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Bigman, G.; Popa, D.; Rusu, M.E. The Role of Vitamin K in Humans. Encyclopedia. Available online: (accessed on 24 February 2024).
Bigman G, Popa D, Rusu ME. The Role of Vitamin K in Humans. Encyclopedia. Available at: Accessed February 24, 2024.
Bigman, Galya, Daniela-Saveta Popa, Marius Emil Rusu. "The Role of Vitamin K in Humans" Encyclopedia, (accessed February 24, 2024).
Bigman, G., Popa, D., & Rusu, M.E. (2022, May 06). The Role of Vitamin K in Humans. In Encyclopedia.
Bigman, Galya, et al. "The Role of Vitamin K in Humans." Encyclopedia. Web. 06 May, 2022.
The Role of Vitamin K in Humans

As human life expectancy is rising, the incidence of age-associated diseases will also increase. Scientific evidence has revealed that healthy diets, including good fats, vitamins, minerals, or polyphenolics, could have antioxidant and anti-inflammatory activities, with antiaging effects. Recent studies demonstrated that vitamin K is a vital cofactor in activating several proteins, which act against age-related syndromes. Thus, vitamin K can carboxylate osteocalcin (a protein capable of transporting and fixing calcium in bone), activate matrix Gla protein (an inhibitor of vascular calcification and cardiovascular events) and carboxylate Gas6 protein (involved in brain physiology and a cognitive decline and neurodegenerative disease inhibitor). 

vitamin K phylloquinone menaquinone menadione osteocalcin matrix Gla protein bone health COVID-19 osteoporosis vascular calcification

1. Introduction

Aging is a multifactorial process that gradually deteriorates the physiological functions of various organs, including the brain, musculoskeletal, cardiovascular, metabolic, and immune system leading to numerous pathological conditions with high rates of morbidity and mortality. Oxidative stress (OS) and chronic inflammation are fundamental pathophysiological mechanisms in the aging progression [1][2][3].
As human life expectancy is rising, age-related diseases will increase as well. Recent studies validated the importance of modifiable lifestyle factors, diet included, in the attenuation of pathological changes in mature adults [4]. Healthy fats, vitamins, minerals, polyphenolics, with antioxidant and anti-inflammatory activity, can increase the quality of life and influence the aging process, and among these factors, vitamin K (VK) has an important part [5].
VK is known for its role in synthesizing some blood-clotting proteins (K for koagulation in German). VK represents a fat-soluble family of compounds with a common chemical structure, a 2-methyl-1,4-naphthoquinone ring and a variable aliphatic side-chain. The variable aliphatic chain differentiates two isoforms: vitamin K1 (VK1) or phylloquinone (PK) and vitamin K2 (VK2), usually designated as menaquinone (MK). MK exists in multiple structures, which are distinguished by the number of isoprenyl units and saturation in the side-chain (MK-n, where n is the number of isoprenyl units) [6]. These acronyms were used interchangeably throughout this entry. The most common subtypes in humans are the short-chain MK-4, which is the only MK produced by systemic conversion of phylloquinone to menaquinone, and MK-7 through MK-10, which are synthesized by bacteria. VK3 (menadione), without side-chain and classified as a pro-vitamin, is a synthetic form of this vitamin (Figure 1).
Antioxidants 10 00566 g001 550
Figure 1. Vitamin K chemical structures. Vitamins K1 (VK1), K2 (VK2), and K3 (VK3) share the naphthoquinone ring; VK1 has a phytyl side-chain; VK2 has a side-chain with a varying number of isoprenyl units; VK3 has no side-chain.
Dark green leafy vegetables are the main sources for dietary PK (e.g., collards, turnip, broccoli, spinach, kale), 70–700 μg/100 g, as well as several fruits (e.g., dried prunes, kiwifruit, avocado, blueberries, blackberries, grapes), 15–70 μg/100 g, and some nuts (pine nuts, cashews, pistachios), 10–75 μg/100 g [7][8]. In contrast, the main sources of VK2 are fermented foods, cheeses, eggs, and meats (Table 1) [9][10].
Table 1. Vitamin K2: food category, sources, and amount.
Food Category Food Source VK2 *
Fermented foods Natto
850–1000 (90% MK-7, 8% MK-8)
5.5 (31% MK-6, 23% MK-9, 17% MK-5 and -8)
Hard cheeses   50–80 (15–67% MK-9, 6–22% MK-4, 6–22% MK-8)
Soft cheeses   30–60 (20–70% MK-9, 6–20% MK-4, 6–20% MK-8)
Eggs Yolk 15–30 (MK-4)
Meats Pork, beef, chicken 1.4–10 (MK-4)
*—μg/100 g food sample; MK-n—menaquinone.
Although dietary PK in vegetables is the major source of the VK intake (80–90%), only 5–10% is absorbed, whereas MKs from dairy products are almost completely absorbed. PK, tightly bound to plant chloroplasts, as well as PK digested with some phytochemicals (e.g., saponins, tannins, fibers, phytates) found in pulses, is less bioavailable to human. Though, PK from collards and broccoli is more bioavailable than PK from spinach [11][12].
Both VK1 and VK2 are recognized as cofactors for enzyme γ-glutamyl carboxylase (GGCX), which converts glutamic acid (Glu) to a new amino acid γ-carboxyglutamic acid (Gla), in VK-dependent proteins (VKDPs) during their biosynthesis [13]. These VKDPs require carboxylation to become biologically active, and the negatively charged γ-carboxyglutamic acid residues have a high affinity for positively charged calcium ions [14].
VKDPs can be classified as hepatic and extrahepatic. The hepatic VKDPs are largely involved in blood coagulation. Extrahepatic VKDPs perform different tasks: osteocalcin (OC) regulates the bone formation and mineralization, the matrix Gla protein (MGP) is a potent inhibitor of vascular calcification, nephrocalcin is involved in kidney functions, the growth arrest-specific protein 6 (Gas6) in the development and differentiation of nervous system [15]. Additionally, some extrahepatic VKDPs (proteins C and S) inhibit coagulation by inactivating specific coagulation factors necessary to form blood clots [16].
Recent findings revealed the novel role of VK as an antioxidant and implicitly anti-inflammatory agent independent of its GGCX cofactor activity [17]. The antioxidant properties of VK are based on a protective action against oxidative cellular damage and cell death by (1) direct reactive oxygen species (ROS) uptake [17]; (2) the limiting of free radical intracellular accumulation [18], and (3) inhibition of the activation of 12-lipoxygenase [19].
Scientific evidence suggests that VK also has anti-inflammatory activity, a vital component against various chronic aging diseases [20]. VK inhibits the activation of the nuclear factor kappa B (NF-кB) and thus decreases the production of proinflammatory cytokines [17]. VK is significantly and inversely related to individual inflammatory biomarkers and inflammatory processes due to its anti-inflammatory effects [21].
The daily reference intake of VK is based mostly on bleeding-associated studies, and it varies between countries. US dietary guidelines recommend daily intakes of 90 and 120 μg for women and men, respectively, while the guidelines in the United Kingdom are set at 1 μg/kg body weight/day [11]. However, these recommendations are insufficient to induce complete carboxylation of all VKDPs. Only MK-7, having higher bioavailability and longer half-life, proved to promote γ-carboxylation of extrahepatic VKDPs at the current recommended levels, while the recommended levels of both PK and MK-4 have been shown to decrease γ-carboxylation of VKDPs [22].
