Altered vitamin K biodistribution and metabolism in experimental and human chronic kidney disease.

Chronic kidney disease (CKD) is accompanied with extensive cardiovascular calcification, in part correlating with functional vitamin K deficiency. Here, we sought to determine causes for vitamin K deficiency beyond reduced dietary intake. Initially, vitamin K uptake and distribution into circulating lipoproteins after a single administration of vitamin K1 plus K2 (menaquinone 4 and menaquinone 7, respectively) was determined in patients on dialysis therapy and healthy individuals. The patients incorporated very little menaquinone 7 but more menaquinone 4 into high density lipoprotein (HDL) and low-density lipoprotein particles than did healthy individuals. In contrast to healthy persons, HDL particles from the patients could not be spiked with menaquinone 7 in vitro and HDL uptake was diminished in osteoblasts. A reduced carboxylation activity (low vitamin K activity) of uremic HDL particles spiked with menaquinone 7 vs. that of controls was confirmed in a bioassay using human primary vascular smooth muscle cells. Kidney menaquinone 4 tissue levels were reduced in 5/6-nephrectomized versus sham-operated C57BL/6 mice after four weeks of a vitamin K rich diet. From the analyzed enzymes involved in vitamin K metabolism, kidney HMG-CoA reductase protein was reduced in both rats and patients with CKD. In a trial on the efficacy and safety of atorvastatin in 1051 patients with type 2 diabetes receiving dialysis therapy, no pronounced vitamin K deficiency was noted. However, the highest levels of PIVKA-II (biomarker of subclinical vitamin K deficiency) were noted when a statin was combined with a proton pump inhibitor. Thus, profound disturbances in lipoprotein mediated vitamin K transport and metabolism in uremia suggest that menaquinone 7 supplementation to patients on dialysis therapy has reduced efficacy.

Vitamin K deficiency: an emerging player in the pathogenesis of vascular calcification and an iatrogenic consequence of therapies in advanced renal disease.

Vascular calcification is a known complication of chronic kidney disease (CKD). The prevalence of vascular calcification in patients with non-dialysis-dependent CKD stages 3-5 has been shown to be as high as 79% (20). Vascular calcification has been associated with increased risk for mortality, hospital admissions, and cardiovascular disease (6, 20, 50, 55). Alterations in mineral and bone metabolism play a pivotal role in the pathogenesis of vascular calcification in CKD. As CKD progresses, levels of fibroblast growth factor-23, parathyroid hormone, and serum phosphorus increase and levels of 1,25-(OH)2 vitamin D decrease. These imbalances have been linked to the development of vascular calcification. More recently, additional factors have been found to play a role in vascular calcification. Matrix G1a protein (MGP) in its carboxylated form (cMGP) is a potent inhibitor of vascular calcification. Importantly, carboxylation of MGP is dependent on the cofactor vitamin K. In patients with CKD, vitamin K deficiency is prevalent and is exacerbated by warfarin, which is frequently used for anticoagulation. Insufficient bioavailability of vitamin K reduces the amount of cMGP available, and, therefore, it may lead to increased risk of vascular calcification. In vitro studies have shown that in the setting of a high-phosphate environment and vitamin K antagonism, human aortic valve interstitial cells become calcified. In this article, we discuss the pathophysiological consequence of vitamin K deficiency in the setting of altered mineral and bone metabolism, its prevalence, and clinical implications in patients with CKD.

Vitamin K2 Needs an RDI Separate from Vitamin K1.

Vitamin K and its essential role in coagulation (vitamin K [Koagulation]) have been well established and accepted the world over. Many countries have a Recommended Daily Intake (RDI) for vitamin K based on early research, and its necessary role in the activation of vitamin K-dependent coagulation proteins is known. In the past few decades, the role of vitamin K-dependent proteins in processes beyond coagulation has been discovered. Various isoforms of vitamin K have been identified, and vitamin K2 specifically has been highlighted for its long half-life and extrahepatic activity, whereas the dietary form vitamin K1 has a shorter half-life. In this review, we highlight the specific activity of vitamin K2 based upon proposed frameworks necessary for a bioactive substance to be recommended for an RDI. Vitamin K2 meets all these criteria and should be considered for a specific dietary recommendation intake.

The Relationship between Vitamin K and Osteoarthritis: A Review of Current Evidence.

