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

Abstract

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 in muscle strength and falls, cardiovascular and neurological diseases, insulin-resistance and diabetes, malignancies, autoimmune diseases and infections. Vitamin D appears to be a hormone with several actions and is fundamental for many biological systems including bone, skeletal muscle, brain and heart.

The estimated worldwide prevalence of vitamin D deficiency of 50% in elderly subjects underlines the importance of vitamin 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 D deficiency 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 diseases 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 irradiation 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).

Figure 1.  Types of Vitamin D.

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 25(OH)D concentration <50 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 levels >30 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].

Figure 2.  Cut-off of Vitamin D deficiency.

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 significant 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 (<20 ng/ml), and the majority had vitamin D insufficiency (<30 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 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 explaining this phenomenon remain unclear, age-related changes in renal function (with the consequent decrease 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.

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-score <−1.5) 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 (n = 223) 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-hydroxyvitamin 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) = −1.69; 95% CI = −2.28; −1.10], and with serum 25-OHD of 10–20 ng/ml (B = −0.46; 95% CI = −0.90; −0.03). 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 (OR = 2.21; 95% CI = 1.00−4.87; and OR = 2.01; 95% CI = 1.06−3.81), 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 (n = 1008) and appendicular skeletal muscle mass (n = 331, using dual-energy X-ray absorptiometry) were measured in 1995–1996 and after a 3-year follow-up.
		Results and conclusion: Persons with low (<25hairsp;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 (>50 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 (<10 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.
		Results and conclusion: Compared with participants in the highest quartile of serum 25(OH)D (>26.5 ng/ml) (to convert to nmol/l, multiply by 2.496), those in the lowest quartile (<10.5 ng/ml) had increased risk of all-cause mortality (Hazard Ratio (HR) 2.11, 95% CI: 1.22–3.64, P = 0.007) and cardiovascular disease mortality (HR: 2.64, 95% CI: 1.14–4.79, P = 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) = 0.95, 95% CI = 0.92–0.98, per 10 nmol/l 25[OH]D). The association appeared stronger for CVD mortality (adjusted HR = 2.36, 95% CI = 1.17–4.75, for subjects with 25[OH]D levels <25.0 nmol/l vs. those ≥100.0 nmol/l) than for non-CVD mortality (adjusted HR = 1.42, 95% CI = 0.73–2.79, for subjects with 25[OH]D levels <25.0 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; P = 0.005) and 4.78 (1.95–11.69; P = 0.001), respectively. After fully-adjustement, the HRs remained significant for all-cause [1.97 (1.08–3.58; P = 0.027)] and for cardiovascular mortality [5.38 (2.02–14.34; P = 0.001)]. Conclusions: 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)D <25hairsp;nmol/l)] with persons in the optimal range [25(OH)D > or  = 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-trend = 0.007), 9.8% lower concentration of fasting plasma insulin (P-trend = 0.001), and 12.7% lower HOMA-IR score (P-trend < 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% CI = 0.10–0.81) 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; P < 0.0001). Eight years later, plasma 25OHD had decreased in patients (81.5 ± 2.6 nmol/l; P = 0.04). 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; P < 0.0001) and at follow-up (77.1 ± 2.8 nmol/l vs. 87.2 ± 4.5 nmol/l; P = 0.048). 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.
		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 (P = 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 trend = 0.02) and overall mortality (P trend = 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% CI = 32–89%) compared with lower than 50 nmol/l, P(trend) = 0.02. 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 trend = 0.05). Inverse associations were apparent for both dietary (RR: 0.72, 95% CI: 0.46–1.14, P for trend = 0.16) and supplemental (RR: 0.66, 95% CI: 0.43–1.00, P for trend = 0.03) 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) (n = 21), rheumatoid arthritis (RA) (n = 29) and osteoarthritis (n = 12).
		Results and conclusion: In patients with SLE the levels of 25-OH D3 were below those of the healthy controls (P = 0.0008) and OA (P = 0.0168). 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 (P < 0.001). 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, 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 [P = 0.10]), 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-Hänninen 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; P = .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 (P = 0.39, 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.
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 (n = 2426) 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; P = 0.02) and achieved 25-hydroxyvitamin D(3) concentration (25(OH)D concentration: <60 nmol/l vs. ≥60 nmol/l; P = 0.005). High-dose supplemental vitamin D reduced fall risk by 19% (pooled relative risk (RR): 0.81, 95% CI: 0.71–0.92; n = 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.
		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; P = 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; P = 0.03) but did not affect antigen-stimulated IFN-gamma secretion.
		Conclusions: Clinical trials should be performed to determine whether vitamin D supplementation 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.

