Reviews in Clinical Gerontology 2014 24; 158171 First published online 3 March 2014

Cambridge University Press 2014 doi:10.1017/S0959259814000045

Vitamin D in older people

Miles D Witham and Gavin Francis
Ageing and Health, Medical Research Institute, University of Dundee, UK

Summary by one of the authors, supplemented by PubMed

Vitamin D has a wide range of biological effects
searches (key search terms vitamin D AND [trial
beyond calcium and bone metabolism, and low OR systematic review]). Searches were focused
25-hydroxyvitamin D levels have been associated by incorporation of further terms specific to each
with many disease states in recent years, including topic area, and were then further supplemented by
cardiovascular disease, diabetes, infections and cancer. inclusion of references from the authors personal
Association studies of vitamin D are notoriously prone library.
to confounding and to reverse causality, however,
and current intervention trial data for non-skeletal
indications have been disappointing. Vitamin D is Vitamin D metabolism
indicated for treatment of osteomalacia in older people, Vitamin D synthesis
falls prevention in institutionalized older people, and
as adjunctive therapy for osteoporosis. Large trials Endogenous vitamin D is synthesized when UVB
currently underway will ascertain whether potentially radiation (UVB) reaches the 7-dehydrocholesterol
beneficial effects of vitamin D supplementation on all- (7-DHC) contained in the skin layers, with
cause mortality in older people are borne out. further conversion from pre-vitamin D3 to the
Key words: vitamin D, older people, clinical trials. vitamin D3 molecule (cholecalciferol). From
here it preferentially binds to the vitamin D-
binding protein (VDBP) and enters the circulation.
Introduction Cutaneous production is limited by factors such as
the zenith angle of the sun, skin pigmentation and
The role of vitamin D in calcium homeostasis and proportion of skin exposed to sunlight.1
bone health has been recognized for decades, and
it continues to be an important agent in preventing
osteomalacia and reducing fragility fractures in Other sources of vitamin D
older people. Given the wide range of physiological Vitamin D is also obtained from the diet, present
systems that vitamin D affects, interest remains as vitamin D3 (cholecalciferol) or vitamin D2
high in other potential therapeutic uses for (ergocalciferol). A few foods contain vitamin
vitamin D particularly around cancer prevention, D3 such as fatty fish, fish liver oils and
cardiovascular health and immune function. This small amounts in liver, cheese and egg yolks.
review article will outline the physiological role of Mushrooms, particularly those irradiated by UVB,
vitamin D, the disease processes that have been contain vitamin D2. A number of foods such
associated with insufficiency and examine whether as cereals, cheese and yoghurt are fortified with
vitamin D supplementation can ameliorate these vitamin D. Ingested vitamin D is absorbed in
disease processes in older people. the gut and transported in chylomicrons before
binding VDBP in the circulation. Few populations
achieve sufficient vitamin D intake from the diet;
Search strategy endogenous production from sunlight accounts for
The content of this review was based on results the majority of vitamin D supply.2,3
from several recent systematic reviews performed
Vitamin D metabolism
Address for correspondence: Dr Miles Witham, Ageing
and Health, Medical Research Institute, University
Vitamin D itself is a prohormone, and must
of Dundee, Ninewells Hospital, Dundee DD1 9SY. undergo two hydroxylations to produce the final,
Email: [email protected] biologically active moiety. The first of these
 Vitamin D in older people 159

occurs in the liver, converting vitamin D to variant which is highly specific for 1,25OHD,
25-hydroxyvitamin D or 25OHD (calcidiol), binds 25OHD and 1,25OHD with similar affinity.
the main circulating form of vitamin D. The Given that circulating levels of 25OHD are a
hydroxylation is controlled by four hepatic thousandfold higher than 1,25OHD levels, it is
cytochrome P-450 enzymes. Three are micro- conceivable that this cytoplasmic variant might
somal forms (CYP2R1, CYP2J2 and CYP3A4), therefore be physiologically activated by 25OHD.
whilst CYP27A1 is mitochondrial. The second The large number of cell types that express VDR
hydroxylation occurs mainly, but not exclusively, gives biological plausibility to the range of health
in the kidney where 25OHD becomes active conditions and physiological functions with which
1,25-dihydroxyvitmain D or 1,25OHD (calcitriol). vitamin D has been associated.
Control is via CYP27B1 (1-hydroxylase) acti-
vity.4 Importantly, 1- hydroxylation can occur
Classical effects of vitamin D
at other sites, including in macrophages and
other target tissues, potentially allowing high local The classical effects of vitamin D on calcium
concentrations of 1,25OHD to be delivered to metabolism and bone health have been recognized
target organs.5 for decades. Vitamin D promotes calcium
Vitamin D metabolite levels are regulated absorption in the gut and, in response to low
through several feedback loops. UVB radiation serum calcium levels, PTH and 1,25OHD act
leads to increased skin melanin content, which together on bone to maintain serum calcium
competes with the 7-DHC to absorb photons and levels. Vitamin D metabolites act directly on
limit conversion to previtamin D3. Some of the both osteoblasts and osteoclasts, and are critical
previtamin D3 forms biologically inert lumisterol in driving mineralization of osteoid; hence the
or tachysterol. Low blood calcium levels lead to occurrence of rickets and osteomalacia in severe
parathyroid hormone (PTH) increase, increased vitamin D deficiency.
CYP27B1 expression and onward increase in
1-hydroxylase activity in the kidney. Higher levels
Non-classical effects of vitamin D
of 1,25OHD provide negative feedback for PTH
and 1- hydroxylase expression within the kidney, For many years it was thought that vitamin D had
which is also influenced by calcium, phosphate influence only upon bone health and calcium, but it
and fibroblast growth factor-23 levels. Further is now known that VDR are present in most tissues
regulation of active vitamin D occurs via control in the body, suggesting a much more widespread
of hydroxylation to 24,25-hydroxyvitamin D, an set of physiological roles for vitamin D. Similarly,
inactive metabolite. 1--hydroxylase is also widely distributed,
allowing vitamin D derivatives to act in a
paracrine or autocrine fashion by delivering high
concentrations of 1,25OHD to the target tissue.
Vitamin D targets
In the final 1,25OHD form there is binding to
Vitamin D insufficiency
vitamin D receptors (VDR) and activity upon cells
and organs in a hormone-like manner. The VDR Controversy continues as to the level of vitamin
dimerizes with the retinoid X receptor (RXR), D necessary for optimum health, and the amount
forming a 1,25(OH)2DVDRRXR complex of vitamin D required to reach these levels.
which binds to vitamin D-responsive elements Recommended levels are gradually being revised
(VDREs). These are capable of regulating the upwards (e.g. the maximum tolerable dose set
transcription of various genes in target cells.6 by Canada recently rose to 2000 units per
There are various other reactions in which day), although such recommendations are not
the 1,25OHD plays a role, including inducing based on robust evidence of increased efficacy.
more rapid responses in tissues, e.g. secretion The exhaustive US Institute of Medicine report7
of insulin by -cells in the pancreas. It has suggested that a level of 50 nmol l1 of 25OHD was
been postulated that these more rapid actions sufficient, and that the recommended daily intake
are mediated by a cytoplasmic variant of the for older people should remain at 800 IU per day
vitamin D receptor which, unlike the nuclear of vitamin D3.
160 Miles D Witham and Gavin Francis

