Non-musculoskeletal benefits of vitamin D– Wimalawansa – Sept 2016

Journal of Steroid Biochemistry & Molecular Biology online 20 September 2016
Sunil J. Wimalawansa, MD, PhD, MBA, FACP, FRCP, FRCPath, DSc, Professor of Medicine
Endocrinology & Nutrition, Cardio Metabolic Institute, 661 Darmody Avenue, North Brunswick, NJ, USA
Different minimum amounts of vitamin D are needed for treatment (Fig 2)

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Abstract

The aim of this study is to determine and critically evaluate the plausible relationships of vitamin D with extra-skeletal tissues in humans. Severe vitamin D deficiency results in rickets in children and osteomalacia in adults; these beneficial effects in the musculoskeletal system and certain physiological functions are well understood. Nevertheless, mounting reports support additional beneficial effects of vitamin D, outside the musculoskeletal system. This review explores the recent advances in knowledge about the non-skeletal effects of vitamin D. Peer-reviewed papers were extracted from research databases using key words, to assess correlations between vitamin D and extra-skeletal diseases and conditions. As per the guidelines of the Preferred Reporting Items for Systematic Reviews (PRISMA); general interpretations of results are included; taking into consideration the broader evidence and implications.
This review summarizes current knowledge of the effects of vitamin D status on extra- skeletal tissues with special attention given to relationships between vitamin D status and various diseases commonly affecting adults; the effects of intervention with vitamin D and exposure to sunlight.
Evidence suggests that vitamin D facilitates the regulation of blood pressure; and cardiac; endothelial; and smooth muscle cell functions; playing an important role in cardiovascular protection.
In addition; 1,25(OH)2D improves immunity; subdues inflammation; and reduces the incidence and severity of common cancers; autoimmune diseases and infectious diseases. Almost all adequately powered; epidemiological and biological studies that use; adequate doses of vitamin D supplementation in D- deficient populations have reported favorable outcomes. These studies have concluded that optimizing 25(OH)D status improves the functionality of bodily systems; reduces comorbidities; improves the quality of life; and increases survival. Although accumulating evidence supports biological associations of vitamin D sufficiency with improved physical and mental functions; no definitive evidence exists from well-designed; statistically powered; randomized controlled clinical trials. Nevertheless, most studies point to significant protective effects of vitamin D in humans when the minimum 25(OH)D serum level exceeds 30ng/mL and is maintained throughout the year.

Introduction

Factors affecting Vitamin D levels

Skin synthesis and dietary intake of vitamin D are the two natural ways of obtaining vitamin D by humans. Vitamin D and its precursors are present in only a few foods and even then occur in small amounts. Therefore, supplements maybe necessary for those who cannot or do not sufficiently expose their skin surfaces to sunlight and for those living in northern climates during the winter months. For the vast majority of people, it is impossible to attain vitamin D sufficiency by the commonly consumed diets [1]. Therefore, for those who have inadequate sun exposure, especially during the winter months, and those who live in northern and southern latitudes, supplementation becomes a necessity [2].
Sunlight causes the photo-production of vitamin D3 in the skin. Exposure to sunlight is a major source of vitamin D for most people, yet public health advice focuses overwhelmingly on avoiding exposure of unprotected skin, because of the risks of erythema and potential skin cancer [3]. Meanwhile, humans are expected to generate 80% of their daily vitamin D requirement though exposure to sunlight. Moreover, not everyone has the capacity to generate similar amounts of vitamin D following exposure to ultraviolet B (UVB) rays (280-315 nm). The efficiency of cutaneous generation of vitamin D is dependent on the intensity of sunlight, amount of skin exposed, duration of exposure to UVB rays, the zenith angle of the sun, thickness of the skin, and the skin color [2,4].
Considering the abundance of sunshine, one would expect most inhabitants living near the equator (as in south Asia and GULF countries), to be vitamin D sufficient. However, this is not the case [5-7]. In addition, there are several barriers for vitamin D synthesis in the skin, including time of day of the exposure (i.e., exposures to early morning and late afternoon exposures to sunshine generate less vitamin D) and having darker skin, which is a barrier to UVB penetration. In certain conditions, the synthesis of vitamin D may not occur at all [8-11].

Dietary sources of vitamin D are insufficient

Many people do not ingest or generate the estimated needed daily requirement for vitamin D from dietary sources, including society seeking comfort and fewer outdoor activities, a sedentary lifestyle, and limited sun exposure, public health efforts should be geared to encouraging safe sun-exposure and prioritizing food fortification and adequate oral vitamin D intake, as well as interventions to increase physical activity [12].
Most foods do not contain meaningful amounts of vitamin D. Despite stipulations and regulations, fortified food contains variable ad sub-optimal amounts of vitamin D. Thus, safe exposure to sunlight provides the most reliable and optimal way to obtain the daily vitamin D requirement [13]. However, aging, sun avoidance, the use of sunscreen, and the change in the zenith angle of the sun (time of the day) can markedly change the body’s cutaneous production of vitamin D3.
Dietary sources of vitamin D are inadequate and thus, insufficient for the daily requirement. In addition, many dietary sources are inadequately fortified with vitamin D (including milk) and some do not provides the amount stated on the label [14]. Among commonly consumed fish, only salmon and mackerel have reasonable amounts of vitamin D, but the contents within species can vary markedly. For example, farmed salmon had approximately 25% of the vitamin D content as wild salmon [14].

Generation of vitamin D with reference to geographical location

Europeans living in northern latitudes have higher levels of serum vitamin D than do those living in southern latitudes and closure to the equator [1,15-17]. The discrepancy is due in part to the sun-avoidance behaviors of those who live closer to the equator and the greater consumption of eating fatty fish by those who live in northern latitudes. Still, in both populations, the median serum 25(OH)D levels are less than the optimal [9]. In the case of those who live near the equator, having hypovitaminosis D is attributable in part, (A) sun avoidance because of excessive heat and fear of erythema, sunburns and cancer, (B) darker skin pigmentation and (C) personal and cultural habits [16,18].

Evolution, generation of vitamin D, and survival

In evolutionary terms, thousands of years ago, when the original human inhabitants of tropical central Africa with darker skin started to migrate from Africa to more northern climates, they were exposed to less sunlight [2]. They had a major survival disadvantage (i.e., the inability to produce adequate amounts of vitamin D with lesser amounts of available sun). Consequently, as a survival advantage, genetic mutations in skin cells occurred, leading to the production of less melanin. Because such mutation- dependent skin color changes occur over many generations, during this migratory period, almost all of these people likely experienced vitamin D deficiency [19].
The degree of skin pigmentation reduces the penetration of UV radiation and consequently, the photosynthesis of 25(OH)D. Despite living in higher latitudes and altitudes and exposure to less sunlight, people who developed lighter skin colors were able to produce more vitamin D than were those with darker skins [20,21]. Those who developed lighter skin through mutations of melanin and other genes also had a major reproductive and procreative advantage [22-24] because adequate amounts of vitamin D are essential for male and female reproductive functions, as well as the safe delivery of an infant. Meanwhile, a small study (n = 17) concluded that there are no ethnic differences in the synthesis of 25(OH)D between Caucasian and south Asians [25], which contradicts most other published data.
The reproductive health declined in the migrants who moved northward from africa, and continued to have darker skin. Those with hypovitaminosis D had fewer offspring, and succumbed to infectious diseases such as tuberculosis, more often than did those who experienced mutation to lighter skin. In addition, in Northern countries, the conception rate is higher during the summer period when there is a seasonal increase in blood 25(OH)D levels, which further support this theory [26,27].
The effects of vitamin D on endometrial and oocyte development may be a part of the explanation for decreased female fertility. In addition, in vitro studies have reported that the ovarian production of progesterone, estradiol and estrone, and anti- Mullerian hormone expression in granulosa cells are stimulated by 1,25(OH)2D [28]. Even today, those with darker skin who live in northern climates generate significantly less vitamin D than do those with lighter skin [16,18,27].

