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Vitamin D &amp; K

September 2010

Vitamin D and vascular calcification.

PURPOSE OF REVIEW: Vascular calcification is frequently found in patients with osteoporosis, atherosclerosis and chronic kidney disease, leading to high morbidity and mortality rates. The effects of vitamin D excess and deficiency on vascular calcification are reviewed in this article. RECENT FINDINGS: There is evidence from experimental studies that mediacalcinosis induced by vitamin D excess is an active and reversible process. Vitamin D excess, however, is rarely seen in the general human population. Experimental data also demonstrate that physiologic vitamin D actions include the inhibition of processes that are important for intimal and medial artery calcification such as pro-inflammatory cytokine release, adhesion molecule release, and proliferation and migration of vascular smooth muscle cells. In uremic rats, low levels of the vitamin D hormone calcitriol are associated with massive vascular and soft tissue calcifications. Whereas retrospective studies already indicate a beneficial effect of active vitamin D on mortality rates in chronic kidney disease, little is yet known about the effect of vitamin D deficiency on cardiovascular morbidity and mortality in the general population. SUMMARY: Available data indicate that vitamin D exerts a biphasic ‘dose response’ curve on vascular calcification with deleterious consequences not only of vitamin D excess but also of vitamin D deficiency.

Curr Opin Lipidol. 2007 Feb;18(1):41-6

25-hydroxyvitamin D levels inversely associate with risk factor developing coronary artery calcification.

Vitamin D deficiency associates with increased risk for cardiovascular events and mortality, but the mechanism driving this association is unknown. Here, we tested whether circulating 25-hydroxyvitamin D concentration associates with coronary artery calcification (CAC), a measure of coronary atherosclerosis, in the Multi-Ethnic Study of Atherosclerosis. We included 1,370 participants: 394 with and 976 without chronic kidney disease (estimated GFR <60 ml/min per 1.73 m(2)). At baseline, CAC was prevalent among 723 (53%) participants. Among participants free of CAC at baseline, 135 (21%) developed incident CAC during 3 yr of follow-up. Lower 25-hydroxyvitamin D concentration did not associate with prevalent CAC but did associate with increased risk for developing incident CAC, adjusting for age, gender, race/ethnicity, site, season, physical activity, smoking, body mass index, and kidney function. Further adjustment for BP, diabetes, C-reactive protein, and lipids did not alter this finding. The association of 25-hydroxyvitamin D with incident CAC seemed to be stronger among participants with lower estimated GFR. Circulating 1,25-dihydroxyvitamin D concentrations among participants with chronic kidney disease did not significantly associate with prevalent or incident CAC in adjusted models. In conclusion, lower 25-hydroxyvitamin D concentrations associate with increased risk for incident CAC. Accelerated development of atherosclerosis may underlie, in part, the increased cardiovascular risk associated with vitamin D deficiency.

J Am Soc Nephrol. 2009 Aug;20(8):1805-12

Vitamin D and cardiovascular disease.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Recently vitamin D deficiency has been identified as a potential risk factor for many diseases not traditionally associated with vitamin D, such as cancer and CVD. This review discusses the evidence suggesting an association between low 25-hydroxyvitamin D levels and CVD and the possible mechanisms mediating it. Vitamin D deficiency has been associated with CVD risk factors such as hypertension and diabetes mellitus, with markers of subclinical atherosclerosis such as intima-media thickness and coronary calcification as well as with cardiovascular events such as myocardial infarction and stroke as well as congestive heart failure. It could be suggested that vitamin D deficiency contributes to the development of CVD through its association with risk factors, such as diabetes and hypertension. However, direct effects of vitamin D on the cardiovascular system may also be involved. Vitamin D receptors are expressed in a variety of tissues, including cardiomyocytes, vascular smooth muscle cells and endothelial cells and vitamin D has been shown to affect inflammation and cell proliferation and differentiation. While much evidence supports a potential antiatherosclerotic effect of vitamin D, prospective, placebo-controlled randomized as well as mechanistic studies are needed to confirm this association. Since vitamin D deficiency is easy to screen for and treat, the confirmation of such an association could have important implications for both, patient care and health policy.

