Rachel , John , and Michael Y: Cardiovascular calcification and bone: A comparison of the effects of dietary and serum vitamin K and its dependent proteins.

Introduction

Vitamin K, formerly thought to be merely a coagulation inducer, is now exciting considerable interest over its effect on cardiovascular (CV) calcification and bone. Several studies have found an association between severe CV calcification and osteoporosis1,2 and we have previously shown that some of the nutrients and micronutrients that benefit arteries are generally also beneficial for bone3–5. Fat-soluble vitamin K occurs naturally in two forms: phylloquinone (vitamin K1), found in vegetables, which is the more commonly ingested, and menaquinone (vitamin K2), synthesised by fermentation. Despite large quantities of menaquinones being synthesised in the gut, little appears to be bioavailable6, although use of antimicrobials can cause deficiency7. Menaquinone may take 14 different forms, of which MK4 and MK7 are the most studied, with high quantities of MK7 found in the Japanese food natto, made from fermented soy. Both forms of vitamin K can function as enzyme cofactors in the -carboxylation of glutamic acid residues to produce the calcium-binding -carboxyglutamate (Gla) proteins, which impact blood coagulation, CV calcification and bone formation, with the mechanisms for all three being similar8,9.

There are 17 vitamin K-dependent proteins discovered so far10, of which the principal proteins involved in CV and bone mineralisation are matrix Gla protein (MGP) and bone Gla protein (osteocalcin), respectively. Once MGP and osteocalcin (OC) are -carboxylated, the resultant Gla residues give it a calcium ion-binding property but if the protein is undercarboxylated, calcium binding can be severely attenuated8. The total circulating MGP and OC is the sum of its carboxylated (c) and undercarboxylated (uc) forms8, although older assays cannot distinguish between them11. This calcium binding property may determine whether calcium ends up in bone (full carboxylation) or soft tissue (undercarboxylation) although the study of MGP carboxylation has now become more complicated by the parallel assessment of its serine phosphorylation, thought to promote the cellular release of MGP, so that both -carboxylation and serine phosphorylation can impact CV calcification12. The recent discovery of Gla-rich protein (GRP) may additionally be of relevance since it also has calcium-binding properties and regulated extracellular calcium metabolism13; both cGRP and ucGRP have been found at sites of microcalcification14. Similarly the vitamin K-dependent protein Gas-6 affects apoptosis of VSMCs and bone metabolism, while periostin regulates angiogenesis14, although very limited studies have so far been carried out.

Many patients with CV calcification may also be on warfarin, a vitamin K antagonist. Warfarin blocks the -carboxylation of MGP, primarily produced by vascular smooth muscle cells (VSMCs)15 and inhibits the effect of 1,25(OH)2D on OC production from new bone synthesis16. Warfarin treatment significantly increased coronary, iliac and femoral artery, and cardiac valve calcification presence and coronary artery calcification extent in CV patients17,18 and was associated with increased plasma ucMGP19. Recent studies found that only age and duration of warfarin predicted breast arterial calcification, an effect which was cumulative and may be irreversible20, while in chronic kidney disease (CKD) patients, vitamin K antagonist treatment was the most important variable explaining variation in dp-ucMGP levels, which were correlated with the calcification score21. Furthermore, in CKD patients followed up after 4 years, those with the CG/ GG genotype of the gene encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), the enzyme target of warfarin, had higher baseline CAC scores, increased risk of CAC progression and four times higher mortality compared with those with the CC genotype22. Since warfarin also inhibits the -carboxylation of OC, it was thought that these patients would also have increased fracture risk and lowered bone mineral density (BMD) but curiously most studies show no association23.