The importance of adequate skin exposure to sunlight

In a person, the amount of vitamin D generated in vivo is relatively proportionate to the surface area of the skin exposure to UVB, time of day, and duration of exposure. Therefore, unless an adequate area of skin is exposed to sunlight for a reasonable amount of time, the production of vitamin D is likely to be insufficient.
The duration of exposure needed in individual person depends on the skin pigmentation, presence of sun blockers (clothing, creams, etc.) and the inherent ability of the skin to generate vitamin D. Other factors that influence vitamin D generation includes, the intensity of sunlight, time of day (the direction of the UV rays), and health of the skin and age of the person, and cultural and personal habits (e.g., the sun blocking effects of clothing) [29-31].
The exposure required to gain the oral-equivalent doses of vitamin D, as functions of latitude, season, skin type and skin area exposed, expressed in minimum erythema doses has been investigated. A daily intake of 400 IU can be readily achieved through casual sun exposure in the midday "lunch hour” (casual sun exposure without the risk of erythema, for all latitudes). However, to generate a dose of 1000 IU during lunchtime sun exposure requires a greater exposure of skin areas, but a daily dose in excess of 4000 IU is hardly achievable with such short exposure [3].
The regular use of sunscreen and the strength of the sunscreens are major factors that reduce or prevent the ability of the skin to produce vitamin D [29,30,32]. It has been shown that sunscreens

Fig. 1. Pathways of generation and activation of vitamin D.

Generation and activation of vitamin D. The activation of cholecalciferol and ergocalciferol into, 25(OH)D in the liver and l,25(OH)2D, and interacting with the vitamin D receptors (VDRs) in target tissues, leading to physiological actions [modified from Wimalawansa [[l]. with sun-protection factor (SPF) greater than 15 would completely cut off the UVB skin penetration [33-35], but other studies contradict that finding [36,37]. Nevertheless, human physiology is designed to derive most of the daily need of vitamin D through sun exposure (Fig. 1).

Vitamin D—physiology

Physiological importance of vitamin D

Vitamin D has many functions in humans, including calcium and phosphate homeostasis. Once absorbed from the gut or produced in the skin, vitamin D is hydroxylated in the liver into 25- hydroxyvitamin D [25(OH)D] and then in the kidney into 1,25- dihydroxyvitamin D [1,25(OH)2D]. Thereafter, the active metabolite circulates through the blood stream, enters cells and binds to the vitamin D receptor (VDR) in a vitamin D-responsive gene, such as that of calcium-binding protein producing its action of assisting calcium absorption.
Vitamin D deficiency causes growth retardation and rickets in children, and precipitate and exacerbates osteopenia, and osteoporosis, and increases the risk of fractures in adults [38,39]. In addition, the affinity of vitamin D-binding protein, circulating halflives, enzymatic transformations of vitamin D metabolites, and so forth modulate its biological and physiologic actions, in a given tissue [40]. In the longer-term, the levels of 25(OH)D in the circulation required to activate some of its functions vary depending on the tissue [17,41]. Fig. 2 illustrates the estimated serum 25(OH)D levels needed to alleviate various disease states.
Intestinal calcium absorption varies depending on the serum ionized calcium levels, activity of the calcium binding proteins, and serum 1,25(OH)2D [42]. Vitamin D also regulates the secretion of parathyroid hormone (PTH), which in turn controls calcium homeostasis and bone turnover [2,43]. Severe vitamin D deficiency leads to a failure of skeletal calcification and thus leads to accumulation of osteoid tissues [43]. Unless treated, this can lead to rickets in children and osteomalacia in adults.
The key function of vitamin D is to provide adequate calcium and phosphorus to the body and body fluids to maintain optimal metabolic functions [44]. Vitamin D deficiency also impairs fertility and reproductive success [22-24]. Vitamin D modulates the transcription of cell cycle proteins that decrease cell proliferation and increase cell differentiation, such as in osteoclastic precursors, enterocytes, and keratinocytes; these actions of vitamin D are reflected in bone resorption, intestinal calcium transport, and skin cell turnover, respectively [43]. In the case of the latter, the cell-differentiation and immuno-modulatory properties of vitamin D have led to the topical use of vitamin D and its metabolites in the treatment of psoriasis and other skin disorders.
Circulating vitamin D, the parent compound, likely plays an important physiological role with respect to the vitamin D endocrine/autocrine system, including providing as a substrate to produce its active hormone [40]. Based on emerging data from the laboratory, clinical trials, and studies on circulating 25(OH)D, accumulated during past few years, we can conclude, it is likely that for the optimal functioning of these systems, significant amount of vitamin D should be available on a daily basis to ensure, stable circulating concentrations [40].
Thus, the unphysiological variations (e.g., fluctuations) of 25 (OH)D levels in blood secondary to infrequent vitamin D dosing (i.e., administration every 3 months to yearly) could lead to negative outcomes as reported in clinical trials. This is in part because of the shorter circulating half-life of intact vitamin D and the marked fluctuation of bio-available vitamin D in the circulation and within cells [40,45]. Reported negative outcomes in certain clinical studies represent (poor) failure of the study designs, not necessarily the lack of efficacy of vitamin D.

The physiological blood level of 25(OH)D

Having physiological levels of vitamin D over a long period, decreases the incidence and severity of type 1 and type 2 diabetes, insulin resistance, metabolic syndrome, cardiovascular diseases (CVDs), depression, and certain cancers, including cancer of the breast, colon, and prostate [44,46-55]. Fig. 3 illustrates the different mean serum 25(OH)D levels in four different ethnic groups.
Based on these data from the United States, more than 90% of the non-Hispanic African Americans (15ng/mL) and Hispanics (mean level of 20 ng/mL) have hypovitaminosis D [55,56], whereas non-Hispanic Whites have mean serum 25(OH)D levels of 26 ng/ mL. Dark-skinned people in central Africa living in traditional cultures had mean serum 25(OH)D levels of 46 ng/mL. The latter should be considered as the true physiologic level of 25(OH)D in humans [55,56]. In addition, a variety of data have been reported on the relationships among ethnicity, skin color, and serum 25(OH) D levels [19,57-59].
In addition to the aforementioned, it has been suggested that the socioeconomic factors are the strongest determinant of skin- color based health disparities in the United States (and perhaps other) population [60]. Fig. 4 illustrates the odds ratios of 25(OH)D deficiency in relation to the lowest quartile of serum 25(OH)D levels by race [58].
Data presented were from the National Health and Nutrition Survey III. Compared with non-Hispanic Whites, non-Hispanic African Americans are 10-times likely to be vitamin D deficient (p < 0.001).