Curr Vasc Pharmacol. 2009 Jul;7(3):414-22

Vitamin D receptor activators can protect against vascular calcification.

An apparent conflict exists between observational studies that suggest that vitamin D receptor (VDR) activators provide a survival advantage for patients with ESRD and other studies that suggest that they cause vascular calcification. In an effort to explain this discrepancy, we studied the effects of the VDR activators calcitriol and paricalcitol on aortic calcification in a mouse model of chronic kidney disease (CKD)-stimulated atherosclerotic cardiovascular mineralization. At dosages sufficient to correct secondary hyperparathyroidism, calcitriol and paricalcitol were protective against aortic calcification, but higher dosages stimulated aortic calcification. At protective dosages, the VDR activators reduced osteoblastic gene expression in the aorta, which is normally increased in CKD, perhaps explaining this inhibition of aortic calcification. Interpreting the results obtained using this model, however, is complicated by the adynamic bone disorder; both calcitriol and paricalcitol stimulated osteoblast surfaces and rates of bone formation. Therefore, the skeletal actions of the VDR activators may have contributed to their protection against aortic calcification. We conclude that low, clinically relevant dosages of calcitriol and paricalcitol may protect against CKD-stimulated vascular calcification.

J Am Soc Nephrol. 2008 Aug;19(8):1509-19

25-hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey.

OBJECTIVE: Serum 25-hydroxy-vitamin D [25(OH)D] levels are inversely associated with important cardiovascular disease (CVD) risk factors. However, the association between 25(OH)D levels and prevalent CVD has not been extensively examined in the general population. METHODS: We performed a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey (1988-1994) and examined the association between serum 25(OH)D levels and prevalence of CVD in a representative population-based sample of 16,603 men and women aged 18 years or older. Prevalence of CVD was defined as a composite measure inclusive of self-reported angina, myocardial infarction or stroke. RESULTS: In the whole population, there were 1308 (8%) subjects with self-reported CVD. Participants with CVD had a greater frequency of 25(OH)D deficiency [defined as serum 25(OH)D levels <20 ng/mL] than those without (29.3% vs. 21.4%; p<0.0001). After adjustment for age, gender, race/ethnicity, season of measurement, physical activity, body mass index, smoking status, hypertension, diabetes, elevated low-density lipoprotein cholesterol, hypertriglyceridemia, low high-density lipoprotein cholesterol, chronic kidney disease and vitamin D use, participants with 25(OH)D deficiency had an increased risk of prevalent CVD (odds ratio 1.20 [95% confidence interval (CI) 1.01-1.36; p=0.03]). CONCLUSIONS: These results indicate a strong and independent relationship of 25(OH)D deficiency with prevalent CVD in a large sample representative of the US adult population.

Atherosclerosis. 2009 Jul;205(1):255-60

The role of vitamin D in the development of cardiac failure.

Congestive heart failure is a chronic disease, whose incidence is especially growing in the subpopulation of elderly people. The majority of these patients have vitamin D levels in the insufficient range. Skin synthesis is the most important vitamin D source for humans. Congestive heart failure patients have relatively low outdoor activities. Consequently, a disease-related sedentary lifestyle is an important cause for the insufficient vitamin D status in patients. However, there is an accumulating body of evidence that vitamin D insufficiency plays a role in the etiology and pathogenesis of congestive heart failure. Vitamin D has direct effect on heart cells and indirect effect on the risk factors of the disease. Four major potential mechanisms may be important to explain the direct effects of vitamin D against congestive heart failure: the effect on myocardial contractile function, the regulation of natriuretic hormone secretion, the effect on extracellular matrix remodelling and the regulation of inflammation cytokines. It has been demonstrated that vitamin D has a high impact on congestive heart failure main risk factors as hypertension, renin-angiotensin system malfunction and atherosclerosis. In spite of the robust preclinical data only few clinical observations prove the positive effect of vitamin D on congestive heart failure.