Based on estimated dietary consumption, PK accounts for 50%, MK-4 makes up 10%, and MK-7, -8, and -9 represent 40% of total absorbed VK [23]. Being a fat-soluble vitamin, VK is taken up in the small intestine in the presence of dietary fat. A key mediator of intestinal VK absorption is Niemann–Pick C1-like 1 (NPC1L1) protein, a cholesterol and phytosterol transporter found in enterocytes and hepatocytes [24][25]. After absorption, PK is delivered to the liver and other tissues. It can be used unchanged, or it may be metabolized by certain types of microbiota into VK2 or into menadione in the human intestinal cells. A portion of menadione is transformed to MK-4, the dominant MK form in animal tissues [26]. However, there are tissue-specific VK distribution patterns. PK was found in all tissues with relatively high levels in the liver and heart but lower levels in the brain, lung and kidney. Compared to PK, MKs seem to be more important for extrahepatic tissues [27]. MK-4 levels were high in the brain and kidney and low in the liver, heart and lungs. The increased quantities of MK-4 in the brain suggest that this K vitamin is the active form of VK in this region [28]. Growing evidence advocates that MK-4 has a number of biological functions, including promoting growth factor of neuron-like cells, mediating apoptosis in several cancer cells, controlling glucose homeostasis [29]. In the central nervous system (CNS), MK-4 controls the activity of proteins involved in tissue renewal and cell growth control, myelination, mitogenesis, chemotaxis, neuroprotection [30]. The medium and long side-chain MKs were recovered mostly in the liver samples [31]. MK-7 and MK-4 converted from MK-7 increase collagen production and bone mineral density, promoting bone quality and strength [17]. As VK1, MK-4, and MK-7 have distinct bioavailability and biological activities, their recommended levels should be established based on their relative activities [32].

2. Vitamin K in Bone Health

The musculoskeletal system, comprised primarily of muscle and bone, and the adipose tissue are connected through biological mechanisms underlying the physiological and pathophysiological crosstalk among muscle, bone, and fat [17]. Thus, several myokines (interleukin-6 (IL-6), myostatin) secreted by muscle have been identified as having effects on bone. Osteokines, especially OC, has been shown to have an endocrine impact on muscle, while adipokines (leptin, adiponectin, resistin) could act on either muscle or bone [33]. An in vitro study revealed that both carboxylated OC (cOC) and undercarboxylated OC (ucOC) increased secretion of adiponectin and the anti-inflammatory cytokine IL-10 and also inhibited secretion of tumor necrosis factor-α (TNF-α), but only cOC suppressed inflammatory IL-6 cytokine [34].
Thus, modifiable risk factors, such as healthy diets and physical activity, can positively affect these tissues. The role of calcium and vitamin D (vitD) in preventing osteoporosis is well established. However, more recent evidence suggests that other foods, such as fruit and vegetable, may have an essential role in bone health. Physical activity contributes to bone health by increasing serum total OC (tOC) and adiponectin, reducing leptin, and lowering insulin resistance [35].
Bone strength is determined by bone mineral content (BMC) and its quality and is associated with biological senescence and vitamin (B, D, K) deficiencies. As VK activates tissue-specific VKDPs, such as prothrombin, OC, or MGP, via the γ-carboxylation of Glu to Gla molecules, insufficient VKDPs γ-carboxylation is a sensitive, tissue-specific marker of VK deficiency [36]. Several studies revealed that VK is involved in bone metabolism and inhibits bone resorption in a dose-dependent manner. Binkley et al. showed that more than 250 µg/d VK intake is required for γ-carboxylation of OC [37].
Circulation OC is a marker of bone turnover. Of the total amount of OC that is released into the circulation, 40 to 60% is ucOC. This fraction of OC, being sensitive to VK intake, is a marker for VK status, usually revealing a lower VK availability [38]. Low dietary VK consumption and a high proportion of ucOC are independent risk factors for bone fractures in mature populations [39][40][41][42][43].
Table 2 summarizes the studies that showed an association between VK intake and bone parameters in mature subjects.
Table 2. The effect of VK intake on bone outcome parameters.
Author, Year, Country [Ref.] Subjects (W:M)
Age (Mean ± SD)
Design (Length) Intervention
Shiraki et al. 2000 Japan [40] 241 PMO
67.2 y
2 y
45 mg/d MK-4
vs. control
↓ ucOC (p < 0.0001)
↑ cOC (p = 0.0081)
↓ fracture risk (p = 0.0273)
Iwamoto et al. 2001 Japan [44] 72 PMO
65.3 y
2 y
45 mg/d MK-4 + Ca
vs. Ca
↓ vertebral fractures (p < 0.0001)
↑ BMD (forearm) (p < 0.0001)
Purwosunu et al. 2006 Indonesia [45] 63 PMO
60.8 y
48 w
45 mg/d MK-4 + Ca
vs. Ca
↓ ucOC (p ˂ 0.01)
↑ BMD (lumbar) (p < 0.05)
Bolton-Smith et al. 2007 UK [41] 244 healthy W
68.2 y
2 y
200 μg/d VK1 + 10 μg/d vitD3 + Ca vs. placebo ↓ ucOC (p < 0.001)
↑ BMD (ultradistal radius) (p < 0.01)
Knapen et al. 2007 Netherlands [46] 325 PMW
66.0 y
3 y
45 mg/d MK-4
vs. placebo
↑ BMC (p < 0.05) and bone strength (femoral neck)
Booth et al. 2008
USA [47]
452 (267:185)
68.4 y
3 y
500 μg/d PK
vs. control
↓ ucOC (p ˂ 0.0001)
Cheung et al. 2008
Canada [48]
400 PMOa
59.1 y
2–4 y
5 mg/d VK1
vs. placebo
↓ fracture risk (p = 0.04)
Hirao et al. 2008 Japan [49] 44 PMW
68.4 y
1 y
45 mg/d VK2 + 5 mg/d alendronate vs. 5 mg/d alendronate ↓ ucOC (p = 0.014)
↓ ucOC:cOC (p = 0.007)
↑ BMD (femoral neck) (p = 0.03)
Tsugawa et al. 2008 Japan [50] 379 W
63.0 y
3 y
high VK1 vs. low VK1 ↓ vertebral fracture risk (p < 0.001)
Binkley et al. 2009 USA [42] 381 PMW
62.5 y
1 y
1 mg/d VK1 or 45 mg/d MK-4 vs. placebo ↓ ucOC (p < 0.001) for both VK1 and MK-4 groups
Yamauchi et al. 2010 Japan [51] 221 healthy W
60.8 ± 9.5 y
cross-sectional 260±85 μg/d VK ↓ ucOC (p < 0.0001)
↑ BMD (lumbar) (p = 0.015)
Je et al. 2011
Korea [52]
78 PMW
67.8 y
6 mo
45 mg/d MK-4 + vitD + Ca vs. vitD + Ca ↓ ucOC (p = 0.008)
↑ BMD (lumbar) (p = 0.049)
Kanellakis et al. 2012 Greece [53] 173 PMW
62.0 y
12 mo
100 μg PK or
MK-7 + vitD + Ca
vs. control
↓ ucOC (p = 0.001) *
↑ BMD (lumbar) (p < 0.05) *
Knapen et al. 2013 Netherlands [54] 244 PMW
60.0 y
3 y
180 μg/d MK-7
vs. placebo
↓ ucOC (p < 0.001)
↑ BMD (lumbar spine, femoral neck), bone strength (p < 0.05)
Jiang et al. 2014 China [55] 213 PMW
64.4 y
1 y
45 mg/d MK-4 + Ca
vs. Ca
↓ ucOC (p < 0.001)
↑ BMD (lumbar) (p < 0.001)
Rønn et al. 2016 Denmark [43] 148 PMOa
67.5 y
1 y
375 µg/d MK-7
vs. placebo
↓ ucOC (p < 0.05)
↓ ucOC:cOC (p < 0.05)
↑ bone structure (tibia) (p < 0.05)
Bultynck et al. 2020 UK [56] 62 (42:20)
80.0 ± 9.6 y
Prospective ↑ serum VK ↓ hip fracture risk
Moore et al. 2020
UK [57]
374 PMO
68.7 y
cross-sectional ↑ serum VK1 ↓ fracture risk (p = 0.04)
Sim et al. 2020
Australia [58]
30 (10:20)
61.8 ± 9.9 y
12 w
136.7 μg/d VK ↓ ucOC and ucOC:tOC (p ≤ 0.01)
BMC—bone mineral content; BMD—bone mineral density; cOC—carboxylated osteocalcin; M—men; PMW—postmenopausal women; PMO—postmenopausal osteoporosis; PMOa—postmenopausal osteopenia; RCT—randomized controlled trial; SD—standard deviation; tOC—total osteocalcin; ucOC—undercarboxylated osteocalcin; W—women; ↑—increase; ↓—decrease. * for both VK1 and MK-4 groups.