Vitamin D: associations and comorbidities

Vitamin D plays an essential role in developing and maintaining a healthy skeleton for humans and other land vertebrates. The major biological function of 1,25(OH)2D is to keep the serum calcium and phosphorus concentrations within the normal range. It is essential to maintaining cellular functions and, enzymatic activities, and promoting mineralization of the skeleton [13].
Associations have been reported between vitamin D intake and dose-dependent risk reduction for falls and osteoporosis [61,62], diabetes [63,64], multiple sclerosis [65], rheumatoid arthritis [66], and cancer [32,67]. Published reports indicate that those who live in higher latitudes not only have low serum 25(OH)D levels that are associated with the increased prevalence of hypertension [68], autoimmune diseases, type 1 diabetes [69] and multiple sclerosis [70,71].
Recent data from epidemiological, cross-sectional, and longitudinal studies suggest that vitamin D adequacy can minimize or prevent many of the aforementioned chronic diseases. Such associations include reduction in the risks of diabetes [63,64,72,73], multiple sclerosis [65], rheumatoid arthritis [66], osteoporosis [61,74], and certain types of cancer [75,76]. However, none of these studies was designed to use vitamin D supplementation as the primary intervention or address specific disease risk reduction as the primary end point.
Therefore, evidence reported through these ecological/observational studies, although demonstrating strong associations, also includes confounders. These include, failures in study design, randomization bias, inadequate statistical power, drug interferences that are not controlled between groups, variations of body mass index, age and gender disproportions, variability of taking diet and supplements, nutritional status, sun exposure, smoking and alcohol use, physical activities, and skin pigmentation, etc. The lack of control over these confounders can influence the outcome of these associations. Therefore, the resulting data cannot be fully relied upon nor can be used to make firm or overreaching conclusions or policy making.

Consequences of vitamin D deficiency

? ? mineralization and development of fetal rickets [77-79], and perhaps suboptimal brain development [80-84]. Long-term vitamin D insufficiency can lead to other effects, such as type 1 diabetes, cancer, and multiple sclerosis, and several other diseases [32,82-84]. Table 1 identifies some common diseases and conditions that are associated with vitamin D deficiency.
Signs and symptoms of vitamin D deficiency include lethargy, increased vulnerability to bacterial and viral infections, exacerbation of existing chronic diseases, the inability to lose weight and visceral obesity, insulin resistance, low back pain, proximal muscle weakness muscle aches, and spontaneous throbbing bone pain. Painful skeletal sites at times can be identified as pseudo-fractures using routine plain x-rays.

Benefits of vitamin D in the musculoskeletal systems

Vitamin D plays an important role in stimulating the intestinal absorption of calcium and maintaining physiological blood levels of calcium and phosphorous, bone development and ossification, mineralization, and preservation. Vitamin D deficiency increases muscle weakness and falls and thus fractures [62,85,86]. Studies have shown that vitamin D supplementation will aid in maintaining bone strength, and reduce the risk of falls, fractures, and bone loss in elderly individuals, especially those with inadequate calcium and/or vitamin D intake [39,87-90].
Vitamin D adequacy not only supports healthy bone development and growth in children and adults but also can promote healthy remodeling and rebuilding of new bones. Hypovitaminosis D has profound effects on pancreas, leading to prediabetes and diabetes [91,92], and in the brain causing neurocognitive dysfunction and impairment of balance [93]. There is strong evidence for the protective effects of vitamin D in muscular system

Table 1 Diseases and conditions that are associated with or aggravated by vitamin D deficiency.

Osteomalacia/osteoporosis
Muscle function and falls
Autoimmune disorders
Tuberculosis/infections
Cancer (breast, colon, skin, pancreas, prostate)
Fibromyalgia
Chronic fatigue syndrome
Cardiovascular mortality
Demyelinating diseases
Infections
Athletic performance
Seasonal affective disorder
Depression
Obesity
Rheumatoid arthritis
Parkinson's disease
Cardiovascular events
Overall mortality
Psoriasis
   From Wimalawansa [1].

In people of all ages, vitamin D deficiency negatively affects health outcomes. Recent studies have confirmed that during fetal life, maternal vitamin D deficiency causes a reduction in fetal bone
[11,94-97], including prevention of falls [62,85,98] and fractures [39,99]. Nevertheless, in the elderly in particular, it is necessary to reduce the fall risks from other factors, such as arthritis, disabilities, poor balance [90,100], impaired vision and hearing; unsafe home setting; peripheral neuropathy; and environmental hazards [1,9].
It is common to find vitamin D deficiency in those who are having increased falls and impaired physical function [101]. Although some data suggest that serum 25(OH) D levels greater than 15 to 20ng/mL are adequate to prevent rickets and osteomalacia [102], other data including recent cohort reports, animal data, and a number of epidemiological studies indicate that much higher serum 25(OH)D levels are required for cancer prevention and protective immune responses [79,103].

Non-skeletal effects of vitamin D deficiency

Non-skeletal effects of vitamin D can be broadly categorized into (A) regulatory effects on the endocrine and immune systems; (B) cardiovascular functions, metabolic syndrome-obesity, and diabetes; (C) sarcopenia and gait; (D) memory and neurological dysfunction; and (E) cancer and chronic kidney diseases. VDR knock-out mice cell-based models, and genome-wide association studies have provided some insight to a variety of non-skeletal effects of vitamin D.
Because vitamin D is an important mediator of calcium metabolism, its actions have been implicated in the pathophysiology of several extra-skeletal conditions. Some of the extra-skeletal benefits (non-calciotropic functions) such a cell proliferation, hypertension, renal disease, and insulin resistance, apoptosis and immunity of vitamin D arising from extra-renal synthesis; autocrine and paracrine effects of the active metabolite, 1,25 (OH)2D [104].
Statistically significant inverse associations between 25(OH)D levels and CVD risk factor were reported in dose-responses (an inverse association exhibiting a linear biological gradients, and cellular-level causative mechanisms and biological pathways with increased risk for CVD with mediators, such as dyslipidemia, hypertension and diabetes mellitus n the with hypovitaminosis D [105]. Table 2 illustrates common conditions that are thought to aggravate vitamin D deficiency.
As per the Vitamin D Life [www.vitad.org], vitamin D reduces the severity of more than 70 different diseases. Some of these key diseases and conditions incudes, rickets, osteomalacia, falls, hip fractures, diabetes, metabolic syndrome, influenza, certain cancers (breast, colon and prostate cancer), pregnancy risks, chronic kidney disease, cystic fibrosis, rheumatoid arthritis, osteoarthritis, tuberculosis, respiratory and urinary tract

Table 2: Skeletal and non-skeletal effects of vitamin D.