Table 1. Definition of stages of vitamin D and those who do not expose their skin for cultural
insufficiency reasons. Also at risk are people with dark coloured
skin and older people these groups do not
Vitamin D
produce vitamin D efficiently in the skin. People
Serum 25OHD range nutritional status
with hepatic or renal impairment are unable to
>75 nmol l1 (>30 ng ml1 ) Optimal convert vitamin D to the active form. People with
>50 nmol l1 (>20 ng ml1 ) Sufficient poor nutritional intake or malabsorption are also
3050 nmol l1 (1220 ng ml1 ) Insufficient at an increased risk of vitamin D insufficiency.
1230 nmol l1 (512 ng ml1 ) Deficient Within-person vitamin D levels change
<12 nmol l1 (<5 ng ml1 ) Severely deficient
markedly throughout the year, depending upon
season and exposure to sunlight. A study of
healthy individuals aged between 20 and 94 years
Definitions of vitamin D deficiency and found that the average 25OHD level was lowest
insufficiency in AprilMay (73 nmol l1 ) and at its highest in
The short half-life of 1,25OHD (only a few October (96 nmol l1 ).10 The 1958 British Cohort
hours), and lack of correlation between vitamin Study looked at 25OHD levels in 7437 white
D production and 1,25OHD levels means that individuals and found that vitamin D insufficiency
25OHD is used instead to define levels of vitamin D was very common during winter and spring,
sufficiency. There are a number of different figures with 87% <75 nmol l1 , 47% <40 nmol l1
quoted for the half-life of 25OHD, ranging from and 16% <25 nmol l1 . During the summer and
3 weeks to over 2 months.8 Table 1 highlights one autumn months these figures were 61, 15 and 3%,
suggested categorization of vitamin D nutritional respectively.11
status in relation to different levels of 25OHD.
The definition adopted depends on which
physiological system one is examining. A threshold Prevalence of vitamin D insufficiency
of 2530 nmol l1 was traditionally used to define
deficiency as, above this level, rickets or frank The UK National Diet and Nutrition Survey
osteomalacia are unlikely; these diseases become published in 1998 found that 5% of men and 6%
progressively more prevalent as levels decline of women aged 6574 years had a serum 25OHD
below 25 nmol l1 . A study, examining 35 UK level <25 nmol l1 . This figure rose to 13% of
South Asian adults with clinically confirmed osteo- men and 25% of women over the age of 85, and
malacia, found that the concentration of 25OHD over a third of both sexes living in care homes
was below 7.5 nmol l1 in all the affected patients.9 over the age of 65. The Health Survey for England
As discussed below, levels for optimum health (HSE) 2000 also examined vitamin D levels in older
in other organ systems, including bone, cardio- adults12 and found that, amongst men living in
vascular and immune function may be higher. private households, the mean 25OHD level was
58 nmol l1 for those aged 6579, falling to
48 nmol l1 for those over the age of 80 years.
For men living in institutional care these levels
Who is at risk of vitamin D insufficiency?
fell to 40 and 37 nmol l1 for the respective age
Vitamin D insufficiency is a common problem in groups. In women living in private households the
many parts of the world. The people most likely to mean 25OHD levels were 49 nmol l1 for those
be affected are those living in areas of high latitude, aged 6579 and 45 nmol l1 for those aged over
who have limited exposure to sunlight for long 80 years. Amongst those living in institutions this
periods of time during the year. Even at the latitude fell to 37 and 36 nmol l1 for the respective
of London, UK, there is insufficient ultraviolet light age groups. These low levels persisted on re-
between October and March to drive vitamin D examination 5 years later.13
synthesis; the low angle that the sun subtends to Certain groups are even more likely to have
the horizon causes marked extinction of ultraviolet low vitamin D levels, such as those admitted with
light, even at midday. Groups who receive little osteoporotic fractures14 and those attending falls
exposure to sun are also at risk.3 These include clinics 72% of those attending a falls clinic in
the housebound, people living in institutional care, London, UK had 25OHD levels of <50 nmol l1 .15
 Vitamin D in older people 161

Figure 1. Potential pathways linking vitamin D to disease

Results from observational and intervention fractures tend to have lower levels of 25OHD
studies than individuals without a history of fracture;
studies of older people admitted to hospital with
A huge number of studies now link low 25OHD
hip fracture have shown that between 75 and
levels to a myriad of different disease states.
92% have serum 25OHD of <50 nmol l1 , with
However, interpreting observational data in this
68% having serum 25OHD of <30 nmol l1 .14
field is fraught with difficulty due to the problems
In another study looking at vertebral fractures
of reverse causality and confounding factors.
in patients with established osteoporosis it was
Firstly, any illness is likely to reduce activity
found that 39% had serum 25OHD levels of
levels and hence sun exposure, leading to low
<30 nmol l1 .
25OHD levels. Secondly, inflammation suppresses
Insufficiency of vitamin D is associated with an
25OHD levels 25OHD levels 48 h after elective
increased risk of falling. Body sway increases as
knee surgery fell significantly compared with pre-
25OHD levels fall below 50 nmol l1 , and muscle
operative levels.16 Furthermore, smoking, older
weakness occurs when these levels fall below
skin and obesity are all independent causes of lower
30 nmol l1 .19 A correlation exists between
circulating 25OHD levels,17,18 and fully adjusting
25OHD levels and proximal lower limb muscle
for the confounding effect of these variables is
strength, and a 23% difference in quadriceps
extremely difficult. Hence, however attractive the
strength exists depending on the VDR polymorph-
observational data, only interventional trial data
ism present in non-obese women over the age of
can really dissect out which disease states vitamin
70 years.20
D supplementation is likely to improve. A summary
of potential causal and confounding pathways is
given in Fig. 1.
Intervention data
There remains considerable uncertainty over
Osteoporosis, falls and fractures whether vitamin D supplementation affects muscle
strength and the risk of falls and fractures in
Obeservational data
older adults, despite a number of large randomized
Vitamin D insufficiency is particularly common controlled trials. Results differ significantly
in patients with osteoporotic fractures. It has depending on the population under study, and
been shown that those patients with osteoporotic whether calcium is co-administered. Meta-analysis
162 Miles D Witham and Gavin Francis

