33,34].
In summary, even though mouse and rat models seem to be
convincing regarding the protective effects of vitamin D on the
CV system, the outcomes of those evaluating associations of
the vitamin with serum lipids in particular are highly
controversial and inadequately clear. In fact, even if correlations are proven in the future in such metabolic studies,
questions will still remain about the translatability of the
ndings to humans.
2.4. Proposed effects of vitamin D on the CV system
In their recent review article, Messa et al. neatly listed the putative effects of vitamin D on the CV system, both direct and indirect, primarily based on ndings of metabolic studies. Positive

Fig. 1. Transcriptional regulation of hepatic Cyp7a1.

Adapted by Gonzalez and Moschetta [22].

133

aldosterone system (RAAS) activity, the reduction of apoptosis of

vascular smooth muscle cells (VSMCs) and cardiomyocytes, endothelial protection, and osteopontin upregulation, while the only
direct negative effect is the increase of VSMCs that results in
osteoblast cell transition [8].
Most of the CV effects of vitamin D on the CV system are exerted
indirectly and the vast majority of these indirect effects are benecial, including reductions in blood pressure secondary to RAAS
inhibition, sodium/potassium balance improvement, reduction in
VSMC proliferation and tone, and stimulation of vascular
relaxation.
The mechanism underlying the inverse association between
serum lipids and vitamin D levels is thought to be reduced intestinal absorption and synthesis of lipids as well as lipolysis
with increasing concentrations of vitamin D. Additionally,
secretion and sensitivity of insulin are both thought to be
increased reducing the risk of both diabetes mellitus and
metabolic syndrome, and improved metabolism of both glucose
and lipids has been reported. Platelet aggregation and thrombogenicity are inhibited which, combined with the favored
brinolysis, result in decreased thrombopropensity. Reduction in
vascular calcication appears to be owing to reduced parathyroid hormone (PTH) levels as well as increases in Klotho
expression (a protein produced in the distal tubule functioning
as an FGF23 co-receptor and as an independent hormone),
which may be a possible interpretation of the possible protective
effects of vitamin D on the CV system, as Klotho and FGF23 have
been shown to affect CV outcomes and global mortality. The
other possible mechanism of vitamin D-protective properties on
the CV system may be reductions in vascular wall inammation
(suppressed release of IL-1, IL-6 and TNF-a), secondary to the
inhibition of macrophage migration [2]. Finally, improvements in
renal function have also been described [8].
Negative indirect effects are principally associated with
increased vascular calcication due to increased serum calcium and
phosphorus levels and the excessive reduction in PTH levels. Lastly,
vitamin D may affect cardiac morphology secondary to inducing
the production of FGF23, high levels of which are thought to cause
left ventricular hypertrophy [8].
Table 1 summarizes the proposed effects (direct and indirect)
of vitamin D on the CV system with special reference to serum
lipids.

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D. Challoumas / Atherosclerosis 235 (2014) 130e139

Table 1
Summary of the proposed effects of vitamin D on a) cardiovascular parameters other
than serum lipids, and b) serum lipids specically. CV: cardiovascular; BP: blood
pressure; VSMC: vascular smooth muscle cells; VC: vascular calcication; PTH:
parathyroid hormone; LVH: left ventricular hypertrophy [8].
Proposed effects of
vitamin D on CV
parameters other
than serum lipids

Positive
Reduces BP due to RAAS inhibition, decreased VSMC
tone, better control of Na/K balance, and vascular
relaxation
Increases insulin secretion and sensitivity that may
prevent diabetes mellitus
Decreases platelet aggregation
Reduces VC by decreasing PTH levels and increasing
Klotho expression
Lowers thrombogenicity, inhibits platelet aggregation
and improves brinolysis
Enhances glucose metabolism and exerts antiinammatory actions
Reduces VSMC and suppresses cardiomyocyte
apoptosis
Negative
Increases VC by increasing calcium and phosphorus
levels and by causing a dynamic bone disease
secondary to excessive PTH reduction
Causes LVH by upregulating FGF23 levels

Proposed effects of
vitamin D on serum
lipids

Positive
Reduces intestinal absorption and synthesis of lipids
Enhances lipolysis
Improves lipids metabolism
Improves insulin action that may prevent metabolic
syndrome
Reduces cholesterol levels by inhibiting bile acid
synthesis

