REVIEW

Vitamin D in older population: new roles for this ‘classic actor’?

FULVIO LAURETANI1, MARCELLO MAGGIO2, GIORGIO VALENTI2,

ELISABETTA DALL’AGLIO2, & GIAN PAOLO CEDA2

1Geriatric Unit and Laboratory of Movement Analysis, Geriatric-Rehabilitation Department, University Hospital of Parma,

Parma, Italy and 2Department of Internal Medicine and Biomedics Sciences, Section of Geriatrics, University of Parma,

Parma, Italy

(Received 5 November 2009; revised 16 February 2010; accepted 17 February 2010)

AbstractVitamin D is a group of lipophilic hormones with pleiotropic actions. It has been traditionally related to bone metabolism,although several studies in the last decade have suggested its role in muscle strength and falls, cardiovascular and neurologicaldiseases, insulin-resistance and diabetes, malignancies, autoimmune diseases and infections. Vitamin D appears to be ahormone with several actions and is fundamental for many biological systems including bone, skeletal muscle, brain andheart.

The estimated worldwide prevalence of vitamin D deficiency of 50% in elderly subjects underlines the importance ofvitamin D deficiency for public health.

In this review, we will describe changes in vitamin D levels with age in both sexes, cut off values to define Vitamin D status,the impact of vitamin D deficiency in age-related disease and finally different therapeutic options available to treat Vitamin Ddeficiency in older populations.

Keywords: Vitamin D3, deficiency, therapy, older people

Introduction

Vitamin D is a group of lipophilic hormones with

pleiotropic actions. It has been traditionally related to

bone metabolism, although several studies in the last

decade have suggested its role on cardiovascular

diseases, diabetes, malignancies, autoimmune dis-

eases and infections.

There are two active types of vitamin D: vitamin D3

(colecalciferol) derived by the irradiation in the skin of

7-dehydrocholesterol, the precursor of vitamin D3

and vitamin D2 (ergocalciferol) derived from irradia-

tion in the skin of the ergosterol, which is the

precursor of the vitamin D2 from plant origin.

Because vitamin D is fat soluble, it is readily taken

up by fat cells. Then, vitamin D3 and vitamin D2 are

hydroxylated to 25 (OH) vitamin D (or calcidiol or

calciferol) by several tissue (mainly by the liver) and

hydroxylated in the kidneys to the active form.

25(OH) vitamin D is further hydroxylated to the

active form of vitamin D3 to 1,25 (OH)D (or

calcitriol). 1,25(OH)2 Vitamin D produced by the

kidneys enters into circulation and travels to its major

target tissues such as the intestine and bone, where

after interaction with its receptor enhances intestinal

calcium adsorption and modulates the osteoclastic

activity (Figure 1).

Knowledge of the different ways of vitamin D

synthesis is important to understand the available

therapeutic options of vitamin D. For example, the

pharmaceutical form of vitamin D in the United

States is vitamin D2 (ergocalciferol), while in Canada,

Europe, Japan and India, vitamin D3 (colecalciferol)

is the principal pharmaceutical form.

Epidemiology of the vitamin-D deficiency

Older persons are prone to develop low vitamin D

concentrations. This phenomenon is the effect of the

reduced capacity of the skin to produce vitamin D.

The reduced dermal synthesis of vitamin D is

unlikely to be compensated by dietary intake of

vitamin D in the elderly. The estimated worldwide

prevalence of vitamin D deficiency among the elderly

of about 50% underlines the importance of vitamin

D deficiency for public health [1].

Much debate has taken place over the definition of

vitamin D deficiency [2]. There is evidence that

Correspondence: Fulvio Lauretani, Geriatric Unit and Laboratory of Movement Analysis, Geriatric-Rehabilitation Department, University Hospital of Parma,

Parma, Italy. Tel: þ39-0521-703315. Fax: þ39-0521-703330. E-mail: flauretani@ao.pr.it

The Aging Male, December 2010; 13(4): 215–232

ISSN 1368-5538 print/ISSN 1473-0790 online � 2010 Informa UK, Ltd.

DOI: 10.3109/13685538.2010.487551

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25(OH)D concentration550 nmol/l, or 20 ng/ml, is

an indicator of vitamin D deficiency, whereas a

25(OH)D concentration of 51–74 nmol/l, or 21–29

ng/ml indicate insufficiency; finally vitamin D serum

levels430 ng/l or 75 nmol/l suggest a status of

vitamin D sufficiency [3]. This evidence is based

on intestinal calcium absorption that is maximised

above 80 nmol/l, or 32 ng/ml, in postmenopausal

women [4]. On the other hand, parathyroid hormone

(PTH) concentrations in adults continue to decline

and reach their nadir at 75–100 nmol/l, or 30–40 ng/

ml of vitamin D levels (Figure 2) [4]. It has been

assumed that children have the same demand of

vitamin D of those of adults although no comparable

studies have been carried out on intestinal calcium

transport or PTH levels in this population [4].

Independent of the cut-off used to define vitamin

D deficiency, low levels of 25(OH)D are extremely

common in older persons, and particularly in the

oldest old and in the female sex. This is due to

specific physiological and lifestyle factors linked to

advanced age, such as impaired production of 7-

dehydrocholesterol in the skin, insufficient exposure

to sunlight (and/or excess clothing), poor dietary

intake of vitamin D, as well as to chronic diseases,

pharmacological treatments and disability [5].

Although vitamin D deficiency has originally been

reported more prevalent at higher latitudes, even

free-living older Southern Europeans are at signifi-

cant risk of developing vitamin D deficiency [4].

In a recent population study performed in the

Chianti area, known for its temperate climate and

sunny countryside, a high prevalence was found of

low 25(OH)D levels. Serum levels of vitamin D

diminish with age in both sexes, but the decline starts

substantially earlier and it is steeper in women from

the perimenopausal period, while in men it becomes

apparent 20 years later starting from 7th decade [6].

In another study conducted in a U.S. cohort of older

men in the United States, both vitamin D deficiency

and insufficiency were common. Approximately one-

fourth had 25(OH)D levels below the threshold of

frank deficiency (520 ng/ml), and the majority had

vitamin D insufficiency (530 ng/ml). Vitamin D

deficiency was particularly common during the

winter and spring time (especially in the northern

communities) and in the oldest and more obese

subjects. In fact, 86% of these subjects with multiple

risk factors were vitamin D deficient [7].

Causes of different decline in vitamin D levels

in men and women

The distinctive pattern of age-related decline in

25(OH)D in men and women is unlikely to be

explained by differences in the hormonal milieu

between the two sexes. Although estrogens may

Figure 2. Cut-off of Vitamin D deficiency.

Figure 1. Types of Vitamin D.

216 F. Lauretani et al.

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modulate renal 1-alfa-hydoxylase activity [6], 17-

beta-estradiol is not recognised as a modulator of

vitamin D or 25(OH)D production. Skin synthesis of

7-dehydrocholesterol is not influenced by estrogens,

although skin thinning, an age-related factor capable

of lowering serum 25(OH)D, does occur as a

consequence of menopause [6].

The crucial finding of the InCHIANTI study

concerns the modulating effect of age on the PTH–

25(OH)D relationship. Although a clear threshold in

25(OH)D levels below which calcium homeostasis is

stressed and PTH increases was not identified, older

participants need higher 25(OH)D levels to offset age-

associated hyperparathyroidism, which inevitably

determines bone loss and increases the risk of

osteoporosis. Although the precise mechanisms ex-

plaining this phenomenon remain unclear, age-related

changes in renal function (with the consequent de-

crease in production of 1,25(OH)2D) and resistance to

suppression of PTH secretion mediated by 25(OH)D

and 1,25(OH)2D, are possible causative factors [6].

Mechanism of vitamin D on bone and other

systems

Figure 3 showed almost all sites of action of vitamin

D. They include bone, muscle, heart, B and T

lymphocytes, pancreatic cells and cell growth and

differentiation. Table I reports studies concerning

the effects of vitamin D (associative and clinical

trials) on various systems that is discussed below.

Vitamin D and bone

Vitamin D deficiency has both direct and indirect

consequences on bone cell function [1]. Direct effects

mainly concern reduced recruitment and differentia-

tion of osteoclastic progenitors into mature osteo-

clasts, mostly mediated by osteoblast secretion of

activating factors. There is also a diminished synthesis

of specific collagenous and non-collagenous proteins

in the osteoblasts. The main indirect consequences of

vitamin D deficiency on bone cell function are

defective mineralisation of osteoid seams, due to

inadequate intestinal absorption of calcium and

phosphate, and an age-related form of compensatory

hyperparathyroidism, which drives an accelerated

bone loss. Recently, it has been suggested that the

minimal 25(OH)D serum concentrations needed to

avoid compensatory hyperparathyroidism are signifi-

cantly higher at older ages [6]. In a prospective,

observational study designed to analyse risk factors for

fracture in an ambulatory population aged 455 years,

73 (88%) had evidence of osteopenia or osteoporosis

(T-score571.5) and/or low 25VitD [9]. Similar

results were observed in patients enrolled in two

Finnish hospitals for fracture during approximately 13

months with hip fracture, fresh of previous [10].

