Interest in vitamin D has increased dramatically in recent years. As shown in figure 1, the number of journal articles published and indexed in the PubMed database has multiplied almost by 4 from 2000 to 2016.
Vitamin D, which maintains its name by habit or history related to its discovery, is actually a complex hormonal system [1], its structure being very similar to that of steroid hormones.
Hormone D, as it should actually be termed [2], began to be studied and related to bone mineral metabolism. It is well known that its deficiency produces a skeletal disease in children referred to as rickets and osteomalacia in adults [3]. Subsequently and already in the 20th century, it was verified that practically all the cells of the organism have receptors for this hormone. Thus our knowledge was expanding into other pathophysiological and clinical aspects, including osteoporosis [3-5] as in other bone diseases. The relationship of vitamin D to these processes has been termed “extra-bone effects of vitamin D” [3,6-9].
Nowadays we have a better understanding of vitamin D’s relation with muscle and falls [1], with diabetes mellitus, both type 1 and 2 [10], with arterial hypertension and ischemic heart disease [11], immune system and autoimmune diseases [12], respiratory infections [13], Bronchial asthma [14] or cancer [3,7,8,15], to name some of the relationships on which an increasing number of articles have been published.

Vitamin D is actually not a vitamin in the strict sense of the word. It is not an essential dietary component, and it is entirely possible, in most places, to obtain it through exposure to the sun, as it is synthesized in the skin by the influence of solar ultraviolet rays [1] (Figure 1).
In order to be functional, hydroxylation is needed in the liver, where it is converted into 25-hydroxy-vitamin D3 or 25-hydroxycholecalciferol (25-HCC). Subsequently another hydroxylation occurs in the renal tubule, becoming 1,25 dihydroxy-vitamin D3 (1,25-DHCC) or calcitriol, the true hormone D, with physiological actions in individuals of all ages [2,3] (Table 1).

After the 19th century rickets epidemic, caused by vitamin D deficiency due to inadequate sun exposure, insufficient vitamin D (deficiency or insufficiency) is once again recognized as a universal pandemic with serious consequences for human health1. Prolonged vitamin D deficiency causes rickets in children and osteomalacia in adults, while vitamin D insufficiency is a major contributor to osteopenia and osteoporosis, loss of bone mass and muscle weakness, falls and fractures [1-4]. In addition, vitamin D deficiency has been associated with an increased risk of certain chronic and degenerative diseases such as cancers, autoimmune processes, infectious diseases, hypertension and cardiovascular disease, among others [1-5].
Vitamin D has a dual origin, on the one hand, by the synthesis of skin under the influence of solar energy by ultraviolet B (UVB) radiation (wavelength, 290-315 nm); on the other, by oral intake, through limited natural sources of vitamin D and fortified foods.
The concept of “vitamin D” means the combination of vitamin D2 and vitamin D. Vitamin D2 was believed to be less effective than vitamin D3 in maintaining 25-hydroxyvitamin D [25-HCC] or calcidiol levels because of its more rapid metabolism [2]. Recently, it has been shown that both are equipotent for maintaining serum 25-HCC levels.
Vitamin D is metabolized in the liver to 25-hydroxyvitamin D, the major metabolite of the endocrine system of vitamin D, which has a long half-life (between 10 and 19 days), and is commonly accepted as a clinical indicator of vitamin D status in the body [6] as it reflects levels of intake and cutaneous synthesis.

The importance of vitamin D in bone development during childhood has been known since the beginning of the last century. As early as 1554, Thedosius published an observation of rickets taken from an individual, but its relationship to vitamin D was not established until 1917, when McCollum et al. isolated an anti-rickets factor in cod liver oil and suggested the term vitamin D 1.
Since then, the disease has been extensively studied. In addition to the nutritional cause, genetic causes and resistance to vitamin D have been discovered, as well as its relation with hypophosphatemia.
However, in the course of the study of adult osteoporosis, low levels of vitamin D have also been found to endanger the bone, without necessarily reaching levels that produce osteomalacia (the equivalent of rickets in adults). Although this aspect will be discussed more fully elsewhere in this paper, it has been established that vitamin D values below 30 ng/ml may be detrimental to bone metabolism in adults. However, can these limits be applied to the growing individual? In other words, is vitamin D deficiency the same in children as in adults? Throughout this paper, we will discuss various issues regarding hypovitaminosis D in children and adolescents.
Since the cited studies offer values of 25-hydroxy vitamin D in different units (either ng/ml, or nmol/ l), to give uniformity to the review all results are shown in ng/Ml, after converting them according to the equivalence 1 ng/ml=2.5 nmol/l.

There is increasing interest to learn how vitamin D acts. Both its established or classic functions such as bone metabolism, as well as the emerging areas of study into the different stages of women’s lives. In this review, we will pay special attention to the latter even as we recognize the limited amount of quality information currently available.