In a study including 221 healthy women, VK intake was significantly and negatively correlated with ucOC [51]. Correspondingly, higher VK consumption was associated with beneficial effects on fracture risk and bone health. Following an increased dietary green leafy vegetable intake by consuming approximately 200 g/d, 30 healthy individuals substantially reduced serum tOC, ucOC, and ucOC:tOC levels, suggesting increased entry of OC into the bone matrix, improvement of bone quality and lower fracture risk [58].
Moore et al. investigated the association between circulating VK1 with fracture risk in a study, including osteoporosis, in postmenopausal women. The results showed that serum VK1 concentrations were significantly higher in the group with fewer fractures and negatively associated with fracture risk [57]. The results of a 3-year study had the same conclusions: subjects with low plasma VK1 concentration had significantly higher susceptibility for vertebral fracture, independently of BMD, compared to the high VK1 group [50].
Postmenopausal women with osteopenia who received 5 mg of VK1 supplementation daily for 4 years had a significantly lower rate of fractures (p = 0.04) [48].
Besides leafy vegetables, dried plums (Prunus domestica L.), a rich source of VK1, demonstrated bone-protective effects. In a study of 84 osteopenic, postmenopausal women, 65–79 years of age, daily consumption of 50 g of dried plums for 6 months revealed less total body, hip, and lumbar bone mineral density (BMD) loss compared with that of the control group (p < 0.05), which can be explained by the ability of dried plums to suppress bone turnover and inhibit bone resorption [59]. Dried plums are rich in VK, potassium and minerals that are important to bone metabolism [60]. Booth et al. assessed the spine and hip BMD change in healthy elderly subjects, and after three years of follow-up, the daily PK supplementation did not present any additional benefit to BMD. However, the level of ucOC, associated with increased risk of bone fracture in older adults, significantly decreased [47]. Similar to the previous study, Emaus et al. observed that the daily intake of 360 µg MK-7 for one year increased cOC and decreased ucOC serum levels (p < 0.001) [61]. Feskanich et al. showed that women aged 38–74 years with higher daily VK intake had lower serum concentrations of ucOC and a 30% reduction in the risk of hip fracture compared to women with an intake of less than 109 μg VK per day [62]. Equally, the prevalence of VK deficiency was found to be higher in older patients (mean age 80.0) with hip fractures than those without [56].
In an intervention study, the use of 150 μg VK1 per day, in combination with physiological relevant doses of genistein, an important isoflavone [63], vitD, and polyunsaturated fatty acids (eicosapentaenoic and docosahexaenoic acids), could reduce fracture risk, at least at the hip, and prevent osteoporosis in postmenopausal women [64]. On one hand, VK2 supplementation might enhance the efficacy of vitD in bone and muscle health, improve bone quality, and reduce fracture risk in osteoporotic patients. On the other hand, vitD enhanced the carboxylation of OC, thus promoting the incorporation of calcium into the bone matrix and supporting bone metabolism [65]. Increased vitD intake should be accompanied by VK and magnesium supplementation to prevent long-term health risks, including hypercalcemia, a calcium buildup leading to calcification of the blood vessels and eventually osteoporosis. Hypercalcemia is not a vitD hypervitaminosis but rather a VK deficiency and higher serum concentrations of ucOC that inhibit calcium absorption in the bones [66].

3. Vitamin K in the Prevention and Therapy of Vascular Calcification and Cardiovascular Diseases

Aging and several pathologic states, such as obesity, diabetes, or chronic kidney disease (CKD), cause degenerative changes of the vascular walls, including inflammation and vascular calcification (VC), leading to arterial stiffening and increased cardiovascular (CV) morbidity and mortality [67].
Ample evidence has shown that VK deficiency is related to the pathogenesis of VC [67][68][69][70]. VK has been suggested to inhibit VC and protect against cardiovascular disease (CVD) through the activation of VKDPs, such as MGP. To accomplish its potent calcification inhibitory function, MGP, secreted in the inactive form, needs activation (carboxylation), which takes place in the presence of VK. Upon activation, MGP binds calcium with high affinity, thereby inhibiting the VC process [68].
VC, a hallmark of senescence and a strong predictor of CV events, is another chronic inflammatory state induced via the generation of proinflammatory cytokines and mediated by the NF-кB signaling pathway. A high VK status may exert anti-inflammatory effects and prevent VC through antagonizing NF-кB signaling [69]. Growing evidence shows that VK as well as nuclear factor erythroid 2–related factor 2 (Nrf2) signaling could play a vital role in blocking ROS generation, cellular senescence, DNA damage, and inflammaging [70].
In CKD, a pathological condition characterized by osteoporosis, sarcopenia, and increase CVD events [71], VC is widespread even at early stages. Besides careful attention to calcium and phosphate balance, no particular therapy enabling regression or inhibiting the progression of VC existed [72]. Accumulating evidence describes the VC mechanism as an active process involving calcification promoters and inhibitors. The biologically active MGP, highly dependent on VK status, is viewed as a strong inhibitor of vascular elastic fiber damage and VC [73] and also the only factor that can actually reverse the process [74]. The inactive, uncarboxylated form of this protein reflected the deficiency of VK status and has been linked with VC and CV events. Growing scientific data show that VK-dependent MGP could offset age-related wear and tear on the arteries, VC, and CVD development [75].
To date, a number of experiments and observational studies examined the effects of VK supplementation and dietary intake on vascular calcification and CVD (Table 3) in mature populations.
Table 3. The effects of VK supplementation on vascular calcification.