Recent data from the Osteoporotic Fractures in

Men (MrOS) study performed in healthy older men

and focussing on osteoporosis showed that 25(OH)D

level520 ng/ml is associated with greater rates of hip

bone loss, while rates of bone loss were similar

among men with higher levels of total 25(OH)D [9].

The association between 25(OH)D levels and bone

loss was stronger among men 75 years and older [8].

These findings suggest that low 25(OH)D levels are

detrimental to bone mineral density (BMD) in older

men [8].

Bishoff-Ferrari et al. published a systematic review

of English and non-English articles using MEDLINE

and the Cochrane Controlled Trials Register (1960–

2005), and EMBASE (1991–2005). They found that a

vitamin D dose of 700–800 IU/day reduced the relative

risk (RR) of hip fracture by 26% (three RCTs with

5572 persons; pooled RR, 0.74; 95% confidence

interval [CI]: 0.61–0.88) and any non-vertebral

fractures by 23% (five RCTs with 6098 persons;

pooled RR, 0.77; 95% CI: 0.68–0.87) versus calcium

or placebo. Oral vitamin D supplementation (700–800

IU/day) reduces the risk of hip and any non-vertebral

fractures in ambulatory or institutionalised elderly

Figure 3. Vitamin D actions.

Vitamin D in older population 217

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Table I. Studies of vitamin D (associative and clinical trials) on various systems.

Systems Authors Observational studies (cross-sectional and longitudinal)

Part 1

Vitamin D and

bone

Ensrud et al. [8] Setting and Participants: Prospective cohort study in six U.S. centers. A total of 1279

community-dwelling men aged 65 year or older with 25(OH)D levels and hip bone mineral

density (BMD) at baseline and repeat hip BMD an average of 4.4 year later participated in

the study.

Conclusions: In this cohort of community-dwelling older men, men with 25(OH)D levels below

20 ng/ml had greater subsequent rates of hip bone loss, but rates of loss were similar among

men with higher levels.

Seton et al. [9] Setting: Prospective, observational study designed to analyse risk factors for fracture in an

ambulatory, ethnically diverse, urban population aged�55 years.

Results and conclusion: Of the 83 persons enrolled, 73 (88%) had evidence of osteopenia or

osteoporosis (T-score571.5) and/or low 25Vit D. All fractures in the community in

person�55 year, with or without a history of antecedent trauma, should be assessed with BMD

and screening for 25Vit D.

Nurmi et al. [10] Setting: Consecutive patients with a fresh hip fracture (n¼223) in two Finnish hospitals during 12

months and 15 months were registered prospectively

Results and conclusion: Half of the patients with a hip fracture suffered from hypovitaminosis D.

The situation was worst in institutional and residential care, although there are personnel for

taking care of vitamin D supplementation. In the late summer, one-third and in late winter two-

thirds of the patients suffered from hypovitaminosis D. The geographical location of Finland

indicates extensive efforts to increase the use of vitamin D supplements among elderly.

Vitamin D and

muscle strength

and falls

Boxer et al. [11] Setting and participants: Outpatient university heart failure program in Connecticut. Sixty patients

with an ejection fraction of 40% or less.

Results and conclusion: Longer 6-min walk distance was correlated with higher 25-hydro-

xyvitamin D (25OHD) level.

Twenty-five-hydroxyvitamin D and hsCRP levels may contribute to lower aerobic capacity and

frailty in patients with heart failure

Wicherts et al.

[12]

Design: The study consisted of a cross-sectional and longitudinal design (3-year follow-up) within

the Longitudinal Aging Study Amsterdam. Setting: An age- and sex-stratified random sample

of the Dutch older population was used. Other participants: Subjects included 1234 men and

women (aged 65 year and older) for cross-sectional analysis and 979 (79%) persons for

longitudinal analysis.

Results and conclusion: Compared with individuals with serum 25-OHD levels above 30 ng/

ml, physical performance was poorer in participants with serum 25-OHD less than 10 ng/ml

[regression coefficient (B)¼71.69; 95% CI¼72.28; 71.10], and with serum 25-OHD of

10–20 ng/ml (B¼70.46; 95% CI¼70.90; 70.03). After adjustment for confounding

variables, participants with 25-OHD less than 10 ng/ml and 25-OHD between 10 and 20

ng/ml had significantly higher odds ratios (OR) for 3-year decline in physical performance

(OR¼ 2.21; 95% CI¼ 1.0074.87; and OR¼2.01; 95% CI¼1.0673.81), compared with

participants with 25-OHD of at least 30 ng/ml. Serum 25-OHD concentrations below 20

ng/ml are associated with poorer physical performance and a greater decline in physical

performance in older men and women.

Visser et al. [13] Participants: In men and women aged 65 yr and older, participants of the Longitudinal Aging

Study Amsterdam, grip strength (n¼ 1008) and appendicular skeletal muscle mass (n¼331,

using dual-energy X-ray absorptiometry) were measured in 1995–1996 and after a 3-year

follow-up.

Results and conclusion: Persons with low (525hairsp;nmol/l) baseline 25-OHD levels were

2.57 (95% CI: 1.40–4.70, based on grip strength) and 2.14 (0.73–6.33, based on muscle

mass) times more likely to experience sarcopenia, compared with those with high (450

nmol/l) levels.

The associations were similar in men and women. The results of this prospective, population-

based study show that lower 25-OHD and higher PTH levels increase the risk of sarcopenia in

older men and women.

Snijder et al. [14] Design: This was a prospective cohort study. SETTING: An age- and sex-stratified random

sample of the Dutch older population was determined. SUBJECTS: Subjects included 1231

men and women (aged 65 yr and older) participating in the Longitudinal Aging Study

Amsterdam

Results and conclusion: Low 25(OH)D (510 ng/ml) was associated with an increased risk of

falling. After adjustment for age, sex, education level, region, season, physical activity, smoking,

and alcohol intake, the odds ratios (95% confidence interval) were 1.78 (1.06–2.99) for subjects

who experienced two falls or more as compared with those who did not fall or fell once and 2.23

(1.17–4.25) for subjects who fell three or more times as compared with those who fell two times

or less. Poor vitamin D status is independently associated with an increased risk of falling in the

elderly, particularly in those aged 65–75 yr.

Vitamin D and

CVD, kidney

disease and all-

cause mortality

Semba et al. [15] Setting: Serum 25(OH)D as well as all-cause and cardiovascular disease mortality were examined

in 1006 adults, aged�65 years, who participated in the InCHIANTI (Invecchiare in Chianti,

Aging in the Chianti Area) study, a population-based, prospective cohort study of aging in

Tuscany, Italy.

(continued)

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Table I. (Continued).

Systems Authors Observational studies (cross-sectional and longitudinal)

Results and conclusion: Compared with participants in the highest quartile of serum 25(OH)D

(426.5 ng/ml) (to convert to nmol/l, multiply by 2.496), those in the lowest quartile (510.5

ng/ml) had increased risk of all-cause mortality (Hazard Ratio (HR) 2.11, 95% CI: 1.22–3.64,

P¼0.007) and cardiovascular disease mortality (HR: 2.64, 95% CI: 1.14–4.79, P¼ 0.02).

Older community-dwelling adults with low serum 25(OH)D levels are at higher risk of all-cause

and cardiovascular disease mortality.

Ginde et al. [16] Setting: Non-institutionalised U.S. civilian population. Participants: Three thousand four

hundred eight NHANES III participants aged 65 and older enrolled from 1988 to 1994 and

followed for mortality through 2000.

Results and conclusion: During the median 7.3 years of follow-up, there were 1493 (44%) deaths,

including 767 CVD-related deaths. Baseline 25(OH)D levels were inversely associated with all-

cause mortality risk (adjusted hazard ratio (HR)¼ 0.95, 95% CI¼ 0.92–0.98, per 10 nmol/l

25[OH]D). The association appeared stronger for CVD mortality (adjusted HR¼2.36, 95%

CI¼ 1.17–4.75, for subjects with 25[OH]D levels525.0 nmol/l vs. those�100.0 nmol/l) than

for non-CVD mortality (adjusted HR¼1.42, 95% CI¼0.73–2.79, for subjects with 25[OH]D

levels525.0 nmol/l vs. those�100.0 nmol/l). In non-institutionalised older adults, a group at

high risk for all-cause mortality, serum 25(OH)D levels had an independent, inverse association

with CVD and all-cause mortality.

Pilz et al. [17] Design and patients: The Hoorn Study is a prospective population-based study among older men

and women.

