Vitamin D and Health

compliled by John G. Connor, M.Ac., L.Ac., edited by Barbara Connor, M.Ac., L.Ac.

Table of Contents
Studies on the Relationship between Vitamin D and Bone Mineral Density
Studies on the Relationship between Vitamin D Levels and Cancer
Studies on the Relationship between Vitamin D levels and Triglyceride Levels
Studies on the Relationship between Vitamin D Levels and Hepatitis C Virus
Studies on the Health Benefits of Vitamin D in Other Conditions
lmportance of Combining Vitamin D with Vitamin K

Vitamin D is produced in skin upon exposure to UVB radiation from the sun or from limited dietary sources such as fish and irradiated mushrooms and fortified foods such as milk and orange juice. Vitamin D (D3 from skin only and D2 or D3 from dietary sources) enters the circulation and is hydroxylated in the 25- position by the 25-hydroxylase to form its major circulating form, 25(OH)D, which has a circulating half-life of ~3 wk. The 25(OH)D then circulates to the kidney and is hydroxylated in the 1-position by the 1α-hydroxylase to form the hormonal form of vitamin D, 1,25(OH)2D. Other tissues such as the epithelial lining of the lung and immune cells in the lung also possess the 1α-hydroxylase to produce local concentrations of 1,25(OH)2D. Proposed extrarenal effects of 1,25(OH)2D produced by epithelial and lung cells include increasing antimicrobial peptide production, regulation of the inflammatory response, and airway remodeling. Vitamin D may also play a role in respiratory muscle function. (Finklea et al 2011)

Foods of animal origin rich in vitamin D3 include egg yolk, dairy fat, liver, and oily fish. Modest amounts of vitamin D come from food sources, but the majority of vitamin D (up to 90%) comes from endogenous production in the skin. As a result, wide variability in vitamin D status occurs due to differences in geographic location, season, sun avoidance behaviors, sunscreen use, increasing age and skin pigmentation (due to decreased skin synthesis of vitamin D), obesity (due to fat sequestration of vitamin D), and other lifestyle factors. Vitamin D deficiency is surprisingly common, especially among the elderly, blacks, and residents of northern climates. (Crew KD 2013)

Given the essential role vitamin D plays in maintaining bone health and the gathering proof of widespread deficiency within the UK population, it is essential that the most efficacious source of vitamin D is elucidated. Therefore, the aim of this systematic review and meta-analysis was to determine whether there is a difference in the efficacy of vitamin D2 compared with vitamin D3 in the raising of the serum 25(OH)D status within the context of randomized controlled trials (RCTs). Our results suggest a favoring toward cholecalciferol rather than ergocalciferol supplementation with respect to the more effective improvement of vitamin D status. When the frequency of dosage administration was compared, there was a significant response for vitamin D3 when given as a bolus dose (P = 0.0002) compared with administration of vitamin D2, but the effect was lost with daily supplementation. (Tripkovic et al 2012)

 Studies on the Relationship between Vitamin D and Bone Mineral Density
Vitamin D deficiency coexists with low bone mineral density (BMD) in our study group. Serum 25(OH)D needs to be documented in women having low BMD. Calcium and vitamin D need to be supplemented as part of therapy in post-menopausal women. (Harinarayan et al 2011)

Vitamin D3 & Calcium – Combined calcium and vitamin D3 supplementation was effective in reducing the rate ofbone mineral density loss in women with moderate chronic kidney disease. (Bosworth et all 2012)Vitamin D – In utero and during childhood, vitamin D deficiency can cause growth retardation and skeletal deformities and may increase the risk of hip fracture later in life. Vitamin D deficiency in adults can exacerbateosteopenia and osteoporosis, cause osteomalacia and muscle weakness, and increase the risk of fracture. (Szabo A 2011)

Vitamin D – In addition to enhancing calcium absorption from the intestine and mineralization of the osteoid tissue, vitamin D has many other physiological effects, including neuromodulation, improving muscle strength and coordination, insulin release, immunity and prevention of infections, and curtailing cancer. (Wimalawansa SJ 2011)