3. Vitamin D and lipid prole e randomized controlled trials

Despite the promising data of the observational studies, RCTs
fail to indicate a causal association between vitamin D consumption
and a favorable lipid prole. Out of 19 RCTs found in the literature
up to date, only 1 demonstrated benecial effects of vitamin D
supplementation on serum lipid levels, while, importantly, the only
meta-analysis identied, reported statistically signicant adverse
outcomes in some parameters [35e53].
3.1. Selection of studies and inclusion criteria
For the identication and selection of all available papers in the
literature, two articles were initially used from which all available
papers up to 2012 were extracted: the review article by Jorde and
Grimnes (2011) and the meta-analysis by Wang et al. (2012)
[54,55]. Ten studies are listed and discussed in the former and 12 in
the latter.
For the identication of all relevant articles from 2012 until
present as well as any possible studies missed by the two aforementioned papers, a systematic literature search was conducted via
MEDLINE, Cochrane Library and EMBASE for RCTs reporting on the
effects of vitamin D supplementation on any parameter(s) of the
lipid prole (triglycerides, total cholesterol, LDL, HDL, and LDL/HDL
ratio) up to March 2014. The keywords used (in all elds) were as
follows: (vitamin D OR calcitriol OR vitamin D3 OR cholecalciferol
OR ergocalciferol OR 25-hydroxyvitamin D) AND (lipids OR triglycerides OR cholesterol OR LDL OR HDL) with no language or time
restrictions. After exclusion of duplicate articles, a manual selection
of titles, rst, and then abstracts followed, which resulted in 19
studies that met the requirements of the present study.
The only inclusion criterion was at least one treatment group
receiving vitamin D monotherapy which was compared to placebo
with regards to any parameters of the lipid prole. The study by

Pfeifer and colleagues (2001) included in both the article by Jorde

and Grimnes and the meta-analysis was excluded from this review
as their treatment group received a combination of vitamin D plus
calcium supplements [56]. The treatment group of one study (Maki
et al., 2011) received vitamin D plus a multivitamin and mineral
regimen, it was however included in the present analysis as the
subjects of their control group were administered the same
multivitamin and mineral regimen instead of placebo [53]. Similarly, both the treatment and the control groups in the study by
Jorde et al. were administered calcium supplements, therefore the
study was not excluded. Finally, there were treatment groups in
another three studies (Heikkinen et al., 1997, Sai et al., 2011, and
Chai et al., 2013) that received regimens other than vitamin D
monotherapy, including a combination of vitamin D supplements
plus other regimens (hormone-replacement therapy, conjugated
equine estrogens/medroxyprogesterone, and calcium respectively);
neither of these three studies were excluded and only the treatment arms receiving vitamin D monotherapy compared to those
receiving placebo were analyzed [43,44,46].
The RCTs discussed are listed and summarized in Table 2 with
their key characteristics and results [35e53].
3.2. Benecial effects
Kane et al. randomized 49 patients with inadequate vitamin D
status to either placebo or vitamin D3 titrated between 1000 and
3000 IU daily to achieve serum 25-OH D concentrations equal to
and over 25 ng/ml. Vitamin D supplementation had no effects on
cholesterol or cholesterol subfractions except for a borderline signicant drop in LDL in patients receiving atorvastatin. Furthermore,
total serum 25-OH D was not associated with decreases in lipids,
whereas free 25-OH D levels were inversely correlated at statistical
signicance with triglycerides in all participants and with triglycerides, LDL and total cholesterol in statin-treated groups. The
authors conclusion is therefore that vitamin D is probably effective
at lowering lipid levels only in statin-treated individuals and free
25-OH D levels may be superior to total 25-OH D in detecting relationships between lipids and vitamin D status [35].
3.3. Neutral or adverse effects
3.3.1. Single-dose or periodical supplementation
Short-term (8-week) supplementation with 50,000 IU of
vitamin D3 weekly did not appear to improve lipid prole in
another RCT of 151 vitamin D decient (<20 ng/ml) patients with
increased risk for CV disease. Serum 25-OH D was measured and
found higher in the treatment group compared to placebo at 4 and
8 weeks of intervention. Between treatment and placebo groups, no
signicant differences were found with regards to either the primary outcome (small LDL particle number) or the secondary outcomes (total cholesterol, LDL, HDL, triglycerides). In fact, short-term
repletion of serum 25-OH D was associated with signicantly raised
serum LDL and LDL particle number that were secondary to raised
serum calcium and decreased serum PTH, according to the authors.
In conclusion, acute repletion of vitamin D levels not only does it
not improve lipid prole but it may actually raise LDL due to increases in calcium and reductions in PTH levels [36].
Witham et al. found that a single dose of 100,000 IU of vitamin
D3 was not effective in altering the lipid prole compared to placebo at either 4 or 8 weeks in South Asian women living in the UK,
although it had a benecial outcome on platelet activation
inhibitor-1 and tissue plasminogen activator, both of which were
signicantly lower in the treatment group. Baseline characteristics
may have inuenced outcomes, though, as serum PTH levels, which
are known to exert effects on the CV system, were signicantly