Results and conclusion: After a mean follow-up period of 6.2 years, 51 study participants died

including 20 deaths due to cardiovascular causes. In the first when compared with the upper

three 25 (OH)D quartiles were 2.24 (1.28–3.92; P¼0.005) and 4.78 (1.95–11.69; P¼ 0.001),

respectively. After fully-adjustement, the HRs remained significant for all-cause [1.97 (1.08–

3.58; P¼0.027)] and for cardiovascular mortality [5.38 (2.02–14.34; P¼0.001)]. Conclu-

sions: Low 25(OH)D levels are associated with all-cause mortality and even more pronounced

with cardiovascular mortality.

Pilz et al. [18] Design, setting and participants: We measured 25-hydroxyvitamin D [25(OH)D] levels in 3299

Caucasian patients who were routinely referred to coronary angiography at baseline (1997–

2000).

Results and conclusion: During a median follow-up time of 7.7 year, 116 patients died due to

heart failure and 188 due to SCD. After adjustment for cardiovascular risk factors, the hazard

ratios (with 95% confidence intervals) for death due to heart failure and for SCD were 2.84

(1.20–6.74) and 5.05 (2.13–11.97), respectively, when comparing patients with severe vitamin

D deficiency [25(OH)D525hairsp;nmol/l)] with persons in the optimal range [25(OH)D4or

¼ 75 nmol/l]. Low levels of 25(OH)D and 1,25-dihydroxyvitamin D are associated with

prevalent myocardial dysfunction, deaths due to heart failure, and SCD.

Vitamin D and

insulin

resistance and

diabetes

Liu et al. [19]

(cross-

sectional

study)

Setting and participants: Plasma 25(OH)D concentrations were measured in 808 non-diabetic

participants of the Framingham Offspring Study.

Results and conclusion: Compared with the participants in the lowest tertile category of plasma

25(OH)D, those in the highest tertile category had a 1.6% lower concentration of fasting

plasma glucose (P-trend¼0.007), 9.8% lower concentration of fasting plasma insulin (P-

trend¼0.001), and 12.7% lower HOMA-IR score (P-trend5 0.001). Among adults without

diabetes, vitamin D status was inversely associated with surrogate fasting measures of insulin

resistance. These results suggest that vitamin D status may be an important determinant for

type 2 diabetes mellitus.

Knekt et al. [20] Methods: Two nested case–control studies, collected by the Finnish Mobile Clinic in 1973–1980,

were pooled for analysis. The study populations consisted of men and women aged 40–74 years

and free of diabetes at baseline. During a follow-up period of 22 years, 412 incident type 2

diabetes cases occurred and 986 controls were selected by individual matching.

Results and conclusion: Men had higher serum vitamin D concentrations than women and

showed a reduced risk of type 2 diabetes in their highest vitamin D quartile. The relative odds

between the highest and lowest quartiles was 0.28 (95% CI¼0.10–0.81) in men and 1.14

(0.60–2.17) in women. The results support the hypothesis that high vitamin D status

provides protection against type 2 diabetes. Residual confounding may contribute to this

association.

Littorin et al.

[21]

Setting: The nationwide Diabetes Incidence Study in Sweden (DISS) covers 15- to 34-year-old

people with newly diagnosed diabetes. At diagnosis, plasma 25OHD levels were significantly

lower in patients with type 1 diabetes than in control subjects (82.5+ 1.3 vs. 96.7+2.0 nmol/l;

P50.0001). Eight years later, plasma 25OHD had decreased in patients (81.5+2.6 nmol/l;

P¼0.04). Plasma 25OHD levels were significantly lower in diabetic men than in diabetic

women at diagnosis (77.9+ 1.4 vs. 90.1+2.4 nmol/l; P5 0.0001) and at follow-up

(77.1+2.8 nmol/l vs. 87.2+ 4.5 nmol/l; P¼0.048). The plasma 25OHD level was lower at

diagnosis of autoimmune type 1 diabetes than in control subjects, and may have a role in the

development of type 1 diabetes.

Vitamin D and

cancer

Yin et al. [22] Setting: Relevant prospective cohort studies and nested case–control studies published until July

2009 were identified by systematically searching Ovid Medline, EMBASE and ISI Web of

Knowledge databases and by cross-referencing.

(continued)

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Table I. (Continued).

Systems Authors Observational studies (cross-sectional and longitudinal)

Results and conclusion: Overall, 11 original articles were included, 10 of which reported on the

association between serum vitamin D levels and prostate cancer (PC) incidence and one article

reported on the association with PC mortality. Meta-analysis of studies on PC incidence

resulted in a summary OR (95% CI) of 1.03 (0.96–1.11) associated with an increase of

25(OH)D by 10 ng/ml (P¼ 0.362). According to available evidence from longitudinal studies,

serum 25(OH)D is not associated with PC incidence.

Yin et al. [23] Setting: Relevant studies published until September 2008 was identified by systematically

searching Ovid Medline, EMBASE, and ISI Web of Knowledge databases and by cross-

referencing.

Results and conclusion: Overall, eight original articles reporting on the association between serum

25(OH) D and CRC risk were included. In meta-analyses, summary ORs (95% CI) for the

incidence of CRC, colon cancer and rectal cancer associated with an increase of 25(OH)D by

20 ng/ml were 0.57 (0.43–0.76), 0.78 (0.54–1.13) and 0.41 (0.11–1.49). Our results support

suggestions that serum 25(OH)D is inversely related to CRC risk.

Ng et al. [24] Setting: Prospectively examined the influence of post-diagnosis predicted 25(OH)D levels on

mortality among 1017 participants in the Nurses’ Health Study and Health Professionals

Follow-Up Study who were diagnosed with colorectal cancer from 1986 to 2004.

Results and conclusion: Higher predicted 25(OH)D levels were associated with a significant

reduction in colorectal cancer-specific (P trend¼ 0.02) and overall mortality (P trend¼ 0.002).

Compared with levels in the lowest quintile, participants with predicted 25(OH)D levels in the

highest quintile had an adjusted HR of 0.50 (95% CI: 0.26–0.95) for cancer-specific mortality

and 0.62 (95% CI: 0.42–0.93) for overall mortality. Higher predicted 25(OH)D levels after a

diagnosis of colorectal cancer may be associated with improved survival.

Freedman et al.

[25]

Setting: A total of 16,818 participants in the Third National Health and Nutrition Examination

Survey who were 17 years or older at enrollment were followed from 1988–1994 through 2000.

Results and conclusion: Colorectal cancer mortality was inversely related to serum 25(OH)D

level, with levels 80 nmol/l or higher associated with a 72% risk reduction (95% CI¼ 32–89%)

compared with lower than 50 nmol/l, P(trend)¼0.02. Our results do not support an association

between 25(OH)D and total cancer mortality, although there was an inverse relationship

between 25(OH)D levels and colorectal cancer mortality

Vitamin D and

infection

disease

Nnoaham et al.

[26]

Setting: Observational studies published between 1980 and July 2006 (identified through

Medline) that examined the association between low serum vitamin D and risk of active

tuberculosis.

Results and conclusion: For the review, seven papers were eligible from 151 identified in the

search. The pooled effect size in random effects meta-analysis was 0.68 with 95% CI 0.43–0.93.

The potential role of vitamin D supplementation in people with tuberculosis and

hypovitaminosis D-associated conditions like chronic kidney disease should be evaluated.

Vitamin D and

autoimmune

diseases

Merlino et al.

[27]

Methods: We analysed data from a prospective cohort study of 29,368 women of ages 55–69 years

without a history of RA at study baseline in 1986.

Results: Through 11 years of followup, 152 cases of RA were validated against medical records.

Greater intake (highest vs. lowest tertile) of vitamin D was inversely associated with risk of RA

(RR: 0.67, 95% CI: 0.44–1.00, P for trend¼0.05). Inverse associations were apparent for both

dietary (RR: 0.72, 95% CI: 0.46–1.14, P for trend¼ 0.16) and supplemental (RR: 0.66, 95%

CI: 0.43–1.00, P for trend¼0.03) vitamin D. Conclusion: Greater intake of vitamin D may be

associated with a lower risk of RA in older women, although this finding is hypothesis

generating.

Muller et al. [28] Setting: Young patients with systemic lupus erythematosus (SLE) (n¼ 21), rheumatoid arthritis

(RA) (n¼ 29) and osteoarthritis (n¼ 12).

Results and conclusion: In patients with SLE the levels of 25-OH D3 were below those of the

healthy controls (P¼0.0008) and OA (P¼0.0168). Although the cause of the reduced 25-OH

D3 levels in patients with SLE is unclear, possible beneficial effects of administration of vitamin

D to these patients should be considered

Vitamin D and

cognition and

other

neurological

disorder

Hoogendijk et al.

[29]

Setting and participants: The Netherlands. Population-based cohort study (Longitudinal Aging

Study Amsterdam). One thousand two hundred eighty-two community residents aged 65–95

years.

Results and conclusion: Levels of 25(OH)D were 14% lower in 169 persons with minor

depression and 14% lower in 26 persons with major depressive disorder compared with levels in

1087 control individuals (P50.001). Results of this large population-based study show an

association of depression status and severity with decreased serum 25(OH)D levels and

increased serum PTH levels in older individuals.