Figure 3.  Vitamin D actions.

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 differentiation of osteoclastic progenitors into mature osteoclasts, 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 significantly higher at older ages [6]. In a prospective, observational study designed to analyse risk factors for fracture in an ambulatory population aged >55 years, 73 (88%) had evidence of osteopenia or osteoporosis (T-score <−1.5) 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 level <20 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 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, degenerative joint disease, arthritis, chronic fatigue syndrome 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 between walking speed and vitamin D serum levels are show in Figure 4 [52]. Interestingly, persons with low (<25hairsp;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 (>50 nmol/l) levels [13].

Figure 4.  Relationship between vitamin D and physical functions.

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 outcomes' [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 synthesis 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 sarcopenia 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-hydroxyvitamin 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) = –1.69; 95% confidence interval (CI) = −2.28; −1.10], and with serum 25-OHD of 10–20 ng/ml (B = −0.46; 95% CI = −0.90; −0.03). 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 (OR = 2.21; 95% CI = 1.00−4.87; and OR = 2.01; 95% CI = 1.06−3.81), compared with participants with 25-OHD of at least 30 ng/ml [12].

In a meta-analysis recently published, this relationship 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 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 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 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 [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 prospective cohort study of older persons enrolled in the Longitudinal Aging Study Amsterdam, low levels of 25(OH)D (<10 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, 0.64−0.92) 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 calcium reduces the risk of falls (corrected pooled odds ratio, 0.65; 95% CI, 0.4−1.0) [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 (n = 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; n = 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 interventions 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 concentration 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 deficiency 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 Prevention 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 (combined odds ratio: 0.67, 95% confidence interval: 0.53–0.85) [63]. Moreover, a study in Finland found an association between dietary vitamin D supplementation 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 concentrations are associated with reduced insulin sensitivity 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. Vitamin D exerts its effects through nuclear vitamin D receptors [68], which are found in a wide variety of tissues, including the pancreatic islet β-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 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 relationship 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 quartile <20 ng/ml. At baseline, the odds ratios for cognitive impairment (defined as 3MS score < 80 or Trails B test time > 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 significant 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 cognitive 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 >70 years are currently defined as 10 μg/day (400 IU) and 15 μg/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 appropriate intake amounts to support brain function in older adults remain to be determined. This conclusion 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 between 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 performance 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 immunomodulatory activity on monocytes and activated T and B lymphocytes [80]. Then, increased production of 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 prevented 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 tuberculosis 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 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; P = 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 of <50 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 >400 IU vitamin D/day had a markedly reduced risk of developing several cancers, including pancreas and oesophagus and non-Hodgkin lymphoma [83]. Lappe et al. [85] reported that postmenopausal 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 maintaining both protective immunity and self-tolerance, as immature dendritic cells promote T cell tolerance, whereas mature dendritic cells activate naïve 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 >400 IU vitamin D/day were found to have a >40% 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 erythematosus (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 measuring vitamin D in the context of either bone mineral density (BMD) or fractures or both included a study documenting severe 25 (OH)D deficiency (<25hairsp;nmol/l or 1 ng/ml) in 8% of 107 consecutive 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 of <50 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 (n = 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 independently associated with cardiovascular events in patients with and without hypertension suggesting a role of vitamin D for the maintenance of cardiovascular 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 concentrations are associated with a higher prevalence of peripheral arterial disease [101]. Furthermore, results 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, 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 annually 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): cholecalfiferol 300,000 IU i.m. biannually.

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

• Kidney diseases: calcitriol 0.5 μg/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 associated with parathyroid hormone levels, regardless of the degree of chronic renal failure. Parathyroid glands convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin 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 m² 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-dihydroxyvitamin 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 compounds 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 responsible for the content and writing of the paper.