Table 2
Randomized Controlled Trials (double-blinded) investigating the effects of vitamin D supplementation on serum lipids from 1987 to present. vitD: vitamin D; M: males; F: females; IU: international units; d: day; TC: total
cholesterol; TGL: triglycerides; LDL: low-density lipoprotein; HDL: high-density lipoprotein; yrs: years; PTH: parathyroid hormone; CV: cardiovascular [35e53].

Ljunghall
et al, 1987
Scragg et al,
1995

Heikkinen
et al, 1997

Population (sex; age)

Study
period

Intervention

Key ndings

Evaluate the possible clinical signicance of the role of

vitD in insulin secretion.
A possible role for vitD deciency in contributing to the
winter increase in cardiovascular disease mortality was
investigated by testing the effect of vitD
supplementation on blood pressure and other
cardiovascular risk factors during winter.
The long-term effects of hormone replacement therapy
and vitD on the concentrations of serum lipids were
studied in a population-based prospective 3-year study.

n 65 Swedish with impaired glucose tolerance (all

M; 61e65 yrs)
n 189 New Zealanders (104 F; 63e76 yrs)

12 weeks

30 IU/d vitD or Placebo

5 weeks

Single dose of 100,000 IU

vitD (n 95) or placebo
(n 94).

hTC, TG, HDL between treatment

and placebo groups (p > 0.05).
hTC (p 0.81), HDL (p > 0.05) and
LDL (p > 0.05) between treatment
and placebo groups.

n 464 postmenopausal Finnish (all F;

postmenopausal)
For vitD only and control groups n 178

3 years

300 IU/d vitD (n 83) or

placebo (n 95)

400 IU/d vitD (n 56)

or 800 IU/d vitD (n 61)
or placebo (n 56)
120,000 IU/fortnightly
(n 50) or placebo
(n 50)

Andersen
et al, 2009

Investigate possible negative effects of vitD

supplementation on serum lipids and lipoproteins.

n 173 Pakistani immigrants (89 F; 18e64 yrs)

1 year

Nagpal et al,
2009

To determine the short-term effect of vitD

supplementation on insulin sensitivity in apparently
healthy, middle-aged, centrally obese men.

n 100 obese Indians (all M; >34 yrs)

6 weeks

Zittermann
et al, 2009

Investigate the effect of vitamin D on weight loss and

traditional and nontraditional cardiovascular disease
risk markers in overweight subjects.

n 165 healthy obese Germans in a weightreduction program (102 F; 48  10 yrs)

1 year

3320 IU/d vitD (n 83) or

placebo (n 82)

Jorde et al,
2010

Evaluate the effects of vitD supplementation on weight

loss (primary endpoint), blood pressure, lipids and
glucose levels (secondary endpoints).

n 438 obese Norwegians (211 F; 49  11 yrs)

1 year

von Hurst
et al, 2010

Investigate the effect of improved vitD status on insulin

resistance and other secondary outcome variables (lipid
prole and high sensitivity C-reactive protein).
Test whether vitD supplementation could reduce blood
pressure and improve markers of vascular health in
patients who had previously suffered a stroke.
Compare the effect of 100,000 and 200,000 IU doses of
vitD on endothelial function, blood pressure and
markers of glycemic control in patients with type 2
diabetes.
Assess the effects of vitamin D supplementation on
serum 25-OH D and HDL in subjects with high waist
circumference.