suggests a small benefit of borderline statistical (95% CI 0.580.86) when comparing 25OHD
significance on postural sway (effect size 0.20, levels between lowest and highest tertiles.33 Such
95% CI 0.39 to 0.01, P = 0.04) and timed relationships extend to older people; a study of 237
Up-and-Go test (effect size 0.19, 95% CI 0.35 individuals aged 65 and over found a significant
to 0.02, P = 0.03), with no effects on upper negative association between 25OHD levels and
limb grip strength, and improvement in lower limb both systolic BP (r = 0.15, P = 0.02) and
strength confirmed to those with 25OHD levels diastolic BP (r = 0.15, P = 0.02).34 Vitamin D
<25 nmol l1 .21,22 Vitamin D supplementation affects vascular smooth muscle cell proliferation,
does not appear to be of significant benefit to older inflammation, vascular calcification and the renin
hospitalized patients; no effect was seen on indices angiotensin system,35 all of which are known
of physical function or falls in older hospitalized to be risk factors for cardiovascular disease and
patients,23,24 and another study found that frail, may provide a biological basis for the association
older people who had recently been in-patients in between low vitamin D levels and hypertension.
hospital and were treated with vitamin D did not The Framingham study showed that not only did
gain any benefit in terms of physical function or low 25OHD levels predict incident cardiovascular
rehabilitation.25 events, but the combination of hypertension
Calcium and vitamin D therapy reduced the and low vitamin D was a particularly powerful
risk of hip fracture by 43% in French care predictor of future cardiovascular events.36
home residents after 18 months of treatment with
800 IU day1 vitamin D and 1200 mg day1
calcium. Since this seminal study,26 a number of Intervention data
other large trials have been performed. Recent Several small trials have now examined the effects
meta-analyses agree that, in institutionalized older of vitamin D supplementation on blood pressure.
people, the combination of calcium and vitamin D Meta-analysis37 suggests a small (4/3 mmHg)
does reduce falls and fractures (relative risk 0.84 reduction in blood pressure in studies with a mean
for hip fractures, 95% CI 0.73 to 0.96).27 Whether baseline blood pressure of >140/90, but no effect
vitamin D alone also reduces fractures is much on those without hypertension at baseline. More
less clear, with different analyses reaching different recent studies have been mixed; a study in black
conclusions.27,28 Older people outside institutional Americans suggested a modest reduction in blood
care appear to benefit less from supplementation, pressure38 but a trial of intermittent, high-dose
as evidenced by the lack of effect of calcium and vitamin D3 given for 1 year to patients aged 70 and
vitamin D supplementation in the MRC RECORD over with isolated systolic hypertension39 failed to
trial, amongst others.29 The dose and route of show any reduction in blood pressure.
vitamin D delivered may also be important a
single 300,000 unit intramuscular dose of vitamin
D given once yearly did not reduce fractures in Diabetes
older women,30 and a very large (500,000 unit)
Observational data
oral dose of vitamin D even appeared to increase
falls in the first few months after dosing in a recent Low levels of 25OHD are associated with impaired
osteoporosis trial.31 glucose tolerance, type 2 diabetes and insulin
resistance.4042 In both animals and humans it
has been shown that vitamin D insufficiency
Blood pressure is associated with impaired pancreatic insulin
secretion and glucose intolerance. There is also
Observational data
evidence that type 1 diabetes in some populations
Meta-analysis of cross-sectional and longitudinal is associated with certain polymorphisms within
studies confirms that low 25OHD levels are the VDR gene.43 These observational data are,
associated with higher blood pressure and an however, prone to confounding due to the strong
increased risk of incident arterial hypertension.32 relationship between obesity and impaired glucose
Aggregate data from 283,537 individuals from homeostasis; obesity could explain both the lower
the general population suggest the relative risk 25OHD levels and the increased risk of diabetes
for incident arterial hypertension was 0.70 seen in prospective observational studies.
 Vitamin D in older people 163

Intervention data range for vitamin D (<50 nmol l1 ). A meta-

analysis of seven studies with 47,809 participants
A small number of studies have examined the
and 926 cerebrovascular events showed that the
effect of supplementation on markers of glucose
risk of cerebrovascular disease was reduced in
metabolism and also on the incidence of diabetes.
those with high 25OHD levels.50 The relative risk
No effect was evident on HbA1c levels in a
from highest to lowest tertile was 0.60 (95% CI
recent meta-analysis;42 patients with frank diabetes
0.480.72). This result is similar to another meta-
or impaired fasting glucose showed a small
analysis of prospective studies including 1214
improvement in insulin resistance in another meta-
stroke cases, which demonstrated a relative risk of
analysis.44 In the small number of trials examining
stroke of 1.52 (95% CI 1.201.85) for the lowest
diabetes incidence as a secondary endpoint, no
versus highest 25OHD tertile.51
reduction in the incidence of diabetes was seen.45

Cardiovascular events Intervention data

Observational data No trials have tested the ability of vitamin

D supplementation to reduce stroke as their
A series of large observational studies have shown primary aim. One trial52 showed no significant
that low 25OHD levels are associated with an improvement in markers of vascular health with
increased risk of future cardiovascular events, vitamin D supplementation in patients who had
with a 3050% increase in risk of events in the had a previous stroke, and a meta-analysis of stroke
lowest quantile of serum 25OHD compared with rates in osteoporosis trials48 suggested no reduction
the highest quantile.46 Adjustment for risk factors in stroke rates with supplementation (odds ratio
including obesity, smoking and age attenuate, but (OR) 1.05, 95% CI 0.881.25; P = 0.59).
do not abolish, such associations. Associations
have been demonstrated in health community-
dwelling patients,36 patients with known vascular
disease and patients attending for coronary Heart failure
angiography, amongst others.47 Observational data
Heart failure patients almost universally have
low 25OHD levels. This may in part be due
Intervention data
to their poor exercise capacity and lack of
No trials have specifically set out to test whether sunlight exposure from outdoor activity. There are
vitamin D can reduce cardiovascular events. correlations between low levels of 25OHD and
However, meta-analysis of cardiovascular events in worse left ventricular function, disease severity53
osteoporosis trials does not support an association and higher levels of natriuretic peptides.54 In an
between vitamin D therapy and myocardial Israeli population study of 3009 patients, vitamin
infarction48 (hazard ratio (HR) 1.02, 95% CI 0.93 D deficiency (25OHD < 25 nmol l1 ) was an
1.13). Large trials underway in the USA, New independent predictor of increased mortality in
Zealand and Finland are designed to answer this patients with heart failure55 with HR of 1.52 (95%
question, and will start reporting in 2017. CI 1.211.92).
The vitamin D receptor is present in multiple
cardiovascular tissues, including endothelial cells,
Stroke myocytes and vascular smooth muscle cells. Being
a steroid hormone, vitamin D influences the
Observational data
expression of many genes that regulate cytokines
Low levels of vitamin D, reduced bone mineral and hormones that play a prominent role in the
density and an increased risk of fracture exist in progression of heart failure, including the renin
long-term stroke survivors, and patients admitted angiotensin system, pro-inflammatory cytokines
with acute stroke have lower levels of vitamin D such as tumour necrosis factor alpha, and
on admission than controls.49 Seventy-seven per vasculotoxic factors such as parathyroid hormone
cent (34 out of 44) fell within the insufficient (PTH).56
164 Miles D Witham and Gavin Francis

