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Vitamin D: drug of the future. A new therapeutic approach
Archives of Gerontology and Geriatrics 54 (2012) 222–227
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Vitamin D: drug of the future. A new therapeutic approach N. Gueli, W. Verrusio, A. Linguanti, F. Di Maio, A. Martinez, B. Marigliano, M. Cacciafesta * Department of Aging Science, Policlinico Umberto I, ‘‘Sapienza’’ University of Rome, Viale del Policlinico, 155, I-00161 Roma, Italy
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 October 2010 Received in revised form 25 February 2011 Accepted 28 February 2011 Available online 1 April 2011
Besides increasing calcium absorption in the bowel and promoting the normal formation and mineralization of bone, vitamin D exerts relevant pleiotropic effects in different tissues. Serum levels of vitamin D show correlation with the risk of infections, cardiovascular diseases, cancer and autoimmune disorders. The possible therapeutic role of vitamin D in different kind of diseases: inflammatory, immunologic, infectious and neoplastic ones, explains the growing interest in this vitamin due to its pleiotropic effects, and makes it a candidate to become a potential drug in the next future. ß 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: Vitamin D Pleiotropic effects of vitamin D Supplementation therapy
1. Introduction
2. Synthesis and metabolism
Vitamins are micronutrients which cannot be synthesized by our organism, so that it is indispensable that they are assumed with food in adequate quantities to impede the development of a deficiency syndrome. They act as biological catalysts and are classified as water-soluble and lipo-soluble ones. Vitamin D, identified in 1919 as an anti-rachitic agent, was widely used especially between 1930 and 1940 to combat the nutritional deficiencies produced by the great economic and social crisis of those years. It is lipo-soluble, travels in the blood bound to an alpha-globulin and is present in two forms: (a) ergocalciferol or activated ergosterol or vitamin D2 present in irradiated yeast and (b) cholecalciferol or activated 7-dehydrocholesterol or vitamin D3, which is produced in the cuties after exposure to ultraviolet radiation and is found in elevated quantities in fish liver oil and egg yolk. Milk is enriched with both of these forms. Vitamin D is effectively a pre-hormone which acts via metabolites of which the most active is 1,25(OH)2D or 1,25dihydroxycholecalciferol or calcitriol; this binds to specific receptors, the vitamin D receptors (VDRs) functioning as nuclear transcription factors. The principal functions of this vitamin are: (a) augmentation of intestinal absorption of calcium and (b) promotion of normal bone formation and mineralization (Morris, 2005).
The 7-dehydrocholesterol or pro-vitamin D3 is present in the cutis, and in a photochemical process due to exposure to ultraviolet B rays is converted to pre-vitamin D3. Then, in the basal cells of the epidermis, it is isomerized to vitamin D3, circulates in blood bound to vitamin-D binding protein (DBP) and at the hepatic level it is hydroxylated a first time to 25(OH)D3 or 25-dihydroxycholecalciferol, which is the principal circulatory form, being scarcely active metabolically. In the kidney it is hydroxylated a second time with the formation of 1,25(OH)2D3 or calcitriol, a metabolically more active form which constitutes the hormone-vitamin D; this process is stimulated by parathyroid hormone (PTH) and by hypophosphatemia, suppressed by calcium and by calcitriol itself. The quantity of vitamin D metabolites circulating is limited by the degradation processes operated by 25-hydroxyvitamin D-24-hydroxylase (CYP24A1) and by subsequent excretion of the metabolites of which calcitroic acid is the principal one (Holick, 2007). Vitamins D2 and D3 of alimentary origin are incorporated into the chylomicrons and transported through the lymphatic system to the venous circulation; they are deposited in the adipose tissue, whence they may be released (Holick, 2007). To determine the blood vitamin D level, the 25(OH)D is measured: its values in the plasma of healthy subjects are in the range 30–100 ng/ml with preferential values between 30 and 60 ng/ml; 1,25-(OH)2D3 values vary from 25 to 45 pg/ml. 3. The mechanism of action
* Corresponding author at: Via Panama, 102, I-00198, Roma, Italy. Tel.: +39 06 4450 208; fax: +39 06 4456 316. E-mail address: [email protected] (M. Cacciafesta). 0167-4943/$ – see front matter ß 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2011.03.001
The 1,25(OH)2D3 (1,25-dihydroxy vitamin D3) or calcitriol is a steroid hormone and acts by activation of the VDRs which are expressed by both the osteoblasts and the osteoclasts.
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The most important known role of 1,25(OH)2D3 is control of osteoclastogenesis and of osseous re-absorption by modulation of the gene which codifies for the receptor activator of nuclear factorkB ligand (RANKL) present in the osteoblasts. At this level 1,25(OH)2D3 is recognized by its receptor and determines augmented RANKL expression, which, binding to the RANK receptor present in the pre-osteoclasts induces their maturation into mature osteoclasts, favors re-absorption of calcium and phosphorous from the bones and contributes to maintaining calcium and phosphorous homeostasis. Another effect of 1,25(OH)2D3 consists of augmenting intestinal absorption of calcium interacting with VDR–RXR (vitamin D receptor–retinoic acid x-receptor complex), a heterodimeric complex of retinoic acid and vitamin D receptors, which activates or represses the transcription of numerous genes and regulates certain physiological functions: among these it augments the expression of the epithelial calcium TRPV6 and calbindin 9k transport channel, a protein which binds to calcium (Morris, 2005). The quota of vitamin D activated at the renal level only determines certain endocrine activities (homeostasis of calcium, regulation of arterial pressure, immunomodulation); to explain the actions at the cellular level (autocrine, paracrine and intracrine) it is necessary to also take into account local vitamin activation by diverse tissues whose physiology is currently still little known (Morris, 2005). The regulatory effects exerted by calcitriol on the keratinocytes through a duplex mechanism of action are particularly interesting: at low concentrations it stimulates cellular growth, and when the level is elevated, it induces apoptosis. The cause of this phenomenon is not yet known although it has been demonstrated how vitamin D metabolites control the activity of numerous genes of the keratinocytes utilizing both the autocrine and paracrine mechanisms. Current experimental research will also clarify the therapeutic effects in inflammatory, immunological, infective and neoplastic type pathologies (Lehmann, 2009). Numerous reports suggest the mechanisms with which calcitriol has diverse extra-skeletal effects (Table 1): (a) there are receptors in the encephalon, prostate, breast, colon and in the immune systems cells; (b) these receptors control, directly or indirectly, numerous genes implicated in cellular differentiation and proliferation processes, apoptosis and angiogenesis; (c) cellular proliferation is reduced in both normal and neoplastic cells, inducing differentiation; (d) augment myocardial contractility and insulin synthesis; (e) renin synthesis is inhibited; and (f) immunomodulatory functions are evident. 4. The hypovitaminosis D Generally caused by insufficient exposure to the sun and/or poor alimentation, this determined rickets in children and osteomalacia in adults (Table 2). Numerous epidemiological studies have hypothesized a causal nexus between variation in
Table 1 Biological effects of vitamin D. On the target
Effects
Calcium metabolism Infections Cardiovascular system Cancer
Strengthens skeleton and muscles Tuberculosis and influence in immune response Cares atherosclerosis, hypertension, heart failure Prevents breast, colon, prostate cancers and metastases Improves depression and schizophrenia Reduces the risk of falls to the ground Prevents autoimmune diseases, like multiple sclerosis and diabetes type 1
Neurological diseases Muscle functions Immunomodulators
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Table 2 The possible causes of vitamin D-deficiency. Reduction in skin synthesis and absorption, due to Hereditary and acquired disorders of metabolism and activity, Excessive use of sunscreens, Skin pigmentation: melanin reduces the absorption of UVB radiation up to 99%, Aging: reduction of 7-dehydrocholesterol, skin reduces the synthesis of vitamin about 70% by the 70 years of age. Environment: Zenith angle of the sun varies by season, latitude, time of day and in parallel is more oblique, the lower the number of photons that reach the earth. Malabsorption: Cystic fibrosis, celiac disease, Whipple disease, Crohn’s disease, intestinal bypass surgery, obesity (vitamin D is confined to the skin and fat, and scarcely available). Catabolism: Anticonvulsants, glucocorticoids, drugs for AIDS and transplant rejection accelerate the transformation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in an inactive form. Breastfeeding: Human milk contains little vitamin D and therefore the child is at risk of hypovitaminosis if no other sources of nutrition are available. Hepatic failure and malabsorption in severe cases reduce vitamin synthesis. Nephrotic syndrome: Urinary loss of 25 OHD with the transport protein. Chronic renal failure: Initially hyperphosphatemia reduces the activity of 25-hydroxyvitamin D-1a-hydroxylase and therefore the synthesis of 1,25-dihydroxy D, then because of hypovitaminosis develops hypocalcemia with secondary hyperparathyroidism.