Orv Hetil. 2009 Jul 26;150(30):1397-402

Vitamin K-controlled diet: problems and prospects.

Different natural (phylloquinone and menaquinone) and synthetic (menadione) compounds carry out the same action of vitamin K in the human body. Vitamin K is a substrate for the enzyme catalysing the posttranslational conversion of specific glutamyl residues to gamma-carboxyglutamyl residues in certain proteins connected with the coagulation (Factors II, VII, IX, X), the anticoagulation (Proteins C and S) and other organic functions (osteocalcin). Foods rich in vitamin K (1/4) and the action of gut bacteria (3/4) can give rise to changes in vitamin K status. Dietary factors, alterations of gut bacteria or/and troubles in the absorption of this vitamin can cause a lack, which at first interferes in the normal hemostatic function and later on it leads to modifications in the bone structure. Therefore, it is necessary to pay a lot of attention to dietary intake, adequacy, bioavailability, absorption and metabolism of vitamin K and compounds with an action similar to it for understanding the signs of lack, choosing the most suitable therapy and managing accurately the coumarin-based oral anticoagulants.

Clin Ter. 2005 Jan-Apr;156(1-2):41-6

Vitamin K in the Norwegian diet and osteoporosis.

BACKGROUND: In search of vitamin K literature, interesting results were discovered. A summary is presented. MATERIAL AND METHODS: The literature was found by using Medline. The level of vitamin K1 in the Norwegian diet was estimated from tables of food consumption and vitamin K1 per 100 g. RESULTS: Vitamin K is required for the carboxylation of the amino acid glutamic acid to gamma-carboxyglutamic acids on proteins, which is essential for the calcium binding capacity of Gla proteins (such as osteocalcin). These proteins are found in tissues such as bone, brain, pancreas and lungs, showing that Gla proteins have further important functions. Low intakes of the vitamin may be an important factor for osteoporosis and possibly also for atherosclerosis. The level of vitamin K1 in the Norwegian diet (purchase level) is estimated to be 60 micrograms K1/day before correction of waste. This level is lower than the recommended dietary allowance (1 microgram/kg body weight/day). INTERPRETATION: There is a discussion in the literature of whether the allowances should be considerably higher (375 micrograms K1/day). Deep green vegetables and soybean oil are the best sources of vitamin K1, while cheese gives some K2. On the basis of this knowledge about the importance of vitamin K and osteoporosis, an intervention test should be done with respect to the high incidence of osteoporosis in Norway. Analysis of Norwegian foods for vitamin K1 and K2 is needed.

Tidsskr Nor Laegeforen. 2001 Sep 20;121(22):2614-6

The riddle of vitamin K1 deficit in the newborn.

Vitamin K in the fetus and newborn is maintained at levels less than that necessary to achieve full gamma-carboxylation of the K-dependent proteins, including those required for hemostasis. As the infant matures and even into adulthood, there is no significant storage pool for this vitamin, and a K1-deficient state can be produced by placing an adult on a K-deficient diet for 7 to 10 days. Questions arise as to why the level of vitamin K is so rigidly controlled and why the placental gradient in humans and other mammals maintains the fetus in a K- “deficient” state. The evidence is reviewed that suggests that K-dependent proteins are ligands for receptor tyrosine kinases, which, in the rapidly proliferating cell milieu of the fetus, control growth regulation. Increased stimuli may result in growth dysregulation whereas conversely, the further depletion of vitamin K-dependent proteins, as in warfarin toxicity, depletes the required stimuli for normal embryogenesis. These findings argue for the need for tightly controlled levels of vitamin K consistent with normal embryogenesis.

Semin Perinatol. 1997 Feb;21(1):90-6

Effects of vitamin K2 on osteoporosis.