Musculoskeletal effects
Essential for calcium homeostasis
Enhanced GI absorption of calcium
Enhanced osteoblast function
Necessary for bone mineralization
Prevent rickets and osteomalacia
Decrease sarcopenia
Improve balance and prevention of falls
Prevention of osteoporosis and fractures
Non-skeletal effects
Improved immunity
Decrease severity of autoimmunity and neurological disorders
Prevention of type 1 and type 2 diabetes
Prevention of cancer
Decreased cardiovascular diseases
Decreased all-cause mortality
Decreased pulmonary morbidities From Wimalawansa [1].
Less morbidities and improved survival

Vitamin D inadequacy and cancer incidences

In many industrialized countries, cancer is the second most common cause of death. Vitamin D is involved in control of the cell cycle and thus likely is a key mechanism in cancer reduction [106,107]. Consequently, low vitamin D status is associated with increased risks of various cancers. Among those who live at higher latitudes in the United States, an increased risk of dying of common cancers has been documented [108,109], including the risk of developing and dying of colon, breast, prostate, and other cancers [108-112]. Correlations also have been reported between an inability to produce vitamin D3 through the skin and living at higher latitudes [113-115].
The mechanisms and effects of vitamin D on cancer are complicated. Moreover, VDR polymorphisms may also have an association with cancer, which suggests gene-environment interactions for such outcomes but data are inadequate to make firm conclusions [116-120]. It is possible that the genetic variations of vitamin D effector system or the VDR pleomorphism, together with epigenetics, may further modify cancer incidence [116,121].
In addition, vitamin D metabolism and perhaps its effects also are influenced by diet, medications, the balance between energy intake and expenditure, and environmental pollutants [122]. Many research gaps exist in this area that needs to be addressed via large randomized controlled clinical trials (RCTs). Without such definitive studies, it is not possible to effectively predict or guide treatments, or modify the susceptibility of people/communities to protect them using dietary and vitamin D interventions.
In addition, evidence supports the relation between vitamin D deficiency and the incidence of certain cancers. Data from ecological studies demonstrate significant inverse correlations between solar UVB doses and the incidence of a number of cancers as well as the mortality rate associated with them [123-126]. Whether this is in part attributable to sun avoidance or some other phenomenon, such as frailty and aging, is remains unknown.
Epidemiological studies have suggested links between exposure to sunlight and low mean serum 25(OH)D levels, with higher incidences of breast [127-129], colon (digestive tract), prostate, and ovarian cancers, and non-Hodgkin’s lymphoma and certain leukemias [46,94,130-133]. However, it is unknown whether the risks of cancer would decrease with normalization of vitamin D status in the longer term [134,135]. Vitamin D decreases cell proliferation and increase cell differentiation, decrease angiogenesis, and has anti-inflammatory effects; impeding cancer cell growth [136] and decreasing cancer metastasis [137-140]. Nevertheless, it is not clear whether hypovitaminosis D itself, leads to increase incidence of certain cancers, but most studies support this notion.
Epidemiological studies have suggested an inverse association between increased sunlight exposure [surrogate for an increase in serum 25(OH)D levels] and decreased incidences of several types of cancers, including those of the breast [127-129,141,142], colon, prostate, and ovaries, as well as certain leukemias and non- Hodgkin’s lymphoma [46,94,120,126,130-133,143]. Recent data point to increasing incidences of similar types of cancers in those who live in northern latitudes [124,144-148]. Thus, it is tempting to postulate that this increasing incidence of cancer is at least in part attributable to the prevailing high incidence of vitamin D deficiency.
One study reported that postmenopausal women who received 1100 IU vitamin D3 and 1000 mg calcium daily (i.e., dual effect) experienced 60% fewer cancers over a 4-year period [149-151]. These data have been supported by meta-analyses demonstrating that increasing the intake of vitamin D3 by 1000 IU a day was associated with a 50% reduction in colorectal and breast cancer risks [152-154]. Those who increase their vitamin D intake modestly (e.g., 400 IU vitamin D/day) also had reduced risk of certain cancers, such as pancreatic and esophageal [155], and non- Hodgkin’s lymphoma [156-161].
In the Women’s Health Initiative study, women supplemented with calcium and vitamin D had a significantly lower risk of total breast and invasive breast cancers (14-20%), and non-significant reduction in the risk of colorectal cancer (17%) [162]. The mechanisms whereby vitamin D reduces the risk of cancer are complex. These include, reducing inflammation, effects on cellular differentiation, apoptosis, reduced angiogenesis around tumors and reduced metastasis [125,163]. Data from experimental studies suggest that VDR activation exerts anti-cancer effects on virtually all steps of carcinogenesis [134].
A series of reports indicates that those who are exposed to more sunlight throughout their lives (not just one summer) were less likely to die of cancer [50-54]. This concept was supported by prospective and retrospective studies that have documented circulating 25(OH)D levels [135]. For example, a 30% to 50% risk reduction of colorectal, breast, prostate, and several other cancers in adults over two decades was reported in those with serum 25 (OH)D levels more than 20ng/mL (50 nmol/L) [164-168]. Fig. 5 illustrates associations between serum vitamin D levels and various diseases.
Not every study finds positive relationships between vitamin D and cancer. For example, in the United Kingdom [[where approximately, 600,000 deaths from cancer occur each year [[169]] a community-based study compared 100,000 IU of vitamin D3 administered every 4 months (less than 1000 IU a day, given on an infrequent basis) with a placebo in 2686 men and women aged 65 to 85 years; there were no differences between the interventional and placebo groups (RR, 1.09; 95% CI, 0.86 to 1.36) and total cancer mortality (RR, 0.86; 95% CI, 0.61 to 1.20) for the two groups was statistically comparable after 5 years of followup [170]. In this study, the dose provided was inadequate to attain the minimum levels necessary to have a meaningful reduction in cancer incidence [i.e., mean serum level beyond 30 (or 40) ng/mL], and the administration (i.e., the dosing schedule) was too infrequent, preventing the possibility of a positive outcome.
Nevertheless, the overall evidence from ecological and RCTs suggests that having serum 25(OH)D concentration above 30 ng/ mL (75 nmol/L) is likely to reduce the risks of having cancer and improve the survival, if cancer is developed [124,154]. On a population basis, to achieve such serum level, in the presence of casual exposure to sunlight, one needs to ingest vitamin D, approximately 2000 IU/day [171].

Cardiovascular effects of vitamin D

Evidence is also emerging with reference to associations between vitamin D deficiency and an increased incidence of cardiovascular mortality and all-cause mortality [172-177]. Vitamin D has anti-inflammatory and cardiovascular protective effects [178,179]. Its cardiovascular protective effects are mediated through lowering blood pressure and vascular tone [180,181], preventing vascular calcification [41,177,182,183], improving cardiac and smooth muscle cell functions, and maintaining the health of the endothelium [184-186].
The association between CVD and serum 25(OH)D is based on both, longitudinal and cross-sectional observational studies [187]. Such studies have reported associations between serum 25(OH)D levels and cardiovascular risk, including stroke, myocardial infarction, heart failure, and the ensuing cardiovascular mortality [79,187]. Increased PTH levels are known to promote insulin resistance, weight gain, left ventricular hypertrophy, hypertension, and the inflammatory-acute phase responses, which further increase the risk for cardiac arrhythmias and cardiovascular mortality [188].
The increased PTH levels in blood (secondary hyperparathyroidism) that are common in those with vitamin D deficiency have been suggested to be a contributor to the progression of CVD [187], but, no such correlation has been found between blood vitamin D and lipid levels [189,190]. However, others have fund beneficial effects of vitamin D supplementation on lipids, including a reduction in the apolipoproteins, Apo A1 and B [191].
Intervention: studies have reported significant clinical improvements in patients with heart failure with vitamin D supplementation [187]. Interaction of vitamin D with its receptors on the vasculature and the myocardium seems to be the mechanistic path of action in the reduction of the wall thickness, decreasing the severity of cardiac failure [192]. The cardiovascular protective effects of vitamin D also encompass suppression of matrix metalloproteinases and FGF-23, and remodeling of the myocardium and the vasculature [187,193].
A recent meta-analysis reported that the circulating levels of 25 (OH)D were lower in patients with peripheral artery disease, compared to those who do not have such [194]. Hypovitaminosis D was associated with peripheral artery disease, especially in those patients with critical limb ischemia. Authors concluded that low 25 (OH)D contributes to the development of advanced peripheral vascular disease [194]. Additional cellular level, beneficial effects of vitamin D includes its actions on anti-inflammatory effects, renin- angiotensin system, parathyroid hormone, etc. [187,193,195].
Sufficient blood levels of vitamin D may reduce deaths associated with heart disease, all-cause mortality, and strokes secondary to hypertension [176]. Meanwhile, intervention studies have reported clinical improvements in patients with heart failure after vitamin D supplementation [187]. Most of the associations reported between vitamin D deficiency and non-skeletal diseases are based on retrospective analyses, cohort studies, case reports, and epidemiological studies. Evidence from prospective randomized clinical studies would be helpful in reaching conclusions about the reported associations.