n 81 South Asians (all F; 23e68 yrs)

6 months

40,000 IU/week (n 114)

or 20,000 IU/week
(n 104) or placebo
(n 112)
4000 IU/day (n 42) or
placebo (n 39)

n 58 Scottish stroke patients (16 F; mean age

67  10 yrs)

16 weeks

100,000 IU once (n 30)

or placebo (n 28)

n 58 Scottish diabetics (20 F; 65  10 yrs)

16 weeks

n 60 subjects with high waist-circumference (18

e79 yrs)

8 weeks

100,000 IU once (n 19)

or 200,000 IU once
(n 18) or placebo
(n 21)
Daily multivitamin &
mineral (n 30) or Daily
multivitamin & mineral
plus 1200 IU/d vitD
(n 30)

Witham et al,
2010
Witham et al,
2010

Maki et al,
2011

[LDL in vitD group compared to

baseline (p 0.035) and did not
change in placebo group (p > 0.05).
YHDL in vitD group compared to
baseline (p 0.001) but also Y in
placebo group (p 0.006).
YHDL/LDL ratio in vitD group
compared to baseline (p < 0.001)
and unchanged in placebo group
(p > 0.05).
hTC and TG between vitD and
placebo groups (p > 0.05).
hTC, TG, LDL, HDL and LDL/HDL
between treatment and placebo
groups (p > 0.05).
hTC (p 0.48), TG (p 0.21), LDL
(p 0.21), HDL (p 0.11) and VLDL
(p 0.24) between treatment and
placebo groups.
[LDL in treatment group compared
to placebo group (p < 0.001).
hTG (p 0.71) and HDL (p 0.41)
between treatment and placebo
groups.
hTC, TG, LDL and HDL between
placebo and treatment groups
(P > 0.05).

D. Challoumas / Atherosclerosis 235 (2014) 130e139

Aims

hTC, TG, LDL, HDL and TG/HDL

between treatment and placebo
groups (p > 0.05).
hTC (p 0.61) and LDL (p 0.66)
between treatment and placebo
groups.
hTC between 100,000 IU group and
placebo group (p 0.51) and
between 200,000 IU group and
placebo group (p 0.18).
hTC, TG, LDL and HDL between
treatment and placebo groups
(p > 0.05).

(continued on next page)

135

136

Table 2 (continued )
Population (sex; age)

Study
period

Intervention

Key ndings

Examine the effect of conjugated equine estrogens

alone (ET), conjugated equine
estrogens medroxyprogesterone (EPT), calcitriol
alone, calcitriol EPT/ET, or placebo on serum lipid
prole.
Test whether vitD supplementation could improve
endothelial function and other markers of vascular
function in patients with a history of myocardial
infarction.
Investigate the effect of vitamin D supplementation on
endothelial function in patients with type 2 diabetes
mellitus.

n 489 postmenopausal Americans

(all F; 65e77 yrs).
For vitD-only and placebo groups n 213

3 years

20 IU/d. vitD (n 101)

or placebo (n 112)

hTC, TGL, HDL, LDL, HDL/LDL

between vitD-only and placebo
groups (p > 0.05).

n 75 patients with history of myocardial

infarction (33 F; mean age 66 yrs)

6 months

n 100 Hong Kong diabetics (50 F; mean age

65 yrs)

12 weeks

300,000 IU vitD (n 39)

given at baseline, 2 and 4
months follow-up or
placebo (n 36)
5000 IU/d vitD (n 50) or
placebo (n 50)

Estimate the effects of calcium or vitD supplementation

or a combination of both on blood pressure and serum
lipid and carotenoid levels.
Investigate effects of correcting inadequate vitD status
on lipids and determine whether free 25-OH D is better
correlated with lipids than total 25-OH D.

n 92 colorectal adenoma patients (28 F; 30

e75 yrs).
For vitD-only and placebo groups n 46
n 49 vitD-inefcient American adults (23 F;
60  10 yrs)

6 months

800 IU/d vitD (n 23) or

placebo (n 23)

12 weeks

1000e3000 IU/d vitD

(n 26) or placebo
(n 23)

Ponda et al,
2013

Determine the short-term effects of vitD repletion on

the lipid prole.