Author, Year, Country (Ref.) Subjects (W:M)
Age (Mean ± SD)
Design (Length) Intervention
Geleijnse et al. 2004 Netherlands [76] 4807 (2971:1836)
67.5 y
7 y Q1 ˂ 21.6 μg/d VK2
Q2 21.6–32.7μg/d VK2
Q3 ˃ 32.7 μg/d VK2
↓ CHD mortality: RR = 0.43 (95% CI: 0.24–0.77, p = 0.005) Q3 vs. Q1
↓ AC: OR = 0.48 (95% CI: 0.32–0.71, p ˂ 0.001) Q3 vs. Q1
Gast et al. 2009
Netherlands [77]
16,057 W
57.0 ± 6.0 y
8.1 y
211.7μg/d VK1
29.1μg/d VK2
↓ CHD risk for 10 μg VK2: HR = 0.91 (95% CI: 0.85–1.00, p = 0.04)
Shea et al. 2009 USA [78] 388 (235:153)
68 y
3 y
500 μg/d VK1 vs. control ↓progression of CAC
Schurgers et al. 2010 France [79] 107 (43:64)
67 ± 13 y
18 mo VK levels
↓ VK levels
↑ dp-ucMGP levels with CKD stage
Ueland et al. 2010
Norway [80]
147 (66:81)
74.0 ± 10 y
20 mo VK levels
↓ VK levels
↑ dp-ucMGP in symptomatic AS
Schlieper et al. 2011
Serbia [81]
188 (89:99)
58 ± 15 y
1104 days
VK levels
↓ dp-cMGP
↑ CV: HR = 2.7 (95% CI: 1.2–6.2, p = 0.015)
↑ All-cause: HR = 2.16 (95% CI:
1.1–4.3, p = 0.027)
Ueland et al. 2011
Norway [82]
179 (39:140)
56 y
2.9 y VK levels
↓ VK levels; ↑ dp-ucMGP
↑ heart failure: HR=5.62 (95% CI: 2.05–15.46, p = 0.001)
Westenfeld et al. 2011 Germany [83] 103 (48:55)
˃ 60.5 y
6 w
G1–45 µg/d MK-7
G2–135 µg/d MK-7
G3–360 µg/d MK-7
↓ dp-ucMGP by 77–93% G2 and G3 vs. control
Dalmeijer et al. 2012
Netherlands [84]
60 (36:24)
59.5 y
12 w
G1–180 μg/d MK-7
G2–360 μg/d MK-7
↓ dp-ucMGP by 31% G1 and 46% G2 vs. placebo
van den Heuvel et al. 2013 Netherlands [85] 577 (322:255)
59.9 ± 2.9 y
Follow-up 5.6 y VK levels
↓ VK levels; ↑ dp-ucMGP
↑ CVD: HR=2.69 (95% CI: 1.09–6.62, p = 0.032)
Caluwé et al. 2014
Norway [86]
165 (83:82)
70.8 y
8 w
360, 720 or 1080 μg MK-7 thrice weekly ↓ dp-ucMGP by 17–33–46%
Liabeuf et al. 2014
France [87]
198 (40:158)
64 ± 8 y
Cross-sectional VK levels
↓ VK levels; ↑ dp-ucMGP
↑ PAC: OR = 1.88 (95% CI: 1.14–3.11, p = 0.014)
Cheung et al. 2015 USA [88] 3401 (2245:1156)
61.9 y
13.3 y
↑ VK daily intake ↓ CVD mortality: HR = 0.78 (95% CI: 0.64–0.95, p = 0.016)
Knapen et al. 2015
Norway [89]
244 PMW
59.5 ± 3.3 y
3 y
180 µg/d MK-7 vs. placebo ↓ Stiffness Index β: −0.67 ± 2.78 vs. +0.15 ± 2.51, p = 0.018
↓ cfPWV: −0.36 ± 1.48 m/s vs. +0.021 ± 1.22 m/s, p = 0.040
Kurnatowska et al. 2015 Poland [90] 42 (20:22)
58 y
270 days
90 μg/d MK-7 + 10 μg/d vitD vs. control ↑ CAC
Asemi et al. 2016
Iran [91]
66 (31:35)
65.5 y
12 w
180 µg/d MK-7 + 10 µg/d vitD + 1 g/d Ca vs. placebo ↓ levels of left CIMT (p = 0.02)
↓ insulin (−0.9 vs. +2.6, p = 0.01)
↓ HOMA-IR (−0.4 vs. +0.7, p = 0.01)
Fulton et al. 2016
UK [92]
80 (36:44)
77 ± 5 y
6 mo
100 µg MK-7 vs. placebo ↓dp-ucMGP (p < 0.001)
Kurnatowska et al. 2016 Poland [93] 38 (17:21)
58.6 y
9 mo
90 μg/d MK-7 + 10 μg/d vitD vs. control ↓dp-ucMGP by 10.7%
Sardana et al. 2016
USA [94]
66 (6:60) T2D
62 ± 2 y
Cross-sectional VK levels
↓ VK levels; ↑ dp-ucMGP
↑ cfPWV (β = 0.40, p = 0.011)
Aoun et al. 2017
Lebanon [95]
50 (20:30)
71.5 y
4 w
360 μg/d MK-7 ↓ dp-ucMGP by 86%
Brandenburg et al. 2017 Germany [96] 99 (18:81)
69.1 y
1 y
2 mg/d VK1 vs. placebo ↓ progression of AVC (10.0% vs. 22.0%)
Shea et al. 2017
USA [97]
1061 (615:446)
74 ± 5 y
12.1 y
VK1 levels
↑ CVD risk in HBP patients (n = 489): HR = 2.94 (95% CI: 1.4–6.13, p ˂ 0.01)
Puzantian et al. 2018
USA [98]
137 (8:129)
59.6 y
  VK levels
↓ VK levels; ↑ dp-ucMGP
↑ cfPWV (β = 0.21; p = 0.019)
Dal Canto et al. 2020
Netherlands [99]
601 (303:298)
70 ± 6 y
7 and 17 y
↓ VK levels
↓ vitD levels
↑ LVMI: β = 5.9 g/m2.7
(95% CI: 1.8–10.0 g/2.7)
↑ All-cause mortality: HR = 1.64 (95% CI: 1.12–2.39, p = 0.011)
Roumeliotis et al. 2020 Greece [100] 66 (31:35)
diabetic CKD
68.5 ± 8.6 y
7 y
VK levels
↓ VK levels; ↑ dp-ucMGP
↑ CVD mortality: HR = 2.82 (95% CI: 1.07–7.49, p = 0.037)
Shea et al. 2020
USA [101]
3891 (2154:1737)
65 ± 11 y
13 y
↓ VK1 levels ↑ CVD risk: HR = 1.12 (95% CI, 0.94–1.33)
↑ All-cause mortality
Wessinger et al. 2020 USA [102] 60 (11:49) chronic stroke
61.7 ± 7.2 y
Cross-sectional VK dietary intake Among stroke survivors, 82% reported consuming below the Dietary Reference Intake for VK
AC—aortic calcification; AS—aortic stenosis; AVC—aortic valve calcification; CAC—coronary artery calcification; cfPWV—carotid-femoral pulse wave velocity; CHD—coronary heart disease; CIMT—carotid intima-media thickness; CKD—chronic kidney disease; dp-ucMGP —dephosphorylated—undercarboxylated matrix gla protein; CVD—cardiovascular diseases; HF—heart failure; HR—hazard ratio; LVMI—left ventricular mass index; M—men; MK—menaquinone; OR—odds ratio; PAC—peripheral arterial calcification; PMW—postmenopausal women; PMO—postmenopausal osteoporosis; PMOa—postmenopausal osteopenia; RCT—randomized controlled trial; RR—relative risk; SD—standard deviation; W—women; ↑—increase; ↓—decrease.
Several studies demonstrated that higher dietary consumption of VK2 significantly reduced the incidence of VC and coronary heart disease (CHD) [76][77]. In these studies, no association between VK1 intake and CHD was detected while controlling for confounders. After monitoring 2987 participants during a median follow-up time of 11 years, only dietary MKs, but not VK1 intake, were significantly associated with a lower risk of CHD [103]. Scientific evidence specified that VK1 mainly carboxylate VK-dependent factors in the liver, while VK2 is responsible for the carboxylation of VKDPs in the extrahepatic tissues [104]. Nonetheless, it was demonstrated that higher doses of VK1, namely 2 mg/d, can also act in extrahepatic tissues and delay the progression of VC [96]. Furthermore, low plasma VK1 status was linked with higher all-cause mortality risk [101] and with an increased risk for CVD in older patients treated for hypertension [97].