Vitamin K is a cofactor of γ-glutamyl carboxylase, which plays an important role in the activation of γ-carboxyglutamate (gla)-containing proteins that negatively regulate calcification. Thus, vitamin K status might be associated with osteoarthritis (OA), in which cartilage calcification plays a role in the pathogenesis of the disease. This review collates the evidence on the relationship between vitamin K status (circulating or dietary intake level of vitamin K, or circulating uncarboxylated gla proteins) and OA from human observational studies and clinical trial, to examine its potential as an agent in preventing OA. The current literature generally agrees that a sufficient level of vitamin K is associated with a lower risk of OA and pathological joint features. However, evidence from clinical trials is limited. Mechanistic study shows that vitamin K activates matrix gla proteins that inhibit bone morphogenetic protein-mediated cartilage calcification. Gla-rich proteins also inhibit inflammatory cascade in monocytic cell lines, but this function might be independent of vitamin K-carboxylation. Although the current data are insufficient to establish the optimal dose of vitamin K to prevent OA, ensuring sufficient dietary intake seems to protect the elderly from OA.

Vitamin K role in mineral and bone disorder of chronic kidney disease.

Vitamin K is a key cofactor for the activation of proteins involved in blood coagulation, apoptosis, bone mineralization regulation, and vessel health. Scientific evidence shows an important role of activated osteocalcin and matrix-Gla protein in bone and vessels, markedly affected along the course of chronic kidney disease (CKD). In fact, CKD corresponds to an unique condition of vitamin K deficiency caused by dietary restriction, intestinal dysfunction, and impaired vitamin K recycling. Clinical data suggest that vitamin K status can be modulated and this prompts us to speculate whether patients with CKD might benefit from vitamin K supplementation. However, as important as whether the improvement in vitamin K status would be able to result in better bone quality, less vascular calcification, and lower mortality rates, several issues need to be clarified. These include better standardized methods for measuring vitamin K levels, and definition of the optimal concentration range for supplementation in different subgroups. Here, we review the literature data concerning the impact of vitamin K deficiency and supplementation on CKD-associated mineral and bone disorders (CKD-MBD). We present and discuss the available evidence from basic science and clinical studies, and highlight perspectives for further research.

Association of the Inactive Circulating Matrix Gla Protein with Vitamin K Intake, Calcification, Mortality, and Cardiovascular Disease: A Review.

Matrix Gla Protein (MGP), a small Gla vitamin K-dependent protein, is the most powerful natural occurring inhibitor of calcification in the human body. To become biologically active, MGP must undergo vitamin K-dependent carboxylation and phosphorylation. Vitamin K deficiency leads to the inactive uncarboxylated, dephosphorylated form of MGP (dpucMGP). We aimed to review the existing data on the association between circulating dpucMGP and vascular calcification, renal function, mortality, and cardiovascular disease in distinct populations. Moreover, the association between vitamin K supplementation and serum levels of dpucMGP was also reviewed.

α-Tocopherol Intake Decreases Phylloquinone Concentration in Bone but Does Not Affect Bone Metabolism in Rats.

Previous studies have shown that α-tocopherol intake lowers phylloquinone (PK) concentration in some extrahepatic tissues in rats. The study's aim was to clarify the effect of α-tocopherol intake on vitamin K concentration in bone, as well as the physiological action of vitamin K. Male Wistar rats were divided into 4 groups. Over a 3-mo period, the K-free group was fed a vitamin K-free diet with 50 mg RRR-α-tocopherol/kg, the E-free group was fed a diet containing 0.75 mg PK/kg without vitamin E, the control group was fed a diet containing 0.75 mg PK/kg with 50 mg RRR-α-tocopherol/kg, and the E-excess group was fed a diet containing 0.75 mg PK/kg with 500 mg RRR-α-tocopherol/kg. PK concentration in the liver was higher in E-excess rats than in E-free rats, was lower in the tibias of control rats than in those of E-free rats, and was lower in E-excess rats than in control rats. Menaquinone-4 (MK-4) concentration in the liver was higher in E-excess rats than in E-free and control rats. However, MK-4 concentrations in the tibias of E-free, control, and E-excess rats were almost the same. Blood coagulation activity was lower in K-free rats than in the other rats but was not affected by the level of α-tocopherol intake. Additionally, dietary intake of PK and α-tocopherol did not affect uncarboxylated-osteocalcin concentration in the serum, femur density, or expression of the genes related to bone resorption and formation in the femur. These results suggest that α-tocopherol intake decreases PK concentration in bone but does not affect bone metabolism in rats.