Intervention data Intervention data

Few intervention studies have examined the effect Trial data are sparse, but do not support a role for
of vitamin D in heart failure. Trials to date have vitamin D supplementation in COPD. No effect
shown no effect on exercise capacity, ventricular on the frequency of exacerbations was seen in
remodelling or quality of life.5759 One study a trial of 182 patients with moderate to severe
showed a reduction in tumour necrosis factor COPD, despite receiving monthly doses of 100,000
(TNF)-alpha levels, another showed a reduction in units of vitamin D3.64 Vitamin D has also been
B-type natriuretic peptide (BNP) levels, but these trialled as an adjunct to antimicrobial therapy
effects were not consistent across studies. One in tuberculosis;65 again, no clinically important
study combined low-dose vitamin D (10 mg daily) difference was noted between intervention and
with several other vitamins and minerals60 and placebo groups, although the intervention group
demonstrated a significant improvement in exercise had a non-significantly shorter time to sputum
capacity, but the combined intervention makes it conversion (36 vs 44 days; P = 0.14).
impossible to attribute any benefit to vitamin D
alone. These results do not exclude a beneficial
effect on death and hospitalization in the longer Cancer
term, but much larger studies will be needed to
Observational data
examine these outcomes.
Recent meta-analysis results have thrown into
doubt the relationship between vitamin D status
and cancer. Vitamin D levels are lower in patients
with cancer than in healthy controls, and the
Pulmonary disease degree of aggressiveness of a variety of cancers
Observational data (e.g. melanoma, breast cancer) correlates inversely
with 25OHD levels. However, this may again
Cross-sectional analysis of the Third National
be due to confounding due to ill-health and the
Health Nutrition and Examination Survey
degree of inflammation precipitated by aggressive
found that there was a significant relationship
tumours, and meta-analysis of prospective cohort
between vitamin D insufficiency and reduced
studies do not support a link between low 25OHD
lung function.61 Similar studies have shown a
levels and most cancers including lung, breast,
correlation between worse disease (measured by
skin, ovarian, prostate and oesophageal cancer.42
GOLD stage: Global Initiative for Obstructive
There is, however, a higher incidence of colorectal
Lung Disease) and lower 25OHD levels;
cancer in people with lower baseline 25OHD levels
25-OHD levels correlated significantly with forced
(pooled OR 0.66, 95% CI 0.540.81).66
expiratory volume in 1 s (FEV1) (r = 0.28,
P < 0.0001). Compared with 31% of the smokers
with normal lung function, as many as 60 and
Intervention data
77% of patients with GOLD stages 3 and 4
exhibited deficient 25-OHD levels <20 ng ml1 It has been suggested by the authors of one study67
(P < 0.0001)62 . There are several possible mech- that treating a group of post-menopausal women
anisms for this, including the anti-inflammatory with calcium and vitamin D for osteoporosis
effect of vitamin D and possibly effects upon lung could reduce the incidence of cancer. The numbers
remodelling. In addition, certain variants of the of patients who developed cancer in either the
VDR have been associated with an increased risk of calcium, the calcium plus vitamin D or the
chronic obstructive pulmonary disease (COPD).63 placebo group were very small, however, and
Longitudinal data examining whether low vitamin although significantly fewer cancers were found
D levels predispose to more rapid declines in in the calcium+D group compared with placebo,
lung function or hospital admissions are, however, there was no significant difference between cancer
lacking; and it is therefore equally possible that incidence in the calcium arm and the calcium+D
low vitamin D levels in COPD are a result of arm. No reduction in colorectal cancer was seen
reduced physical activity and consequently lower in the Womens Health Initiative (WHI) trial of
sun exposure. calcium and vitamin D68 , although the dose of
 Vitamin D in older people 165

vitamin D used in this study (400 units per day) and higher rates of dementia. The effect of
was very small. 25OHD insufficiency is modest; participants
who were severely 25OHD deficient declined
by an additional 0.3 MMSE points per year
Age-related macular degeneration compared with those with sufficient levels of
25OHD.76 Observational studies show a strong
Vitamin D insufficiency has been associated with
cross-sectional relationship between depressive
early age-related macular degeneration (ARMD),69
symptoms and 25OHD levels,42 which would be
but this link has not been seen in those with
expected given the impact of depression on physical
advanced ARMD, and not all observational studies
activity levels.
support an association.70 Vitamin D could in
The only trial to have examined the effect
theory have a beneficial effect as a result of its
of vitamin D supplementation on cognition to
anti-inflammatory or anti-angiogenic properties,
date was a substudy of the WHI trial; 4143
but intervention data are lacking.
post-menopausal women received either 1 g per
day of calcium plus 400 units vitamin D3 or
dual placebo. No difference in the rate of new
Periodontal disease
dementia diagnoses (HR 1.11, 95% CI 0.71
It has been demonstrated in one study that there 1.74) or new mild cognitive impairment diagnoses
is an inverse relationship between vitamin D levels (HR 0.95, 95% CI 0.721.25) was evident over
and periodontal disease in men and women over a mean 8-year follow-up.77 Although several
the age of 50 years. This relationship persisted studies have examined the impact of vitamin D
after adjustment for bone mineral density.71 No supplementation on mood, most studies to date
clinical trials have yet reported on whether have not focused on older people and have not
supplementation with vitamin D can improve focused on patients with confirmed depression.
periodontal disease, although a secondary analysis Most studies to date have been negative, but
of one osteoporosis trial found a lower rate of tooth one trial assessing the effect of vitamin D on
loss in the supplementation group (OR 0.5, 95% depressive symptoms in obese patients78 showed
CI 0.20.9).72 improvement in Beck Depression Inventory scores
after 1 year of treatment compared with placebo.

Infections
No intervention trials have specifically set out to All-cause mortality
examine the effect of vitamin D supplementation Observational data
on reducing infections in older people. However,
a reanalysis of data from the MRC RECORD A meta-analysis of prospective studies examining
fracture prevention study suggested a non- the relationship between 25OHD levels and all-
significant trend to reduced infection rates in the cause mortality confirms a strong association;
group receiving 800 IU oral vitamin D3 per day mortality was lower in the highest category of
(adjusted OR 0.90, P = 0.23).73 No reduction 25OHD levels versus the lowest level (HR 0.71,
in infection rates was seen in the MAVIS trial 95% CI 0.500.91)79 . Although most studies
of multivitamins in community-dwelling older suggest progressively reduced mortality even at
people, although the vitamin D dose was very low the highest levels of 25OHD, a very large Danish
(only 200 IU per day).74 A pooled analysis of the study (250,000 people)80 suggested a U-shaped
effect of vitamin D supplementation on influenza- relationship, with the lowest mortality at between
like illness also failed to show benefit,75 a finding 50 and 60 nmol l1 .
reflected by other, similar analyses.42