VK intake slowed the progression of preexisting coronary artery calcification (CAC), a well-known independent predictor of CVD risk, in asymptomatic older men and women [78]. Moreover, adequate consumption of VK-rich foods has been suggested as both preventing action and prospective adjuvant therapy against atherosclerosis and stroke [102].
A combination of low VK and vitD status is associated with the increased left ventricular mass index, a parameter for cardiac structure, which has been shown to predict higher mortality, as well as the augmented risk of all-cause mortality in older populations [99]. In diabetic patients with stable CHD, combined supplementation with MK-7, vitD, and Ca was associated with a significant reduction in maximum levels of left carotid intima-media thickness (a parameter positively linked with diabetes, blood pressures, lipid profiles, inflammatory cytokines), C-reactive protein (CRP) and malondialdehyde (MDA) levels, and a significant increase in high-density lipoprotein (HDL)-cholesterol levels [91].
A functional VK deficiency is strongly associated with an increase in uncarboxylated VK-dependent protein levels, the hepatic protein induced by vitamin K absence-II (PIVKA-II) and extrahepatic dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP) [85]. Scientific findings reported that VK could modulate dp-ucMGP levels and that plasma dp-ucMGP levels decline after VK intake in a dose-dependent manner [83][86]. Circulating plasma dp-ucMGP levels augmented progressively in many diseases and were directly correlated with the severity of VC, cardiac function and long-term mortality [79][80][81][82]. Equally, in a study involving 2318 subjects, elevated dp-ucMGP increased the risk of CV (p = 0.027) and all-cause (p ≤ 0.008) mortality [105]. Similarly, in diabetes patients with high CV risk, elevated levels of dp-ucMGP and lower levels of total ucMGP (t-ucMGP) are independently related to the severity of peripheral artery calcification [87]. Moreover, higher dp-ucMGP values were independently associated with carotid-femoral pulse wave velocity (cfPWV) in diabetes and CKD patients and may lead to large arterial stiffening [94][98].


  1. Franco, R.; Navarro, G.; Martínez-Pinilla, E. Hormetic and Mitochondria-Related Mechanisms of Antioxidant Action of Phytochemicals. Antioxidants 2019, 8, 373.
  2. Bjørklund, G.; Chirumbolo, S. Role of oxidative stress and antioxidants in daily nutrition and human health. Nutrition 2017, 33, 311–321.
  3. Maurya, P.K.; Kumar, P.; Chandra, P. Biomarkers of oxidative stress in erythrocytes as a function of human age. World J. Methodol. 2015, 5, 216–222.
  4. Rusu, M.E.; Gheldiu, A.-M.; Mocan, A.; Vlase, L.; Popa, D.-S. Anti-aging potential of tree nuts with a focus on phytochemical composition, molecular mechanisms and thermal stability of major bioactive compounds. Food Funct. 2018, 9, 2554–2575.
  5. Harshman, S.; Shea, M. The Role of Vitamin K in Chronic Aging Diseases: Inflammation, Cardiovascular Disease, and Osteoarthritis. Curr. Nutr. Rep. 2016, 5, 90–98.
  6. Braasch-Turi, M.; Crans, D.C. Synthesis of Naphthoquinone Derivatives: Menaquinones, Lipoquinones and Other Vitamin K Derivatives. Molecules 2020, 25, 4477.
  7. Schurgers, L.; Vermeer, C. Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations. Haemostasis 2000, 30, 298–307.
  8. Turck, D.; Bresson, J.-L.; Burlingame, B.; Dean, T.; Fairweather-Tait, S.; Heinonen, M.; Hirsch-Ernst, K.I.; Mangelsdorf, I.; McArdle, H.; Naska, A.; et al. Dietary reference values for vitamin K. EFSA J. 2017, 15, e04780.
  9. Elder, S.J.; Haytowitz, D.B.; Howe, J.; Peterson, J.W.; Booth, S.L. Vitamin K Contents of Meat, Dairy, and Fast Food in the U.S. Diet. J. Agric. Food Chem. 2006, 54, 463–467.
  10. Melse-Boonstra, A. Bioavailability of Micronutrients from Nutrient-Dense Whole Foods: Zooming in on Dairy, Vegetables, and Fruits. Front. Nutr. 2020, 7, 101.
  11. Booth, S.L. Vitamin K: Food composition and dietary intakes. Food Nutr. Res. 2012, 56, 5505.
  12. Margier, M.; Antoine, T.; Siriaco, A.; Nowicki, M.; Halimi, C.; Maillot, M.; Georgé, S.; Reboul, E. The Presence of Pulses within a Meal can Alter Fat-Soluble Vitamin Bioavailability. Mol. Nutr. Food Res. 2019, 63, e1801323.
  13. Halder, M.; Petsophonsakul, P.; Akbulut, A.C.; Pavlic, A.; Bohan, F.; Anderson, E.; Maresz, K.; Kramann, R.; Schurgers, L. Vitamin K: Double Bonds beyond Coagulation Insights into Differences between Vitamin K1 and K2 in Health and Disease. Int. J. Mol. Sci. 2019, 20, 896.
  14. Wei, F.-F.; Trenson, S.; Verhamme, P.; Vermeer, C.; Staessen, J.A. Vitamin K-Dependent Matrix Gla Protein as Multifaceted Protector of Vascular and Tissue Integrity. Hypertension 2019, 73, 1160–1169.
  15. Gröber, U.; Reichrath, J.; Holick, M.F.; Kisters, K. Vitamin K: An old vitamin in a new perspective. Dermato Endocrinol. 2015, 6, e968490.
  16. Bender, D.; Vitamin, K. Nutritional Biochemistry of the Vitamins; Cambridge University Press: Cambridge, UK, 2003; pp. 131–147. ISBN 9780521803885.
  17. Simes, D.; Viegas, C.; Araújo, N.; Marreiros, C. Vitamin K as a Diet Supplement with Impact in Human Health: Current Evidence in Age-Related Diseases. Nutrients 2020, 12, 138.
  18. Li, J.; Lin, J.C.; Wang, H.; Peterson, J.W.; Furie, B.C.; Furie, B.; Booth, S.L.; Volpe, J.J.; Rosenberg, P.A. Novel Role ofVitamin K in Preventing Oxidative Injury to Developing Oligodendrocytes and Neurons. J. Neurosci. 2003, 23, 5816–5826.
  19. Sinbad, O.O.; Folorunsho, A.A.; Olabisi, O.L.; Ayoola, A.O.; Temitope, J. Vitamins as Antioxidants. J. Food Sci. Nutr. Res. 2019, 2, 214–235.
  20. Rusu, M.E.; Simedrea, R.; Gheldiu, A.-M.; Mocan, A.; Vlase, L.; Popa, D.-S.; Ferreira, I.C.F.R. Benefits of tree nut consumption on aging and age-related diseases: Mechanisms of actions. Trends Food Sci. Technol. 2019, 88, 104–120.
  21. Fusaro, M.; Gallieni, M.; Rizzo, M.A.; Stucchi, A.; Delanaye, P.; Cavalier, E.; Moysés, R.M.A.; Jorgetti, V.; Iervasi, G.; Giannini, S.; et al. Vitamin K plasma levels determination in human health. Clin. Chem. Lab. Med. 2017, 55, 789–799.
  22. DiNicolantonio, J.J.; Bhutani, J.; O’Keefe, J.H. The health benefits of vitamin K. Open Hear 2015, 2, e000300.
  23. Akbulut, A.; Pavlic, A.; Petsophonsakul, P.; Halder, M.; Maresz, K.; Kramann, R.; Schurgers, L. Vitamin K2 Needs an RDI Separate from Vitamin K1. Nutrients 2020, 12, 1852.