Vitamin K deficit and elastolysis theory in pulmonary elasto-degenerative diseases.

Elastin is a unique protein providing deformability and resilience to dynamic tissues, such as arteries and lungs. It is an absolute basic requirement for circulation and respiration. Elastin can be degraded by elastases and has a high calcium affinity. Elastin calcification and elastin degradation are two pathological processes that impair elastin's functioning. Furthermore, elastin degradation can be associated to elastin calcification. Matrix Gla Protein (MGP) is probably the most potent natural inhibitor of elastin calcification and requires vitamin K for its activation. Measuring circulating levels of inactive MGP (dp-ucMGP) is a frequently used method to assess vitamin K status. Dp-ucMGP reflects the burden of vitamin K-dependent proteins that have not been activated by vitamin K and could therefore best be regarded as a biomarker of a vitamin K deficit. Dp-ucMGP levels decrease after vitamin K supplementation. Since the amino acids desmosine and isodesmosine (DES) are unique to crosslinked elastin fibers, systemic elastin degradation can be assessed with the plasma DES assay. Recently, we discovered a strong correlation between plasma dp-ucMGP and plasma DES levels in both patients with chronic obstructive pulmonary disease (COPD) and controls. The 'Vitamin K deficit and elastolysis theory' posits that elastin degradation causes a rise in the vitamin K deficit and implies that vitamin K supplementation could be preventing elastin degradation. If this hypothesis holds true and is universally found in every state and condition, it will have an unprecedented impact on the management of every single pulmonary disease characterized by accelerated elastin degradation, such as alpha-1 antitrypsin deficiency, bronchiectasis, COPD and cystic fibrosis. Theoretically, a plasma dp-ucMGP concentration of zero would be associated with a near-complete standstill of elastin degradation and disease progression in patients with any of these debilitating conditions.

Vitamin K and musculoskeletal health in postmenopausal women.

Aside from its important role in blood clotting, vitamin K is an important dietary factor in regulating bone and cartilage mineralization. The vitamin K requirements to maintain musculoskeletal health may be more than the current recommendations and subclinical vitamin K deficiency may be involved in the pathogenesis of osteoporosis and osteoarthritis. Observational studies suggest that diets low in vitamin K are associated with increased risk of fractures and osteoarthritis in older adults. However, so far randomized controlled trials of vitamin K supplementation in Caucasian populations have not shown clinically significant improvements in bone mineral density at major skeletal sites. Supplementation with vitamin K may reduce the risk of fractures, but this conclusion comes from clinical trials with methodological limitations. At this time, only one randomized controlled trial has examined the effect of vitamin K supplementation on radiographic hand osteoarthritis and found no overall effect. Large well-designed randomized controlled trials are needed to compare the efficacies of vitamin K1 and K2 on fractures and osteoarthritis among older adults. In summary, currently there is not enough evidence to recommend the use of vitamin K supplements for the prevention of bone loss, fractures, or osteoarthritis in postmenopausal women.

Excess α-tocopherol decreases extrahepatic phylloquinone in phylloquinone-fed rats but not menaquinone-4 in menaquinone-4-fed rats.

SCOPE: The effects of vitamin E on vitamin K metabolism were elucidated by comparing the effect of tocopherol intake on vitamin K concentrations in rats fed phylloquinone (PK) or menaquinone (MK)-4. METHODS AND RESULTS: Initially, the dietary effect of RRR-α-tocopherol, but not RRR-γ-tocopherol, in decreasing extrahepatic PK concentrations was confirmed. Subsequently, rats were fed a PK or MK-4-containing diet (0.75 mg/kg) with RRR-α-tocopherol (0, 10, 50, or 500 mg/kg) for 6 weeks. In rats fed PK, α-tocopherol consumption decreased PK in kidney, lung, heart, muscle, testis, and brain but not in serum and liver. However, in rats fed MK-4, α-tocopherol consumption did not decrease MK-4 in serum and tissues. Finally, vitamin K- and E-depleted rats were administered PK or MK-4 (0.2 mg) with RRR-α-tocopherol (0, 1, or 10 mg) by gavage. After PK administration, α-tocopherol was observed to decrease PK in kidney, adrenal gland, lung, testis, and brain but not in serum and liver, whereas, after MK-4 administration, α-tocopherol did not affect MK-4 in serum and tissues. CONCLUSION: Excess α-tocopherol decreased extrahepatic PK in rats fed PK but not MK-4 in rats fed MK-4.