Slinin et al. [30] Setting: We measured 25(OH)D and assessed cognitive function using the Modified Mini-Mental

State Examination (3MS) and Trail Making Test Part B (Trails B) in a cohort of 1604 men

enrolled in the Osteoporotic Fractures in Men Study and followed them for an average of 4.6

years for changes in cognitive function.

Results and conclusion: There was a trend for an independent association between lower

25(OH)D levels and odds of cognitive decline by 3MS performance (multivariable OR: 1.41,

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220 F. Lauretani et al.

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Table I. (Continued).

Systems Authors Observational studies (cross-sectional and longitudinal)

95% CI: 0.89–2.23 for Q1; 1.28, 0.84–1.95 for Q2; and 1.06, 0.70–1.62 for Q3, compared with

Q4 [P¼0.10]), but no association with cognitive decline by Trails B. We found little evidence

of independent associations between lower 25-hydroxyvitamin D level and baseline global and

executive cognitive function or incident cognitive decline.

Soilu-Hanninen

et al. [31]

Setting: Measurement of 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH),

calcium, phosphate, magnesium, chloride, alkaline phosphatase, albumin and thyroid

stimulating hormone in serum every 3 months and at the time of relapse over 1 year in 23

patients with MS and in 23 healthy controls. MRI burden of disease and T2 activity were

assessed every 6 months.

Results and conclusion: 25(OH)D serum levels were lower and intact PTH (iPTH) serum levels

were higher during MS relapses than in remission. There is an inverse relationship between

serum vitamin D level and MS clinical activity. The role of vitamin D in MS must be explored

further.

Munger et al.

[32]

Setting and participants: Prospective, nested case–control study among more than 7 million

US military personnel who have serum samples stored in the Department of Defense Serum

Repository. Multiple sclerosis cases were identified through Army and Navy physical

disability databases for 1992 through 2004, and diagnoses were confirmed by medical

record review.

Results and conclusion: Among whites (148 cases, 296 controls), the risk of multiple sclerosis

significantly decreased with increasing levels of 25-hydroxyvitamin D (odds ratio [OR] for a 50-

nmol/l increase in 25-hydroxyvitamin D, 0.59; 95% CI: 0.36–0.97). Only the OR for the

highest quintile, corresponding to 25-hydroxyvitamin D levels higher than 99.1 nmol/l, was

significantly different from 1.00 (OR: 0.38; 95% CI: 0.19–0.75; P¼ .006). The results of our

study suggest that high circulating levels of vitamin D are associated with a lower risk of

multiple sclerosis.

Part 2 Randomised clinical trials and meta-analysis

Vitamin D and

bone

Avenell et al.

[33]

Selection criteria: Randomised or quasi-randomised trials comparing vitamin D or related

compounds, alone or with calcium, against placebo, no intervention, or calcium alone,

reporting fracture outcomes in older people.

Main results: Forty-five trials were included. Vitamin D alone appears unlikely to be effective in

preventing hip fracture (nine trials, 24,749 participants, RR: 1.15, 95% CI: 0.99–1.33),

vertebral fracture (five trials, 9138 participants, RR: 0.90, 95% CI: 0.42–1.92) or any new

fracture (10 trials, 25,016 participants, RR: 1.01, 95% CI: 0.93–1.09).Vitamin D with calcium

reduces hip fractures (eight trials, 46,658 participants, RR: 0.84, 95% CI: 0.73–0.96). Authors’

conclusions: Frail older people confined to institutions may sustain fewer hip fractures if given

vitamin D with calcium. Vitamin D alone is unlikely to prevent fracture.

Bischoff-Ferrari

et al. [34]

Data sources: A systematic review of English and non-English articles using MEDLINE and the

Cochrane Controlled Trials Register (1960–2005) and EMBASE (1991–2005). Search terms

included randomised controlled trial (RCT), controlled clinical trial, random allocation,

double-blind method, cholecalciferol, ergocalciferol, 25-hydroxyvitamin D, fractures, humans,

elderly, falls and bone density.

Results and conclusion: A vitamin D dose of 700–800 IU/day reduced the relative risk (RR) of hip

fracture by 26% (3 RCTs with 5572 persons; pooled RR: 0.74; 95% CI: 0.61–0.88) and any

nonvertebral fracture by 23% (5 RCTs with 6098 persons; pooled RR: 0.77; 95% CI: 0.68–

0.87) versus calcium or placebo. Oral vitamin D supplementation between 700 and 800 IU/day

appears to reduce the risk of hip and any non-vertebral fractures in ambulatory or

institutionalised elderly persons.

Dawson-Hughes

et al. [35]

We studied the effects of 3 years of dietary supplementation with calcium and vitamin D on

bone mineral density and the incidence of non-vertebral fractures in 176 men and 213

women 65 years of age or older who were living at home. They received either 500 mg of

calcium plus 700 IU of vitamin D3 (cholecalciferol) per day or placebo. The difference

between the calcium-vitamin D and placebo groups was significant at all skeletal sites after

one year, but it was significant only for total-body bone mineral density in the second and

third years. In men and women 65 years of age or older who are living in the community,

dietary supplementation with calcium and vitamin D moderately reduced bone loss

measured in the femoral neck, spine and total body over the three-year study period and

reduced the incidence of nonvertebral fractures.

Lips et al. [36] Setting: Community setting (Amsterdam and surrounding area). PATIENTS: 2578 persons

(1916 women, 662 men) 70 years of age and older (mean age+SD, 80+ 6 years) living

independently, in apartments for elderly persons, or in homes for elderly persons. Intervention:

Participants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or

placebo for a maximum of 3.5 years.

Results and conclusion: Hip fractures occurred in 48 persons in the placebo group and 58 persons

in the vitamin D group (P¼0.39, intention-to-treat analysis). Our results do not show a

decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly

persons after vitamin D supplementation.

(continued)

Vitamin D in older population 221

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Table I. (Continued).

Systems Authors Observational studies (cross-sectional and longitudinal)

Vitamin D and

muscle

strength and

falls

Annweiler et al.

[37]

Methods: An English and French Medline search ranging from January 2004 to November 2008

indexed under the Medical Subject Heading (MeSH).

Results and conclusion: Of the 102 selected studies, 16 met the selection criteria and were included in

the final analysis. There were 8 observational studies and 8 interventional studies. The number of

participants ranged from 24 to 33,067. A majority of studies examined community-dwelling older

women. Five observational studies showed a significant positive association, whereas three studies

did not. Four of the five studies and two of the three studies which tested the vitamin D

supplementation effect, respectively on balance and gait, showed no significant effect. Four

studies showed a significant effect on muscle strength, while this effect was not observed in three

others studies. In addition, there was no significant association between vitamin D

supplementation and an improvement of the sit-to-stand test results in 50% of the studies.

Conclusions: The findings show that the association between vitamin D and physical performance

remains controversial. Observational studies and clinical trials yielded divergent results, which

highlights the complex and to date still poorly understood association between serum vitamin D

concentration or vitamin D supplementation and physical performance.

Bischoff-Ferrari

et al. [38]

Data sources: We searched Medline, the Cochrane central register of controlled trials, BIOSIS

and Embase up to August 2008 for relevant articles.

Results and conclusion: Eight randomised controlled trials (n¼2426) of supplemental vitamin D

met our inclusion criteria. Heterogeneity among trials was observed for dose of vitamin D

(700–1000 IU/day vs. 200–600 IU/day; P¼0.02) and achieved 25-hydroxyvitamin D(3)

concentration (25(OH)D concentration: 560 nmol/l vs.�60 nmol/l; P¼0.005). High-dose

supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR): 0.81, 95% CI:

0.71–0.92; n¼ 1921 from seven trials), whereas achieved serum 25(OH)D concentrations of 60

nmol/l or more resulted in a 23% fall reduction (pooled RR: 0.77, 95% CI: 0.65–0.90).

Gillespie et al.

[39]

Strategy: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register,

CENTRAL (The Cochrane Library 2008, Issue 2), MEDLINE, EMBASE, CINAHL and

Current Controlled Trials (all to May 2008). Selection criteria: Randomised trials of

interventions to reduce falls in community-dwelling older people. Primary outcomes were rate

of falls and risk of falling.

Main results: We included 111 trials (55,303 participants). Overall, vitamin D did not reduce falls

(RR: 0.95, 95%CI: 0.80–1.14; RR: 0.96, 95%CI: 0.92–1.01), but may do so in people with

lower vitamin D levels.

Conclusions: Exercise interventions reduce risk and rate of falls. Research is needed to confirm the

contexts in which multifactorial assessment and intervention, home safety interventions,

vitamin D supplementation and other interventions are effective.

Vitamin D and

CVD and

all-cause

mortality

Autier et al. [40] Methods: The literature up to November 2006 was searched without language restriction using

the following databases: PubMed, ISI Web of Science (Science Citation Index Expanded),

EMBASE and the Cochrane Library.