CV calcification

The few studies of vitamin K intake generally show no association of phylloquinone intake and the CAC score, CAC progression or abdominal aortic calcification (AAC) presence24–29, although in postmenopausal women, a higher intake of MK4 (48.5mcg/d vs 18mcg/d), but not other menaquinones, was associated with a lower CAC score24 and was inversely associated with severe AAC (28.8mcg/d vs 25.6mcg/d)25 but some studies show no association between menaquinone intake and CAC presence28. Similarly, a systematic review showed that there was a significant inverse association between incidence of CHD and intake of menaquinone, but not phylloquinone30, while later studies indicate that phylloquinone intake is significantly lower in those at high CV risk31. In CKD patients those with higher vitamin K intake had a lower risk of all-cause and CVD mortality32. Similarly, there was no correlation between serum phylloquinone concentrations and extreme CAC progression26 or presence of aortic valve calcification (AVC), mitral annulus calcification (MAC) or thoracic aorta calcification (TAC) in postmenopausal women after 8.5 years33, although one study found that serum phylloquinone was positively associated with increased CAC presence, serum cholesterol, triglyceride and ionised calcium concentrations in CKD and non-CKD subjects34. The association with triglycerides and cholesterol is possibly because both forms of vitamin K are transported by triglyceride-rich lipoproteins, while menaquinone, but not phylloquinone, may also be transported by low density lipoproteins8. By contrast, serum MK4 deficiency predicted aortic calcification, while MK7 deficiency predicted iliac calcification in CKD patients but curiously MK5 deficiency appeared protective against calcification27. In the only human trial investigating CV calcification, 500mcg/d phylloquinone supplemented for three years in older adults showed significantly less CAC progression, independent of changes in serum MGP35. Similarly, animal and in vitro studies also show that phylloquinone and MK4 reduce CV and renal calcification36,37, with MK4 proving more effective than phylloquinone38.

Vitamin K may also work indirectly through -carboxylation of vitamin K-dependent proteins. Serum MGP was significantly elevated in postmenopausal women with minor carotid calcification compared to those without carotid calcification (104mcg/l vs 80mcg/l); the threshold for serum MGP appeared to be 87.9mcg/l39. Healthy subjects had significantly higher ucMGP compared to CAD, aortic stenosis, CKD and calciphylaxis patients40, while those with calcification had lower concentrations but ucMGP was found colocalised with calcification, suggesting that deposition of ucMGP at the site of CV calcification reduces the circulating fraction40,41. A study of healthy women found no association between total ucMGP, dp-ucMGP or dp-cMGP and the CAC score, although when taking the log of the CAC score it was found to be associated only with total ucMGP28. By contrast, in CKD and T2D patients serum ucMGP levels correlated inversely with CAC and peripheral arterial calcification scores42,43 although plasma dp-ucMGP levels were positively correlated with calcification scores43 and mortality44, but not with risk of CHD or stroke after 11.5 years45. Similarly, a large study of asymptomatic subjects found that higher dp-ucMGP was associated with higher mortality, including cardiovascular mortality, but lower coronary event incidence46, possibly reflecting the protective effect of coronary calcification by stabilising plaque. Likewise, lower levels of dp-cMGP were associated with a higher calcification score and all-cause and CV mortality in CKD47. Both dp-ucMGP and dp-cMGP were higher in symptomatic aortic stenosis and heart failure patients44 and among patients who had suffered a CV event, those in the highest quartile of dp-ucMGP and dp-cMGP had a higher risk of all-cause and CV mortality after five years48. Although it had been thought that MGP and OC had their distinct spheres of effect (arteries and bone respectively)49, a recent study showed that in older Caucasian men higher baseline total OC (carboxylation status not assessed) predicted 10 year progression of abdominal aortic calcification and lower mortality rate50, while MGP appears also to be implicated in bone and cartilage formation51.