Vitamin K and bone health in older adults.

Vitamin K is one of several nutrients that have been linked with bone health. In particular, there is an emerging literature regarding the questionable efficacy of vitamin K supplementation in reducing age-related bone loss. This review aims to summarize the role of vitamin K in bone health in older adults and discuss the clinical implications from a select few human studies. The evidence for vitamin K supplementation in older adults is mixed. Although the observational studies have shown linkages between vitamin K intake and lower risk of fractures in this population, the current evidence from randomized controlled trials is not strongly supportive of vitamin K supplementation in older adults for the intent of improving bone health.

Impaired vitamin K recycling in uremia is rescued by vitamin K supplementation.

In chronic kidney disease, vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein, are largely uncarboxylated indicating that functional vitamin K deficiency may contribute to uremic vascular calcification. Since the effects of uremia on the vitamin K cycle are unknown, we investigated the influence of uremia and vitamin K supplementation on the activity of the vitamin K cycle and extraosseous calcification. Uremia was induced in rats by an adenine-supplemented diet and vitamin K1 or K2 was administered over 4 and 7 weeks. After 4 weeks of adenine diet, the activity of the vitamin K cycle enzyme γ-carboxylase but not the activities of DT-diaphorase or vitamin K epoxide reductase were reduced. Serum levels of undercarboxylated matrix Gla protein increased, indicating functional vitamin K deficiency. There was no light microscopy-detectable calcification at this stage but chemically determined aortic and renal calcium content was increased. Vitamin K treatment reduced aortic and renal calcium content after 4 weeks. Seven weeks of uremia induced overt calcification in the aorta, heart, and kidneys; however, addition of vitamin K restored intrarenal γ-carboxylase activity and overstimulated it in the liver along with reducing heart and kidney calcification. Thus, uremic vitamin K deficiency may partially result from a reduction of the γ-carboxylase activity which possibly contributes to calcification. Pharmacological vitamin K supplementation restored the vitamin K cycle and slowed development of soft tissue calcification in experimental uremia.

Vitamin K-dependent carboxylation of osteocalcin: friend or foe?

Osteocalcin originates from osteoblastic synthesis and is deposited into bone or released into circulation, where it correlates with histological measures of bone formation. The presence of 3 vitamin K-dependent γ carboxyglutamic acid residues is critical for osteocalcin's structure, which appears to regulate the maturation of bone mineral. In humans, the percentage of the circulating osteocalcin that is not γ-carboxylated (percent ucOC) is used as a biomarker of vitamin K status. In contrast, when ucOC is not corrected for total osteocalcin, the interpretation of this measure is confounded by osteoblastic activity, independent of vitamin K. Observational studies using percent ucOC have led to the conclusion that vitamin K insufficiency leads to age-related bone loss. However, clinical trials do not provide overall support for the suggestion that vitamin K supplementation of the general population will reduce bone loss or fracture risk. More recently, results from in vitro and in vivo studies using animal models indicate that ucOC is an active hormone with a positive role in glucose metabolism. By inference, vitamin K, which decreases ucOC, would have a detrimental effect. However, in humans this hypothesis is not supported by the limited data available, nor is it supported by what has been established regarding osteocalcin chemistry. In summary, the specific function of osteocalcin in bone and glucose metabolism has yet to be elucidated.

Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects.

Vitamin K is required for the carboxylation of Gla-proteins in the liver (coagulation factors) and extra-hepatic tissues, such as bone (osteocalcin, OC), and arterial wall (matrix Gla-protein, MGP). Although the coagulation factors are essentially fully carboxylated under normal conditions, 10-40 % of OC and MGP remains undercarboxylated. We were therefore interested to study the dose-response effects of extra intake of menaquinones on the carboxylation of the extra-hepatic Gla-proteins. A total of forty-two healthy Dutch men and women aged between 18 and 45 years were randomised into seven groups to receive: placebo capsules or menaquinone-7 (MK-7) capsules at a daily dose of 10, 20, 45, 90, 180 or 360 µg. Circulating uncarboxylated OC (ucOC), carboxylated OC (cOC) and desphospho-uncarboxylated MGP were measured by ELISA. The ucOC:cOC ratio was calculated from circulating ucOC and cOC values. Endogenous thrombin potential and peak height were determined by calibrated automated thrombography. To increase the statistical power, we collapsed the treatment groups into three dosage groups: placebo, low-dose supplementation (doses below RDA, Commission Directive 2008/100/EC), and high-dose supplementation (doses around RDA, Commission Directive 2008/100/EC). MK-7 supplementation at doses in the order of the RDA (Commission Directive 2008/100/EC) increased the carboxylation of circulating OC and MGP. No adverse effects on thrombin generation were observed. Extra MK-7 intake at nutritional doses around the RDA (Commission Directive 2008/100/EC) improved the carboxylation of the extra-hepatic vitamin K-dependent proteins. Whether this improvement contributes to public health, i.e. increasing the protection against age-related diseases needs further investigation in specifically designed intervention trials.