Vitamin K2 is a cofactor of gamma-carboxylase, which converts the glutamic acid (Glu) residue in osteocalcin molecules to gamma-carboxyglutamic acid (Gla), and is, therefore, essential for gamma-carboxylation of osteocalcin. Available evidence suggests that vitamin K2 also enhances osteocalcin accumulation in the extracellular matrix of osteoblasts in vitro. Osteocalcin-knockout mice develop hyperostosis, suggesting that the Gla-containing osteocalcin promotes normal bone mineralization. Although the precise role of osteocalcin in bone mineralization remains obscure, it probably regulates the growth of hydroxyapatite crystals. Furthermore, vitamin K2 also inhibits the expression of the osteoclast differentiation factor (ODF)/RANK ligand, tartrate-resistant acid phosphatase activity, and mononuclear cell formation, and induces osteoclast apoptosis in vitro. There is some evidence indicating that vitamin K2 prevents bone resorption in ovariectomized rats, retards the increase in bone turnover in orchidectomized rats, ameliorates the increase in bone resorption and decrease in bone formation in sciatic neurectomized rats, and prevents the decrease in bone formation in glucocorticoid-treated rats. These findings suggest that vitamin K2 may not only stimulate bone formation but also suppress bone resorption in vivo. Clinically, vitamin K2 sustains the lumbar bone mineral density (BMD) and prevents osteoporotic fractures in patients with age-related osteoporosis, prevents vertebral fractures in patients with glucocorticoid-induced osteoporosis, increases the metacarpal BMD in the paralytic upper extremities of patients with cerebrovascular disease, and sustains the lumbar BMD in patients with liver-dysfunction-induced osteoporosis. Vitamin K deficiency, as indicated by an increased circulating level of undercarboxylated osteocalcin, may contribute to osteoporotic fractures. Even though the effect of vitamin K2 on the BMD is quite modest, this vitamin may have the potential to regulate bone metabolism and play a role in reducing the risk of osteoporotic fractures. No randomized well-controlled prospective studies conducted on a sufficiently large number of patients have been reported yet, therefore, further studies are needed to confirm the efficacy of vitamin K2 in the treatment of osteoporosis.

Curr Pharm Des. 2004;10(21):2557-76

Role of vitamin K2 in the treatment of postmenopausal osteoporosis.

Vitamin K2, raloxifene, and bisphosphonates, such as etidronate, alendronate, and risedronate, are widely used in the treatment of postmenopausal osteoporosis in Japan. A meta-analysis study has demonstrated the efficacy of anti-resorptive agents: raloxifene and etidronate have been shown to reduce the incidence of vertebral fractures, and alendronate and risedronate have been shown to reduce the incidence of both vertebral and hip fractures. Furthermore, a report of the World Health Organization (WHO) has provided evidence from a randomized controlled trial suggesting that vitamin K2, which may stimulate bone formation via gamma-carboxylation of osteocalcin and/or steroid and xenobiotic receptors (SXRs), reduces the incidence of vertebral fractures, despite having only modest effects on the bone mineral density (BMD). Based on the weight of the currently available evidence, it is recommended that alendronate and risedronate, rather than vitamin K2, should be chosen initially for the treatment of postmenopausal osteoporosis, because these agents have been shown to be the most efficacious for reducing the incidence of both vertebral and hip fractures among the current range of commercially available agents. However, the more potent anti-fracture efficacy of combined treatment with the anti-resorptive and commercially available anabolic agents may need to be established. Some studies have shown that combined treatment with a bisphosphonate and vitamin K2 may be more effective than treatment with a bisphosphonate alone in preventing vertebral fractures. On the other hand, the results of a preclinical study do suggest the possible efficacy of combined treatment with vitamin K2 and raloxifene in the prevention of vertebral and hip fractures in postmenopausal women, although no clinical studies have reported on the effects of combined treatment with vitamin K2 and raloxifene in postmenopausal women with osteoporosis. Vitamin K deficiency, as indicated by high serum levels of undercarboxylated osteocalcin, has been shown to contribute to the occurrence of hip fractures in elderly women. Thus, we propose that the important role of vitamin K2 used in combination with bisphosphonates or raloxifene should not be underestimated in the prevention of fractures in postmenopausal women with osteoporosis with vitamin K deficiency.

Curr Drug Saf. 2006 Jan;1(1):87-97

Beyond deficiency: potential benefits of increased intakes of vitamin K for bone and vascular health.