In healthy older adults, plasma ucMGP was significantly higher with lower concentrations of plasma phylloquinone and supplementation of 500mcg/d phylloquinone for three years significantly decreased plasma ucMGP, although there was no association between ucMGP and CAC. Any association between phylloquinone intake and change in CAC was not analysed but the authors suggest that phylloquinone impacts CAC progression independent of changes in serum MGP.52 Short-term MK7 supplementation dose dependently reduced dp-ucMGP in both CKD patients and healthy subjects, which was significant only with the higher dose (360mcg/d vs135mcg/d)53–55, although another study found an effect on dp-ucMGP, but not dp-cMGP, with 135mcg/d47. None of these studies investigated CV calcification. Ongoing clinical trials such as VitavasK (NCT01742273), VitaK-CAC (NCT01002157), VITAKANDOP (NCT01232647), SAFEK (NCT01533441), and OVWAK VII (NCT00990158) should provide greater insight into the effect of vitamin K on CV calcification.

Bone

A 2007 review showed that dietary and serum vitamin K manifests a positive correlation with BMD and is inversely associated with fracture risk8. More recent studies have generally confirmed these association with respect to phylloquinone intake, although menaquinone intake appears to have no association with fracture risk56. An effective intake for phylloquinone was found to be >/=116mcg/d52, with little benefit to higher amounts. Phylloquinone intake was generally inversely associated with serum ucOC57 and with the ratio of serum ucOC/OC levels among elderly Japanese patients58. In Japanese men, intake of natto (largely MK7) was also inversely associated with serum ucOC and positively associated with BMD but this association became insignificant after adjusting for ucOC levels59.

In the elderly, serum ucOC is regularly elevated compared to pre- and early postmenopausal women60. Among older women, a large prospective study showed that baseline serum ucOC, but not total OC, concentrations were positively associated with hip fracture risk61 and smaller studies have generally confirmed these results62,63. In general, serum ucOC was inversely associated with BMD in early postmenopausal women64,65 but results are mixed with respect to an association between serum ucOC/OC and BMD63,64,66, with the ratio being significantly greater in carriers of the apoE4 phenotype, normally a risk factor for atherosclerosis34 while lower ucOC was associated with apoE2 genotype49. This may be due to the apoE4 phenotype giving markedly faster hepatic clearance of chylomicrons and very low density lipoproteins, which lowers circulating vitamin K relative to the apoE2 phenotype8. Ethnicity may also play a role in generating inconsistent results; among Chinese postmenopausal women, plasma phylloquinone was significantly higher and plasma ucOC was significantly lower than among British or Gambian women, while only among British women was plasma phylloquinone inversely associated with ucOC49. Among healthy women, serum phylloquinone and MK7, but not serum MK4, were generally inversely correlated with ucOC and the ucOC/OC ratio67, while there appears to be a gender difference with respect to the meaning of high plasma OC; in those aged >/=75, but not younger, higher plasma OC was associated with reduced CVD risk in men but with increased risk in women68.

Several recent meta-analyses and reviews of the effects of vitamin K supplementation show a positive effect on BMD and indices of bone strength, with reduced fracture incidence in mainly postmenopausal women; the majority of long-term trials supplemented MK4 to Japanese8,69,70. A subsequent study confirmed the beneficial effect of vitamin K1 supplementation on BMD in postmenopausal women, with doses of 80mcg/d phylloquinone proving effective66. There were, however, mixed results for MK4, with one trial showing that 45mg/d, together with vitamin D and calcium, had a beneficial effect on BMD in Korean postmenopausal women71, while another showed that MK4 enhanced the effect of bisphosphonates in Japanese postmenopausal females72 but a larger study over three years found no effect on BMD, although BMC and femoral neck width were increased compared to placebo73. 180mcg/d MK7 also significantly improved BMD in postmenopausal women74, although 360mcg/d MK7 failed to show a difference in bone loss relative to the placebo group75 but this may have been because the placebo was olive oil, which also has a beneficial effect on bone3.