Studies on the Relationship between Vitamin D Levels and Cancer
Vitamin D – This study supports the hypothesis that higher serum 25(OH)D levels reduce the risk of breast cancer. According to the review of observational studies, a serum 25(OH)D level of 47 ng/ml was associated with a 50% lower risk of breast cancer. (Mohr et al 2011)

Vitamin D  – Intake of 2000 IU/day of Vitamin D(3), and, when possible, very moderate exposure to sunlight, could raise serum 25(OH)D to 52 ng/ml, a level associated with reduction by 50% in incidence of breast cancer,according to observational studies. (Garland et al 2007)

Vitamin D – deficiency may be associated with poor outcomes in patients with luminal-type breast cancer. (Kim et al 2011)

Vitamin D – These findings support a role of vitamin D in the pathogenesis of urothelial bladder cancer (UBC) and show that 25(OH)D(3) levels are associated with FGFR3 expression in the tumor. Because FGFR3 mutation and overexpression are markers of better outcome, our findings suggest that individuals with low levels of plasma 25(OH)D(3) may be at high risk of more aggressive forms of UBC. (Amaral et al 2012)

Vitamin D(3) – Our findings showed that Vitamin D(3), VK(3,) and VK(5) inhibited the growth of dacarbazine resistant human melanoma cells, while ATRA, VE, and VK(1) had little effect on the cell growth. The effects of VK(3) and VK(5) were observed at concentrations lower than 10 μmol/L, which are suggested to have resulted from apoptosis-induction in the melanoma cells. (Ishibashi et al 2012)

Vitamin D – Higher 25(OH)D score was associated with a lower risk of pancreatic cancer in these two prospective cohort studies. (Bao et al 2010)

Studies on the Relationship between Vitamin D levels and Triglyceride levels
Vitamin D – Subjects with metabolic syndrome exhibit lower 25(OH)Vit D serum levels compared with non-MetS individuals. Low 25(OH)Vit D is associated with higher small dense low-density lipoprotein cholesterol (sdLDL-C) levels possibly through elevated triglycerides. (Makariou et al 2012)

Vitamin D – Low serum vitamin D levels in children is associated with high triglyceride levels. (Rodriguez-Rodriguez et al 2011)

Studies on the Relationship between Vitamin D Levels and Hepatitis C Virus
Vitamin D – This study demonstrates for the first time a direct anti-viral effect of vitamin-D in an in-vitro infectious virus production system. It proposes an interplay between the hepatic vitamin-D endocrine system and hepatitis C virus (HCV), suggesting that vitamin-D has a role as natural anti-viral mediator. Importantly, our study implies that vitamin-D might have an interferon sparing effect thus improving antiviral treatment of HCV-infected patients. (Gal-Tanamy et al 2011)

Vitamin D –  Chronic hepatitis C is the primary cause of death in patients with end-stage liver disease. Its prognosis depends on the accumulation of fibrosis over time due to various mechanisms of tissue damage caused by viral infection, ultimately leading to the development of cirrhosis and related complications. The development of hepatic fibrosis is most directly correlated with necro-inflammation, and several other host and viral factors have been associated with the rate of fibrosis progression, including older age, alcohol consumption, duration of infection, viral co-infections, steatosis, insulin resistance, and vitamin D deficiency. (Villa et al 2012)

Studies on the Health Benefits of Vitamin D in Other Conditions
Vitamin D – Our data suggest that any improvement in vitamin D status will improve expression of genes that have a wide variety of biologic functions that are associated with cellular proliferation, differentiation, immune function, DNA repair etc. whether the 25(OH)D concentration is as low as 10 ng/ml or as high as 40 ng/ml. These genes are linked to cancer, autoimmune disorders and cardiovascular disease and have been associated with vitamin D deficiency. (Hossein-nezhad et al 2013)