vitamin D synthesis and mortality from chronic pathologies: for example, there is a direct correlation between a higher mortality rate for chronic diseases and a greater distance from the equator of the home, and it is known that the survival of patients with cardiovascular or neoplastic (pulmonary, breast, colon) disease is higher when the diagnosis is formulated in the summer months that in other seasons (Autier and Gandini, 2007). A meta-analysis of 18 randomized, controlled studies evaluated the impact of vitamin D supplements on mortality from all causes in 57,311 subjects, demonstrating that individuals who had taken vitamin D showed a mortality reduced by 7% (Grant, 2003). There are numerous scientific reports on the anti-tumoral action. Diverse studies have reported that populations residing at higher latitudes present higher incidence of neoplasias such as Hodgkin’s lymphoma and tumors of the colon, of the pancreas, of the prostate, of the ovaries, of the breast, with respect to those living at lower latitudes and who thus have longer exposition to sunlight (Lappe et al., 2007). It appears that a level of 25hydroxyvitamin D <20 ng/ml is associated with a risk higher by 30–50% of contracting and dying of malignant neoplasia. In this field, an analysis by the Nurses’ Health Study Cohort of 32,826 subjects indicated that the risk of manifesting a colonrectal tumor was inversely proportional to the mean of serum levels of 25-hydroxyvitamin D, while it was independent of the blood levels of 1,25-dihydroxyvitamin D (Wu et al., 2007). However, as it is the latter which induces the apoptosis of malignant cells and slows angiogenesis of tumor tissues, it is considered that the anti-tumoral effect may also be determined by a local production of the active metabolite which does not then pass into blood circulation and thus does not modify the blood level. Participants in the Women’s Health Initiative who presented, at the first check up, a blood concentration of 25-hydroxyvitamin D <12 ng/ml, had a 253% increase in the risk of colon-rectal cancer at the 8 year follow-up (Wactawski-Wende et al., 2006). In another study, men who worked outdoors contracted prostate cancer 3–
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5 years later that those working in closed environments (Santos Arrontes et al., 2007). 5. Toxicity Vitamins D2 and D3 are lipo-soluble and are accumulated in the adipose tissue when assumed excessively, for too long in the diet. They have no toxic effects as such, although the active metabolite quota does, being regulated by hydroxylation by the liver and kidneys. Reaching a toxic dose depends solely on the assumption of calcitriol in a single elevated dose (exceeding 50 mg) or in low daily doses (below 1 mg) assumed over long periods of time (Hathcock et al., 2007). In these cases one may observe the following symptoms: hypercalcemia, abdominal cramps, nausea, vomiting, constipation alternating with diarrhea, thirst, polyuria, itching, muscular and articular pain, disorientation and coma. 6. Effects on the osteo-articular structure Osteomalacia is a defect of bone mineralization due to a vitamin D deficiency. In adults, when the bone is mature, it is manifested by the presence of osteoid tissue, while in children, while bones are growing, it causes rickets, in which there is a defect in the calcification of the osteoid matrix with hypertrophy of the epiphysary cartilage. In general, the vitamin D level is inadequate due to insufficient exposure to sunlight or a poor alimentary supply, although there are rarer cases of: (a) an alteration of the vitamin metabolism or tissue resistance to its action; (b) hypoparathyroidism; (c) a hereditary pathology, like family hypophosphatemic rickets resistant to vitamin D, which is dominant and is linked to the X chromosome; and (d) a disease which interferes with vitamin D absorption or with the formation of its active metabolites (Kocia´n and Brunova´, 1989). Demineralization affects, above all, the spine, pelvis and the lower limbs; a bone X-ray reveals fibrous lamellae and area of incomplete ribbon demineralization (pseudo-fractures, Looser zones, Milkman’s syndrome). The long bones curve under the weight, the vertebrae shorten and the lower pelvic girdle narrows. Calcemia may be either reduced or normal depending on the PTH levels (secondary hyperparathyroidism); urinary calcium is generally low, except in cases of acidosis, while the alkaline phosphatase value is high. Osteoporosis is a systemic pathology characterized by reduced bone mass and qualitative alterations. It is often associated with vitamin D deficit. The National Osteoporosis Foundation (NOF) guidelines for the prevention of fractures from osteoporosis in the elderly recommend the assumption of vitamin D (800 IU/day) and calcium (1 g/ day) to obtain a significant reduction in the risk of fractures of the hip (27%) and non vertebral fractures (23%). These, in fact, determine a significant increase in morbidity and mortality; in particular, those of the hip increase with age through to the ninth decade of life in which they affect 1 woman in 3 and 1 man in 6. The consequences to the patient are grave as they cause permanent disability in 50% of cases and mortality within one year in 10–20%; the social costs of providing assistance are also elevated, and are destined to rise with the aging of the population (Boonen and Singer, 2008). 7. Effects on the cardiovascular system Diverse epidemiological studies demonstrate that environmental factors such as latitude, altitude, season, residence in the city or in the country are associated with cardiovascular disease mortality; as these factors influence the duration of exposure to
ultraviolet light and thus vitamin D synthesis. A role of this vitamin is hypothesized in reducing the cardiovascular risk markers, such as elevated blood levels of fibrinogen, of PAI 1, of homocysteine, of asymmetric dimethylarginine, C-reactive protein (CRP), of type B natriuretic peptide (BNP) (Dobnig et al., 2008; Michos and Melamed, 2008). A recent work showed that vitamin D, through diverse mechanisms such as augment insulin secretion, downregulation of the renin–angiotensin system, the inhibition of cellular proliferation and modulation of inflammatory processes, is directly implicated in certain pathophysiological processes correlated with the development of the cardiovascular diseases (Wang et al., 2010). Through regulation of calcium homeostasis, it influences cardiac contractility so a vitamin deficit may cause myocardial dysfunctions and cardiac insufficiency, with a risk of sudden death (Pilz et al., 2008); on the contrary, optimal levels of intracellular calcium are correlated with reduction of cardiovascular risk, in particular with reference to ischemic heart disease. Optimal levels of intracellular calcium inhibit fatty acid synthesis, augment insulin synthesis and sensitivity, inhibit platelet aggregation and induce vaso-relaxation (Wang et al., 2010). Low levels of 25(OH)D are associated with increased risk of hypertension, while normal levels, together with correct exposure to UVB radiation appear to favor a reduction in arterial pressure (Forman et al., 2008). A recent work noted that the administration of a statin, rosuvastatin, not only reduces cholesterolemia levels but also augments plasma levels of 25-hydroxy and 1,25-dihydroxyvitamin D, determining, at the same time, consensual decrease in alkaline phosphatase levels. The authors hypothesize then that the reduction in cardiovascular risk consequent to statin therapy is not linked solely with the improvement in the lipid metabolism, but also with the pleiotropic effects such as augmented 7dehydrocholesterol synthesis and, as a consequence also synthesis of vitamin D, whose level is inversely correlated with cardiovascular mortality (Yavuz et al., 2009). Recent research, supporting the cardio-protective role of vitamin D, highlights, in subjects undergoing dialysis, an inverse correlation between vitamin D supplementing and cardiovascular mortality (Naves-Dı´az et al., 2008). 