Vitamin K is well known for its role in the synthesis of a number of blood coagulation factors. During recent years vitamin K-dependent proteins were discovered to be of vital importance for bone and vascular health. Recommendations for dietary vitamin K intake have been made on the basis of the hepatic requirements for the synthesis of blood coagulation factors. Accumulating evidence suggests that the requirements for other functions than blood coagulation may be higher. This paper is the result of a closed workshop (Paris, November 2002) in which a number of European vitamin K experts reviewed the available data and formulated their standpoint with respect to recommended dietary vitamin K intake and the use of vitamin K-containing supplements.

Eur J Nutr. 2004 Dec;43(6):325-35

Role of vitamin K and vitamin K-dependent proteins in vascular calcification.

OBJECTIVES: To provide a rational basis for recommended daily allowances (RDA) of dietary phylloquinone (vitamin K1) and menaquinone (vitamin K2) intake that adequately supply extrahepatic (notably vascular) tissue requirements. BACKGROUND: Vitamin K has a key function in the synthesis of at least two proteins involved in calcium and bone metabolism, namely osteocalcin and matrix Gla-protein (MGP). MGP was shown to be a strong inhibitor of vascular calcification. Present RDA values for vitamin K are based on the hepatic phylloquinone requirement for coagulation factor synthesis. Accumulating data suggest that extrahepatic tissues such as bone and vessel wall require higher dietary intakes and have a preference for menaquinone rather than for phylloquinone. METHODS: Tissue-specific vitamin K consumption under controlled intake was determined in warfarin-treated rats using the vitamin K-quinone/epoxide ratio as a measure for vitamin K consumption. Immunohistochemical analysis of human vascular material was performed using a monoclonal antibody against MGP. The same antibody was used for quantification of MGP levels in serum. RESULTS: At least some extrahepatic tissues including the arterial vessel wall have a high preference for accumulating and using menaquinone rather than phylloquinone. Both intima and media sclerosis are associated with high tissue concentrations of MGP, with the most prominent accumulation at the interface between vascular tissue and calcified material. This was consistent with increased concentrations of circulating MGP in subjects with atherosclerosis and diabetes mellitus. CONCLUSIONS: This is the first report demonstrating the association between MGP and vascular calcification. The hypothesis is put forward that undercarboxylation of MGP is a risk factor for vascular calcification and that the present RDA values are too low to ensure full carboxylation of MGP.

Z Kardiol. 2001;90 Suppl 3:57-63

Genomic approaches to bone and joint diseases. New insights into molecular mechanisms underlying protective effects of vitamin K on bone health.

Vitamin K is a nutrient originally identified as an essential factor for blood coagulation. Accumulated evidence indicates that subclinical non-hemostatic vitamin K deficiency in extrahepatic tissues, particularly in bone, exists widely in the otherwise healthy adult population. Both vitamin K1 and K2 have been shown to exert protective effects against osteoporosis. The new biological functions of vitamin K in bone are considered to be attributable, at least in part, to promotion of gamma-carboxylation of glutamic acid residues in vitamin K-dependent proteins, which is shared by both vitamins K1 and K2. A recent evidence of significant correlation between polymorphism of gamma-glutamyl carboxylase gene and bone mineral density supports the role of gamma-carboxylation-dependent actions of vitamin K. In contrast, vitamin K2-specific,gamma-carboxylation-unrelated functions have recently attracted scientific attention. Recent findings of vitamin K2-specific transactivation of steroid and xenobiotic receptor (SXR/PXR) may lead to new research avenue. The impact of genotype of apoE, a major vitamin K transporter, on ostepporosis as well as Alzheimer disease and atherosclerosis, raises a question whether vitamin K is involved in the pathogenesis of these diseases. Molecular bases of coagulation-unrelated pleiotropic actions of vitamin K and its implications in bone health deserve further investigations.

Clin Calcium. 2008 Feb;18(2):224-32

Effect of low dose vitamin K2 (MK-4) supplementation on bio-indices in postmenopausal Japanese women.