In addition, a 2009 review and subsequent study showed that phylloquinone can dose-dependently reduce ucOC in postmenopausal women, with a consistently effective dose being 1mg/d, although there were inconsistent results for total OC69,76. Phylloquinone can also increase cOC in older adults77 and lower ucOC/OC78 but results for younger adults are inconclusive77,79. Furthermore, 45mg/d MK4 significantly decreased ucOC in postmenopausal women71,72,76,80,81, increased cOC and generally increased total OC80,81, although 1.5mg/d may be sufficient to decrease serum ucOC and ucOC/OC while increasing cOC82; a dose of 1.5mg/d accords with the amount of MK4 obtainable from diet, whereas 45mg/d is pharmacological83. In the few studies of MK7, 360mcg/d reduced ucOC and increased cOC in early postmenopausal women75, although a lower dose may also be effective in increasing cOC9,55. Nevertheless, reduction of serum ucOC is not always accompanied by improvement in BMD76.

There is also an interaction between vitamin K and vitamin D, and Vitamin D may also be important for normal -carboxylation of osteocalcin84. When vitamin D status is assessed as well as vitamin K, plasma 25(OH)D, phylloquinone and MK7 concentrations correlated with each other in elderly males85. In vitamin D deficiency 45mg/d MK4 can raise serum 1,25(OH)2D86 and where 1,25(OH)2D is elevated MK4 can inhibit its induction of osteoclast formation87. Serum 1,25(OH)2D also correlates with serum OC in osteoporotic females88 and Vitamin D supplementation can increase serum OC in postmenopausal women89 and regulate its osteoblastic induction16, transcription and translation83, although there are mixed results in correlating serum ucOC concentration with 25(OH)D among elderly females62,65. Menaquinone enhances this 1,25(OH)2D-induced OC mRNA production but could not substitute for 1,25(OH)2D in OC mRNA expression16. A comparison study of postmenopausal osteoporotic Chinese women showed no significant difference in BMD increase between 45mg/d MK4 and vitamin D; interestingly vitamin D also decreased ucOC, although the decrease was greater in the MK4 group90. Where vitamin D is supplemented with either phylloquinone or MK4, most studies show generally improved results compared with either vitamin alone8,91, although some found no additional benefit to bone parameters or the carboxylation of OC92. Furthermore, MK4 improved bone mass to a greater extent in those with higher serum 25(OH)D93. The synergistic effect of combined vitamins K and D on bone loss is also reflected in animal studies8,94 but possibly only if calcium intake is optimal95. Other nutrient interactions include high dose alpha-tocopherol, which can antagonise vitamin K and reduce tissue levels96 and fat, but not in hydrogenated form, which can enhance the bioavailability of menaquinone97. Zinc can also enhance the effect of MK7 in increasing bone calcium content in vitro98, while combined supplementation had a synergistic effect on bone in female rats99.

Mechanisms of effect of vitamin K

MGP appears to act to prevent hydroxyapatite deposition by, variously, binding calcium ions, binding to and inhibiting bone morphogenetic proteins (particularly BMP-2, known to trigger the transformation of VSMCs to osteoblast-like cells), altering cell differentiation, binding to extracellular matrix components and regulating apoptosis100. Arterial calcified lesions contain elevated concentrations of ucMGP, together with unbound BMP-2, while BMP-2 binds to the Gla-containing region of cMGP in the presence of ionised calcium, suggesting further that it is the binding of BMP-2 which inhibits arterial calcification101. OC acts in a similar manner by adhering to hydroxyapatite and influencing bone remodelling but its main function has been suggested as a regulator of bone maturation and turnover, rather than a marker of bone formation8,83. Neither can bind to hydroxyapatite unless carboxylated, since undercarboxylated proteins have a poor affinity for calcium102.