8. Anti-tumoral effects Diverse scientific evidences indicate an important role in both the prevention of tumors of the colon and a contribution (as yet little known, but possible) in that of the prostate and breast. Indeed, in the latter 1,25(OH)2D inhibits cellular proliferation, induces differentiation and apoptosis, arresting angiogenesis (Garland et al., 2006; Jenab et al., 2010). Experimental studies in lung cancer show that 1,25(OH)2D arrests the proliferation of tumoral cell lines, and favors differentiation and, in animal models, impedes metastasization (Deeb et al., 2007; Chung et al., 2009). A trial effected on Finnish smokers however denied these protective effects, showing an increased risk of pancreatic cancer in association with elevated levels of vitamin D (Stolzenberg-Solomon et al., 2006). It is known that the addition of 1,25(OH)2D to a tumor cell culture causes inhibition of their growth; particularly evident results are obtained with prostate cells (Miller, 1998–1999). A recent study hypothesizes that the development of certain tumors is due to alterations in the expression of the VDR and of the hydroxylases (25, 1a, 24) indispensable to the synthesis and catabolism of calcitriol (1,25(OH)2D3). Indeed this acts as an antiproliferative factor, determining the arrest of the cellular cycle in G0/G1, differentiation and apoptosis, modulation of the intracellular signaling routes, inhibition of tumoral angiogenesis, rein-
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forcement of the anti-tumoral effects of the platinum analogs and of the taxanes (Chung et al., 2009). As to prostate cancer, a study conducted on 932 white nonHispanic men and on 114 white Hispanics from South Texas demonstrated that the interaction between certain polymorphisms of VDR (nuclear vitamin D receptor, which modulates the effect of vitamin D) and of SRD5A2 (type II 5alpha-reductase, which converts testosterone into dihydrotestosterone in the prostate) determines the growth of neoplastic cells (Torkko et al., 2008). In colon adenocarcinoma cells the CYP24A1 (24hydroxylase) enzyme is hyper-expressed, which catabolizes vitamin D neutralizing the anti-proliferative effects (Horva´th et al., 2010). On the basis of laboratory data, pre-clinical studies were effected on animals and anti-tumoral effects were obtained with vitamin D administration in intermittent high dosage schemas. These results give credibility to the hypothesis that the metabolites of vitamin D may have a role in cancer prevention and therapy although their use is limited by the risk of causing hypercalcemia. This is the motive for experimentation of a vitamin D analog (Deuterated Gemini DG), which acts as a selective modulator of the VMD receptor (SVDRM): this has produced promising results in colo-rectal cancer and did not determine alterations in calcemia (Spina et al., 2007). 9. Neurological effects Normal vitamin D levels during pregnancy and in the perinatal phase appear fundamental to correct development of the encephalon and its normal function; low levels appear to predispose schizophrenia and depression. An observational study of 1282 subjects, age ranging from 65 to 95 years, with depressive disturbances and low serum levels of 25(OH)D3 and elevated PTH levels, demonstrated that in the elderly, a vitamin D supplement improves mood disturbances. This vitamin may therefore be used in mood tone disturbance therapy in the elderly population in association with a diet rich in vitamin D or enriched and with greater exposure to sunlight (Hoogendijk et al., 2008). Some authors also hypothesize a role in Parkinson’s disease; in fact, 55% of patients present insufficient vitamin levels with respect to 36% in healthy subjects; this disease impacts the nerve cells in dopaminergic districts (the substantia nigra) which present an elevated level of vitamin D receptors (Evatt et al., 2008).
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effect due to augmented action by cathelicidin (CAMP), a peptide produced by white blood cells, whose synthesis is stimulated by vitamin D. CAMP is part of the innate immune system, deputed to furnishing a first line response to penetration attempts by microorganisms such as viruses, bacteria, fungi and parasites (Gombart et al., 2005). People of African origin who are more susceptible to tubercular infection, have lower levels of 25(OH)D and poor production of the RNA messenger for cathelicidin. The pathogen antigens interact with the macrophages augmenting gene expression for vitamin D receptor and the 1hydroxylase enzyme (Hewison et al., 2004). Serum levels of 25(OH)D are inversely associated with the frequency of upper respiratory tract infections. This correlation is more evident in subjects with co-morbidity and, in the winter, when 25(OH)D levels fall below 30 ng/ml (Ginde et al., 2009). The distinct seasonality of epidemic influences is caused by a ‘‘seasonal stimulus’’ which may be attributed to variation in the intensity of solar radiation through the diverse seasons of the years which are correlated with vitamin D synthesis; indeed, this presents the lowest blood levels in the winter months, when viral infection reaches peak diffusion and the immune system response is the greatest. The ‘‘seasonal stimulus’’ is thus the immunomodulatory action of 1,25(OH)2D, which impedes the excessive production of inflammatory cytokines, augments macrophage activity and stimulates neutrophil granulocytes, the monocytes, the natural killer cells and the respiratory tract epithelia to produce peptides with anti-microbial action (Cannell et al., 2006). A study of 884 seropositive pregnant women who were provided vitamin supplements showed that low vitamin D levels favor HIV transmission from mother to child; in fact, at blood levels below 32 ng/ml, the risk was some 50% at the sixth week of pregnancy (Mehta et al., 2009). Low blood levels of vitamin D3 may explain the greater prevalence of auto-immune diseases, such as rheumatoid arthritis (RA), in correlation with higher latitudes and greater gravity of the clinical situation in the winter months (Cutolo et al., 2007; Baeke et al., 2008). Vitamin D interferes with inflammatory response and fibrogenesis and recent scientific reports demonstrate a relationship between the blood level and certain chronic hepatic pathologies. In this, a study of 197 chronic hepatitis C patients showed that low blood levels of this vitamin are correlated to greater severity of the hepatic pathology itself, and lesser efficacy of antiviral therapy (Petta et al., 2010).