Results and conclusion: We identified 18 independent randomised controlled trials, including

57,311 participants. A total of 4777 deaths from any cause occurred during a trial size-adjusted

mean of 5.7 years. Daily doses of vitamin D supplements varied from 300 to 2000 IU. The trial

size-adjusted mean daily vitamin D dose was 528 IU. In nine trials, there was a 1.4- to 5.2-fold

difference in serum 25-hydroxyvitamin D between the intervention and control groups. The

summary relative risk for mortality from any cause was 0.93 (95% confidence interval, 0.87–0.99).

Conclusions: Intake of ordinary doses of vitamin D supplements seems to be associated with

decreases in total mortality rates. The relationship between baseline vitamin D status, dose of

vitamin D supplements and total mortality rates remains to be investigated. Population-based,

placebo-controlled randomised trials with total mortality as the main end point should be

organised for confirming these findings.

Palmer et al. [41] Data sources: MEDLINE (January 1966 to July 2007), EMBASE (January 1980 to July 2007) and

Cochrane databases were searched without language restriction. Study selection: Randomised,

controlled trials of vitamin D compounds in chronic kidney disease were identified. Data

extraction: Two authors independently extracted data.

Data synthesis: Seventy-six trials were identified for inclusion; 3667 participants were enrolled.

Vitamin D compounds did not reduce the risk for death, bone pain, vascular calcification or

parathyroidectomy.

Conclusion: Vitamin D compounds do not consistently reduce PTH levels, and beneficial effects

on patient-level outcomes are unproven. The value of vitamin D treatment for people with

chronic kidney disease remains uncertain.

Vitamin D and

insulin

resistance

Avenell et al.

[42]

Vitamin D supplementation and type 2 diabetes: a substudy of a randomised placebo-controlled

trial in older people (RECORD trial, ISRCTN 51647438).

Vitamin D and

cancer

Wactawski-

Wende et al.

[43]

Methods: We conducted a randomised, double-blind, placebo-controlled trial involving 36,282

postmenopausal women from 40 Women’s Health Initiative centres: 18,176 women received

500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 [corrected] twice

daily (1000 mg of elemental calcium and 400 IU of vitamin D3) and 18,106 received a

matching placebo for an average of 7.0 years.

(continued)

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Table I. (Continued).

Systems Authors Observational studies (cross-sectional and longitudinal)

Results: The incidence of invasive colorectal cancer did not differ significantly between women

assigned to calcium plus vitamin D supplementation and those assigned to placebo (168 and

154 cases; hazard ratio, 1.08; 95% confidence interval, 0.86–1.34; P¼ 0.51), and the cancer

characteristics were similar in the two groups. The frequency of colorectal-cancer screening and

abdominal symptoms was similar in the two groups. There were no significant treatment

interactions with baseline characteristics.

Conclusions: Daily supplementation of calcium with vitamin D for seven years had no effect on

the incidence of colorectal cancer among postmenopausal women.

Vijayakumar

et al. [44]

In this article, we review the clinical trials and consider the future directions of the use of vitamin

D and its analogues in the treatment or chemoprevention of prostate cancer. First, we

summarise the epidemiological evidence leading to the hypothesis that vitamin D has

anticancer activity. We then review the clinical trials using vitamin D analogues that involve

patients with prostate cancer and conclude with a brief overview of our planned study with

vitamin D5, [1alpha(OH)D5], which will begin shortly.

Vitamin D and

infection

disease

Yamshchikov

et al. [45]

Methods: We conducted a systematic review of randomised controlled clinical trials that studied

vitamin D for treatment or prevention of infectious diseases in humans. Studies from 1948

through 2009 were identified through search terms in PubMed and Ovid MEDLINE.

Results and conclusion: Thirteen published controlled trials were identified by our search criteria.

Ten trials were placebo controlled, and 9 of the 10 were conducted in a rigorous double-blind

design. The selected clinical trials demonstrated substantial heterogeneity in baseline patient

demographics, sample size and vitamin D intervention strategies. On the basis of studies

reviewed to date, the strongest evidence supports further research into adjunctive vitamin D

therapy for tuberculosis, influenza and viral upper respiratory tract illnesses.

Wilkinson et al.

[46]

Methods: A double-blind randomised controlled trial was conducted in 192 healthy adult TB

contacts in London, United Kingdom. Participants were randomised to receive a single oral

dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks.

Results and conclusion: Vitamin D supplementation significantly enhanced the ability of

participants’ whole blood to restrict BCG-lux luminescence in vitro compared with placebo

(mean luminescence ratio at follow-up, 0.57, vs. 0.71, respectively; 95% confidence interval for

difference, 0.01–0.25; P¼ 0.03) but did not affect antigen-stimulated IFN-gamma secretion.

Conclusions: Clinical trials should be performed to determine whether vitamin D supplementa-

tion prevents reactivation of latent TB infection.

Vitamin D and

autoimmune

diseases

Randomised controlled trials of vitamin D supplementation in older adults are warranted to

determine whether this association in causal and reversible.

Vitamin D and

cognition and

other

neurological

disorder

Annweiler et al.

[31]

Setting: Of the 99 selected studies, five observational studies met the selection criteria and were

included in the final analysis. No prospective cohort study was found. The number of

participants ranged from 32 to 9556 community-dwelling older adults (45–65% women).

Results and conclusion: Three studies showed four significant positive associations between serum

25OHD concentrations and global cognitive functions, whereas three other studies exploring

specific aspects of cognition showed 11 non-significant associations. This systematic review

shows that the association between serum 25OHD concentrations and cognitive performance is

not yet clearly established.

persons [34]. These data confirm previous results of

two landmark randomised clinical trials [35,36].

By contrast, a recent review on the effect of vitamin

D and vitamin D analogues for preventing fractures

associated with involutional osteoporosis showed that

institutionalised frail older people treated with

vitamin D and calcium but not with Vitamin D

alone may sustain fewer hip fractures [33]. These

results are also confirmed by an other study derived

by pooled data seven major randomised trials of

vitamin D with calcium or vitamin D alone, yielding

a total of 68,517 participants [47].

Vitamin D and skeletal muscle and falls

Muscle weakness has long been associated with

vitamin D deficiency. A vitamin D receptor is present

in skeletal muscle [48], and vitamin D deficiency has

been associated with proximal muscle weakness,

increase in body sway and an increased risk of falling

[49].

Vitamin D deficiency in adults can also cause a

skeletal mineralisation defect. The unmineralised

osteoid provides little structural support for the

periosteal covering. As a result, patients with

osteomalacia often complain of isolated or global

bone discomfort along with aches and pains in their

joints and muscles [50]. These patients may be

misdiagnosed with fibromyalgia, dysthymia, degen-

erative joint disease, arthritis, chronic fatigue syn-

drome and other diseases [51].

Speed performance and proximal muscle strength

were markedly improved when 25-hydroxyvitamin D

levels increased from 4 to 16 ng/ml (10–40 nmol/l)

and continued to improve as the levels increased to

more than 40 ng/ml (100 nmol/l) The relationship

Vitamin D in older population 223

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between walking speed and vitamin D serum levels

are show in Figure 4 [52]. Interestingly, persons with

low (525hairsp;nmol/l) baseline 25-OHD levels

were 2.57 (95% confidence interval 1.40–4.70, based

on grip strength) and 2.14 (0.73–6.33, based on

muscle mass) times more likely to experience

sarcopenia, compared with those with high (450

nmol/l) levels [13].

Low serum 25-hydroxyvitamin D levels have even

been associated with impaired physical performance

in a previous cross-sectional analysis conducted at

baseline in the InCHIANTI study [53,54]. Low

25(OH)D may affect physical performance and

frailty, defined as ‘a biologic syndrome of decreased

reserve and resistance to stressors, resulting from

cumulative declines across multiple physiologic

systems and causing vulnerability to adverse out-

comes’ [53], via effects on muscle strength. Vitamin

D receptors (VDRs) are located in skeletal muscle

cells, and low 25(OH)D may result in decreased

muscle strength from both decreased muscle synth-

esis and altered contractile properties of muscle.

Muscle protein synthesis is initiated by binding 1,25-

(OH)2D to its nuclear receptor. The influence of

1,25-(OH)2D on calcium homeostasis is believed to

influence contractile properties of muscle cells via

both a VDR-mediated genomic pathway and a non-

genomic rapid mechanism. Thus, the association

between low 25(OH)D and frailty may be explained

by associations of insufficient 25(OH)D with sarco-

penia and muscle weakness because both are a

central role for the development of the frailty

syndrome. In a cross-sectional study, 6-min walk

distance was correlated with higher 25-hydroxyvita-

min D (25OHD) level even in patients affected by

chronic heart disease [11]. In the Longitudinal Aging

Study Amsterdam, an association between vitamin D

and physical function has been described. Compared

with individuals with serum 25-OHD levels above

30 ng/ml, physical performance was poorer in

participants with serum 25-OHD less than 10 ng/

ml [regression coefficient (B)¼ –1.69; 95% confi-

dence interval (CI)¼72.28; 71.10], and with

serum 25-OHD of 10–20 ng/ml (B¼70.46; 95%

CI¼70.90; 70.03). After adjustment for con-

founding variables, participants with 25-OHD less

than 10 ng/ml and 25-OHD between 10 and 20 ng/

ml had significantly higher odds ratios (OR) for 3-

year decline in physical performance (OR¼ 2.21;

95% CI¼ 1.0074.87; and OR¼ 2.01; 95%

CI¼ 1.0673.81), compared with participants with

25-OHD of at least 30 ng/ml [12].