Vitamin K may influence bone independently of OC, as seen in its upregulation of gene transcription for bone alkaline phosphatase, osteoprotegerin and osteopontin mRNA in osteoblasts and modulation of the cytokines osteoprotegerin and interleukin-6 (IL-6)8,83. It can also inhibit expression of the receptor for nuclear factor kappa-B ligand (RANKL), the activity of tartrate-resistant acid phosphatase (TRACP), mononuclear cell formation and induction of osteoclast apoptosis87. Poor vitamin K status has been associated with high concentrations of cytokines involved in bone turnover (IL-6 and osteoprotegerin)87. MK4, specifically, can inhibit osteoclast formation and activity via suppression of RANKL expression and inhibit induction of osteoclast apoptosis through its geranylgeraniol side chain, an effect which was not blocked by warfarin treatment8,87,103, although the phylloquinone side chain, phytol, had no significant effect103. Independently of its geranylgeraniol side chain, MK4 can also inhibit cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) expression87 and dose-dependently inhibit bone resorption induced by IL-1 and PGE2, while MK7 can inhibit osteoclastogenesis and bone resorption through inhibition of PGE2104. Finally, intake of one vitamin K form may impact on levels of the other; phylloquinone can be converted into MK4 in the body via removal of the isoprenoid side-chain while MK4 increases serum phylloquinone concentrations105.

A number of bone studies have shown a synergistic effect of vitamins D and K8. OC synthesis by 1,25(OH)2D occurs through a vitamin D response element in the promoter region of the OC gene, while the increase in -glutamyl carboxylase activity and mRNA in osteoblasts is promoted by 1,25(OH)2D106. MK4, but not phylloquinone, also enhanced the 1,25(OH)2D– induced mineralisation of osteoblasts and osteocalcin mRNA production16 and inhibited vitamin D- or PGE2-induced calcium release from mouse bone, which appears to be independent of its -carboxylation activity since warfarin did not affect the result103. It is not known whether this synergistic effect is equally applicable in arteries, although vitamin D is known to be involved in the regulation of MGP gene expression107; Fraser et al have shown that the MGP promotor contains a vitamin D response element that is responsible for a 2-3 fold enhancement of MGP expression after vitamin D binding108.

Discussion

This review has shown that the -carboxylation of the vitamin K-dependent proteins MGP and its bone equivalent, OC, generally ensures that hydroxyapatite is kept out of the arteries and is retained in bone, irrespective of the extent of hydroxyapatite present8. Nevertheless, not all forms of vitamin K are equally effective. In the arteries, menaquinone consistently appears to be the active form and is also associated with reduced CHD. Dietary and serum phylloquinone can often have little effect, although a deficiency appears to be a risk factor for CV disease but this may be because phylloquinone, deriving mainly from vegetables, is also an indicator of a generally healthier diet, while some beneficial effects of MK7 from natto may in fact be due to the isoflavones from the soyabeans83. Phylloquinone appears to be much more effective than menaquinone in observational studies of bone, although Japanese clinical trials of MK4 also show positive results. Vermeer et al suggest that the success of these pharmacological doses of MK4 (45mg/d is greatly in excess of the dose needed to normalise -carboxylation of vitamin K-dependent proteins) demonstrate that there is an additional mechanism of action, such as the anti-inflammatory action of vitamin K metabolites demonstrated in vitro109. Nevertheless, vitamin K intake from a normal healthy diet is insufficient to maintain OC, and possibly MGP, in its fully carboxylated form, which can require up to 1,000mcg/d phylloquinone, suggesting that possibly full carboxylation is not necessary, particularly in view of the studies showing that ucOC is protective110.

The fact that not all studies show a direct association with arteries and bone may be because vitamin K can act through the carboxylation of MGP and OC respectively and also the phosphorylation of MGP. Studies fairly uniformly show that both phylloquinone and menaquinone lower plasma ucMPG or dp-ucMGP, yet some results of the effect of MGP are counter-intuitive, with higher ucMGP being protective against calcification. Results are clearer in patient, as opposed to healthy populations, where ucMGP correlated inversely with calcification presence and extent and dp-ucMGP concentrations correlated positively and dp-cMGP correlated inversely with calcification, yet both dp-ucMGP and dp-cMGP were elevated in those who had suffered heart failure or a CV event or were at risk of five-year mortality. It has been suggested that ucMGP may be a marker for CV calcification, whereas dp-ucMGP might be a predictor of CV disease events and mortality10. The contradictions may also indicate that absolute values of uc and cMGP are unhelpful and that a ratio of ucMGP/cMGP would be more informative. Similarly in bone studies, serum phylloquinone and MK7 generally correlated with ucOC and the ucOC/OC ratio, although the relationship between serum ucOC/OC and BMD seems uncertain, possibly because vitamin K may alter OC production110, suggesting again that a ratio of ucOC/cOC may be more helpful.