10. Muscular effects and prevention of bone fractures 12. Effects in respiratory diseases The fragile elderly at high risk of falls and non traumatic fractures have been studied in diverse trials and it was observed that vitamin D improves postural stability and reduces the incidence of fractures. A meta-analysis of five randomized clinical studies conducted on 1237 subjects demonstrated a 22% reduction in the risk of falling in subjects who had taken vitamins with respect to those in therapy with calcium alone or with a placebo; the frequency of falls also fell by 72% taking 800–1000 U/day of vitamin D3 with calcium (Boonen and Singer, 2008). A vitamin supplement is also always necessary in the case of low exposure to sunlight. 11. Immunomodulatory effects There are numerous scientific reports which support the hypothesis that vitamin D has immunomodulatory effects: The VDR is present in immune system cells (Hewison, 2010) Activated dendritic cells produce calcitriol (Cheung et al., 2002). Heliotherapy, that is prolonged exposure to sunlight, experimented in the early 1900s to cure tuberculosis, is linked with a antimicrobial
Vitamin D through its immunomodulatory effects regulates pulmonary inflammatory responses while simultaneously improving the innate defense mechanisms against respiratory pathogens (Hughes and Norton, 2009). Control of serum 25-OH D levels in 414 (ex)-smokers aged over 50 indicated that vitamin D deficiency is frequent in BPCO and is correlated with the gravity thereof (Janssens et al., 2010). Another study supported the hypothesis that vitamin D, inhibiting the proliferation of smooth musculature cells in the respiratory tract may be an efficacious treatment to re-model the airways in asthma. In general, if the 25(OH)D level is over 35 ng/ml, respiratory function improves, if lower, the risk of bronchial asthma increases (Clifford and Knox, 2009). 13. Effects on kidney diseases Oral administration of a VDR agonist reduces both inflammation and albuminuria; the benefits of the drug cannot be attributed to improved pressure, to falls in the glomerular filtration rate or
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improved PTH levels. The ligand in fact appears to act with an independent effect through a mechanism, which is still unclear, determining improved survival. An association of vitamin D with a type 1 (ARB) angiotensin II receptor blocker reduces he renal damage deriving from diabetic nephropathy (Weir, 2008). 14. Therapy with vitamin D Laboratory tests are available to measure the levels of both 25(OH)D and 1,25(OH)2D. At least an annual 25(OH)D dosage is necessary as this is correlated with the total vitamin D quantity produced by both the skin and assumed in the diet. Vitamins D2 and D3 have low biological activity. It is not useful to measure 1,25D levels as these may be normal even in the presence of vitamin D deficit. Diagnostic significance of blood 25(OH)D levels: normality = 30–100 ng/ml (75–250 nmol/l); deficit for values below 10 ng/ ml (<0–25 nmol/l); hypovitaminosis = 10–30 ng/ml (25–75 nmol/ l); toxic effects above 100 ng/ml (>250 nmol/l). The cutis synthesizes 20,000 IU of vitamin D3 after 20 min exposure to sunlight. Where this is insufficient or possible, it is necessary to assume foods or drugs containing elevated quantities of vitamin D in the form of cholecalciferol (D3) and ergocalciferol (D2). In brief, these are the principal pharmacological approaches. (a) Ergocalciferol (D2) 400,000 IU/phial: 1–2 phials/week orally or i.m. (b) Cholecalciferol (D3): drops 10,000 IU/ml: 3–4 drops/day (equal to 750–1000 IU vitamin D3) or 20 drops once a week (equal to 5000 IU D3). (c) Phial orally/i.m. 100,000 IU/ml: 1 phial orally or i.m. every 4–6 months; phial orally/i.m. 300,000 IU/ml: 1 phial orally or i.m. once per year. (d) Calcitriol cp 0.25–0.50 mg: from 0.5 to 1 mg/day (adverse effect due to accumulation; monitor calcemia values: if exceeding normal value by 1 mg suspend). Conflict of interest statement None. References Autier, P., Gandini, S., 2007. Vitamin D supplementation and total mortality: a metaanalysis of randomized controlled trials. Arch. Intern. Med. 167, 1730–1737. Baeke, F., Van Etten, E., Gysemans, C., Overbergh, L., Mathieu, C., 2008. Vitamin D signaling in immune-mediated disorders: evolving insights and therapeutic opportunities. Mol. Aspects Med. 29, 376–387. Boonen, S., Singer, A.J., 2008. Osteoporosis management: impact of fracture type on cost and quality of life in patients at risk for fracture I. Curr. Med. Res. Opin. 24, 1781–1788. Cannell, J.J., Vieth, R., Umhau, J.C., Holick, M.F., Grant, W.B., Madronich, S., Garland, C.F., Giovannucci, E., 2006. Epidemic influenza and vitamin D. Epidemiol. Infect. 134, 1129–1140. Cheung, C.Y., Poon, L.L., Lau, A.S., Luk, W., Lau, Y.L., Shortridge, K.F., Gordon, S., Guan, Y., Peiris, J.S., 2002. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 360, 1831–1837. Chung, I., Han, G., Seshadri, M., Gillard, B.M., Yu, W.D., Foster, B.A., Trump, D.L., Johnson, C.S., 2009. Role of vitamin D receptor in the antiproliferative effects of calcitriol in tumor-derived endothelial cells and tumor angiogenesis in vivo. Cancer Res. 69, 967–975. Clifford, R.L., Knox, A.J., 2009. Vitamin D—a new treatment for airway remodelling in asthma? Br. J. Pharmacol. 158, 1426–1428. Cutolo, M., Otsa, K., Uprus, M., Paolino, S., Seriolo, B., 2007. Vitamin D in rheumatoid arthritis. Autoimmun. Rev. 7, 59–64. Deeb, K.K., Trump, D.L., Johnson, C.S., 2007. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat. Rev. Cancer 7, 684–700. Dobnig, H., Pilz, S., Scharnagl, H., Renner, W., Seelhorst, U., Wellnitz, B., Kinkeldei, J., Boehm, B.O., Weihrauch, G., Maerz, W., 2008. Independent association of low serum 25-hydroxyvitamin D and 1,25 dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch. Intern. Med. 168, 1340–1349. Evatt, M.L., Delong, M.R., Khazai, N., Rosen, A., Triche, S., Tangpricha, V., 2008. Prevalence of vitamin D insufficiency in patients with Parkinson disease and Alzheimer disease. Arch. Neurol. 65, 1348–1352.