n 151 vitD-decient patients with increased risk

for CV disease (83 F; 18e85 yrs)

8 weeks

50,000 IU/week vitD

(n 76) or placebo
(n 75)

Witham et al,
2013

Evaluate whether vitD supplementation could improve

markers of vascular health in South Asian women with
low 25-OH D levels.

n 50 South Asians (all F; mean age 41 yrs)

8 weeks

Single dose of 100,000 IU

vitD (n 50) or placebo
(n 50)

Zhou et al,
2013

Study the effect of oral vitD supplementation on VitD

status and serum lipid in Chinese obese and healthy
normal-weight men.

n 43 Chinese (all M; 20e69 yrs)

Obese group (BMI>28 kg/m2) n 21
Control group (BMI<24 kg/m2) n 22

8 weeks

50,000 IU vitD/week

hTC between treatment and

placebo groups at 2 months
(P 0.73) and 6 months (P 0.88)
follow-up.
hTC (p 0.46), TG (p 0.34), LDL
(p 0.37) and HDL (p 0.43)
between treatment and placebo
groups.
hTC (p 0.94) and TGL (p 0.17)
between vitD-only and placebo
groups.
YLDL in participants on atorvastatin
in treatment group (p 0.05).
Free 25-OH D inversely correlated
with TGL (p 0.03) in all subjects
and with TGL (p 0.03, LDL
(p 0.02) and TC (p 0.04) in
statin-treated participants.
No correlation between total 25-OH
D and lipids
hsmall LDL particle number
(P 0.63), TC (P 0.14), LDL
(P 0.13), HDL (P 0.71), TGL
(P 0.43) between treatment and
placebo groups.
In treatment group, elevated serum
calcium and reduced serum PTH
that were secondary to vitD
repletion were associated with
[LDL.
hTC, TG, HDL and, LDL between
treatment and placebo groups at 4
weeks (p 0.10, p 0.60, p 0.52,
p 0.12 respectively) or 8 weeks
(p 0.33, p 0.59, p 0.70,
p 0.39 respectively) follow up.
hTC, LDL and TG between obese and
control groups (P > 0.05).
YHDL (p 0.04) in obese group but
within normal limits.

Sai et al, 2011

Witham et al,
2012

Yiu et al, 2012

Chai et al,
2013
Kane et al,
2013

D. Challoumas / Atherosclerosis 235 (2014) 130e139

Aims

D. Challoumas / Atherosclerosis 235 (2014) 130e139

higher in the placebo group [37]. In a similar study by Witham and

colleagues (2013), 75 patients that previously experienced
myocardial infarction received 100,000 IU vitamin D3 supplements
or placebo at baseline, 2 months and 4 months and measurements
were performed at baseline, 2 and 6 months. Again, no differences
were found in cholesterol between the two treatment groups at 6
months [38].
Another small RCT in China is in accordance with the above
negative ndings as 50,000 IU of vitamin D3 supplements taken
once a week for 8 weeks resulted in no changes in the lipid prole
in 21 obese men and 22 healthy men except for a reduction in
serum HDL within the normal range in the obese group. After
performing measurements of serum 25-OH D, the authors also
concluded that the effect of high-dose vitamin D supplementation
may be weaker on the vitamin D status of obese individuals
compared to those with normal BMI. Baseline differences in all
parameters of the lipid prole existed both before and after supplementation between the two groups [39].
Nagpal and colleagues recruited 100 centrally obese, apparently
healthy men, who received either 3 doses of 120,000 IU vitamin D3
fortnightly or placebo [40]. No changes in lipid prole were seen
with supplementation, which is in support of the ndings of Jorde
et al. (2010): in an RCT of 438 overweight and obese patients who
took either 40,000 IU vitamin D3, 20,000 IU vitamin D3 weekly or
placebo for 1 year, no differences were noted in serum lipids between either of the two treatment groups and the placebo group.
Importantly, calcium supplementation was administered to all
participants, which may have inuenced the outcomes, however
the study is included in the analysis as both the placebo and the
treatment groups received the same amount of calcium supplementation [41]. Additionally, a large number of participants (25%)
dropped out which may decrease the validity of the study.
In an attempt to explain the increased CV mortality observed in
the winter, Scragg et al. randomized 189 elderly adults to either a
single dose of 100,000 IU vitamin D3 or placebo. Measurements 5
weeks later conrmed that serum 25-OH D did rise by vitamin D3
treatment and revealed no effect of short-term vitamin D supplementation on serum total cholesterol (or blood pressure), which
suggests that the winter increase in serum cholesterol (and blood
pressure) is not secondary to vitamin D insufciency [42].
Furthermore, a Scottish study reported no differences in total
cholesterol in 61 diabetics who received a single dose of either
placebo, 100,000 IU vitamin D3 or 200,000 IU vitamin D3 [43].
Another trial in Scotland with 58 patients with a stroke history
found that treatment with a single intervention of 100,000 IU of
vitamin D2 did not change total cholesterol at baseline, 8 and 16
weeks compared to placebo [44].
3.3.2. Daily supplementation
In a small RCT of 92 patients, those who received 800 IU/day
vitamin D3 monotherapy for 6 months did not experience any
changes in their circulating lipid levels compared to the placebo
group. All the participants of the study had a history of colorectal
adenoma and, importantly, serum 25-OH D levels were not
measured in follow-up to assess whether a signicant increase was
achieved with supplementation compared to the placebo group
[45].
Looking at the effect of hormone therapy and calcitriol on the
lipid prole of 489 postmenopausal women for 3 years, Sai and
colleagues reported ndings similar to the remainder RCTs that
showed no effects of vitamin D on the lipid prole. Despite the
signicant association between estrogen receptors and lipid prole
reported, this group found that their calcitriol-only group, who
were administered 20 IU vitamin D/day for 3 years had no signicant changes in total cholesterol, triglycerides, HDL, LDL or LDL/HDL