Autoimmune diseases

Autoimmune diseases such as multiple sclerosis, Hashimoto’s thyroiditis, and inflammatory bowel disease occur because of an inappropriate immune-mediated destruction of specific body tissue and T-cell development and function; these are at least in part regulated through vitamin D [196]. Both 25(OH)D and 1,25 (OH)2D are involved in the regulation of the immune system [197].
In the absence of vitamin D and signals delivered through the VDR, actions through autoreactive T-cells manifest, especially in the presence of insufficient 1,25(OH)2D and VDR activity. Once bound to VDR in immune cells, vitamin D acts as a selective immunosuppressant [198] and decreases the severity of autoimmune diseases [199]. When vitamin D is sufficient, T-cell response is restored and autoimmunity minimized. In persons with type 1 diabetes, multiple sclerosis, and thyroid autoimmunity, serum 1,25 (OH)2D levels are reduced [200].
Low vitamin D levels worsen most autoimmune diseases and increase the susceptibility to autoimmune diseases such as cancer, metabolic syndrome, type 2 diabetes, and infectious diseases [44,54,97,201]. Women with autoimmune diseases who received vitamin D 400 IU/day had a 40% reduction in the risk of multiple sclerosis, chronic fatiguing illnesses, Behcet’s disease, and rheumatoid arthritis [202-205]. Research also suggests an association between low serum vitamin D levels and increased prevalence of inflammatory bowel diseases [206-209] and rheumatoid arthritis [210-213]. However, not all studies agree with this conclusion [214].

Infections

The immune system would not function efficiently in the absence of vitamin D adequacy. This leads to increased susceptibility to bacterial and viral infections, particularly intracellular bacterial infections such as tuberculosis [215]. Adequate vitamin D levels are inversely associated with decreased seasonal infections [216] but also enhance immunity and the ability to overcome bacterial and viral infections [217,218].
Exposure to sunlight is known to enhance recovery from mycobacterial diseases such as mycobacterium tuberculosis [219,220] and leprosy [221,222]. Mycobacterial products increase the activity of the 1a-hydroxylase enzyme within macrophage in granulomatous tissues, thus increasing the intracellular levels of 1,25(OH)2D3 and the expression of the VDR. These together enhance the expression of the gene-encoding, bactericidal protein cathelicidin, which destroys mycobacterium tuberculosis and similar intra-cellular pathogenic organisms. T-cells and macrophages have high concentration of VDRs [223]. VDR activation also increases the synthesis and secretion of the bactericidal peptides cathelicidin and defensins [205,224] while reducing inflammatory cytokines [178,225].
Vitamin D deficiency is strongly associated with pneumonia [226]. Vitamin D adequacy plays an important role in combating bacterial infections, such as tuberculosis, and viral infections, including influenza [22,217,218,227-229]. Hypovitaminosis D is associated with reduced cellular immune function and hyponatremia in patients with H7N9 pneumonia [230]. Nevertheless, some studies do not support this concept [231,232].
A recent publication concluded that due to the heterogeneity of studies, where included studies differed with respect to population, baseline vitamin D levels and study length, and so forth, conclusion is based on vitamin D meta-analysis cannot be relied upon [233]. Future RCTs should be focus on subjects with vitamin D deficient and apply more objective and standardized outcome measurements.

Role of vitamin D in regulation of blood pressure

Vitamin D has been reported to lower blood pressure in vivo in humans by regulating the renin-angiotensin system [234,235]. In addition, some epidemiological and clinical studies have shown that increased dairy consumption and calcium and/or vitamin D supplementation have a beneficial effect on blood pressure [236,237]. Thus, vitamin D therapy has been suggested to be an effective short-term intervention for reducing blood pressure [234,235].
Experimental studies have demonstrated novel actions of vitamin D metabolites on cardiomyocytes and endothelial and vascular smooth muscle cells. Low 25(OH)D levels are associated with left ventricular hypertrophy, vascular dysfunction, and renin- angiotensin system activation [238]. However, despite a large number of smaller experimental, cross-sectional, and prospective studies supporting a key role of suboptimal levels of vitamin D in the pathogenesis of CVDs, a causal relationship remains to be established. Vitamin D reduces vascular stiffness and vascular dysfunction [239]. However, not all studies agree with these findings [240]. Patients with hypertension who had tanning bed exposure nearly doubled their serum 25(OH)D levels and reported a reduction in blood pressure [241,242], but the use of tanning beds is not recommended.

Type 1 and type 2 diabetes mellitus

Several observational studies have reported the effects of vitamin D in reducing the risk of type 2 diabetes (T2D) [177,243,244]. These cohort studies have reported that persons with serum 25(OH)D levels greater than 29 ng/mL had a 20%-50% reduction in the risk of developing T2D [244]. A few studies indicate that those with serum levels greater than 40ng/mL had the lowest incidence for T2D [103,235]. Nevertheless, once a person has T2D, vitamin D may not have a measurable effect on the course of the disease [50,190], except for some reduction in insulin resistance [44,54,97,201].
Release of insulin including secretion in response to glucose from pancreatic b-cells, at least in part seems to be dependent on vitamin D adequacy. Having physiological blood levels of vitamin D reduces the overproduction and tissue-damage caused by free radicals and blocks renin production [245]. This results in decreased islet cell harm from the effects of hyperglycemia and insulin resistance [246,247]. In addition, in persons with T2D, short-term, daily supplementation of vitamin D reduces central obesity and T2D, particularly in the carriers of the AA genotype [248].
Data related to type 1 diabetes (T1D) comes from ecological/ epidemiological studies, small supplementation studies and metaanalyses [249]. In addition to the reduction ofT1D risks and related autoimmunity, vitamin D deficiency in early life is associated with a higher risk of T1D in adulthood [92,250]. A meta-analysis of data supports that supplementation of vitamin D during early infancy reduces the incidence of T1D [251]. Nevertheless, the available data are conflicting on the cause-effect relationship between of vitamin D and diabetes. Although not studied yet, it is plausible that vitamin D supplementation early in the disease—the prediabetes stage, may prevent b-cell damage.
Among the many possible mechanisms, reduction of inflammation [54,178,252], improved insulin sensitivity, and reduced insulin resistance have been proposed [50,52,53,253,254]. In addition, vitamin D has positive physiological effects on the regulation of plasma calcium levels, which indirectly regulate insulin synthesis and secretion, and also have actions on pancreatic b-cell function [50,255,256]. These complex relationships are described mostly in observational and epidemiological studies and their existence have not been substantiated by RCTs [92].