[Vitamin K deficiency in patients with CF despite supplementation]. / Niedobór witaminy K u chorych na mukowiscydoze pomimo stosowanej suplementacji.

INTRODUCTION: Cystic fibrosis (CF) patients are at high risk for vitamin K deficiency. Vitamin K supplementation dose has not been clearly defined, and the effects of the supplementation are very ambiguous. Therefore, the aim of the present study was to assess body resources of vitamin K and determine the suitability of the coagulation parameters in the assessment of vitamin K deficiency in patients undergoing supplementation. MATERIALS AND METHODS: The study comprised 30 CF patients aged from 1.5 to 32 years. In all patients, the concentration of the undercarboxylated prothrombin (prothrombin induced by vitamin K deficiency--PIVKA-II), as a marker of vitamin K deficiency, was estimated. For comparison of the diagnostic value of existing methods of assessment of vitamin K status, the coagulation parameters were evaluated (prothrombin ratio and INR). RESULTS: In spite of applied supplementation vitamin K status was not normal in all CF patients. Increased PIVKA-II concentrations (3.3-97 ng/ml) were found in 8 out of 30 (26.7%) patients, when the cut-off value of 2 ng/ml was used. Abnormal PIVKA-II levels corresponded to pathological values of the coagulation parameters only in one patient. In the remaining 7 CF subjects with increased concentration of the undercarboxylated prothrombin, coagulation parameters were normal. CONCLUSIONS: Vitamin K deficiency occurs in CF patients despite applied supplementation. The accurate supplementation dose should be estimated individually and the assessment of its effectiveness requires studies allowing to determine the real body resources of vitamin K. The coagulation parameters are not a good indicator of vitamin K deficiency.

Metabolism and cell biology of vitamin K.

Naturally occurring vitamin K compounds comprise a plant form, phylloquinone (vitamin K(1)) and a series of bacterial menaquinones (MKs) (vitamin K(2)). Structural differences in the isoprenoid side chain govern many facets of metabolism of K vitamins including the way they are transported, taken up by target tissues, and subsequently excreted. In the post-prandial state, phylloquinone is transported mainly by triglyceride-rich lipoproteins (TRL) and long-chain MKs mainly by low-density lipoproteins (LDL). TRL-borne phylloquinone uptake by osteoblasts is an apoE-mediated process with the LRP1 receptor playing a predominant role. One K(2) form, MK-4, has a highly specific tissue distribution suggestive of local synthesis from phylloquinone in which menadione is an intermediate. Both phylloquinone and MKs activate the steroid and xenobiotic receptor (SXR) that initiates their catabolism, but MK-4 specifically upregulates two genes suggesting a novel MK-4 signalling pathway. Many studies have shown specific clinical benefits of MK-4 at pharmacological doses for osteoporosis and cancer although the mechanism(s) are poorly understood. Other putative non-cofactor functions of vitamin K include the suppression of inflammation, prevention of brain oxidative damage and a role in sphingolipid synthesis. Anticoagulant drugs block vitamin K recycling and thereby the availability of reduced vitamin K. Under extreme blockade, vitamin K can bypass the inhibition of Gla synthesis in the liver but not in the bone and the vessel wall. In humans, MK-7 has a greater efficacy than phylloquinone in carboxylating both liver and bone Gla proteins. A daily supplement of phylloquinone has shown potential for improving anticoagulation control.

Bone health and osteoporosis: the role of vitamin K and potential antagonism by anticoagulants.