Intervention data
Cognition and mental health
Perhaps the strongest evidence that vitamin D
There is some evidence that vitamin D insufficiency supplementation may have important effects
is associated with impaired cognitive function on a range of health outcomes is provided by
166 Miles D Witham and Gavin Francis

meta-analyses examining the effect of vitamin D from Th1-type immune responses to Th2 (allergic)-
supplementation on total mortality.48,81 These type responses. Expectant mothers with serum
analyses of randomized trials suggest that intake vitamin D levels >75 nmol l1 had children with a
of vitamin D supplements may decrease total greater chance of developing eczema aged 9 months
mortality by 56% (an absolute risk reduction of and asthma aged 9 years84 and, in a large cohort
approximately 0.3%). Several of the trials included study, people with 25OHD levels >135 nmol l1
involved frail, older people, often with low levels of had increased levels of circulating IgE.85
25OHD and at risk of falls and fragility fractures. The other recent area of controversy pertains
The reduction in mortality is greater than can be to the use of calcium supplementation. Whilst
explained solely by the effect of calcium and calcium supplementation alone does appear to be
vitamin D on fracture rates, but as most included associated with an increased risk of cardiovascular
trials were designed to enrol patients with events,86 the combination of calcium and vitamin
osteoporosis, the applicability of these results to D has not been found to increase mortality in
the general older population is unclear. Large randomised trials81 a reassuring finding given that
trials in unselected older people are underway the combination has efficacy in reducing falls and
in Finland, New Zealand and the USA, and the fractures that vitamin D alone lacks.
results from these trials will provide an adequate
test of the effect of vitamin D supplementation on
total mortality. What is the optimum level of serum vitamin D?
Despite decades of use, the answer to this question
Safety and side-effects of vitamin D remains unclear; 2530 nmol l1 appears to
be protective against osteomalacia, but levels of
Like any potentially efficacious therapy, vitamin
50 nmol l1 are associated with reductions in
D has adverse effects. These are principally
PTH in studies of older patients with osteoporosis,
connected to its ability to increase serum
suggesting that at least this level is required
calcium, and patients with a predisposition to
for physiological repletion. Observational studies
hypercalcaemia (including those with sarcoidosis,
suggest that patients with levels greater than
primary hyperparathyroidism and metastatic
7580 nmol l1 have the lowest incidence of
cancer) should not receive large doses of vitamin D.
disease including cancer;87 there is a suspicion
Increased calcium excretion in the urine can
from analysis of data from the Framingham cohort
potentially lead to renal calculi, and even at
that the optimum level may be approximately
the low dose of 400 IU day1 , the WHI trial
50 nmol l1 for cardiovascular health, with a slight
found a significant excess of renal calculi in
increase in cardiovascular events above this level.36
the vitamin D group.82 On rare occasions, high-
dose vitamin D can cause malignant calcification
of the kidneys with acute renal failure. Animal
Vitamin D dosing
studies have suggested that high-dose vitamin
D may promote vascular calcification in some Route
models; this observation has not been borne out by
Vitamin D can be given orally, intravenously
experience to date in humans, and indeed, vascular
or intramuscularly. The oral route appears to
calcification in humans is associated with low
have much better pharmacokinetics than the
vitamin D levels.83 However, caution is necessary;
intramuscular route, with a much quicker peak and
an analysis of the Framingham cohort suggests a
higher area under the curve (AUC).88 This finding
trend towards an increased rate of cardiovascular
may explain the lack of effect of intramuscular
events at serum levels above 60 nmol l1 .36 A recent
vitamin D in some large fracture prevention
cohort study80 on a quarter of a million Danes also
trials.30
found a U-shaped curve for mortality, with lowest
mortality rates at 5060 nmol l1 of 25OHD, and
a hazard ratio for death of 1.4 for those with the
Dose
highest 25OHD levels.
Although vitamin D has well-documented anti- The dose of vitamin D needed to increase levels to
inflammatory effects, the downside may be a shift above a threshold of 50 or 75 nmol l1 remains
 Vitamin D in older people 167

unclear, especially in older people, who often have in large trials such as RECORD.29 It also
a very low starting level, may not absorb vitamin D remains unclear whether intermittent dosing has
as readily, and may distribute the drug differently biologically equivalent effects to daily dosing.
from young, healthy volunteers. One American
study tested an algorithm that predicted the dose
of vitamin D3 that was likely to be required to Pharmacological form of vitamin D
ensure adequate levels across a range of patients.
In most studies, vitamin D3 appears to
Doses were altered on several occasions based on
increase serum 25OHD levels considerably more
the response to a starting dose; the mean daily
than vitamin D2 for a given dose.88,92 In
dose predicted to raise levels to >75 nmol l1
patients with significant renal impairment (eGFR
in all patients was 3800 units for those with a
<45 ml min1 ), clinical practice to date has been to
starting level of >55 nmol l1 , and was as high
give 1 alpha hydroxylated vitamin D, on the basis
as 5000 units for those with starting levels of
that patients with significant renal impairment
<55 nmol l1 .89 Other studies have suggested that
will be unable to perform 1 alpha hydroxylation.
1000 units per day may be adequate to replete
However, it is possible that 1-alpha hydroxylation,
healthy post-menopausal women,90 and that there
either by the kidney or by target tissues, may
is little extra benefit in escalating the daily dose
occur in many patients with at least moderate renal
above 2000 units day1 .91 More recent systematic
impairment,95 suggesting that unactivated vitamin
reviews suggest that, on average, each microgram
D could be used instead; recently completed studies
of vitamin D3 (40 IU) increases serum 25OHD
demonstrate that this may indeed be the case.96
levels by approximately 2 nmol l1 .92 However,
Other vitamin D analogues (including parical-
the increase is less at higher baseline 25OHD
citol and doxerocalciferol) have been developed,
levels, and concomitant calcium administration
but their use is currently confined to patients with
leads to smaller increments perhaps due to the
kidney disease, and they fall outside the scope of
lower adherence. Body weight is also an important
this review.
predictor of response to dosing, explaining 34% of
the variation in achieved levels.93 Taken together,
these data suggest that for most older people
Conclusion
(who are likely to have baseline 25OHD levels of
<50 nmol l1 ), a dose of 800 IU per day or Vitamin D exerts a wide range of biological effects
equivalent is sufficient to raise 25OHD level to across many organ systems. Low 25OHD levels
>50 nmol l1 , but to raise levels to >75 nmol l1 are common, especially in older people, but the
requires between 2000 and 5000 IU per day of oral strong associations between low 25OHD and a
vitamin D3. range of illnesses seen in observational studies
are highly prone to confounding and reverse
causality. Intervention trials to date have been
disappointingly negative, with no strong evidence
Interval
to support a role for vitamin D in preventing
Vitamin D can be given daily, weekly, monthly cardiovascular disease, diabetes, infections or
or even longer between doses. High-dose oral COPD exacerbations. Evidence for a role in
preparations have a half-life of 612 weeks. preventing cancer and cognitive decline is lacking.
One study compared daily, weekly and monthly It remains possible that vitamin D may reduce all-
doses in older nursing home residents;94 levels cause mortality in the wider population of older
at 4 months were higher in those receiving people; trials underway currently should be able to
daily doses as opposed to weekly or monthly answer this question.
doses. Nursing staff preferred administering daily For now, vitamin D is indicated in older
doses, although adherence rates were similar with people with frank osteomalacia, as an adjunct
all three dosing intervals. It is unclear whether to bisphosphonate therapy to treat osteoporosis,
daily, weekly or monthly dosing is associated and in combination with calcium in frail,
with better adherence to therapy in community- institutionalized older people to reduce the risk
dwelling patients; adherence to combined calcium of falls and fractures. Trial evidence points to a
and vitamin D supplements has been suboptimal dose of at least 800 IU per day being required
168 Miles D Witham and Gavin Francis