In a meta-analysis recently published, this relation-

ship was further investigated. Of the 102 selected

studies, 16 met the selection criteria and were

included in the final analysis. There were eight

observational studies and eight intervention studies.

The number of participants ranged from 24 to

33,067. A majority of studies examined commu-

nity-dwelling older women. Five observational stu-

dies showed a significant positive association,

whereas three studies did not. Four of the five

studies and two of the three studies that tested the

vitamin D supplementation effect, respectively on

balance and gait, showed no significant effect. Four

studies showed a significant effect on muscle

strength, while this effect was not observed in three

other studies. In addition, there was no significant

association between vitamin D supplementation and

an improvement of the sit-to-stand test in 50% of the

studies. Authors concluded that the association

between vitamin D and physical performance re-

mains controversial. Observational studies and clin-

ical trials yielded divergent results, which highlights

the complex and to date still poorly understood

association between serum vitamin D concentration

or vitamin D supplementation and physical perfor-

mance [37].

Poor vitamin D status is independently associated

with an increased risk of falling in the elderly,

particularly in those aged 65–75 year. In a prospec-

tive cohort study of older persons enrolled in the

Longitudinal Aging Study Amsterdam, low levels of

25(OH)D (510 ng/ml) were associated with an

increased risk of falling. After fully-adjustment, the

odds ratios (95% confidence interval) were 1.78

(1.06–2.99) for subjects who experienced two falls or

more as compared with those who did not fall or fell

once for subjects who fell three or more times as

compared with those who fell two times or less per

years [14].

A meta-analysis of five randomised clinical trials

(with a total of 1237 subjects) revealed that increased

vitamin D intake reduced the risk of falls by 22%

(pooled corrected odds ratio, 0.78; 95% CI,

0.6470.92) as compared with only calcium or

placebo [55]. The same meta-analysis examined the

frequency of falls and suggested that 400 IU of

vitamin D3 per day is not effective in preventing falls,

whereas 800 IU of vitamin D3 per day plus calciumFigure 4. Relationship between vitamin D and physical functions.

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reduces the risk of falls (corrected pooled odds ratio,

0.65; 95% CI, 0.471.0) [56]. In a randomised

controlled trial conducted over a 5-month period,

nursing home residents receiving 800 IU of vitamin

D2 per day plus calcium had a 72% reduction in the

risk of falls as compared with the placebo group

(adjusted rate ratio, 0.28%; 95% CI, 0.11–0.75)

[57].

Recently, the same authors published a new meta-

analysis reporting results from eight randomised

controlled trials (n¼ 2426) of supplemental vitamin

D and risk for falling [38]. They found that high dose

supplemental vitamin D (700–1000 IU/day vs. 200–

600 IU/day) reduced risk of falling by 19% (pooled

relative risk (RR): 0.81, 95% CI: 0.71–0.92; n¼ 1921

from seven trials), whereas achieved serum 25(OH)D

concentrations of 60 nmol/L or more resulted in a

23% fall reduction (pooled RR: 0.77, 95% CI: 0.65–

0.90). However, a recent review published by the

Cochrane Library on randomised trials of interven-

tions to reduce falls in community-dwelling older

people, showed that only exercise interventions

reduce risk and rate of falls. Authors concluded that

research is needed to confirm the contexts in which

multifactorial assessment and intervention, home

safety interventions, vitamin D supplementation

and other interventions are effective [39].

Vitamin D and insulin resistance/diabetes

Hypovitaminosis D has long been suspected as a risk

factor for glucose intolerance. The 25(OH)D con-

centration is lower in patients with type 2 diabetes

than in the non-diabetic control subjects [58]. A

higher prevalence of hypovitaminosis D was noted in

women affected by type 2 diabetes [59]. The

25(OH)D concentrations were lower in patients at

risk for diabetes than in the control group [60].

Furthermore, hypovitaminosis D is associated with

impaired insulin secretion in a population at high risk

for diabetes [60]. Hyper-responsive insulin secretion

after a glucose challenge has been found in older men

with hypovitaminosis D. Recent data show that, in

glucose-tolerant subjects, 25(OH)D concentration

has a positive relation with insulin sensitivity and a

positive effect on ß cell function. These relations are

independent of confounding factors [61].

Several observations have linked vitamin D defi-

ciency to alterations in circulating glucose and

insulin levels and, possibly, insulin sensitivity

[19,20]. Human studies suggest that increased

vitamin D intake early in life may reduce the

subsequent risk of type 1 diabetes. In one study,

infants who received dietary supplementation with

cod liver oil, a rich source of vitamin D, during their

first year of life were found to have a reduced risk of

type 1 diabetes [62]. In the nationwide Diabetes

Incidence Study in Sweden (DISS), the plasma

25OHD level is lower at diagnosis of autoimmune

type 1 diabetes than in control subjects and may have

a role in the development of type 1 diabetes [21].

Similarly, the European Community sponsored

Concerted Action on the Epidemiology and Preven-

tion of Diabetes study found a 33% reduction in the

risk of developing childhood-onset type 1 diabetes in

children who received vitamin D supplementation

compared with non-supplemented children (com-

bined odds ratio: 0.67, 95% confidence interval:

0.53–0.85) [63]. Moreover, a study in Finland found

an association between dietary vitamin D supple-

mentation in the first year of life and a reduced risk of

type 1 diabetes mellitus, even after adjustment for

social confounders [64].

Studies in adults have also suggested that reduced

vitamin D intake and circulating vitamin D concen-

trations are associated with reduced insulin sensitiv-

ity and an increased risk of developing the metabolic

syndrome and type 2 diabetes mellitus. In the

NHANES III cross-sectional survey of American

adults 40–74 years of age, for example, serum 25-

hydroxyvitamin D levels were inversely related to the

presence of type 2 diabetes and to increased insulin

resistance, with odds ratios for diabetes of 0.25 (95%

confidence interval: 0.11–0.6) in non-Hispanic

whites and 0.17 (95% confidence interval: 0.08–

0.37) in Mexican Americans with 25-hydroxyvitamin

D levels�81 nmol/l compared with those with

levels�43.9 nmol/l [65]. An inverse relation has also

been observed between serum 25-hydroxyvitamin D

levels and the prevalence of the metabolic syndrome

in American adults [66] and with approximately

twice the rate (27.5% vs. 13.5%) in those with 25-

hydroxyvitamin D levels�48.4 nmol/l compared with

those with levels�96.4 nmol/l [67].

The mechanisms of action of vitamin D on glucose

and insulin metabolism are probably all mediated by

its receptors. There is evidence that vitamin D may

stimulate pancreatic insulin secretion directly. Vita-

min D exerts its effects through nuclear vitamin D

receptors [68], which are found in a wide variety of

tissues, including the pancreatic islet b-cells [69].

However, the stimulatory effects of vitamin D on

insulin secretion may be manifest only when calcium

levels are adequate. Glucose-stimulated insulin

secretion is lower in vitamin D-deficient rats when

concurrent hypocalcaemia is not corrected than

when it is [70], whereas in vitro glucose-stimulated

insulin release from pancreatic islet cells is stimulated

by 1,25-dihydroxyvitamin D3 treatment in the

presence but not absence of relatively high levels of

calcium [71].

The observed associations between vitamin D and

insulin and glucose metabolism in human have not

yet been confirmed by intervention studies. Hence, a

causal association has not been established. In a non-

randomised study of 10 women with type 2 diabetes,

seven of whom were vitamin D deficient at baseline,

there was a statistically significant 34% increase from

baseline in first-phase insulin secretion during an

intravenous glucose load after 1 month of treatment

Vitamin D in older population 225

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with oral cholecalciferol (D3) at 1332 IU/day [72].

There is also an ongoing randomised placedo-

controlled trial in older people testing the effect of

the vitamin D supplementation on type 2 diabetes

[42].

Vitamin D and cognitive function

Recently, the presence of vitamin D receptor and the

vitamin D activating enzyme, 1,-hydroxylase, in the

brain has suggested a potential beneficial role of

vitamin D in cognitive function. In details, the

vitamin D receptor and catalytic enzymes are

localised in the areas of the brain involved in complex

planning, processing and the formation of new

memories. These findings potentially implicate the

role of vitamin D in neurocognitive function.