It has been reported that treatment with a pharmacological dose (45 mg/d) of menaquinone-4 (MK-4) prevents bone loss in postmenopausal women. However, it is not known whether supplementation with low dose MK-4 has beneficial effects on bone metabolism in healthy women. The aim of this study is to examine the effects of the supplementation of 1.5 mg/d MK-4 for 4 wk on bone and lipid metabolism in healthy postmenopausal Japanese women. The study was performed as a randomized double blind placebo-controlled trial. The participants aged 53-65 y were randomly assigned to 2 groups and supplemented with 1.5 mg/d of MK-4 or a placebo for 4 wk (n=20 for each group). The most marked effects of MK-4 intake were observed on serum osteocalcin (OC) concentrations. Serum undercarboxylated OC (ucOC) concentration decreased, and the gamma-carboxylated OC (GlaOC) and GlaOC/GlaOC+ucOC ratio that indicates the degree of OC gamma-carboxylation increased significantly at 2 and 4 wk compared with that at baseline in the MK-4 group. The serum ucOC and GlaOC concentrations in the MK-4 group were significantly different from those in the placebo group at 2 wk. These results suggest that supplementation with 1.5 mg/d MK-4 accelerated the degree of OC gamma-carboxylation. The concentrations of serum lipids and other indices were not different between the groups at either intervention period. Thus, the additional intake of MK-4 might be beneficial in the maintenance of bone health in postmenopausal Japanese women.

J Nutr Sci Vitaminol (Tokyo). 2009 Feb;55(1):15-21

Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K2 in postmenopausal women.

Alendronate decreases the risk of femoral neck fracture by suppressing bone turnover, and also decreases the serum total osteocalcin level. A low serum carboxylated osteocalcin level or high undercarboxylated osteocalcin level could be risk factors for femoral neck fracture. Vitamin K mediates the carboxylation of osteocalcin, but the effect of alendronate therapy with or without vitamin K(2) supplementation remains unknown. Forty-eight postmenopausal women were enrolled in a 1-year prospective randomized trial and assigned to alendronate monotherapy (5 mg/day) (group A, n = 26) or vitamin K(2) (45 mg/day) plus alendronate (5 mg/day) (group AK, n = 22). Bone mineral density was measured by dual-energy X-ray absorptiometry at 0 and 12 months; bone turnover parameters were measured at 0, 3, and 12 months. Four patients discontinued alendronate therapy, and we analyzed the remaining 44 patients (23 in group A and 21 in group AK) who completed 1 year of treatment. Alendronate decreased undercarboxylated osteocalcin; carboxylated osteocalcin was not affected. Addition of vitamin K(2) enhanced the decrease of undercarboxylated osteocalcin levels and led to a greater increase of femoral neck bone mineral density. Alendronate monotherapy does not decrease carboxylation of osteocalcin, and combination of vitamin K(2) and alendronate brings further benefits on both osteocalcin carboxylation and BMD of femoral neck in postmenopausal women with osteoporosis.

J Bone Miner Metab. 2008;26(3):260-4

Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age.

Although several observational studies have demonstrated an association between vitamin K status and bone mineral density (BMD) in postmenopausal women, no placebo-controlled intervention trials of the effect of vitamin K1 supplementation on bone loss have been reported thus far. 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. During the 3-year treatment period, participants received a daily supplement containing either placebo, or calcium, magnesium, zinc, and vitamin D (MD group), or the same formulation with additional vitamin K1 (MDK group). The main outcome was the change in BMD of the femoral neck and lumbar spine after 3 years, as measured by DXA. The group receiving the supplement containing additional vitamin K1 showed reduced bone loss of the femoral neck: after 3 years the difference between the MDK and the placebo group was 1.7% (95% Cl: 0.35-3.44) and that between the MDK and MD group was 1.3% (95% Cl: 0.10-3.41). No significant differences were observed among the three groups with respect to change of BMD at the site of the lumbar spine. 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.

Calcif Tissue Int. 2003 Jul;73(1):21-6