for these functions, and current evidence supports 10 Maxwell JD. Seasonal variation in vitamin D. Proc
giving vitamin D in combination with calcium, not Nutr Soc 1994; 53: 53343.
alone. In the absence of good evidence for other 11 Hypponen E, Power C. Hypovitaminosis D in
treatment indications, there is currently no case British adults at age 45 y: nationwide cohort study
for measuring or supplementing vitamin D in older of dietary and lifestyle predictors. Am J Clin Nutr
2007; 85: 86068.
people for other indications.
12 Hirani V, Primatesta P. Vitamin D concentrations
among people aged 65 years and over living in
private households and institutions in England:
Conflicts of interest population survey. Age Ageing 2005; 34: 48591.
M.D.W. has received grant funding to conduct 13 Hirani V, Tull K, Ali A, Mindell J. Urgent action
vitamin D trials from Diabetes UK, Scottish needed to improve vitamin D status among older
people in England! Age Ageing 2010; 39: 6268.
Government, Heart Research UK, ME Research
14 Francis RM, Anderson FH, Patel S, Sahota O, van
UK and Chest Heart and Stroke Scotland. Staa TP. Calcium and vitamin D in the prevention
of osteoporotic fractures. QJM 2006; 99: 35563.
15 Dhesi JK, Moniz C, Close JC, Jackson SH, Allain
References TJ. A rationale for vitamin D prescribing in a falls
1 Linos E, Keiser E, Fu T, Colditz G, Chen S, Tang clinic population. Age Ageing 2002; 31: 26771.
JY. Hat, shade, long sleeves, or sunscreen? 16 Reid D, Toole BJ, Knox S et al. The relation
Rethinking US sun protection messages based on between acute changes in the systemic
their relative effectiveness. Cancer Causes Control inflammatory response and plasma
2011; 22: 106771. 25-hydroxyvitamin D concentrations after elective
2 Lamberg-Allardt C. Vitamin D in foods and as knee arthroplasty. Am J Clin Nutr 2011; 93:
supplements. Prog Biophys Mol Biol 2006; 92: 100611.
3338. 17 Martins D, Wolf M, Pan D et al. Prevalence of
3 Macdonald HM, Mavroeidi A, Fraser WD et al. cardiovascular risk factors and the serum levels of
Sunlight and dietary contributions to the seasonal 25-hydroxyvitamin D in the United States: data
vitamin D status of cohorts of healthy from the Third National Health and Nutrition
postmenopausal women living at northerly Examination Survey. Arch Intern Med 2007; 167:
latitudes: a major cause for concern? Osteoporos 115965.
Int 2011; 22: 246172. 18 Isaia G, Giorgino R, Rini GB, Bevilacqua M,
4 Battault S, Whiting SJ, Peltier SL, Sadrin S, Gerber Maugeri D, Adami S. Prevalence of
G, Maixent JM. Vitamin D metabolism, functions hypovitaminosis D in elderly women in Italy:
and needs: from science to health claims. clinical consequences and risk factors. Osteoporos
Eur J Nutr 2013; 52: 42941. Int 2003; 14: 57782.
5 Gottfried E, Rehli M, Hahn J, Holler E, Andreesen 19 Pfeifer M, Begerow B, Minne HW. Vitamin D and
R, Kreutz M. Monocyte-derived cells express muscle function. Osteoporos Int 2002; 13: 18794.
CYP27A1 and convert vitamin D3 into its active 20 Janssen HC, Samson MM, Verhaar HJ. Vitamin D
metabolite. Biochem Biophys Res Commun 2006; deficiency, muscle function, and falls in elderly
349: 20913. people. Am J Clin Nutr 2002; 75: 61115.
6 Haussler MR, Jurutka PW, Mizwicki M, Norman 21 Muir SW, Montero-Odasso M. Effect of vitamin D
AW. Vitamin D receptor (VDR)-mediated actions supplementation on muscle strength, gait and
of 1alpha,25(OH)(2)vitamin D(3): genomic and balance in older adults: a systematic review and
non-genomic mechanisms. Best Pract Res Clin meta-analysis. J Am Geriatr Soc 2011; 59:
Endocrinol Metab 2011; 25: 54359. 2291300.
7 Ross AC, Manson JE, Abrams SA et al. The 2011 22 Stockton KA, Mengersen K, Paratz JD, Kandiah D,
report on dietary reference intakes for calcium and Bennell KL. Effect of vitamin D supplementation
vitamin D from the Institute of Medicine: what on muscle strength: a systematic review and
clinicians need to know. J Clin Endocrinol Metab meta-analysis. Osteoporos Int 2011; 22: 85971.
2011; 96: 5358. 23 Corless D, Dawson E, Fraser F et al. Do vitamin D
8 Vieth R. Vitamin D supplementation, supplements improve the physical capabilities of
25-hydroxyvitamin D concentrations, and safety. elderly hospital patients? Age Ageing 1985; 14:
Am J Clin Nutr 1999; 69: 84256. 7684.
9 Preece MA, Tomlinson S, Ribot CA et al. Studies 24 Burleigh E, McColl J, Potter J. Does vitamin D stop
of vitamin D deficiency in man. QJM 1975; 44: inpatients falling? A randomised controlled trial.
57589. Age Ageing 2007; 36: 50713.
 Vitamin D in older people 169