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Jenab, M., Bueno-de-Mesquita, H.B., Ferrari, P., Van Duijnhoven, F.J., Norat, T., Pischon, T., Jansen, E.H., Slimani, N., Byrnes, G., Rinaldi, S., Tjønneland, A., Olsen, A., Overvad, K., Boutron-Ruault, M.C., Clavel-Chapelon, F., Morois, S., Kaaks, R., Linseisen, J., Boeing, H., Bergmann, M.M., Trichopoulou, A., Misirli, G., Trichopoulos, D., Berrino, F., Vineis, P., Panico, S., Palli, D., Tumino, R., Ros, M.M., Van Gils, C.H., Peeters, P.H., Brustad, M., Lund, E., Tormo, M.J., Ardanaz, E., Rodrı´guez, L., Sa´nchez, M.J., Dorronsoro, M., Gonzalez, C.A., Hallmans, G., Palmqvist, R., Roddam, A., Key, T.J., Khaw, K.T., Autier, P., Hainaut, P., Riboli, E., 2010. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case–control study. Br. Med. J. 340, b5500. Kocia´n, J., Brunova´, J., 1989. Diabetic osteopathies. 3. The effect of diabetic complications on bone mineralization. Vnitr. Lek. 35, 890–898 (in Czech). Lappe, J.M., Travers-Gustafson, D., Davies, K.M., Recker, R.R., Heaney, R.P., 2007. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am. J. Clin. Nutr. 85, 1586–1591. Lehmann, B., 2009. Role of the vitamin D3 pathway in healthy and diseased skin: facts, contradictions and hypotheses. Exp. Dermatol. 18, 97–108. Mehta, S., Hunter, D.J., Mugusi, F.M., Spiegelman, D., Manji, K.P., Giovannucci, E.L., Hertzmark, E., Msamanga, G.I., Fawzi, W.W., 2009. Perinatal outcomes, including mother-to-child transmission of HIV, and child mortality and their association with maternal vitamin D status in Tanzania. J. Infect. Dis. 200, 1022–1030. Michos, E.D., Melamed, M.L., 2008. Vitamin D and cardiovascular disease risk. Curr. Opin. Clin. Nutr. Metab. Care 11, 7–12. Miller, G.J., 1998–1999. Vitamin D and prostate cancer: biologic interactions and clinical potentials. Cancer Metast. Rev. 17, 353–360. Morris, H.A., 2005. Vitamin D: a hormone for all seasons—how much is enough? Clin. Biochem. Rev. 26, 21–32. Naves-Dı´az, M., Alvarez-Herna´ndez, D., Passlick-Deetjen, J., Guinsburg, A., Marelli, C., Rodriguez-Puyol, D., Cannata-Andı´a, J.B., 2008. Oral active vitamin D is associated with improved survival in hemodialysis patients. Kidney Int. 74, 1070–1078. Petta, S., Camma`, C., Scazzone, C., Tripodo, C., Di Marco, V., Bono, A., Cabibi, D., Licata, G., Porcasi, R., Marchesini, G., Craxı´, A., 2010. Low vitamin D serum level is related to severe fibrosis and low responsiveness to Interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology 51, 1158–1167. Pilz, S., Ma¨rz, W., Wellnitz, B., Seelhorst, U., Fahrleitner-Pammer, A., Dimai, H.P., Boehm, B.O., Dobnig, H., 2008. Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J. Clin. Endocrinol. 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Archives of Gerontology and Geriatrics journal homepage: www.elsevier.com/locate/archger
Vitamin D: drug of the future. A new therapeutic approach N. Gueli, W. Verrusio, A. Linguanti, F. Di Maio, A. Martinez, B. Marigliano, M. Cacciafesta * Department of Aging Science, Policlinico Umberto I, ‘‘Sapienza’’ University of Rome, Viale del Policlinico, 155, I-00161 Roma, Italy
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 October 2010 Received in revised form 25 February 2011 Accepted 28 February 2011 Available online 1 April 2011
Besides increasing calcium absorption in the bowel and promoting the normal formation and mineralization of bone, vitamin D exerts relevant pleiotropic effects in different tissues. Serum levels of vitamin D show correlation with the risk of infections, cardiovascular diseases, cancer and autoimmune disorders. The possible therapeutic role of vitamin D in different kind of diseases: inflammatory, immunologic, infectious and neoplastic ones, explains the growing interest in this vitamin due to its pleiotropic effects, and makes it a candidate to become a potential drug in the next future. ß 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: Vitamin D Pleiotropic effects of vitamin D Supplementation therapy
1. Introduction
2. Synthesis and metabolism
Vitamins are micronutrients which cannot be synthesized by our organism, so that it is indispensable that they are assumed with food in adequate quantities to impede the development of a deficiency syndrome. They act as biological catalysts and are classified as water-soluble and lipo-soluble ones. Vitamin D, identified in 1919 as an anti-rachitic agent, was widely used especially between 1930 and 1940 to combat the nutritional deficiencies produced by the great economic and social crisis of those years. It is lipo-soluble, travels in the blood bound to an alpha-globulin and is present in two forms: (a) ergocalciferol or activated ergosterol or vitamin D2 present in irradiated yeast and (b) cholecalciferol or activated 7-dehydrocholesterol or vitamin D3, which is produced in the cuties after exposure to ultraviolet radiation and is found in elevated quantities in fish liver oil and egg yolk. Milk is enriched with both of these forms. Vitamin D is effectively a pre-hormone which acts via metabolites of which the most active is 1,25(OH)2D or 1,25dihydroxycholecalciferol or calcitriol; this binds to specific receptors, the vitamin D receptors (VDRs) functioning as nuclear transcription factors. The principal functions of this vitamin are: (a) augmentation of intestinal absorption of calcium and (b) promotion of normal bone formation and mineralization (Morris, 2005).
The 7-dehydrocholesterol or pro-vitamin D3 is present in the cutis, and in a photochemical process due to exposure to ultraviolet B rays is converted to pre-vitamin D3. Then, in the basal cells of the epidermis, it is isomerized to vitamin D3, circulates in blood bound to vitamin-D binding protein (DBP) and at the hepatic level it is hydroxylated a first time to 25(OH)D3 or 25-dihydroxycholecalciferol, which is the principal circulatory form, being scarcely active metabolically. In the kidney it is hydroxylated a second time with the formation of 1,25(OH)2D3 or calcitriol, a metabolically more active form which constitutes the hormone-vitamin D; this process is stimulated by parathyroid hormone (PTH) and by hypophosphatemia, suppressed by calcium and by calcitriol itself. The quantity of vitamin D metabolites circulating is limited by the degradation processes operated by 25-hydroxyvitamin D-24-hydroxylase (CYP24A1) and by subsequent excretion of the metabolites of which calcitroic acid is the principal one (Holick, 2007). Vitamins D2 and D3 of alimentary origin are incorporated into the chylomicrons and transported through the lymphatic system to the venous circulation; they are deposited in the adipose tissue, whence they may be released (Holick, 2007). To determine the blood vitamin D level, the 25(OH)D is measured: its values in the plasma of healthy subjects are in the range 30–100 ng/ml with preferential values between 30 and 60 ng/ml; 1,25-(OH)2D3 values vary from 25 to 45 pg/ml. 3. The mechanism of action
* Corresponding author at: Via Panama, 102, I-00198, Roma, Italy. Tel.: +39 06 4450 208; fax: +39 06 4456 316. E-mail address: [email protected] (M. Cacciafesta). 0167-4943/$ – see front matter ß 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2011.03.001
The 1,25(OH)2D3 (1,25-dihydroxy vitamin D3) or calcitriol is a steroid hormone and acts by activation of the VDRs which are expressed by both the osteoblasts and the osteoclasts.