Compelling evidence supports a beneficial role for

the active form of vitamin D in the developing brain

and in adult brain function. Vitamin D exhibits

functional attributes that may prove neuroprotective

through antioxidative mechanisms, neuronal calcium

regulation, immunomodulation, enhanced nerve

conduction and detoxification mechanisms [73].

Patients who live at higher latitudes and are at risk

of vitamin D deficiency are also more prone to

developing schizophrenia [74], and vitamin D

deficiency has been associated with depression

[29,75] and also with multiple sclerosis [32,76].

Recent studies suggest that vitamin D metabolites

may be even important for preserving cognitive

function via specific neuroprotective effects [77].

In a recent paper [78] was analysed the relation-

ship between vitamin D and cognitive function. This

editorial was focused on three papers, two cross-

sectional and one longitudinal. In the latest, Slinin

et al. [30] reported results from a longitudinal

assessment of community-dwelling men (65 years)

participating in the Osteoporotic Fractures in Men

(MrOS) Study, enrolled from 2000 to 2002 and

followed for 4.6 years. Cognitive function was

assessed using the modified Mini-Mental State

Examination (3MS), a test of global cognitive

function scored on a scale of 0–100 points, 12 and

by the Trails B test, a timed test of executive

function. Subjects were divided into quartiles based

on baseline serum 25OHD concentrations, with the

lowest quartile520 ng/ml. At baseline, the odds

ratios for cognitive impairment (defined as 3MS

score5 80 or Trails B test time4 225 s) were

between 1.6 and 1.8 in the lowest quartile of

25OHD concentrations compared to the highest

quartile. However, these odds ratios did not reach

statistical significance and were greatly attenuated

after controlling for race/ethnicity and education. For

incident cognitive impairment, the OR for a sig-

nificant decline in 3MS score was 1.5 in the lowest

quartile of 25OHD concentration compared with the

highest quartile and the trend across the quartiles was

significant. Control for confounding by race/ethnicity

and education, however, slightly attenuated the

trend, enough to loose statistical significance.

Change in Trails B test time was not different among

the 25OHD quartiles. The authors conclude that

there is little evidence for an association between

vitamin D status and concurrent or incident cogni-

tive impairment. They suggest that additional studies

should be carried out including women and tests of

other cognitive domains.

Placebo-controlled intervention studies are also

needed, to determine if vitamin D supplements will

protect against age-related cognitive decline. In the

meantime, neurologists and geriatricians should be

aware of the high prevalence of vitamin D deficiency

in their patient populations and the possibility that

supplementation could be beneficial. Adequate

intakes of vitamin D for ages 51–70 years and 470

years are currently defined as 10 mg/day (400 IU) and

15 mg/day (600 IU), respectively, or enough to

maintain a 25(OH)-vitamin D level of 30 ng/mL or

more. These intakes are primarily for maintaining

bone health and are evolving standards. The appro-

priate intake amounts to support brain function in

older adults remain to be determined. This conclu-

sion is also in accordance with a recent meta-analysis

[31], where a revision of 99 selected studies has been

made. Five observational studies met the selection

criteria and were included in the final analysis. No

prospective cohort study was present. The number of

participants ranged from 32 to 9556 community-

dwelling older adults (45–65% women). Three

studies showed significant positive associations be-

tween serum 25OHD concentrations and global

cognitive functions, whereas three other studies

exploring specific aspects of cognition showed

significant associations. The conclusion of this

systematic review is that the association between

serum 25OHD concentrations and cognitive perfor-

mance is not yet clearly established.

Vitamin D and non-skeletal actions

The local production of 1,25-dihydroxyvitamin D3

in non-calcium-regulating tissues such as the colon,

prostate and breast is thought to regulate up to 200

genes, which help to control cell growth and cellular

differentiation and may be responsible for decreasing

the risk of cells transforming into a malignant state

[79]. 1,25-dihydroxyvitamin D3 has been shown to

inhibit cancer cell growth, induce cancer cell

maturation, and apoptosis and decrease angiogenesis

[79]. Brain, prostate, breast and colon tissues, among

others, as well as immune cells have a vitamin D

receptor and respond to 1,25-dihydroxyvitamin D3,

the active form of vitamin D [29]. In addition, some

of these tissues and cells express the enzyme 25-

hydroxyvitamin D-1-hydroxylase [79].

1,25-dihydroxyvitamin D3 has a immunomodula-

tory activity on monocytes and activated T and B

lymphocytes [80]. Then, increased production of

226 F. Lauretani et al.

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1,25-dihydroxyvitamin D3 results in synthesis of

cathelicidin, a peptide capable of destroying M.

tuberculosis and other infectious agents. When serum

levels of 25-hydroxyvitamin D3 fall below 20 ng/ml

(50 nmol/l), the monocyte or macrophage is pre-

vented from initiating this innate immune response,

which may explain why black Americans, often

vitamin D deficient for the sun-protective character

of dark skin, are more prone to contracting tubercu-

losis than white, and tend to have a more aggressive

form of the disease. Observational studies that

examined the association between low serum vitamin

D and risk of active tuberculosis, found that the

pooled effect size in random effects meta-analysis was

0.68 with 95% CI 0.43–0.93 [26]. A double-blind

randomised controlled trial conducted in 192 healthy

adult M. tuberculosis, receiving a single oral dose of

2.5 mg vitamin D or placebo and followed up for 6

weeks, significantly enhanced the ability of partici-

pants’ whole blood to restrict BCG-lux luminescence

in vitro compared with placebo (mean luminescence

ratio at follow-up, 0.57 vs. 0.71, respectively; 95%

confidence interval for difference, 0.01–0.25;

P¼ 0.03) [46]. A systematic review of randomised

controlled clinical trials that studied vitamin D for

treatment or prevention of infectious diseases in

humans supports further research into adjunctive

vitamin D therapy for tuberculosis, influenza and

viral upper respiratory tract illnesses [45].

Evidence of diseases associated with vitamin-D

deficiency

Cancer and vitamin D

More than 80 years ago, it was reported that living at

higher latitudes in the United States is associated

with an increased risk of dying of common cancers

[81]. In the 1980s and 1990s, several studies

confirmed that living at higher latitudes increased

the risk of developing and dying of colon, prostate,

breast and several other cancers [82]. Because living

at higher latitudes diminishes vitamin D production,

an association between vitamin D deficiency and

cancer mortality was hypothesised. Both men and

women exposed to the most sunlight throughout

their lives were less likely to die of cancer. Several

retrospective and prospective studies with data

available on concentrations of vitamin D showed

that vitamin D deficiency increases the risk of

developing and dying from cancer [83]. It has been

reported that adults with vitamin D of550 nmol/l

who were then followed for up to 19 years had a 30–

50% have an increased risk of developing colorectal,

breast, prostate and many other cancers [83]. A

meta-analysis showed that increasing intake of

vitamin D to 1000 IU vitamin D3/day would be

associated with a decreased risk of colorectal and

breast cancer of as much as 50% [84]. Men who

ingested 4400 IU vitamin D/day had a markedly

reduced risk of developing several cancers, including

pancreas and oesophagus and non-Hodgkin lympho-

ma [83]. Lappe et al. [85] reported that postmeno-

pausal women who received 1100 IU vitamin D3 and

1000 mg Ca daily for 4 years reduced their risk of

developing cancer by 60%.

However, recent meta-analysis of longitudinal

studies and clinical trials showed no association

between vitamin D and prostate cancer (PC) [22,44],

whereas several studies reporting the association of

vitamin D and colon cancer risk showed an inverse

relationship between vitamin D and the development

of colon cancer [23–25]. This association has not

been confirmed in the largest clinical trial realised in

postmenopausal women [43].

Autoimmune diseases and vitamin D

The regulatory role of vitamin D in modulating the

immune system activity includes inhibitory effects on

T cells, B cells and dendritic cells [86]. These

suppressive immunologic properties have led to

considering its role in autoimmune diseases. Vitamin

D has also profound effects on dendritic cells.

Dendritic cells have important functions in main-

taining both protective immunity and self-tolerance,

as immature dendritic cells promote T cell tolerance,

whereas mature dendritic cells activate naıve T cells.

Mechanisms of action of vitamin D on dendritic cells

include actions on the differentiation of monocytes

into immature dendritic cells, their maturation and

survival. In addition to its functions in maintaining

self-tolerance, vitamin D has an important role in

protective immunity.

There is a growing body of epidemiologic data

linking low levels of serum 25D with autoimmune

diseases, such as rheumatoid arthritis (RA) [86] and

inflammatory bowel disease [87]. A prospective

study on the relationship between vitamin D intake

and the risk of RA found that a higher vitamin D

intake at baseline provided significant protection

from subsequent development of the disease [86].

Women who received 4400 IU vitamin D/day were

found to have a 440% reduced risk of developing

rheumatoid arthritis [27]. However, these findings in

RA could not be replicated in a study published this

year, which used comparable methods in a different

cohort [88].