25 Latham NK, Anderson CS, Lee A, Bennett DA, 38 Forman JP, Scott JB, Ng K et al. Effect of vitamin
Moseley A, Cameron ID. A randomized, controlled D supplementation on blood pressure in blacks.
trial of quadriceps resistance exercise and vitamin Hypertension 2013; 61: 77985.
D in frail older people: the Frailty Interventions 39 Witham MD, Price RJ, Struthers AD et al.
Trial in Elderly Subjects (FITNESS). J Am Geriatr Cholecalciferol treatment to reduce blood pressure
Soc 2003; 51: 29199. in older patients with isolated systolic
26 Chapuy MC, Arlot ME, Duboeuf F et al. Vitamin hypertension: the VitDISH randomized controlled
D3 and calcium to prevent hip fractures in the trial. JAMA Intern Med 2013; 173: 167279.
elderly women. N Engl J Med 1992; 327: 1637 40 Pittas AG, Chung M, Trikalinos T et al. Systematic
42. review: Vitamin D and cardiometabolic outcomes.
27 Avenell A, Gillespie WJ, Gillespie LD, OConnell Ann Intern Med 2010; 152: 30714.
D. Vitamin D and vitamin D analogues for 41 Pittas AG, Sun Q, Manson JE, Dawson-Hughes B,
preventing fractures associated with involutional Hu FB. Plasma 25-hydroxyvitamin D
and post-menopausal osteoporosis. Cochrane concentration and risk of incident type 2 diabetes
Database Syst Rev 2009; CD000227. in women. Diabetes Care 2010; 33: 202123.
28 Bischoff-Ferrari HA, Willett WC, Orav EJ et al. A 42 Autier P, Boniol M, Pizot C, Mullie P. Vitamin D
pooled analysis of vitamin D dose requirements for status and ill health: a systematic review. Lancet
fracture prevention. N Engl J Med 2012; 367: Diabetes Endocrinol 2013 (epub ahead of print;
4049. doi.org/10.1016/S2213-8587(13)70165-7).
29 Grant AM, Avenell A, Campbell MK et al. Oral 43 Ponsonby AL, Pezic A, Ellis J et al. Variation in
vitamin D3 and calcium for secondary prevention associations between allelic variants of the vitamin
of low-trauma fractures in elderly people D receptor gene and onset of type 1 diabetes
(Randomised Evaluation of Calcium Or vitamin D, mellitus by ambient winter ultraviolet radiation
RECORD): a randomised placebo-controlled trial. levels: a meta-regression analysis. Am J Epidemiol
Lancet 2005; 365: 162128. 2008; 168: 35865.
30 Smith H, Anderson F, Raphael H, Maslin P, 44 George PS, Pearson ER, Witham MD. Effect of
Crozier S, Cooper C. Effect of annual vitamin D supplementation on glycaemic control
intramuscular vitamin D on fracture risk in elderly and insulin resistance: a systematic review and
men and women a population-based, meta-analysis. Diabet Med 2012; 29: e142
randomized, double-blind, placebo-controlled trial. 50.
Rheumatology (Oxford) 2007; 46: 185257. 45 Avenell A, Cook JA, Maclennan GS, McPherson
31 Sanders KM, Stuart AL, Williamson EJ et al. GC. Vitamin D supplementation and type 2
Annual high-dose oral vitamin D and falls and diabetes: a substudy of a randomised
fractures in older women: a randomized controlled placebo-controlled trial in older people (RECORD
trial. JAMA 2010; 303: 181522. trial, ISRCTN 51647438). Age Ageing 2009; 38:
32 Burgaz A, Orsini N, Larsson SC, Wolk A. Blood 6069.
25-hydroxyvitamin D concentration and 46 Scragg R. Vitamin D and public health: an
hypertension: a meta-analysis. J Hypertens 2011; overview of recent research on common diseases
29: 63645. and mortality in adulthood. Public Health Nutr
33 Kunutsor SK, Apekey TA, Steur M. Vitamin D and 2011; 14: 151532.
risk of future hypertension: meta-analysis of 47 Dobnig H, Pilz S, Scharnagl H et al. Independent
283,537 participants. Eur J Epidemiol 2013; 28: association of low serum 25-hydroxyvitamin D
20521. and 1,25-dihydroxyvitamin D levels with all-cause
34 Almirall J, Vaqueiro M, Bare ML, Anton E. and cardiovascular mortality. Arch Intern Med
Association of low serum 25-hydroxyvitamin D 2008; 168: 134049.
levels and high arterial blood pressure in the 48 Elamin MB, Abu Elnour NO, Elamin KB et al.
elderly. Nephrol Dial Transplant 2010; 25: 5039. Vitamin D and cardiovascular outcomes: a
35 Beveridge LA, Witham MD. Vitamin D and the systematic review and meta-analysis. J Clin
cardiovascular system. Osteoporos Int 2013; 24: Endocrinol Metab 2011; 96: 193142.
216780. 49 Poole KE, Loveridge N, Barker PJ et al. Reduced
36 Wang TJ, Pencina MJ, Booth SL et al. Vitamin D vitamin D in acute stroke. Stroke 2006; 37:
deficiency and risk of cardiovascular disease. 24345.
Circulation 2008; 117: 50311. 50 Chowdhury R, Stevens S, Ward H, Chowdhury S,
37 Witham MD, Nadir MA, Struthers AD. Effect of Sajjad A, Franco OH. Circulating vitamin D,
vitamin D on blood pressure: a systematic review calcium and risk of cerebrovascular disease: a
and meta-analysis. J Hypertens 2009; 27: 1948 systematic review and meta-analysis.
54. Eur J Epidemiol 2012; 27: 58191.
170 Miles D Witham and Gavin Francis

51 Sun Q, Pan A, Hu FB, Manson JE, Rexrode KM. pulmonary function and COPD. Chest 2005; 128:
25-Hydroxyvitamin D levels and the risk of stroke: 378183.
a prospective study and meta-analysis. Stroke 64 Lehouck A, Mathieu C, Carremans C et al. High
2012; 43: 147077. doses of vitamin D to reduce exacerbations in
52 Witham MD, Dove FJ, Sugden JA, Doney AS, chronic obstructive pulmonary disease: a
Struthers AD. The effect of vitamin D replacement randomized trial. Ann Intern Med 2012; 156:
on markers of vascular health in stroke patients a 10514.
randomised controlled trial. Nutr Metab 65 Martineau AR, Timms PM, Bothamley GH et al.
Cardiovasc Dis 2012; 22: 86470. High-dose vitamin D(3) during intensive-phase
53 Shane E, Mancini D, Aaronson K et al. Bone mass, antimicrobial treatment of pulmonary tuberculosis:
vitamin D deficiency, and hyperparathyroidism in a double-blind randomised controlled trial. Lancet
congestive heart failure. Am J Med 1997; 103: 2011; 377: 24250.
197207. 66 Gandini S, Boniol M, Haukka J et al.
54 Zittermann A, Schleithoff SS, Tenderich G, Meta-analysis of observational studies of serum
Berthold HK, Korfer R, Stehle P. Low vitamin D 25-hydroxyvitamin D levels and colorectal, breast
status: a contributing factor in the pathogenesis of and prostate cancer and colorectal adenoma. Int J
congestive heart failure? J Am Coll Cardiol 2003; Cancer 2011; 128: 141424.
41: 10512. 67 Lappe JM, Travers-Gustafson D, Davies KM,
55 Gotsman I, Shauer A, Zwas DR et al. Vitamin D Recker RR, Heaney RP. Vitamin D and calcium
deficiency is a predictor of reduced survival in supplementation reduces cancer risk: results of a
patients with heart failure; vitamin D randomized trial. Am J Clin Nutr 2007; 85:
supplementation improves outcome. Eur J Heart 158691.
Fail 2012; 14: 35766. 68 Wactawski-Wende J, Kotchen JM, Anderson GL
56 Witham MD. Vitamin D in chronic heart failure. et al. Calcium plus vitamin D supplementation and
Curr Heart Fail Rep 2011; 8: 12330. the risk of colorectal cancer. N Engl J Med 2006;
57 Witham MD, Crighton LJ, Gillespie ND, Struthers 354: 68496.
AD, McMurdo ME. The effects of vitamin D 69 Parekh N, Chappell RJ, Millen AE, Albert DM,
supplementation on physical function and quality Mares JA. Association between vitamin D and
of life in older patients with heart failure: a age-related macular degeneration in the Third
randomized controlled trial. Circ Heart Fail 2010; National Health and Nutrition Examination
3: 195201. Survey, 1988 through 1994. Arch Ophthalmol
58 Schleithoff SS, Zittermann A, Tenderich G, 2007; 125: 66169.
Berthold HK, Stehle P, Koerfer R. Vitamin D 70 Golan S, Shalev V, Treister G, Chodick G,
supplementation improves cytokine profiles in Loewenstein A. Reconsidering the connection
patients with congestive heart failure: a between vitamin D levels and age-related macular
double-blind, randomized, placebo-controlled trial. degeneration. Eye (Lond) 2011; 25: 112229.
Am J Clin Nutr 2006; 83: 75459. 71 Dietrich T, Joshipura KJ, Dawson-Hughes B,
59 Boxer RS, Kenny AM, Schmotzer BJ, Vest M, Bischoff-Ferrari HA. Association between serum
Fiutem JJ, Pina II. A randomized controlled trial of concentrations of 25-hydroxyvitamin D3 and
high-dose vitamin D3 in patients with heart failure. periodontal disease in the US population. Am J
JACC Heart Fail 2013; 1: 8490. Clin Nutr 2004; 80: 10813.
60 Witte KK, Nikitin NP, Parker AC et al. The effect 72 Krall EA, Wehler C, Garcia RI, Harris SS,
of micronutrient supplementation on quality-of-life Dawson-Hughes B. Calcium and vitamin D
and left ventricular function in elderly patients supplements reduce tooth loss in the elderly. Am J
with chronic heart failure. Eur Heart J 2005; 26: Med 2001; 111: 45256.
223844. 73 Avenell A, Cook JA, Maclennan GS, Macpherson
61 Black PN, Scragg R. Relationship between serum GC. Vitamin D supplementation to prevent
25-hydroxyvitamin D and pulmonary function in infections: a sub-study of a randomised
the third national health and nutrition examination placebo-controlled trial in older people (RECORD
survey. Chest 2005; 128: 379298. trial, ISRCTN 51647438). Age Ageing 2007; 36:
62 Janssens W, Bouillon R, Claes B et al. Vitamin D 57477.
deficiency is highly prevalent in COPD and 74 Avenell A, Campbell MK, Cook JA et al. Effect of
correlates with variants in the vitamin multivitamin and multimineral supplements on
D-binding gene. Thorax 2010; 65: 215 morbidity from infections in older people (MAVIS
20. trial): pragmatic, randomised, double blind,
63 Wright RJ. Make no bones about it: increasing placebo controlled trial. BMJ 2005; 331: 324
epidemiologic evidence links vitamin D to 29.
 Vitamin D in older people 171