  24. Louka, M.; Fawzy, A.; Naiem, A.; Elseknedy, M.; Abdelhalim, A.; Abdelghany, M. Vitamin D and K signaling pathways in hepatocellular carcinoma. Gene 2017, 629, 108–116.
  25. Kim, Y.; Keogh, J.; Clifton, P. Benefits of nut consumption on insulin resistance and cardiovascular risk factors: Multiple potential mechanisms of actions. Nutrients 2017, 9, 1271.
  26. Paul, C.I.; Vitamin, K. Textbook of Natural Medicine, 5th ed.; Pizzorno, J.E., Murray, M.T., Eds.; Churchill Livingstone: St. Louis, MO, USA, 2020; pp. 919–947.e5. ISBN 978-0-323-52342-4.
  27. Vermeer, C.; Raes, J.; van’t Hoofd, C.; Knapen, M.H.J.; Xanthoulea, S. Menaquinone Content of Cheese. Nutrients 2018, 10, 446.
  28. Ferland, G. Vitamin K and brain function. Semin Thromb Hemost. 2013, 39, 849–855.
  29. Beulens, J.W.J.; Booth, S.L.; van den Heuvel, E.G.; Stoecklin, E.; Baka, A.; Vermeer, C. The role of menaquinones (vitamin K₂) in human health. Br. J. Nutr. 2013, 110, 1357–1368.
  30. Ferland, G.; Vitamin, K. An emerging nutrient in brain function. Biofactors 2012, 38, 151–157.
  31. Thijssen, H.; Drittij-Reijnders, M. Vitamin K status in human tissues: Tissue-specific accumulation of phylloquinone and menaquinone-4. Br. J. Nutr. 1996, 75, 121–127.
  32. Sato, T.; Inaba, N.; Yamashita, T. MK-7 and Its Effects on Bone Quality and Strength. Nutrients 2020, 12, 965.
  33. Kirk, B.; Feehan, J.; Lombardi, G.; Duque, G. Muscle, Bone, and Fat Crosstalk: The Biological Role of Myokines, Osteokines, and Adipokines. Curr. Osteoporos Rep. 2020, 18, 388–400.
  34. Hill, H.S.; Grams, J.; Walton, R.G.; Liu, J.; Moellering, D.R.; Garvey, W.T. Carboxylated and uncarboxylated forms of osteocalcin directly modulate the glucose transport system and inflammation in adipocytes. Horm. Metab. Res. 2014, 46, 341–347.
  35. Mohammad Rahimi, G.R.; Niyazi, A.; Alaee, S. The effect of exercise training on osteocalcin, adipocytokines, and insulin resistance: A systematic review and meta-analysis of randomized controlled trials. Osteoporos Int. 2021, 32, 213–224.
  36. Tsugawa, N.; Shiraki, M. Vitamin K Nutrition and Bone Health. Nutrients 2020, 12, 1909.
  37. Binkley, N.C.; Krueger, D.C.; Kawahara, T.N.; Engelke, J.A.; Chappell, R.J.; Suttie, J.W. A high phylloquinone intake is required to achieve maximal osteocalcin gamma-carboxylation. Am. J. Clin. Nutr. 2002, 76, 1055–1060.
  38. Lin, X.; Brennan-Speranza, T.C.; Levinger, I.; Yeap, B.B. Undercarboxylated Osteocalcin: Experimental and Human Evidence for a Role in Glucose Homeostasis and Muscle Regulation of Insulin Sensitivity. Nutrients 2018, 10, 847.
  39. Fusaro, M.; Cianciolo, G.; Brandi, M.L.; Ferrari, S.; Nickolas, T.L.; Tripepi, G.; Plebani, M.; Zaninotto, M.; Iervasi, G.; La Manna, G.; et al. Vitamin K and Osteoporosis. Nutrients 2020, 12, 3625.
  40. Shiraki, M.; Shiraki, Y.; Aoki, C.; Miura, M. Vitamin K2 (menatetrenone) effectively prevents fractuRes. and sustains lumbar bone mineral density in osteoporosis. J. Bone Min. Res. 2000, 15, 515–521.
  41. Bolton-Smith, C.; McMurdo, M.E.; Paterson, C.R.; Mole, P.A.; Harvey, J.M.; Fenton, S.T.; Prynne, C.J.; Mishra, G.D.; Shearer, M.J. Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women. J. Bone Min. Res. 2007, 22, 509–519.
  42. Binkley, N.; Harke, J.; Krueger, D.; Engelke, J.; Vallarta-Ast, N.; Gemar, D.; Checovich, M.; Chappell, R.; Suttie, J. Vitamin K Treatment Reduces Undercarboxylated Osteocalcin but Does Not Alter Bone Turnover, Density, or Geometry in Healthy Postmenopausal North American Women. J. Bone Min. Res. 2009, 24, 983–991.
  43. Rønn, S.; Harsløf, T.; Pedersen, S.; Langdahl, B. Vitamin K2 (menaquinone-7) prevents age-related deterioration of trabecular bone microarchitecture at the tibia in postmenopausal women. Eur. J. Endocrinol. 2016, 175, 541–549.
  44. Iwamoto, J.; Takeda, T.; Ichimura, S. Effect of menatetrenone on bone mineral density and incidence of vertebral fractuRes. in postmenopausal women with osteoporosis: A comparison with the effect of etidronate. J. Orthop. Sci. 2001, 6, 487–492.
  45. Purwosunu, Y.; Muharram; Rachman, I.A.; Reksoprodjo, S.; Sekizawa, A. Vitamin K 2 treatment for postmenopausal osteoporosis in Indonesia. J. Obs. Gynaecol. Res. 2006, 32, 230–234.
  46. Knapen, M.; Schurgers, L.; Vermeer, C. Vitamin K 2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. 2007, 18, 963–972.
  47. Booth, S.L.; Dallal, G.; Shea, M.K.; Gundberg, C.; Peterson, J.W.; Dawson-Hughes, B. Effect of Vitamin K Supplementation on Bone Loss in Elderly Men and Women. J. Clin. Endocrinol. Metab. 2008, 93, 1217–1223.
  48. Cheung, A.M.; Tile, L.; Lee, Y.; Tomlinson, G.; Hawker, G.; Scher, J.; Hu, H.; Vieth, R.; Thompson, L.; Jamal, S.; et al. Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): A randomized controlled trial. PLoS Med. 2008, 5, e196.
  49. Hirao, M.; Hashimoto, J.; Ando, W.; Ono, T.; Yoshikawa, H. Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K2 in postmenopausal women. J. Bone Min. Metab. 2008, 26, 260–264.
  50. Tsugawa, N.; Shiraki, M.; Suhara, Y.; Kamao, M.; Ozaki, R.; Tanaka, K.; Okano, T. Low plasma phylloquinone concentration is associated with high incidence of vertebral fracture in Japanese women. J. Bone Min. Metab. 2008, 26, 79–85.
  51. Yamauchi, M.; Yamaguchi, T.; Nawata, K.; Takaoka, S.; Sugimoto, T. Relationships between undercarboxylated osteocalcin and vitamin K intakes, bone turnover, and bone mineral density in healthy women. Clin. Nutr. 2010, 29, 761–765.
  52. Je, S.H.; Joo, N.-S.; Choi, B.-H.; Kim, K.-M.; Kim, B.-T.; Park, S.-B.; Cho, D.-Y.; Kim, K.-N.; Lee, D.-J. Vitamin K Supplement Along with Vitamin D and Calcium Reduced Serum Concentration of Undercarboxylated Osteocalcin While Increasing Bone Mineral Density in Korean Postmenopausal Women over Sixty-Years-Old. J. Korean Med. Sci. 2011, 26, 1093–1098.