There is also evidence of an association between

vitamin D deficiency and systemic lupus erythema-

tosus (SLE). Initial insights into the prevalence of

vitamin D deficiency in SLE come from studies

primarily focussed on bone health. The first study

measuring vitamin D levels in SLE reported a

deficiency of 1,25D in seven of 12 corticosteroid-

receiving adolescents [89]. Subsequent studies mea-

suring vitamin D in the context of either bone

mineral density (BMD) or fractures or both included

a study documenting severe 25 (OH)D deficiency

(525 nmol/l or 1 ng/ml) in 8% of 107 consecutive

Vitamin D in older population 227

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patients from the Netherlands [90]. A second study

examining BMD in patients with newly diagnosed

SLE, established SLE on corticosteroids and

age-matched controls reported mean 25(OH)D

levels of 27.2+ 10.05 ng/ml, 19.6+ 11.9 ng/ml

and 40.45+ 18 ng/ml (respectively) with statistically

lower 25(OH)D levels in patients with established

SLE compared with controls [91].

A cross-sectional study was specifically evaluated

vitamin D levels in SLE come from Copenhagen in

young patients. They reported statistically lower

levels of 25(OH)D in 21 patients with SLE (mean

13 ng/ml) in comparison with 29 patients with RA

(mean 24 ng/ml), patients with osteoarthritis (mean

32 ng/ml) [28]. A second cross-sectional Canadian

study of 25 Caucasian patients with SLE reported

that more than 50% were vitamin D deficient (using

a cutoff of550 nmol/L or 20 ng/ml) [92].

A recent cross-sectional study recently published

has confirmed these results in patients from Shanghai

area. Levels of 25D were significantly lower in

patients with SLE (11.5 ng/ml) than in patients with

RA (54.6 ng/ml) or controls (59.2 ng/ml) [93].

Another recent study from Israel determined 25D

levels in a number of autoimmune diseases including

MS, myositis, RA, autoimmune thyroid disease and

SLE. The mean 25D levels for all diseases were

below 20 ng/ml. Patients with SLE (n¼ 138) had a

mean 25D level of 11.9+ 11.1 ng/ml, which was

significantly lower than the mean of 21.6 ng/ml in

European controls [94].

Many studies, but not all, have documented an

association between higher disease activity and a low

level of vitamin D. A significant negative correlation

between 25D and Systemic Lupus Erythematosus

Disease Activity Index (SLEDAI) and European

Consensus Lupus Activity Measurement (ECLAM)

scores was reported in European patients [86].

Cardiovascular disease, all-cause mortality

and vitamin D

It has been recently shown that low levels of 25-

hydroxyvitamin D [25(OH)D] are also indepen-

dently associated with cardiovascular events in

patients with and without hypertension suggesting a

role of vitamin D for the maintenance of cardiovas-

cular health [15,95,96]. This hypothesis is further

supported by the ability of vitamin D to suppress the

renin-angiotensin-aldosterone system (RAAS) [16].

Vitamin D deficiency predisposes to up-regulation

of the RAAS and hypertrophy of both the left

ventricle and vascular smooth muscle cells [17,97].

Furthermore, there is accumulating evidence that

vitamin D deficiency may contribute to myocardial

dysfunction and arterial hypertension through an

increase of the parathyroid hormone that directly

produces an increase of blood pressure and an

increase of cardiac contractility [98]. Finally, in

addition to RAAS activation, the up-regulation of

the immune system is often implicated in the

pathophysiology of cardiovascular disease [98].

Experimental studies have suggested that vitamin D

plays a role in the regulation of several important

inflammatory cytokines (such as IL–6 and TNF-

alpha) [98]. It has been shown that low levels

of 25(OH)D are an independent risk factor of total

and cardiovascular mortality in a large cohort of

patients referred to coronary angiography [18].

These results are in line with a recent meta-analysis,

in which a significant reduction of all-cause mortality

was reported for persons receiving vitamin D

supplementation [40]. Most of these studies were

performed in frail elderly people with vitamin D

deficiency [40].

The association between serum 25(OH)D levels

and all-cause mortality was also addressed by the

Longitudinal Aging Study Amsterdam (LASA),

which included 1260 community-dwelling persons

aged 65 years and older at baseline. In that study, low

vitamin D status was a significant predictor of

mortality after adjustments for possible confounders

[99].

There is growing evidence that low serum

25(OH)D levels may contribute to heart failure.

Vitamin D treatment is associated with improved

diastolic function and a regression of myocardial

hypertrophy in patients with haemodialysis [100].

Carotid intima-media thickness was also found to be

inversely and independently correlated with serum

25(OH)D levels. Recent data from NHANES-III

also showed that low serum 25(OH)D concentra-

tions are associated with a higher prevalence of

peripheral arterial disease [101]. Furthermore, re-

sults from the Framingham Offspring Study showed

that patients with 25(OH)D levels below 15 ng/mL

(37.5 nmol/l) are at increased risk of incident

cardiovascular events, even after adjustments for

conventional cardiovascular risk factors [102].

Options for vitamin D therapy

Three options are commonly used to treat vitamin D

deficiency including sunlight, artificial UVB light and

vitamin D supplements. An exposure of 10–15 min

of full-body summer noon-day sun or artificial UVB

radiation (such as tanning beds) will input more than

10,000 IU of vitamin D into the systemic circulation

of most light-skinned adults. One or two such

exposures per week should maintain 25(OH) D

levels in an ideal range.

Holick et al. [4] recently reported that for every

100 IU of vitamin D2 or vitamin D3 ingested, there

is an increase in circulating 25(OH)D levels of only 1

ng/ml, providing some explanation for why men

reporting supplement use have marginally higher

concentrations.

The treatment of choice for vitamin D deficiency

is vitamin D, cholecalciferol, also known as vitamin

D3. Cholecalciferol is available in 400, 1000, 2000,

228 F. Lauretani et al.

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5000, 10,000, 50,000 and even 300,000 UI capsules.

Supplementation with 1000 IU per day will usually

result in about a 10 ng/ml elevation of serum 25

(OH) D when given over 3–4 months. Formulation

of vitamin D3 of 300,000 IU is also present as

intramuscular options, and given 300,000 IU an-

nually corresponds to about 800 IU daily.

The only prescription of vitamin D preparation

available in the United States is the vitamin D

analogue ergocalciferol (Vitamin D2), available as

50,000 IU capsules.

Specific conditions

. Primary and secondary prevention for bone loss:

cholecalfiferol 1000 IU/day plus calcium 1 g/day

or cholecalfiferol 300,000 IU i.m. biannually.

. Inflammatory bowel diseases (IBD): cholecalfi-

ferol 300,000 IU i.m. biannually.

. Liver diseases: calcifediol (25 (OH) D3) or 1-

alpha (OH) calcidiol.

. Kidney diseases: calcitriol 0.5 mg/day plus calcium

1 g/day.

Response to vitamin D treatment

In patients with any stage of chronic kidney disease,

25-hydroxyvitamin D should be measured annually,

targeting vitamin D levels of 30 ng/ml or higher, as

recommended in the Kidney Disease Outcomes

Quality Initiative guidelines from the National

Kidney Foundation [103]. It is a misconception

to assume that patients taking an active vitamin D

analogue have sufficient vitamin D because the

response to treatment is not equal in all individuals.

Levels of 25-hydroxyvitamin D are inversely asso-

ciated with parathyroid hormone levels, regardless

of the degree of chronic renal failure. Parathyroid

glands convert 25-hydroxyvitamin D to 1,25-dihy-

droxyvitamin D, which directly inhibits parathyroid

hormone expression. Patients with stage 4 or 5

chronic kidney disease and an estimated glomerular

filtration rate of less than 30 ml per minute per

1.73 mo˙ of body-surface area, as well as those

requiring dialysis, are unable to make enough 1,25-

dihydroxyvitamin D and need to take 1,25-dihy-

droxyvitamin D3 or one of its less calcaemic

analogues to maintain calcium metabolism and to

decrease parathyroid hormone levels and the risk of

renal bone disease. However, vitamin D com-

pounds do not consistently reduce PTH levels

and beneficial effects on patient-level outcomes are

unproven [41].

Patients with mild or moderate hepatic failure or

intestinal fat-malabsorption syndromes, as well as

patients who are taking anticonvulsant medications,

glucocorticoids, or other drugs that activate steroid

and xenobiotic receptor, require higher doses of

vitamin D [104].

In conclusion, vitamin D appears to be an

hormone with several actions and is fundamental

for many biological systems including bone, skeletal

muscle and heart.

Recent studies suggest that assessment of vitamin

D status should be recommended not only for

prevention and treatment of osteoporosis but also

in the global evaluation of cardiovascular disease,

sarcopenia, insulin-resistance and cancer in older

population.

Declaration of interest: The authors report no

conflicts of interest. The authors alone are respon-

sible for the content and writing of the paper.

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