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The most important known role of 1,25(OH)2D3 is control of osteoclastogenesis and of osseous re-absorption by modulation of the gene which codifies for the receptor activator of nuclear factorkB ligand (RANKL) present in the osteoblasts. At this level 1,25(OH)2D3 is recognized by its receptor and determines augmented RANKL expression, which, binding to the RANK receptor present in the pre-osteoclasts induces their maturation into mature osteoclasts, favors re-absorption of calcium and phosphorous from the bones and contributes to maintaining calcium and phosphorous homeostasis. Another effect of 1,25(OH)2D3 consists of augmenting intestinal absorption of calcium interacting with VDR–RXR (vitamin D receptor–retinoic acid x-receptor complex), a heterodimeric complex of retinoic acid and vitamin D receptors, which activates or represses the transcription of numerous genes and regulates certain physiological functions: among these it augments the expression of the epithelial calcium TRPV6 and calbindin 9k transport channel, a protein which binds to calcium (Morris, 2005). The quota of vitamin D activated at the renal level only determines certain endocrine activities (homeostasis of calcium, regulation of arterial pressure, immunomodulation); to explain the actions at the cellular level (autocrine, paracrine and intracrine) it is necessary to also take into account local vitamin activation by diverse tissues whose physiology is currently still little known (Morris, 2005). The regulatory effects exerted by calcitriol on the keratinocytes through a duplex mechanism of action are particularly interesting: at low concentrations it stimulates cellular growth, and when the level is elevated, it induces apoptosis. The cause of this phenomenon is not yet known although it has been demonstrated how vitamin D metabolites control the activity of numerous genes of the keratinocytes utilizing both the autocrine and paracrine mechanisms. Current experimental research will also clarify the therapeutic effects in inflammatory, immunological, infective and neoplastic type pathologies (Lehmann, 2009). Numerous reports suggest the mechanisms with which calcitriol has diverse extra-skeletal effects (Table 1): (a) there are receptors in the encephalon, prostate, breast, colon and in the immune systems cells; (b) these receptors control, directly or indirectly, numerous genes implicated in cellular differentiation and proliferation processes, apoptosis and angiogenesis; (c) cellular proliferation is reduced in both normal and neoplastic cells, inducing differentiation; (d) augment myocardial contractility and insulin synthesis; (e) renin synthesis is inhibited; and (f) immunomodulatory functions are evident. 4. The hypovitaminosis D Generally caused by insufficient exposure to the sun and/or poor alimentation, this determined rickets in children and osteomalacia in adults (Table 2). Numerous epidemiological studies have hypothesized a causal nexus between variation in
Table 1 Biological effects of vitamin D. On the target
Effects
Calcium metabolism Infections Cardiovascular system Cancer
Strengthens skeleton and muscles Tuberculosis and influence in immune response Cares atherosclerosis, hypertension, heart failure Prevents breast, colon, prostate cancers and metastases Improves depression and schizophrenia Reduces the risk of falls to the ground Prevents autoimmune diseases, like multiple sclerosis and diabetes type 1
Neurological diseases Muscle functions Immunomodulators
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Table 2 The possible causes of vitamin D-deficiency. Reduction in skin synthesis and absorption, due to Hereditary and acquired disorders of metabolism and activity, Excessive use of sunscreens, Skin pigmentation: melanin reduces the absorption of UVB radiation up to 99%, Aging: reduction of 7-dehydrocholesterol, skin reduces the synthesis of vitamin about 70% by the 70 years of age. Environment: Zenith angle of the sun varies by season, latitude, time of day and in parallel is more oblique, the lower the number of photons that reach the earth. Malabsorption: Cystic fibrosis, celiac disease, Whipple disease, Crohn’s disease, intestinal bypass surgery, obesity (vitamin D is confined to the skin and fat, and scarcely available). Catabolism: Anticonvulsants, glucocorticoids, drugs for AIDS and transplant rejection accelerate the transformation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in an inactive form. Breastfeeding: Human milk contains little vitamin D and therefore the child is at risk of hypovitaminosis if no other sources of nutrition are available. Hepatic failure and malabsorption in severe cases reduce vitamin synthesis. Nephrotic syndrome: Urinary loss of 25 OHD with the transport protein. Chronic renal failure: Initially hyperphosphatemia reduces the activity of 25-hydroxyvitamin D-1a-hydroxylase and therefore the synthesis of 1,25-dihydroxy D, then because of hypovitaminosis develops hypocalcemia with secondary hyperparathyroidism.
vitamin D synthesis and mortality from chronic pathologies: for example, there is a direct correlation between a higher mortality rate for chronic diseases and a greater distance from the equator of the home, and it is known that the survival of patients with cardiovascular or neoplastic (pulmonary, breast, colon) disease is higher when the diagnosis is formulated in the summer months that in other seasons (Autier and Gandini, 2007). A meta-analysis of 18 randomized, controlled studies evaluated the impact of vitamin D supplements on mortality from all causes in 57,311 subjects, demonstrating that individuals who had taken vitamin D showed a mortality reduced by 7% (Grant, 2003). There are numerous scientific reports on the anti-tumoral action. Diverse studies have reported that populations residing at higher latitudes present higher incidence of neoplasias such as Hodgkin’s lymphoma and tumors of the colon, of the pancreas, of the prostate, of the ovaries, of the breast, with respect to those living at lower latitudes and who thus have longer exposition to sunlight (Lappe et al., 2007). It appears that a level of 25hydroxyvitamin D <20 ng/ml is associated with a risk higher by 30–50% of contracting and dying of malignant neoplasia. In this field, an analysis by the Nurses’ Health Study Cohort of 32,826 subjects indicated that the risk of manifesting a colonrectal tumor was inversely proportional to the mean of serum levels of 25-hydroxyvitamin D, while it was independent of the blood levels of 1,25-dihydroxyvitamin D (Wu et al., 2007). However, as it is the latter which induces the apoptosis of malignant cells and slows angiogenesis of tumor tissues, it is considered that the anti-tumoral effect may also be determined by a local production of the active metabolite which does not then pass into blood circulation and thus does not modify the blood level. Participants in the Women’s Health Initiative who presented, at the first check up, a blood concentration of 25-hydroxyvitamin D <12 ng/ml, had a 253% increase in the risk of colon-rectal cancer at the 8 year follow-up (Wactawski-Wende et al., 2006). In another study, men who worked outdoors contracted prostate cancer 3–
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5 years later that those working in closed environments (Santos Arrontes et al., 2007). 5. Toxicity Vitamins D2 and D3 are lipo-soluble and are accumulated in the adipose tissue when assumed excessively, for too long in the diet. They have no toxic effects as such, although the active metabolite quota does, being regulated by hydroxylation by the liver and kidneys. Reaching a toxic dose depends solely on the assumption of calcitriol in a single elevated dose (exceeding 50 mg) or in low daily doses (below 1 mg) assumed over long periods of time (Hathcock et al., 2007). In these cases one may observe the following symptoms: hypercalcemia, abdominal cramps, nausea, vomiting, constipation alternating with diarrhea, thirst, polyuria, itching, muscular and articular pain, disorientation and coma. 6. Effects on the osteo-articular structure Osteomalacia is a defect of bone mineralization due to a vitamin D deficiency. In adults, when the bone is mature, it is manifested by the presence of osteoid tissue, while in children, while bones are growing, it causes rickets, in which there is a defect in the calcification of the osteoid matrix with hypertrophy of the epiphysary cartilage. In general, the vitamin D level is inadequate due to insufficient exposure to sunlight or a poor alimentary supply, although there are rarer cases of: (a) an alteration of the vitamin metabolism or tissue resistance to its action; (b) hypoparathyroidism; (c) a hereditary pathology, like family hypophosphatemic rickets resistant to vitamin D, which is dominant and is linked to the X chromosome; and (d) a disease which interferes with vitamin D absorption or with the formation of its active metabolites (Kocia´n and Brunova´, 1989). Demineralization affects, above all, the spine, pelvis and the lower limbs; a bone X-ray reveals fibrous lamellae and area of incomplete ribbon demineralization (pseudo-fractures, Looser zones, Milkman’s syndrome). The long bones curve under the weight, the vertebrae shorten and the lower pelvic girdle narrows. Calcemia may be either reduced or normal depending on the PTH levels (secondary hyperparathyroidism); urinary calcium is generally low, except in cases of acidosis, while the alkaline phosphatase value is high. Osteoporosis is a systemic pathology characterized by reduced bone mass and qualitative alterations. It is often associated with vitamin D deficit. The National Osteoporosis Foundation (NOF) guidelines for the prevention of fractures from osteoporosis in the elderly recommend the assumption of vitamin D (800 IU/day) and calcium (1 g/ day) to obtain a significant reduction in the risk of fractures of the hip (27%) and non vertebral fractures (23%). These, in fact, determine a significant increase in morbidity and mortality; in particular, those of the hip increase with age through to the ninth decade of life in which they affect 1 woman in 3 and 1 man in 6. The consequences to the patient are grave as they cause permanent disability in 50% of cases and mortality within one year in 10–20%; the social costs of providing assistance are also elevated, and are destined to rise with the aging of the population (Boonen and Singer, 2008). 7. Effects on the cardiovascular system Diverse epidemiological studies demonstrate that environmental factors such as latitude, altitude, season, residence in the city or in the country are associated with cardiovascular disease mortality; as these factors influence the duration of exposure to