  53. Kanellakis, S.; Moschonis, G.; Tenta, R.; Schaafsma, A.; van den Heuvel, E.; Papaioannou, N.; Lyritis, G.; Manios, Y. Changes in parameters of bone metabolism in postmenopausal women following a 12-month intervention period using dairy products enriched with calcium, vitamin D, and phylloquinone (vitamin K(1)) or menaquinone-7 (vitamin K (2)): The Postmenopausal Health Study II. Calcif. Tissue Int. 2012, 90, 251–262.
  54. Knapen, M.; Drummen, N.; Smit, E.; Vermeer, C.; Theuwissen, E. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013, 24, 2499–2507.
  55. Jiang, Y.; Zhang, Z.-L.; Zhang, Z.-L.; Zhu, H.-M.; Wu, Y.-Y.; Cheng, Q.; Wu, F.-L.; Xing, X.-P.; Liu, J.-L.; Yu, W.; et al. Menatetrenone versus alfacalcidol in the treatment of Chinese postmenopausal women with osteoporosis: A multicenter, randomized, double-blinded, double-dummy, positive drug-controlled clinical trial. Clin. Interv. Aging 2014, 9, 121–127.
  56. Bultynck, C.; Munim, N.; Harrington, D.; Judd, L.; Ataklte, F.; Shah, Z.; Dockery, F. Prevalence of vitamin K deficiency in older people with hip fracture. Acta Clin. Belg. 2020, 75, 136–140.
  57. Moore, A.E.; Kim, E.; Dulnoan, D.; Dolan, A.L.; Voong, K.; Ahmad, I.; Gorska, R.; Harrington, D.J.; Hampson, G. Serum vitamin K 1 (phylloquinone) is associated with fracture risk and hip strength in post-menopausal osteoporosis: A cross-sectional study. Bone 2020, 141, 115630.
  58. Sim, M.; Lewis, J.R.; Prince, R.L.; Levinger, I.; Brennan-Speranza, T.C.; Palmer, C.; Bondonno, C.P.; Bondonno, N.P.; Devine, A.; Ward, N.C.; et al. The effects of vitamin K-rich green leafy vegetables on bone metabolism: A 4-week randomised controlled trial in middle-aged and older individuals. Bone Rep. 2020, 12, 100274.
  59. Hooshmand, S.; Kern, M.; Metti, D.; Shamloufard, P.; Chai, S.C.; Johnson, S.A.; Payton, M.E.; Arjmandi, B.H. The effect of two doses of dried plum on bone density and bone biomarkers in osteopenic postmenopausal women: A randomized, controlled trial. Osteoporos Int. 2016, 27, 2271–2279.
  60. Higgs, J.; Derbyshire, E.; Styles, K. Nutrition and osteoporosis prevention for the orthopaedic surgeon: A wholefoods approach. EFORT Open Rev. 2017, 2, 300–308.
  61. Emaus, N.; Gjesdal, C.G.; Almås, B.; Christensen, M.; Grimsgaard, A.; Berntsen, G.; Salomonsen, L.; Fønnebø, V. Vitamin K2 supplementation does not influence bone loss in early menopausal women: A randomised double-blind placebo-controlled trial. Osteoporos Int. 2010, 21, 1731–1740.
  62. Feskanich, D.; Weber, P.; Willett, W.C.; Rockett, H.; Booth, S.L.; Colditz, G.A. Vitamin K intake and hip fractuRes. in women: A prospective study. Am. J. Clin. Nutr. 1999, 69, 74–79.
  63. Popa, D.-S.; Rusu, M.E. Isoflavones: Vegetable Sources, Biological Activity, and Analytical Methods for Their Assessment. In Superfood and Functional Food—The Development of Superfoods and Their Roles as Medicine; Shiomi, N., Waisundara, V., Eds.; InTech: London, UK, 2017; ISBN 978-953-51-2942-4.
  64. Lappe, J.; Kunz, I.; Bendik, I.; Prudence, K.; Weber, P.; Recker, R.; Heaney, R.P. Effect of a combination of genistein, polyunsaturated fatty acids and vitamins D3 and K1 on bone mineral density in postmenopausal women: A randomized, placebo-controlled, double-blind pilot study. Eur. J. Nutr. 2013, 52, 203–215.
  65. Capozzi, A.; Scambia, G.; Lello, S. Calcium, vitamin D, vitamin K2, and magnesium supplementation and skeletal health. Maturitas 2020, 140, 55–63.
  66. Goddek, S. Vitamin D3 and K2 and their potential contribution to reducing the COVID-19 mortality rate. Int. J. Infect. Dis. 2020, 99, 286–290.
  67. Mozos, I.; Stoian, D.; Luca, C.T. Crosstalk between Vitamins A, B12, D, K, C, and E Status and Arterial Stiffness. Dis. Markers. 2017, 2017, 8784971.
  68. Jaminon, A.M.G.; Dai, L.; Qureshi, A.R.; Evenepoel, P.; Ripsweden, J.; Söderberg, M.; Witasp, A.; Olauson, H.; Schurgers, L.J.; Stenvinkel, P. Matrix Gla protein is an independent predictor of both intimal and meDial. vascular calcification in chronic kidney disease. Sci. Rep. 2020, 10, 6586.
  69. Shioi, A.; Morioka, T.; Shoji, T.; Emoto, M. The Inhibitory Roles of Vitamin K in Progression of Vascular Calcification. Nutrients 2020, 12, 583.
  70. Dai, L.; Schurgers, L.J.; Shiels, P.G.; Stenvinkel, P. Early vascular ageing in chronic kidney disease: Impact of inflammation, vitamin K, senescence and genomic damage. Nephrol. Dial. Transplant. 2020, 35, ii31–ii37.
  71. Simes, D.C.; Viegas, C.S.B.; Araújo, N.; Marreiros, C. Vitamin K as a Powerful Micronutrient in Aging and Age-Related Diseases: Pros and Cons from Clinical Studies. Int. J. Mol. Sci. 2019, 20, 4150.
  72. Cozzolino, M.; Fusaro, M.; Ciceri, P.; Gasperoni, L.; Cianciolo, G. The Role of Vitamin K in Vascular Calcification. Adv. Chronic Kidney Dis. 2019, 26, 437–444.
  73. Dofferhoff, A.S.M.; Piscaer, I.; Schurgers, L.J.; Visser, M.P.J.; van den Ouweland, J.; de Jong, P.; Gosens, R.; Hackeng, T.; van Daal, H.; Lux, P.; et al. Reduced vitamin K status as a potentially modifiable risk factor of severe COVID-19. Clin. Infect. Dis. 2020, ciaa1258.
  74. Roumeliotis, S.; Dounousi, E.; Salmas, M.; Eleftheriadis, T.; Liakopoulos, V. Vascular Calcification in Chronic Kidney Disease: The Role of Vitamin K- Dependent Matrix Gla Protein. Front. Med. 2020, 7, 154.
  75. Shea, M.K.; Booth, S.L. Vitamin K, Vascular Calcification, and Chronic Kidney Disease: Current Evidence and Unanswered Questions. Curr. Dev. Nutr. 2019, 3, nzz077.
  76. Geleijnse, J.M.; Vermeer, C.; Grobbee, D.E.; Schurgers, L.J.; Knapen, M.H.J.; van der Meer, I.M.; Hofman, A.; Witteman, J.C.M. Dietary Intake of Menaquinone Is Associated with a Reduced Risk of Coronary Heart Disease: The Rotterd. Am. Study J. Nutr. 2004, 134, 3100–3105.