Vitamin D – Moreover, it has been demonstrated that 1,25(OH)(2)D(3) can induce differentiation and inhibit proliferation of normal and malignant cells. Moreover, vitamin D deficiency is associated with an increased risk for nearly all major human diseases such as cancer, autoimmune diseases, cardiovascular, and metabolic diseases.(Verstuyf et al 2010)

Vitamin D – is crucial to activating our immune defenses. Without sufficient intake of the vitamin, the killer cells of the immune system — T cells — are not be able to react to and fight off serious infections in the body. For T cells to detect and kill foreign pathogens such as clumps of bacteria or viruses, the cells must first be ‘triggered’ into action and ‘transform’ from inactive and harmless immune cells into killer cells that are primed to seek out and destroy all traces of a foreign pathogen. It was found that the T cells rely on vitamin D in order to activate and they would remain dormant, ‘naïve’ to the possibility of threat if vitamin D is lacking in the blood. (von Essen et al 2010)

Vitamin D deficiency was a strong independent predictor of all-cause death (odds ratios 2.64, 95% confidence interval 1.901 to 3.662, p <0.0001) after adjusting for multiple clinical variables. Vitamin D supplementation conferred substantial survival benefit (odds ratio for death 0.39, 95% confidence interval 0.277 to 0.534, p <0.0001). In conclusion, vitamin D deficiency was associated with a significant risk of cardiovascular disease andreduced survival. Vitamin D supplementation was significantly associated with better survival, specifically in patients with documented deficiency. (Vacek et al 2012)

Vitamin D – On the basis of this study, we can conclude that vitamin D is useful in prevention of respiratory tract infections. But looking at the availability of only five clinical trials there is need of conduction of more clinical trials so that more valid conclusion can be reached. (Charan et al 2012)

Vitamin D – The risk of all-cause mortality is inversely related to serum 25(OH)D levels. (Saliba et al 2012)

Vitamin D deficiency is common in the young and middle-aged, urban Chinese population, with high prevalence in overweight/obese individuals and patients with metabolic syndrome. Low vitamin D concentration was associated with indices of adiposity and cardiometabolic risk factors. (Yin et al 2012)

Vitamin D deficiency has been linked to various inflammatory diseases. This study identified the upregulation of MKP-1 by vitamin D as a novel pathway by which vitamin D inhibits LPS-induced p38 activation and cytokine production in monocytes/macrophages. (Zhang et al 2012)

Vitamin D – may play a role in glucose metabolism. A low vitamin D level has been associated with increased risk of diabetes mellitus, but the association has not been confirmed in Asians. In conclusion, a low serum vitamin D concentration is associated with a high risk of diabetes mellitus in Korean adults and the concentration is inversely associated with insulin resistance in those who are overweight or obese. (Choi et al 2011)

Vitamin D – Patients with chronic kidney disease (CKD) exhibit a high mortality risk that is not fully explained by the classical cardiovascular risk factors. Vitamin D deficiency highly prevalent among CKD patients is independently associated with an increased mortality risk in this population. By its cardiovascular effects for instance, correction of vitamin D insufficiency might help to reduce the excess of mortality among patients withchronic kidney disease. (Ernandez & Stoermann-Chopard 2012)

Vitamin D – Recent studies have highlighted a possible relationship between vitamin D and Parkinson’s Disease(PD). Vitamin D may be beneficial in PD patients, as one patient showed improved rigidity and akinesia and was able to decrease their levodopa dosage after vitamin D therapy. Genetic studies have provided opportunities to determine what proteins may link vitamin D to PD pathology. Vitamin D can also act through a number of nongenomic mechanisms, including effects on protein expression, oxidative stress, inflammation, and cellular metabolism. Among the many forms of vitamin D, calcitriol (1,25-dihydroxyvitamin D3) is an attractive therapeutic candidate, because it is a particularly active metabolite, and its receptor is expressed in the CNS. (Luong & Nguyen 2012)