Pregnancy

Vitamin D deficiency increases the risks of pre-eclampsia and development of problems in the child in later life [257-259]. Serum 25(OH)D levels are inversely correlated with the incidence of preeclampsia. Current evidence supports an immunological etiology for pre-eclampsia and auto-immunity, and vitamin D deficiency as a predisposing factor for the development of pre-eclampsia [260].
Women with recurrent pregnancy losses and low blood vitamin D have an increased prevalence of autoimmune and cellular immune abnormalities and pre-eclampsia compared with women with recurrent pregnancy losses but with normal vitamin D [261]. The aforementioned is particularly noticeable in pregnant women whose vitamin D intake is below 400 IU per day [262]. Vitamin D supplementation during pregnancy increases the circulating 25 (OH)D levels in the women and fetuses, which is associated with increased birth weight and infant height but not with other maternal and neonatal outcomes [263].
Non-breast-fed infants need higher doses of oral vitamin D supplementation [171]. Another study reported a 6-week supplementation of calcium and vitamin D in pregnant women with gestational diabetes mellitus led to several beneficial outcomes, including decreased cesarean section rate and duration of maternal hospitalization, and decreased macrosomia, hyperbilirubinemia and hospitalization in newborns [264].

Physical Junctions

Several studies have reported performance improvement of athletes after exposure to artificial UVB. Cross-sectional studies also reported that 25(OH)D improves physical performance in older people [265]. Vitamin D increases the quality and the quantity of type II, fast-twitch skeletal muscle fibers. Studies conducted in older individuals show that vitamin D improves their functional capabilities.
Vitamin D has genomic and non-genomic actions on musculoskeletal tissues [266,267]. The genomic pathway involves activation of the 1,25(OH)2D nuclear receptors, resulting in expression of several messenger RNAs and synthesis of key proteins [265,268]. The non-genomic pathway acts directly through secondary messenger systems in the cell and/or by activating protein kinase C [267,269,270].
These are some of the reasons for the myopathy that is associated with rickets and osteomalacia [271,272]. In the case of milder disease, patients may present with a variety of non-specific features, such as muscle pain and tenderness, arthralgia, and paraesthesia. Those with severe vitamin deficiency will present with the classic signs of proximal limb-girdle myopathy (muscle weakness) [271,272].

Sarcopenia and muscle weakness

Vitamin D receptors are widely expressed in muscle cells [273]. Serum 25(OH)D levels and the expression ofVDR in muscle cells as well as testosterone levels decline with age [274]. Collectively, these contribute to sarcopenia and muscle weakness [275]. VDR are located predominantly on the fast-twitch muscle fibers, which respond first in rapid actions, so it is not surprising that vitamin D adequacy increases muscle strength and coordination, enabling the preventing falls [62,171,276].
Vitamin D deficiency leads to proximal muscle weakness with loss of type II muscle fibers. Consequently, muscular symptoms of vitamin D deficiency include easy fatigability, difficulty in rising from a chair or bed, and inability to climb stairs. These abnormalities reverse after replenishment of vitamin D. An age- associated decrease in muscle fiber content, decreased intracellular calcium transportation and the speed of muscle contraction and relaxation have been reported. Associations have been reported with lower limb and grip strengths and serum vitamin D levels [277,278]. However, not all studies agree with these findings [279]. Nevertheless, data suggest that vitamin D provides a physiological important benefit to muscle function.

Difficulty in swallowing

Dysphagia is common in the elderly; approximately half of individuals older than 65 years have swallowing difficulties independent of neurological diseases, such as Parkinson’s disease, stroke, or CVDs. Recent research showed that even healthy older adults, especially those receiving multiple medications, swallow more slowly and generate lower tongue pressures than do younger adults [280].
Dysphagia in the elderly is multifactorial, including abnormal posture, recurrent infections (mostly oropharyngeal yeast), gastroesophageal reflux disease, and frailty, especially among those with vitamin D deficiency [87,281]. Correction of dysphagia is important because it is known to lead to aspiration pneumonia and a vicious cycle of social withdrawal, depression, malnutrition, and sarco- penia, and premature death [282,283].

Overactive bladder

Urinary urgency with or without incontinence, increased frequency of urination, and nocturia are common in the elderly [284]. Overactive bladder occurs in 30% to 40% of adults older than 70 years and more than 70% of residents in nursing homes. Suboptimal vitamin D levels affect the severity of overactive bladder in patients with chronic disabilities. Generalized muscle weakness and poor muscle coordination exacerbate bladder dysfunctions that aggravate control of urination [285].

Pulmonary Junction

There is an age-associated decline in the forced expiratory volume and forced vital capacity [286,287]. Serum vitamin 25(OH) D levels are related to peak airflow and the severity of chronic obstructive airway disease and asthma [287]. In addition, pulmonary function worsens in the presence of vitamin D deficiency and, combined with aging, further increases morbidity and mortality. However, whether the decline of respiratory muscle function is attributable to vitamin D deficiency, chronic airway inflammation, or impaired lung tissue remodeling is not known [286,288].

Age-related macular degeneration

The risk of macular degeneration increases with age, especially in those with vitamin D deficiency [289]. Multivariate models have demonstrated that in women younger than 75 years, increased intake of vitamin D decreased the odds of early age-related macular degeneration [290]. Higher serum 25(OH)D levels are thought to protect against early age-related macular degeneration. Apart from observational studies, no data are available to confirm this. Whether the correction of vitamin D deficiency would decrease the rate of occurrence and/or the severity of macular degeneration is unknown [291].

Vitamin D and pain relief

The elderly, especially those who live in northern latitudes have a high incidence of hypovitaminosis D, which is a risk factor for enhanced perception of pain. Vitamin D deficiency is an independent risk factor for pain and poor prognosis in persons with diabetic peripheral neuropathy [292]. A systematic review concluded an association of vitamin D deficiency with diabetic peripheral neuropathy [293]. In addition, there are other studies showing plausible associations between vitamin D deficiency and diabetic peripheral neuropathy [292-297]. Based on a number of data sets, a mechanistic link has been established between hypovitaminosis D and diabetic neuropathy as well as certain pain symptoms such as, arthritic pain, rheumatism, and fibromyalgia, in the general population [298].
The content of nerve growth factor (NGF) has been studied in experimental, diabetic models [299]. In patients with diabetic neuropathy, NGF skin keratinocytes immunostaining is correlates with skin axon-reflex vasodilation, a measure of painful small (c) fiber neuropathy [294]. In addition, animal studies have reported a preservation of NGF expression in sciatic nerves of diabetic animals, treated with active vitamin D3 analogs, which induce NGF production in human epidermal keratinocytes [300].
Vitamin D also has been shown to reduce demyelination in a cuprizone experimental model of demyelination [296] and in a spinal cord compression model, it induced axonal regeneration [297]. Vitamin D deficiency may lead to selective alterations in target innervation, resulting in presumptive nociceptor hyperinnervation of skeletal muscle, which in turn is likely to contribute to hypersensitivity in muscles and exaggerated pain [295]. These data suggest connections between neuropathic issues and nociception with vitamin D status [292,301]. Nevertheless, a causation cannot be inferred from such cross-sectional studies; thus, specifically designed prospective studies are needed to clarify these issues [295,298].
Calcitonin gene-related peptide (CGRP) is the most potent endogenous vasodilator in humans, which is also a neuromodulator and a nociceptive agent [302-304]. CGRP containing sensory neurons have a distinct vitamin D phenotype and hormonal regulation [305]. Vitamin D deficiency results in increased numbers of axons containing CGRP and growth, and neuronal sprouting in culture. This seems to be regulated by VDR-mediated rapid response signaling pathways [295]. In this regard, a recent clinical trial reported a significant decrease in pain (reduction of total McGill pain score from 19 to 6, p < 0.0001) following a single intramuscular dose of600 000IU of vitamin D that led to an increase in the mean serum 25(OH)D level from 31.7 ±23 to 46.0 ±10ng/mL, in persons with diabetic neuropathy [301].