ultraviolet light and thus vitamin D synthesis. A role of this vitamin is hypothesized in reducing the cardiovascular risk markers, such as elevated blood levels of fibrinogen, of PAI 1, of homocysteine, of asymmetric dimethylarginine, C-reactive protein (CRP), of type B natriuretic peptide (BNP) (Dobnig et al., 2008; Michos and Melamed, 2008). A recent work showed that vitamin D, through diverse mechanisms such as augment insulin secretion, downregulation of the renin–angiotensin system, the inhibition of cellular proliferation and modulation of inflammatory processes, is directly implicated in certain pathophysiological processes correlated with the development of the cardiovascular diseases (Wang et al., 2010). Through regulation of calcium homeostasis, it influences cardiac contractility so a vitamin deficit may cause myocardial dysfunctions and cardiac insufficiency, with a risk of sudden death (Pilz et al., 2008); on the contrary, optimal levels of intracellular calcium are correlated with reduction of cardiovascular risk, in particular with reference to ischemic heart disease. Optimal levels of intracellular calcium inhibit fatty acid synthesis, augment insulin synthesis and sensitivity, inhibit platelet aggregation and induce vaso-relaxation (Wang et al., 2010). Low levels of 25(OH)D are associated with increased risk of hypertension, while normal levels, together with correct exposure to UVB radiation appear to favor a reduction in arterial pressure (Forman et al., 2008). A recent work noted that the administration of a statin, rosuvastatin, not only reduces cholesterolemia levels but also augments plasma levels of 25-hydroxy and 1,25-dihydroxyvitamin D, determining, at the same time, consensual decrease in alkaline phosphatase levels. The authors hypothesize then that the reduction in cardiovascular risk consequent to statin therapy is not linked solely with the improvement in the lipid metabolism, but also with the pleiotropic effects such as augmented 7dehydrocholesterol synthesis and, as a consequence also synthesis of vitamin D, whose level is inversely correlated with cardiovascular mortality (Yavuz et al., 2009). Recent research, supporting the cardio-protective role of vitamin D, highlights, in subjects undergoing dialysis, an inverse correlation between vitamin D supplementing and cardiovascular mortality (Naves-Dı´az et al., 2008). 8. Anti-tumoral effects Diverse scientific evidences indicate an important role in both the prevention of tumors of the colon and a contribution (as yet little known, but possible) in that of the prostate and breast. Indeed, in the latter 1,25(OH)2D inhibits cellular proliferation, induces differentiation and apoptosis, arresting angiogenesis (Garland et al., 2006; Jenab et al., 2010). Experimental studies in lung cancer show that 1,25(OH)2D arrests the proliferation of tumoral cell lines, and favors differentiation and, in animal models, impedes metastasization (Deeb et al., 2007; Chung et al., 2009). A trial effected on Finnish smokers however denied these protective effects, showing an increased risk of pancreatic cancer in association with elevated levels of vitamin D (Stolzenberg-Solomon et al., 2006). It is known that the addition of 1,25(OH)2D to a tumor cell culture causes inhibition of their growth; particularly evident results are obtained with prostate cells (Miller, 1998–1999). A recent study hypothesizes that the development of certain tumors is due to alterations in the expression of the VDR and of the hydroxylases (25, 1a, 24) indispensable to the synthesis and catabolism of calcitriol (1,25(OH)2D3). Indeed this acts as an antiproliferative factor, determining the arrest of the cellular cycle in G0/G1, differentiation and apoptosis, modulation of the intracellular signaling routes, inhibition of tumoral angiogenesis, rein-
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forcement of the anti-tumoral effects of the platinum analogs and of the taxanes (Chung et al., 2009). As to prostate cancer, a study conducted on 932 white nonHispanic men and on 114 white Hispanics from South Texas demonstrated that the interaction between certain polymorphisms of VDR (nuclear vitamin D receptor, which modulates the effect of vitamin D) and of SRD5A2 (type II 5alpha-reductase, which converts testosterone into dihydrotestosterone in the prostate) determines the growth of neoplastic cells (Torkko et al., 2008). In colon adenocarcinoma cells the CYP24A1 (24hydroxylase) enzyme is hyper-expressed, which catabolizes vitamin D neutralizing the anti-proliferative effects (Horva´th et al., 2010). On the basis of laboratory data, pre-clinical studies were effected on animals and anti-tumoral effects were obtained with vitamin D administration in intermittent high dosage schemas. These results give credibility to the hypothesis that the metabolites of vitamin D may have a role in cancer prevention and therapy although their use is limited by the risk of causing hypercalcemia. This is the motive for experimentation of a vitamin D analog (Deuterated Gemini DG), which acts as a selective modulator of the VMD receptor (SVDRM): this has produced promising results in colo-rectal cancer and did not determine alterations in calcemia (Spina et al., 2007). 9. Neurological effects Normal vitamin D levels during pregnancy and in the perinatal phase appear fundamental to correct development of the encephalon and its normal function; low levels appear to predispose schizophrenia and depression. An observational study of 1282 subjects, age ranging from 65 to 95 years, with depressive disturbances and low serum levels of 25(OH)D3 and elevated PTH levels, demonstrated that in the elderly, a vitamin D supplement improves mood disturbances. This vitamin may therefore be used in mood tone disturbance therapy in the elderly population in association with a diet rich in vitamin D or enriched and with greater exposure to sunlight (Hoogendijk et al., 2008). Some authors also hypothesize a role in Parkinson’s disease; in fact, 55% of patients present insufficient vitamin levels with respect to 36% in healthy subjects; this disease impacts the nerve cells in dopaminergic districts (the substantia nigra) which present an elevated level of vitamin D receptors (Evatt et al., 2008).
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effect due to augmented action by cathelicidin (CAMP), a peptide produced by white blood cells, whose synthesis is stimulated by vitamin D. CAMP is part of the innate immune system, deputed to furnishing a first line response to penetration attempts by microorganisms such as viruses, bacteria, fungi and parasites (Gombart et al., 2005). People of African origin who are more susceptible to tubercular infection, have lower levels of 25(OH)D and poor production of the RNA messenger for cathelicidin. The pathogen antigens interact with the macrophages augmenting gene expression for vitamin D receptor and the 1hydroxylase enzyme (Hewison et al., 2004). Serum levels of 25(OH)D are inversely associated with the frequency of upper respiratory tract infections. This correlation is more evident in subjects with co-morbidity and, in the winter, when 25(OH)D levels fall below 30 ng/ml (Ginde et al., 2009). The distinct seasonality of epidemic influences is caused by a ‘‘seasonal stimulus’’ which may be attributed to variation in the intensity of solar radiation through the diverse seasons of the years which are correlated with vitamin D synthesis; indeed, this presents the lowest blood levels in the winter months, when viral infection reaches peak diffusion and the immune system response is the greatest. The ‘‘seasonal stimulus’’ is thus the immunomodulatory action of 1,25(OH)2D, which impedes the excessive production of inflammatory cytokines, augments macrophage activity and stimulates neutrophil granulocytes, the monocytes, the natural killer cells and the respiratory tract epithelia to produce peptides with anti-microbial action (Cannell et al., 2006). A study of 884 seropositive pregnant women who were provided vitamin supplements showed that low vitamin D levels favor HIV transmission from mother to child; in fact, at blood levels below 32 ng/ml, the risk was some 50% at the sixth week of pregnancy (Mehta et al., 2009). Low blood levels of vitamin D3 may explain the greater prevalence of auto-immune diseases, such as rheumatoid arthritis (RA), in correlation with higher latitudes and greater gravity of the clinical situation in the winter months (Cutolo et al., 2007; Baeke et al., 2008). Vitamin D interferes with inflammatory response and fibrogenesis and recent scientific reports demonstrate a relationship between the blood level and certain chronic hepatic pathologies. In this, a study of 197 chronic hepatitis C patients showed that low blood levels of this vitamin are correlated to greater severity of the hepatic pathology itself, and lesser efficacy of antiviral therapy (Petta et al., 2010).