75 Jorde R, Witham M, Janssens W et al. Vitamin D infarction and cardiovascular events:

supplementation did not prevent influenza-like meta-analysis. BMJ 2010; 341: c3691.
illness as diagnosed retrospectively by 87 Bischoff-Ferrari HA, Giovannucci E, Willett WC,
questionnaires in subjects participating in Dietrich T, Dawson-Hughes B. Estimation of
randomized clinical trials. Scand J Infect Dis 2012; optimal serum concentrations of
44: 12632. 25-hydroxyvitamin D for multiple health
76 Llewellyn DJ, Lang IA, Langa KM et al. Vitamin D outcomes. Am J Clin Nutr 2006; 84: 1828.
and risk of cognitive decline in elderly persons. 88 Romagnoli E, Mascia ML, Cipriani C et al. Short
Arch Intern Med 2010; 170: 113541. and long-term variations in serum calciotropic
77 Rossom RC, Espeland MA, Manson JE et al. hormones after a single very large dose of
Calcium and vitamin D supplementation and ergocalciferol (vitamin D2) or cholecalciferol
cognitive impairment in the womens health (vitamin D3) in the elderly. J Clin Endocrinol
initiative. J Am Geriatr Soc 2012; 60: 2197205. Metab 2008; 93: 301520.
78 Jorde R, Sneve M, Figenschau Y, Svartberg J, 89 Aloia JF, Patel M, Dimaano R et al. Vitamin D
Waterloo K. Effects of vitamin D supplementation intake to attain a desired serum 25-hydroxyvitamin
on symptoms of depression in overweight and D concentration. Am J Clin Nutr 2008; 87:
obese subjects: randomized double blind trial. 195258.
J Intern Med 2008; 264: 599609. 90 Wood AD, Secombes KR, Thies F et al. Vitamin
79 Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi D3 supplementation has no effect on conventional
V, Gandini S. Vitamin D deficiency and mortality cardiovascular risk factors. A parallel-group,
risk in the general population: a meta-analysis of double-blind, placebo-controlled RCT. J Clin
prospective cohort studies. Am J Clin Nutr 2012; Endocrinol Metab 2012; 97: 355768.
95: 91100. 91 Hoeck HC, Li B, Qvist P. Changes in
80 Durup D, Jorgensen HL, Christensen J, Schwarz P, 25-Hydroxyvitamin D3 to oral treatment with
Heegaard AM, Lind B. A reverse J-shaped vitamin D3 in postmenopausal females with
association of all-cause mortality with serum osteoporosis. Osteoporos Int 2009; 20: 132935.
25-hydroxyvitamin D in general practice: the 92 Autier P, Gandini S, Mullie P. A systematic review:
CopD study. J Clin Endocrinol Metab 2012; 97: influence of vitamin D supplementation on serum
264452. 25-hydroxyvitamin D concentration. J Clin
81 Rejnmark L, Avenell A, Masud T et al. Vitamin D Endocrinol Metab 2012; 97: 260613.
with calcium reduces mortality: patient level 93 Zittermann A, Ernst JB, Gummert JF, Borgermann
pooled analysis of 70,528 patients from eight J. Vitamin D supplementation, body weight and
major vitamin D trials. J Clin Endocrinol Metab human serum 25-hydroxyvitamin D response: a
2012; 97: 267081. systematic review. Eur J Nutr 2013 (epub ahead of
82 Jackson RD, LaCroix AZ, Gass M et al. Calcium print; doi 10.1007/s00394-013-0634-3).
plus vitamin D supplementation and the risk of 94 Chel V, Wijnhoven HA, Smit JH, Ooms M, Lips P.
fractures. N Engl J Med 2006; 354: 66983. Efficacy of different doses and time intervals of
83 Watson KE, Abrolat ML, Malone LL et al. Active oral vitamin D supplementation with or without
serum vitamin D levels are inversely correlated calcium in elderly nursing home residents.
with coronary calcification. Circulation 1997; 96: Osteoporos Int 2008; 19: 66371.
175560. 95 Jean G, Terrat JC, Vanel T et al. Evidence for
84 Gale CR, Robinson SM, Harvey NC et al. persistent vitamin D 1-alpha-hydroxylation in
Maternal vitamin D status during pregnancy and hemodialysis patients: evolution of serum
child outcomes. Eur J Clin Nutr 2008; 62: 1,25-dihydroxycholecalciferol after 6 months of
6877. 25-hydroxycholecalciferol treatment. Nephron
85 Hypponen E, Berry DJ, Wjst M, Power C. Serum Clin Pract 2008; 110: c5865.
25-hydroxyvitamin D and IgE a significant but 96 Molina P, Gorriz JL, Molina MD et al. The effect
nonlinear relationship. Allergy 2009; 64: 61320. of cholecalciferol for lowering albuminuria in
86 Bolland MJ, Avenell A, Baron JA et al. Effect of chronic kidney disease: a prospective controlled
calcium supplements on risk of myocardial study. Nephrol Dial Transplant 2014; 29: 97109.
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