Vitamin D deficiency and epilepsy

Many studies have shown a link between vitamin D deficiency and epilepsy [306-311]. Children and adolescents treated with antiepileptic drugs are known to develop skeletal problems such as osteomalacia. Children with epilepsy are at risk for poor bone health, and vitamin D therapy may be beneficial. Vitamin D supplementation is recommended for all children with epilepsy to prevent the development of hypovitaminosis D [308,309,311]. In addition, the long-term use of antiepileptic drugs leads to sustained vitamin D deficiency, and is a significant risk factor for epilepsy, especially in children. Targeted strategies such as, vitamin D supplementation and lifestyle advice regarding healthy sunlight exposure behavior, reduce the prevalence of epilepsy in high-risk children [306].
Regular monitoring of vitamin D levels and supplements is needed, especially in the presence of longer duration of antiepileptic medication use, brain magnetic resonance imaging abnormality, abnormal underlying conditions, and in non-ambulatory status [309]. Vitamin D is also thought to have anticonvulsant properties [310]. Irrespective of where they live, a high proportion of children taking antiepileptic drugs on a long-term basis are at risk for vitamin D deficiency [307]. Considering this, monitoring and supplementation and safe sun exposure are important in the care of children on long-term antiepileptic drug regimens.

Dementia, cognitive Junctions, and Alzheimer’s disease

Vitamin D influences brain functions; those who live at higher latitudes and have lower blood levels of 25(OH)D are more predisposed to schizophrenia [312-314] and depression [315]. Vitamin D deficiency has been correlated with worsening Alzheimer’s disease and memory, both of which can lead to increased falls and fractures [62,316]. Vitamin D- and VDR- associated responsive neurohormonal cascades are abundantly expressed in the central nervous system, particularly in areas that are commonly affected by neurodegenerative disorders, such as in the hippocampus [317]. These suggest that such areas could be therapeutic targets for vitamin D actions.
Low serum 25(OH)D levels are associated with cognitive deterioration with age [318]. The use of metformin in diabetics has been associated with impaired cognitive performance [319,320]. In patients with diabetes, vitamin supplements have been reported to alleviate metformin-induced cognitive deteriorations [321]. Vitamin D supplementation has been shown to stabilize Parkinson’s disease for a short period without triggering hypercalcemia [322].
A prospective 30-year follow-up study reported that low 25 (OH)D levels were associated with a 20% increased risk of Alzheimer’s disease and vascular dementia [323]. Vitamin D is also an anti-inflammatory and reduces oxidative stress, enhancing immune response, and is thought to protect the central nervous system [316]. Some have suggested vitamin D supplements as an adjutant therapy for dementia and Alzheimer’s disease [324].

Table 3 The minimum optimal levels of serum 25(OH)D needed to have positive impact of various diseases and disorders.

Disease entity or disorder [References]
Musculoskeletal: 20 to 32ng/mL
• Sarcopenia and muscle weakness [266,267,275,277,278]
• General fractures 32 ng/mL [79,349,350]
• Hip fractures [79,87,351-355]
• Rickets and osteomalacia 20 ng/mL [271,272,352-354,356]
• Fall prevention [62,87,171,276,357]
• Frailty [87,103,338,339]
• Dysphagia in the elderly [280-283]
• Urgency and overactive bladder [284,285]
Cardiovascular (CVD): 30 to 40ng/mL
• Blood pressure [87,176,187,193,195,235-237,241,242,358,359]
• Regulate renin-angiotensin system [234,238]
• Protective effects on CVD [178,179,360,361]
• Vascular tone [180,181,238,239]
• Vascular calcification [41,177,182,183]
• Smooth muscle cell and endothelial functions [184-186]
• Decreasing CVD risks; stroke, myocardial infarction, heart failure [51,176,177,187,193,195]
• Mechanisms of CVD risk-reduction [192,238]
• Cardiovascular mortality [172-177]
• Lipids/apo-proteins (Apo A1 and B ) [191,362]
Cancer: 40 ng/mL
• Cancer [46,94,108-112,120,130-133,143,149-151,363 365]
• Breast cancer and survival [108-112,127-129,162,366-368]
• Colorectal cancers [76,108-112,124,126,152-154,162,342]
• Lymphoma [156-161]
• VDR polymorphisms [116-121]
• Relationship to living in higher latitudes [108,109,113-115,124,144-148]
• Relationship to serum 25(OH)D levels [46,94,124,127-133,135,154,164-167]
• Mechanisms of cancer reduction [125,134,135,163]
• UVB/sun exposure and cancer reduction [44,46-54,108-115,123-125,135]
• Cancer metastasis [137-140]
Respiratory system: 30 to 40 ng/mL
• Respiratory infections [228,369]
• Asthma and chronic obstructive airway diseases [286-288,364,370,371]
• Cystic fibrosis [361,364,372,373]
• Forced expiratory volume and vital capacity [286-288]
Metabolic disorders: 30 to 40 ng/mL
• Type 1 diabetes mellitus [249-251]
• Type 2 diabetes mellitus [44,54,97,177,200,201,235,243,244,248,374,375]
• Insulin resistance [44,50,52-54,97,201,246,247,253,254,376-379]
• Metabolic syndrome [246,247,380]
• Reduced HbA1c levels [362,381]
• Obesity and body mass index [168,382-388]
• Mechanisms [50,54,178,255,256,389-392].
Immunity and autoimmunity: 40 ng/mL
• T-cell function and immune regulation [196,197,202-204]
• General immunity [200,393]
• Multiple sclerosis [200,394]
• Rheumatoid arthritis [210-213,395]
• Inflammatory bowel diseases [206-209]
• Autoimmune liver disease [396]
Infections: 40 ng/mL
• Viral and seasonal infections [22,216-218,227-229]
• Pneumonia [226,231,232,397]
• Tuberculosis and leprosy (mycobacterial infections) [215,219-222,398]
• Hepatitis C [399,400]
• Anti-bacterial/viral mechanisms [178,209,224,225]
Neurological system: 30 to 40 ng/mL
• Cognition and dementia [318-321,323,401,402]
• Alzheimer’s disease [62,316,323,324]
• Depression [205,315,325-329]
• Schizophrenia [312-314]
• Epilepsy [306-311,403]
Pregnancy-related: 30 ng/mL
• Pregnancy outcomes [261,263,264,404-406]
• Fetal developmental problems [257-259,264]
• Preeclampsia [257-261,407,408]
Miscellaneous: 30 ng/mL
• Genomic effects [103,265,268]
• Non-genomic effects [266,267,269,270]
• Anti-inflammatory [50,54,178,179,225,316,390-392].
• Physical performance [265,271,272,275]
• Oral and dental health [333-336]
• Dental caries [331,409]
• Age-related macular degeneration [289-291]
• All-cause mortality [172-177,337,340,341,364]