10. Muscular effects and prevention of bone fractures 12. Effects in respiratory diseases The fragile elderly at high risk of falls and non traumatic fractures have been studied in diverse trials and it was observed that vitamin D improves postural stability and reduces the incidence of fractures. A meta-analysis of five randomized clinical studies conducted on 1237 subjects demonstrated a 22% reduction in the risk of falling in subjects who had taken vitamins with respect to those in therapy with calcium alone or with a placebo; the frequency of falls also fell by 72% taking 800–1000 U/day of vitamin D3 with calcium (Boonen and Singer, 2008). A vitamin supplement is also always necessary in the case of low exposure to sunlight. 11. Immunomodulatory effects There are numerous scientific reports which support the hypothesis that vitamin D has immunomodulatory effects: The VDR is present in immune system cells (Hewison, 2010) Activated dendritic cells produce calcitriol (Cheung et al., 2002). Heliotherapy, that is prolonged exposure to sunlight, experimented in the early 1900s to cure tuberculosis, is linked with a antimicrobial
Vitamin D through its immunomodulatory effects regulates pulmonary inflammatory responses while simultaneously improving the innate defense mechanisms against respiratory pathogens (Hughes and Norton, 2009). Control of serum 25-OH D levels in 414 (ex)-smokers aged over 50 indicated that vitamin D deficiency is frequent in BPCO and is correlated with the gravity thereof (Janssens et al., 2010). Another study supported the hypothesis that vitamin D, inhibiting the proliferation of smooth musculature cells in the respiratory tract may be an efficacious treatment to re-model the airways in asthma. In general, if the 25(OH)D level is over 35 ng/ml, respiratory function improves, if lower, the risk of bronchial asthma increases (Clifford and Knox, 2009). 13. Effects on kidney diseases Oral administration of a VDR agonist reduces both inflammation and albuminuria; the benefits of the drug cannot be attributed to improved pressure, to falls in the glomerular filtration rate or
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improved PTH levels. The ligand in fact appears to act with an independent effect through a mechanism, which is still unclear, determining improved survival. An association of vitamin D with a type 1 (ARB) angiotensin II receptor blocker reduces he renal damage deriving from diabetic nephropathy (Weir, 2008). 14. Therapy with vitamin D Laboratory tests are available to measure the levels of both 25(OH)D and 1,25(OH)2D. At least an annual 25(OH)D dosage is necessary as this is correlated with the total vitamin D quantity produced by both the skin and assumed in the diet. Vitamins D2 and D3 have low biological activity. It is not useful to measure 1,25D levels as these may be normal even in the presence of vitamin D deficit. Diagnostic significance of blood 25(OH)D levels: normality = 30–100 ng/ml (75–250 nmol/l); deficit for values below 10 ng/ ml (<0–25 nmol/l); hypovitaminosis = 10–30 ng/ml (25–75 nmol/ l); toxic effects above 100 ng/ml (>250 nmol/l). The cutis synthesizes 20,000 IU of vitamin D3 after 20 min exposure to sunlight. Where this is insufficient or possible, it is necessary to assume foods or drugs containing elevated quantities of vitamin D in the form of cholecalciferol (D3) and ergocalciferol (D2). In brief, these are the principal pharmacological approaches. (a) Ergocalciferol (D2) 400,000 IU/phial: 1–2 phials/week orally or i.m. (b) Cholecalciferol (D3): drops 10,000 IU/ml: 3–4 drops/day (equal to 750–1000 IU vitamin D3) or 20 drops once a week (equal to 5000 IU D3). (c) Phial orally/i.m. 100,000 IU/ml: 1 phial orally or i.m. every 4–6 months; phial orally/i.m. 300,000 IU/ml: 1 phial orally or i.m. once per year. (d) Calcitriol cp 0.25–0.50 mg: from 0.5 to 1 mg/day (adverse effect due to accumulation; monitor calcemia values: if exceeding normal value by 1 mg suspend). Conflict of interest statement None. References Autier, P., Gandini, S., 2007. Vitamin D supplementation and total mortality: a metaanalysis of randomized controlled trials. Arch. Intern. Med. 167, 1730–1737. Baeke, F., Van Etten, E., Gysemans, C., Overbergh, L., Mathieu, C., 2008. Vitamin D signaling in immune-mediated disorders: evolving insights and therapeutic opportunities. Mol. Aspects Med. 29, 376–387. Boonen, S., Singer, A.J., 2008. Osteoporosis management: impact of fracture type on cost and quality of life in patients at risk for fracture I. Curr. Med. Res. Opin. 24, 1781–1788. Cannell, J.J., Vieth, R., Umhau, J.C., Holick, M.F., Grant, W.B., Madronich, S., Garland, C.F., Giovannucci, E., 2006. Epidemic influenza and vitamin D. Epidemiol. Infect. 134, 1129–1140. Cheung, C.Y., Poon, L.L., Lau, A.S., Luk, W., Lau, Y.L., Shortridge, K.F., Gordon, S., Guan, Y., Peiris, J.S., 2002. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 360, 1831–1837. Chung, I., Han, G., Seshadri, M., Gillard, B.M., Yu, W.D., Foster, B.A., Trump, D.L., Johnson, C.S., 2009. Role of vitamin D receptor in the antiproliferative effects of calcitriol in tumor-derived endothelial cells and tumor angiogenesis in vivo. Cancer Res. 69, 967–975. Clifford, R.L., Knox, A.J., 2009. Vitamin D—a new treatment for airway remodelling in asthma? Br. J. Pharmacol. 158, 1426–1428. Cutolo, M., Otsa, K., Uprus, M., Paolino, S., Seriolo, B., 2007. Vitamin D in rheumatoid arthritis. Autoimmun. Rev. 7, 59–64. Deeb, K.K., Trump, D.L., Johnson, C.S., 2007. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat. Rev. Cancer 7, 684–700. Dobnig, H., Pilz, S., Scharnagl, H., Renner, W., Seelhorst, U., Wellnitz, B., Kinkeldei, J., Boehm, B.O., Weihrauch, G., Maerz, W., 2008. Independent association of low serum 25-hydroxyvitamin D and 1,25 dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch. Intern. Med. 168, 1340–1349. Evatt, M.L., Delong, M.R., Khazai, N., Rosen, A., Triche, S., Tangpricha, V., 2008. Prevalence of vitamin D insufficiency in patients with Parkinson disease and Alzheimer disease. Arch. Neurol. 65, 1348–1352.
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