137

ratio compared to placebo. It is worth noting, however, that there

were statistically signicant baseline differences in LDL and LDL/
HDL ratio among the treatment groups that may have had an
impact on the outcomes and also the dose of calcitriol administered
was substantially lower compared to all other trials [46].
Ljunghall et al. (1987) performed the rst RCT, to the best of our
knowledge, examining the effects of vitamin D on serum lipids.
Daily supplementation with 30 IU of vitamin D3 for 3 months led to
no signicant effects on the lipid prole versus placebo in 65
vitamin D sufcient middle-aged men with impaired glucose
tolerance [47]. A decade later, a Finnish study (1997) showed that
there may, in fact, be unfavorable consequences of vitamin D3
supplementation on serum lipid values, as it signicantly increased
serum LDL compared to the placebo group at 3 years. Total
cholesterol remained unchanged after vitamin D3 treatment
(300 IU/day) and HDL dropped, however it also decreased in the
placebo group and between-groups difference was non-signicant.
The HDL/LDL ratio decreased in the vitamin D3 group compared to
the control group whereas serum triglycerides did not change [48].
This study was different to most of the rest as the placebo group
received calcium tablets, which may have had their own independent effects on participants CV parameters. Finally only 69% of the
participants completed the trial.
A Danish study of 173 Pakistani immigrants aiming to investigate possible negative effects of vitamin D on lipid prole also failed
to nd any associations. Daily supplementation with 400 or 800 IU
vitamin D for 1 year was not associated with unfavorable (or
favorable) outcomes on serum total cholesterol, LDL, HDL, LDL/HDL
ratio, VLDL or triglycerides compared to subjects receiving placebo
[49].
Additionally, a study in New Zealand where 81 insulin-resistant,
vitamin D-decient South Asian women were given 4000 IU
vitamin D3 daily or placebo showed no effects of vitamin D treatment on serum lipids (secondary outcome variable); improvements, however, were observed in insulin sensitivity (primary
outcome variable) [50].
A recent study by Zittermann et al. reinforces the negative, or
even adverse, effects of vitamin D supplementation on LDL as this
was increased after supplementation with 3332 IU/day for 1 year
compared to placebo in 200 healthy overweight participants
(BMI > 27). The same study, however, reported benecial outcomes
of vitamin D on triglycerides, which substantially and signicantly
dropped compared to the control group. Noteworthily, the subjects
of the population group were concurrently participating in a
weight-reduction program; the interventions of this as well as
other weight loss-activities in which the participants might have
engaged may have inuenced lipid prole independently of
vitamin D supplementation [51].
Similarly, neither the HDL nor the LDL were found to change in
diabetic patients who received 5000 IU/day vitamin D supplementation (n 50) for 12 weeks versus the placebo group (n 50)
in Hong Kong [52].
In the study by Maki et al., 60 subjects with high waist
circumference received either a daily multivitamin and mineral
supplement (control group) or a daily multivitamin and mineral
supplement plus 1200 IU of vitamin D (treatment group) for 8
weeks. The results revealed that the treatment group did not have
signicant differences in the CV disease risk markers (including
lipid prole) compared to the control group and interestingly, the
administered dose of vitamin D was not adequate to raise serum
25-OH D to desirable levels (>75 nmol/ml) in 61% of participants.
An important drawback of this study, however, may be the coadministration of the multivitamin/mineral supplement, as one
or more of its elements may have had their own effect on serum
lipid parameters [53].