In the 1970s the link between vitamin D and diabetes (DM) began to be studied with research suggesting resistence to insulin and insulin secretion [1]. Several studies suggest that vitamin D stimulates insulin secretion and decreases insulin resistance [2-5] and correlates with impaired glucose tolerance, fasting hyperglycemia, and type 2 diabetes mellitus (DM2) [6].
In the case of DM2, numerous case-control and cohort studies have been published which analyze the relationship between vitamin D deficiency and the incidence of DM2 with conflicting results. In 2013, Song et al. carried out a meta-analysis to assess the strength and form of the association between the levels of 25-hydroxycholecalciferol (25HCC) and the incidence of DM2 [7]. This meta-analysis includes a total of 21 prospective studies with a population of 76,220 subjects and an incidence of DM2 of 4,996 cases.
Comparing the highest to the lowest levels, the relative risk of developing DM2 was 0.62 (95% CI 0.54-0.70). The highest levels of 25HCC were related to a lower risk of diabetes, regardless of sex, follow-up time in the study, sample size, diagnostic criteria for diabetes or method of vitamin D analysis. This inverse relationship was maintained, although it was diminished when adjusted for adiposity and other metabolic parameters related to obesity. This decreased risk was most evident from levels of 25 HCC greater than 20 ng/ml. In the same meta-analysis, each 4 ng/ml increase in 25 HCC levels was associated with a 4% decrease in DM2 risk.

In the field of rheumatic diseases there is growing evidence that vitamin D plays a relevant role in the pathophysiological mechanisms of autoimmunity. To this must be added that vitamin D deficiency in patients with rheumatic diseases is high. In contrast, there are few clinical trials demonstrating that vitamin D supplementation may contribute to the severity of the activity or the risk of systemic autoimmune diseases.
It seems that with the current schemes of vitamin D3 supplements, autoimmunity is not affected in the expected way1,2, postulating that for the regulation of immunological homeostasis it is necessary to administer doses of vitamin D much higher than those used in standard clinical practice3,4. There is no general consensus on what dose of vitamin D3 should be used, nor as to what levels of 25(OH) vitamin D (25HCC) –the metabolite that best reflects the vitamin D status of the organism– would be optimal to modulate favorably immunity or pain pathways.
As mentioned, most quality studies demonstrate a higher prevalence of 25HCC insufficiency in autoimmune rheumatic diseases5. The causes of this insufficiency could be –in addition to the classic factors for the failure of 25HCC in the general population– others that are characteristic of rheumatologic autoimmune processes such as the use of corticosteroids, photosensitivity, cutaneous fibrosis and intestinal malabsorption, among others have not yet been fully elucidated6,7.
Vitamin D3 could be one of the key factors that would act as an immunomodulator in the control of self-tolerance8.

The so-called fragility fracture is a low-energy fracture that results from a fall from a height equal to or less than its own, or which occurs in the absence of evident prior trauma. It appears when the bone structure, under specific loading conditions, undergoes biomechanical failure as it is unable to withstand the force received by having its resistance capacity degraded1.
Among the factors that are related to the genesis of this bone deterioration vitamin D stands out in a relevant way. Indeed, the low levels of vitamin D induce a persistent increase of the level of PTH and with this a stimulus of the bone resorption, which determines A progressive decrease of the amount of bone formed and a thinning of all its structural elements, with the consequent decrease of the bone resistance. In addition, low vitamin D levels are associated with decreased tone and neuromuscular control, and therefore with the increased risk of falls that induce vitamin D deficiency.
In another section of this study, we have seen how vitamin D deficiency is a real health problem worldwide2 given its high prevalence in all regions and in all population groups and not only in groups traditionally considered at risk3,4. Despite this, vitamin D deficiency is notoriously underdiagnosed possibly due to different factors5, among which, undoubtedly, the failure to consider this disease an etiopathogenic agent stands out6.
Its prevalence increases progressively in the elderly, in the institutionalized and in those who have suffered one or more fractures7. The rates of vitamin D deficiency in patients with hip fracture vary according to the series: 36% in Finland8,9, 40-68% in the United Kingdom10-12, 50-78% in the United States13,14, 62-90% in Japan15,16, 67-91% in Spain17,18 and 96,7% in India19, rates much higher than those found in “healthy” populations and lower than those found in institutionalized individuals20. These studies found that a large number of patients with hip fracture and inadequate vitamin D levels had previously suffered vertebral and non-vertebral fractures, excluding hip fractures9,17-19. Studies focusing on these fractures have demonstrated the existence of high rates of vitamin D deficiency in patients with peripheral fractures11,21 and vertebral fractures15,22,23. This deficit has also been linked to the recurrence of vertebral fractures after kyphoplasty24.
However, despite the clear link between low-energy fractures and vitamin D insufficiency, there is still controversy in the literature about the preventive effect of these, as not all studies support this hypothesis.

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