BACKGROUND: Vitamin K's effects extend beyond blood clotting to include a role in bone metabolism and potential protection against osteoporosis. Vitamin K is required for the gamma-carboxylation of osteocalcin. Likewise, this gamma-carboxylation also occurs in the liver for several coagulation proteins. This mechanism is interrupted by coumarin-based anticoagulants in both the liver and bone. METHODS: A thorough review of the literature on vitamin K, osteocalcin and their role in bone metabolism and osteoporosis, as well as the potential bone effects of anticoagulant therapy was conducted. CONCLUSIONS: Epidemiological studies and clinical trials consistently indicate that vitamin K has a positive effect on bone mineral density and decreases fracture risk. Typical dietary intakes of vitamin K are below the levels associated with better BMD and reduced fracture risk; thus issues of increasing dietary intakes, supplementation, and/or fortification arise. To effectively address these issues, large-scale, intervention trials of vitamin K are needed. The effects of coumarin-based anticoagulants on bone health are more ambiguous, with retrospective studies suggesting that long-term therapy adversely affects vertebral BMD and fracture risk. Anticoagulants that do not affect vitamin K metabolism are now available and make clinical trials feasible to answer the question of whether coumarins adversely affect bone. The research suggests that at a minimum, clinicians should carefully assess anticoagulated patients for osteoporosis risk, monitor BMD, and refer them to dietitians for dietary and supplement advice on bone health. Further research is needed to make more efficacious decisions about vitamin K intake, anticoagulant therapy, and bone health.

Vitamin K deficiency reduces testosterone production in the testis through down-regulation of the Cyp11a a cholesterol side chain cleavage enzyme in rats.

Vitamin K (K) is an essential factor for the posttranslational modification of blood coagulation factors as well as proteins in the bone matrix (Gla proteins). It is known that K is not only distributed in the liver and bones but also abundantly distributed in the brain, kidney, and gonadal tissues. However, the role of K in these tissues is not well clarified. In this study, we used DNA microarray and identified the genes whose expression was affected in the testis under the K-deficient (K-def) state. The expression of genes involved in the biosynthesis of cholesterol and steroid hormones was decreased in the K-def group. The mRNA levels of Cyp11a - a rate-limiting enzyme in testosterone synthesis - positively correlated with the menaquinone-4 (MK-4) concentration in the testis. Moreover, as compared to the control (Cont) and K-supplemented (K-sup) groups, the K-def group had decreased testosterone concentrations in the plasma and testis. These results suggested that K is involved in steroid production in the testis through the regulation of Cyp11a.

Dietary phylloquinone depletion and repletion in postmenopausal women: effects on bone and mineral metabolism.

INTRODUCTION: Vitamin K has been implicated in increased bone fracture risk. Despite a potential role of vitamin K in bone, little is known about the effects of altered dietary phylloquinone intake on the underlying components of bone and mineral metabolism. METHODS: A 84-day in-house dietary phylloquinone (vitamin K) depletion-repletion study was undertaken in 21 postmenopausal women (mean age: 70 years) to assess the effects of altered vitamin K status on intestinal calcium (Ca) absorption, urinary and serum Ca and phosphorus (P), serum calcemic hormones, and serum biomarkers of bone turnover [osteocalcin and N-telopeptide type 1 collagen cross-links (NTx)] and the response to 1,25-dihydroxyvitamin D treatment (1 microg/dayx7 d). RESULTS: The group receiving calcitriol treatment (n=11) had higher Ca absorption, urinary Ca, urinary and serum P and serum osteocalcin and lower serum parathyroid hormone (PTH). There were no significant effects of acute (4-week) phylloquinone depletion on response to 1,25-dihydroxyvitamin D treatment or on measures of bone formation or mineral metabolism. However, phylloquinone treatment had a significant effect (p<0.04) on serum NTx. Phylloquinone repletion, up to five times (450 microg phylloquinone per day) the currently recommended adequate intake level of dietary phylloquinone for women, significantly reduced serum NTx (16.8+/-0.9 nmol bone collagen equivalents (BCE) per liter following repletion vs 18.4+/-1.1 nmol BCE per liter following depletion; p<0.01). CONCLUSIONS: These findings suggest that altering vitamin K status in postmenopausal women by manipulating phylloquinone intake does not have an acute affect on intestinal Ca absorption, renal mineral excretion, or bone formation, but high phylloquinone intake may modestly reduce bone resorption. The impact of high phylloquinone intake on bone mineral density and fracture risk needs to be ascertained in randomized clinical trials.