Vitamin D – A significant association between Alzheimer’s disease (AD) and low levels of vitamin D has been demonstrated. Furthermore, vitamin D supplements appear to have a beneficial clinical effect on AD by regulating micro-RNA, enhancing toll-like receptors, modulating vascular endothelial factor expression, modulating angiogenin, and advanced glycation end products. Vitamin D also exerts its effects on AD by regulating calcium-sensing receptor expression, enhancing amyloid-β peptides clearance, interleukin 10, downregulating matrix metalloproteinases, upregulating heme oxygenase 1, and suppressing the reduced form of nicotinamide adenine dinucleotide phosphate expression. In conclusion, vitamin D may play a beneficial role in AD. (Lu’o’ng & Ecirctilde 2013)

Vitamin D – Prophylaxis with vitamin D is recommended for all subjects using antiepileptic drugs (AEDs). Due to increased catabolism of vitamin D, higher than normally recommended doses (up to 7,000 IU per day) of vitamin D are required for optimal effect, particularly for those with low vitamin D levels, high risk of bone disease and/or with documented low bone mineral density (BMD). In general, in patients undergoing antiepileptic treatment, vitamin D status should be monitored once to twice annually, based on the serum 25(OH)D level (target: 30–60 ng/mL [75–150 nmol/L]). Any deficiency should be treated as required with targeted supplementation in order to prevent osteopathy. For those with documented vitamin D deficiency, treatment with 50,000 IU vitamin D/week for 8 weeks is recommended, followed by 50,000 IU of vitamin D every 2 to 4 weeks thereafter. (Grober & Kisters 2012)

lmportance of Combining Vitamin D with Vitamin K
Vitamin D and Vitamin K increases bone mineral density – Health risk of osteoporosis is increasing in Korean women and there were many trials to reduce and prevent osteoporotic fracture risk . Vitamin K plays a role in bone metabolism and may decrease the risk of fracture . Vitamin K also acts synergistically with Vitamin D on bone mineral density (BMD) and positively influences the balance of calcium, a key mineral in bone metabolism. Addition of vitamin K to vitamin D and calcium supplements in the postmenopausal Korean women increases the L3 BMD and reduces the undercarboxylated osteocalcin (UcOC) concentration.(Sang Hyeon Je et al 2011)

Vitamin D with K1 promotes beneficial effects on the elastic properties of arterial vessel walls:
It is concluded that a supplement containing vitamins K1 and D has a beneficial effect on the elastic properties of the arterial vessel wall. (Braam et al 2004)

The presence of calcification in any arterial wall is associated with a 3-4-fold higher risk for mortality and cardiovascular events. (Rennenberg et al 2009)

Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. In the trial presented here we have investigated the potential complementary effect of vitamin K1 (1 mg/day) and a mineral + vitamin D supplement (8 microg/day) on postmenopausal bone loss. The design of our study was a randomized, double-blind, placebo-controlled intervention study; 181 healthy postmenopausal women between 50 and 60 years old were recruited, 155 of whom completed the study. If co-administered with minerals and vitamin D, vitamin K1 may substantially contribute to reducing postmenopausal bone loss at the site of the femoral neck. (Braam et al 2003)
Vitamin D3 and K2 induce mineralization in human osteoblasts:
In the present study, it was demonstrated that the vitamin K metabolic cycle functions in human osteoblasts as well as in the liver, the post-translational mechanism, by which 1,25(OH)2D3 caused mineralization in cooperation with vitamin K2 was clarified. (Miyake et al 2001)

The 1,25(OH)2D3-induced mineralization promoted by vitamin K2 was probably due to the enhanced accumulation of osteocalcin induced by vitamin K2 in the cell layer. These results suggest that the mechanism underlying the mineralization induced by vitamin K2 in the presence of 1,25(OH)2D3 was different from that of vitamin K2 alone, and that osteocalcin plays an important role in mineralization by osteoblasts in vitro. (Koshihara et al 1996)

Both types of vitamin K treatment – menaquinone-4 (MK-4) and vitamin K(1) – decreased the expression of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor and enhanced the expression of osteoprotegerin/osteoclast inhibitory factor in the stromal cells. Vitamin K might stimulate osteoblastogenesis in bone marrow cells. (Koshihara et al 2003)

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