138

D. Challoumas / Atherosclerosis 235 (2014) 130e139

Perhaps the most important article in the eld, the only metaanalysis, which analyzes 12 RCTs (total of 1346 patients) that
examine the association between vitamin D supplementation and
serum lipids either as primary or secondary end-points, is in
accordance with the latter study as it does not contribute any
support regarding the benecial effects of treating dyslipidaemia
by correcting serum 25-OH D concentrations. Not only did the lipid
prole not improve, some of its parameters actually worsened.
Total cholesterol increased at statistical signicance (P 0.02) and
so did LDL, however the elevation in the latter was only signicant
in obese patients (P 0.04), with supplementation less than a year
(P 0.02) and after exclusion of low quality studies (P 0.03) [55].
The lack of association between LDL and vitamin D supplementation in the long-term may be explained by reduced compliance,
according to the authors [55].
4. Paradox
Even though the associations noted in observational studies are
well established, a causal effect has not yet been proven and a
paradox exists: promising ndings of observational studies versus
discouraging results of interventional studies.
Reasonable explanations have been suggested to provide an
explanation to this discrepancy: insufcient activity is a known risk
factor for unfavorable lipid proles, therefore dyslipidemia may be
the result of reduced outdoor activity; these people may also have
decreased serum vitamin D levels due to inadequate sun exposure
[57]. Moreover, obesity, which is a widely accepted risk factor for CV
disease, may be a cause of decreased serum vitamin D levels due to
a volumetric dilution of the fat-soluble vitamin D in adipose tissue
[58].
Along the same lines, Jorde and Grimmes, in an attempt to
explain this paradox, make a logical assumption: healthy people
stay outdoors longer and are hence exposed to more sunshine
which increases vitamin D production and most likely have better
eating habits as well. This implies that their higher vitamin D levels
may not be the cause of good health but its outcome instead [59].

Finally, trials evaluating the combined effect of vitamin D plus

calcium supplementation on any CV parameter should be studied
as a separate subject to calcium and vitamin D monotherapies; for
this reason such studies have not been included in this review
[56,67].
6. Conclusion
The relationship between vitamin D and lipids in humans is a
topic that has not been adequately investigated and trustworthy
evidence does not yet exist. In spite the fact that some of the
mechanisms by which vitamin D may decrease serum cholesterol
have been proven in mice after molecular analyses, doubts still
remain about their applicability to humans.
Despite the benecial properties of high serum vitamin D concentrations in terms of the lipid prole shown in the observational
studies, interventional studies fail to support the benet of raising
vitamin D levels to improve lipid prole and, in fact, adverse outcomes have been reported in some cases. Therefore, even though
recommendations for the use of vitamin D supplements to enhance
various health parameters have repeatedly been made, we are still
lacking signicant evidence for their potentially positive effects on
serum lipids.
Denitive answers regarding the properties of vitamin D in
terms of lipids will only be given by large, well-designed RCTs that
will achieve high participants completion rates and assure dietary
intake assessment and adjustment. Finally, they will ideally include
vitamin D decient patients with hyperlipidemia and neutralize
confounding factors, including, but not limited to, calcium and PTH
effects on the parameters under investigation [59].
Conict of interest statement
The authors report no relationships that could be construed as a
conict of interest.

5. Vitamin D, calcium and PTH: which is to blame?

References

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independently of which one is administered in interventional
studies or measured in observational studies, therefore extensive
analyses need to me performed for accurate and specic conclusions to be reached.

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