Research into the association of the various fractions of MGP with CV calcification is still relatively new and these somewhat confused and contradictory results indicate that the exact mechanisms are not yet fully understood. Furthermore, bone studies have shown that the apoE genotype and ethnicity may have a bearing on results but these have not been tested in CV studies. Additionally, there is a marked interaction between vitamin K and vitamin D, with one study showing little difference in effect between high dose MK4 and vitamin D on BMD and improved results when both were supplemented together. Animal studies suggest that calcium intake should be adequate for optimal effect. The combination appears to have different effects to either vitamin independently, which suggests that the effect of vitamin K would be enhanced if vitamin D levels were adequate8. The other vitamin K-dependent proteins such as GRP, periostin and Gas-6 may also play a role in regulating arterial and skeletal calcification and could account for the lack of clear results in studies of MGP and OC111. Genetics suggest that the extent of calcification and its effects is also determined by the VKORC1 genotype, which is only rarely taken into account in CV disease studies, while the relevance of the serine phosphorylation status of MGP is largely undetermined; neither of these has been considered in bone.

Concern has been expressed that supplementing vitamin K would either counter warfarin treatment or destabilise INR, causing patients to need anticoagulants. Because carboxylation of the coagulation Gla proteins in the liver is the most essential use of vitamin K, while the Gla proteins in the extrahepatic tissues are non-essential, the vitamin K transport system ensures preferential distribution of dietary vitamin K to the liver and only when these coagulation proteins are fully carboxylated does vitamin K move to extra-hepatic tissue10, suggesting that the body operates a triage system for vitamin K. In osteoporosis patients given MK4 supplementation, haemostatic parameters remained stable despite high plasma MK4112, indicating that additional vitamin K intake will not increase coagulation, provided the coagulation Gla proteins are fully carboxylated. There also appears to be a marked difference in dose/response between the different forms of vitamin K. MK7 supplementation as low as 10–20mcg/d may rapidly destabilise therapeutic anticoagulant control, whereas in patients taking warfarin, 100mcg/d vitamin K improved the stability of anticoagulant therapy113,114, while the threshold phylloquinone dose for causing lowered INR was 150mcg/d, although circulating ucOC did not decrease until a dose of 300mcg/d115. Furthermore, there are now oral anticoagulants such as ximelagatran, which do not affect vitamin K metabolism and could be used when there is a need for vitamin K supplementation for artery or bone health8.

Conclusion

With respect to CV calcification, the only consistent inverse associations to date are between dietary and serum MK4 and the calcium score, which may be reflected in a lower incidence of CHD. In addition, human and animal trials show that both MK4 and phylloquinone significantly reduce CV calcification. While the mechanism may be principally through the -carboxylation of MGP, vitamin K also has anti-inflammatory and other properties. When considering bone, most studies show that phylloqinone is associated with increased BMD and reduced fracture risk, likely through lowered serum ucOC. Supplementation of phylloquinone, MK4 and MK7 improves BMD and indices of bone strength and reduces fracture risk. Nevertheless, there remain many uncertainties over the precise role of the various forms of MGP and OC. Some of this may be explained by genetic polymorphisms and the role of the recently discovered vitamin K-dependent proteins GRP, periostin and Gas-6 in the regulation of arterial and skeletal calcification, as well as an interaction between vitamin K and vitamin D; vitamin K supplementation is more effective if vitamin D and calcium levels are adequate.

Statement of ethical publishing

This paper complies with the ethical requirements for publishing in a biomedical journal116.

Conflict of interest statement:

None of the authors has any conflict of interest to declare or has received any remuneration for this article.

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