Vitamin D deficiency and depression

Several reports indicate an inverse relationship between vitamin D deficiency and depression [325,326]. Lower vitamin D levels are associated with depression: increased odds ratio of depression for the lowest versus the highest vitamin D categories in cross-sectional studies (OR =1.31, 95% Cl, 1.0-1.71) and a significantly increased hazard ratio of depression for the lowest versus the highest vitamin D categories in cohort studies (HR = 2.21, 95% Cl, 1.40-3.49) [327].
Vitamin D affects T- and B-lymphocyte activation, as well as quantity, maturation and function of regulatory natural killer T- cells and their counterparts in the gut. These includes, T-cell receptor-alpha-beta, cluster of differentiation-8-alpha alpha-positive intraepithelial lymphocytes [205]. Consequently, vitamin D deficiency decreases innate and adaptive immunity, leading to persistent infections, chronic inflammation, and fatigue.
Vitamin D deficiency worsens depression and mental health- related quality of life among women [328]. Correction of vitamin D deficiency improves depression, as measured by the Beck Depression Inventory [329]. Vitamin D deficiency, in those with alcohol abuse also showed an inverse relationship with severity of alcohol-use and comorbid major depression [325]. Despite all of these findings, conflicting evidence about the relationship between vitamin D deficiency and depression still exists [327,328,330].

Oral and dental health

Vitamin D’s role in reducing the risk of dental caries has been explored [331]. A placebo-controlled trial reported that vitamin D supplements reduced the incidence of dental caries [332]. A metaanalysis of 24 controlled clinical trials reported significant benefit of vitamin D supplementation on oral health [333]. Other studies have linked vitamin D deficiency to periodontal disease [334] and premature tooth loss [335].
Indirect bactericidal effects of vitamin D may manifest via the induction of cathelicidin in reducing oral infections [336]. Nevertheless, it is more likely that low vitamin D levels could be a surrogate marker for poor oral hygiene malnutrition, and frailty, and reflect a low socio-economic state and less access to care from dentists and oral hygienists.

All-cause morbidity and mortality

Several studies have reported the beneficial effects of vitamin D in reducing all-cause mortality [174,176,337]. Studies have also demonstrated an inverse relationship between 25(OH)D level and frailty [338,339] and the all-cause mortality rate [340,341]. Metaanalysis shows that an increase in serum 25(OH)D levels from 22 to 42 ng/mL (54 to 105 nmol/L) was associated with a statistically significant 15% reduction in the incidence of CVDs [51,176,177] and a 30% reduction in breast and colorectal cancer incidence [124,342].
Cardiovascular disease, including coronary artery disease and stroke, is the leading cause of mortality in most countries and especially in certain racial groups such as African Americans [343]. Although, vitamin D deficiency causes increased morbidity and mortality, it is also an indicator of poor health and nutrition [41,344]. In cross-sectional analysis of 9579 subjects with vitamin D deficiency, higher odds of a poor self-rated health and frailty was reported but not in longitudinal analyses [345]. Authors suggested that vitamin D deficiency may not cause frailty or poor general health but may be a prognostic marker for mortality, independent of the individual’s morbidity.
African American men and women have greater prevalence of vitamin D insufficiency, which may be a factor in their susceptibility to certain cancers. Recommendations for vitamin D should be made for the otherwise "healthy populations in greatest need” of dietary vitamin D due to lack of adequate sun exposure [346]. However, among others, low serum 25(OH)D levels can also be a marker for poor socio-economic status, malnutrition, and general ill-health, and thus may be linked to confounding factors [347,348].
Many cross-sectional studies and RCTs indicate that the minimum optimal serum 25(OH)D concentration is 30 ng/mL or higher. Complementary to Fig. 2, Table 3 illustrates examples from the literature that indicate the minimum levels of serum 25(OH)D needed to have a meaningful effect on reducing the incidences of various disorders and diseases, categorized into systems for easy reference.
Data from multiple studies suggests that the serum 25(OH)D levels that needed to maintain to alleviate different diseases various much. For example, while rickets and osteomalacia could be resolved with serum 25(OH)D levels approximately 20 ng/mL, conditions such as cancer, multiple sclerosis, heart failure, osteoporosis, diabetes metabolic syndrome and so forth, need much higher steady levels of vitamin D in the blood. Summary of such from a large number of studies are illustrated in Fig. 6.

Discussion

Vitamin D supplementation is a highly cost-effective, easy to administer, simple solution to alleviating wide-ranging chronic health problems. Many vitamin D studies report a link between low blood 25(OH)D levels and increased risks of dying prematurely to CVDs, cancer, and several other diseases. Adequate vitamin D status is protective against musculoskeletal disorders, infectious diseases, cancer, autoimmune diseases, CVDs, diabetes mellitus, neurocognitive dysfunctions, other disorders and diseases. Vitamin D deficiency is also increases all-cause mortality [417]. Nevertheless, whether vitamin D supplementation leads to longevity is not clear. Clarifying this issue will require more research and longer duration RCTs with adequate doses of vitamin D to increase and maintain the serum 25(OH)D levels of study participants to more than 30 ng/mL.
The use of RCTs with selection bias (e.g., studies that are not designed to assess the efficacy of calcium and vitamin D supplements) has caused some scientists to raise concerns about the safety of calcium supplements, particularly their potential to cause myocardial infarction [418-421]. However, when calcium intake (i.e., diet plus supplements) does not exceed 1.5 g a day and vitamin D supplementation does not exceed 5000 IU per day, no hazard or worsening of any condition, including CVDs, has been documented [422,423]. Introducing investigator bias and selecting inappropriate data sets to test a given hypothesis would generate misleading conclusions from meta-analyses.
Most of the negative clinical studies with vitamin D published to-date, have faulty study designs: they have used

• too-small dosages (<800 IU/day) [424];
• too high, infrequent dosages (i.e., the use of supra pharmacological doses, once in 3 months, 6 month or yearly);
• treated persons with varying blood levels of 25(OH)D (subjects with wide scatter of serum 25(OH)D levels or vitamin D levels have not been tested),
• provided interventions to those who are not vitamin D deficient; and
• used too small sample size and short study durations [425,426].

Taking into consideration the half-life of vitamin D, and thus the fluctuation in blood levels, supplements given at intervals of greater than once a month are unphysiological, and thus are unlikely to have health benefits or improve the signs and symptoms of deficiency status [62,425,427,428].
Because of the design failures, the three large RCTs that are currently under way using vitamin D as an intervention, are unlikely to provide answers to the questions related to the public health needs of vitamin D. These studies have inherent biases in design, inclusion of persons who are already taking supplements and/or who are vitamin D sufficient (i.e., vitamin D sufficient persons), and so forth. Nevertheless, when the minimum serum levels of 25(OH)D exceed 30 ng/mL and are maintained over a long period, most studies point to significant protective effects of vitamin D in humans.
Alleviation of various diseases and disorders requires, persons to achieve and sustain serum 25(OH)D levels that are appropriate to the disease being treated (e.g., osteomalacia/rickets, musculoskeletal system versus cancer, diabetes, autoimmune disorders, etc.) (Fig. 2 and Table 3). While data are mounting, the current evidence is somewhat inconsistent with reference to blood concentrations of25(OH)D with risks for certain health conditions. As with other physiological phenomena, the goal should be to achieve the optimal serum 25(OH)D levels to obtain the most protective effects for the person [i.e., maintaining the serum 25 (OH)D levels between 30 and 50 ng/mL] that benefit all body tissues with minimal or no adverse effects.