  77. Gast, G.C.M.; De Roos, N.M.; Sluijs, I.; Bots, M.L.; Beulens, J.W.J.; Geleijnse, J.M.; Witteman, J.C.; Grobbee, D.E.; Peeters, P.H.M.; Van Der Schouw, Y.T. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr. Metab. Cardiovasc. Dis. 2009, 19, 504–510.
  78. Shea, M.K.; O’Donnell, C.J.; Hoffmann, U.; Dallal, G.E.; Dawson-Hughes, B.; Ordovas, J.; Price, P.A.; Williamson, M.K.; Booth, S.L. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am. J. Clin. Nutr. 2009, 89, 1799–1807.
  79. Schurgers, L.J.; Barreto, D.V.; Barreto, F.C.; Liabeuf, S.; Renard, C.; Magdeleyns, E.; Vermeer, C.; Choukroun, G.; Massy, Z. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: A preliminary report. Clin. J. Am. Soc. Nephrol. 2010, 5, 568–575.
  80. Ueland, T.; Gullestad, L.; Dahl, C.P.; Aukrust, P.; Aakhus, S.; Solberg, O.G.; Vermeer, C.; Schurgers, L.J. Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis. J. Int. Med. 2010, 268, 483–492.
  81. Schlieper, G.; Westenfeld, R.; Krüger, T.; Cranenburg, E.C.; Magdeleyns, E.J.; Brandenburg, V.M.; Djuric, Z.; Damjanovic, T.; Ketteler, M.; Vermeer, C.; et al. Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD. J. Am. Soc. Nephrol. 2011, 22, 387–395.
  82. Ueland, T.; Dahl, P.; Gullestad, L.; Aakhus, S.; Broch, K.; Skårdal, R.; Vermeer, C.; Aukrust, P.; Schurgers, L. Circulating levels of non-phosphorylated undercarboxylated matrix Gla protein are associated with disease severity in patients with chronic heart failure. Clin. Sci. (Lond.) 2011, 121, 119–127.
  83. Westenfeld, R.; Krueger, T.; Schlieper, G.; Cranenburg, E.C.M.; Magdeleyns, E.J.; Heidenreich, S.; Holzmann, S.; Vermeer, C.; Jahnen-Dechent, W.; Ketteler, M.; et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: A randomized trial. Am. J. Kidney Dis. 2012, 59, 186–195.
  84. Dalmeijer, G.W.; van der Schouw, Y.T.; Magdeleyns, E.; Ahmed, N.; Vermeer, C.; Beulens, J.W.J. The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein. Atherosclerosis 2012, 225, 397–402.
  85. Van Den Heuvel, E.G.H.M.; Van Schoor, N.M.; Lips, P.; Magdeleyns, E.J.P.; Deeg, D.J.H.; Vermeer, C.; Den Heijer, M. Circulating uncarboxylated matrix Gla protein, a marker of vitamin K status, as a risk factor of cardiovascular disease. Maturitas 2014, 77, 137–141.
  86. Caluwé, R.; Vandecasteele, S.; Van Vlem, B.; Vermeer, C.; De Vriese, A.S. Vitamin K2 supplementation in haemodialysis patients: A randomized dose-finding study. Nephrol. Dial. Transplant. 2014, 29, 1385–1390.
  87. Liabeuf, S.; Bourron, O.; Vemeer, C.; Theuwissen, E.; Magdeleyns, E.; Aubert, C.E.; Brazier, M.; Mentaverri, R.; Hartemann, A.; Massy, Z.A. Vascular calcification in patients with type 2 diabetes: The involvement of matrix Gla protein. Cardiovasc. Diabetol. 2014, 13, 85.
  88. Cheung, C.-L.; Sahni, S.; Cheung, B.M.Y.; Sing, C.-W.; Wong, I.C.K. Vitamin K intake and mortality in people with chronic kidney disease from NHANES III. Clin. Nutr. 2015, 34, 235–240.
  89. Knapen, M.H.J.; Braam, L.A.J.L.M.; Drummen, N.E.; Bekers, O.; Hoeks, A.P.G.; Vermeer, C. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial. Thromb. Haemost. 2015, 113, 1135–1144.
  90. Kurnatowska, I.; Grzelak, P.; Masajtis-Zagajewska, A.; Kaczmarska, M.; Stefańczyk, L.; Vermeer, C.; Maresz, K.; Nowicki, M. Effect of vitamin K2 on progression of atherosclerosis and vascular calcification in nondialyzed patients with chronic kidney disease stages 3-5. Pol. Arch. Med. Wewn. 2015, 125, 631–640.
  91. Asemi, Z.; Raygan, F.; Bahmani, F.; Rezavandi, Z.; Talari, H.R.; Rafiee, M.; Poladchang, S.; Mofrad, M.D.; Taheri, S.; Mohammadi, A.A.; et al. The effects of vitamin D, K and calcium co-supplementation on carotid intima-media thickness and metabolic status in overweight type 2 diabetic patients with CHD. Br. J. Nutr. 2016, 116, 286–293.
  92. Fulton, R.L.; McMurdo, M.E.T.; Hill, A.; Abboud, R.J.; Arnold, G.P.; Struthers, A.D.; Khan, F.; Vermeer, C.; Knappen, M.H.J.; Drummen, N.E.A.; et al. Effect of Vitamin K on Vascular Health and Physical Function in Older People with Vascular DiseaseA Randomised Controlled Trial. J. Nutr. Heal Aging 2016, 20, 325–333.
  93. Kurnatowska, I.; Grzelak, P.; Masajtis-Zagajewska, A.; Kaczmarska, M.; Stefańczyk, L.; Vermeer, C.; Maresz, K.; Nowicki, M. Plasma Desphospho-Uncarboxylated Matrix Gla Protein as a Marker of Kidney Damage and Cardiovascular Risk in Advanced Stage of Chronic Kidney Disease. Kidney Blood Press Res. 2016, 41, 231–239.
  94. Sardana, M.; Vasim, I.; Varakantam, S.; Kewan, U.; Tariq, A.; Koppula, M.R.; Syed, A.A.; Beraun, M.; Drummen, N.E.A.; Vermeer, C.; et al. Inactive Matrix Gla-Protein and Arterial Stiffness in Type 2 Diabetes Mellitus. Am. J. Hypertens. 2016, 30, 196–201.
  95. Aoun, M.; Makki, M.; Azar, H.; Matta, H.; Chelala, D.N. High Dephosphorylated-Uncarboxylated MGP in Hemodialysis patients: Risk factors and response to vitamin K2, A pre-post intervention clinical trial. BMC Nephrol. 2017, 18, 191.
  96. Brandenburg, V.; Reinartz, S.; Kaesler, N.; Krüger, T.; Dirrichs, T.; Kramann, R.; Peeters, F.; Floege, J.; Keszei, A.; Marx, N.; et al. Slower Progress of Aortic Valve Calcification With Vitamin K Supplementation: Results From a Prospective Interventional Proof-of-Concept Study. Circulation 2017, 135, 2081–2084.
  97. Shea, M.K.; Booth, S.L.; Weiner, D.E.; Brinkley, T.E.; Kanaya, A.M.; Murphy, R.A.; Simonsick, E.M.; Wassel, C.L.; Vermeer, C.; Kritchevsky, S.B. Circulating Vitamin K Is Inversely Associated with Incident Cardiovascular Disease Risk among Those Treated for Hypertension in the Health, Aging, and Body Composition Study (Health ABC). J. Nutr. 2017, 147, 888–895.
  98. Puzantian, H.; Akers, S.R.; Oldland, G.; Javaid, K.; Miller, R.; Ge, Y.; Ansari, B.; Lee, J.; Suri, A.; Hasmath, Z.; et al. Circulating Dephospho-Uncarboxylated Matrix Gla-Protein Is Associated With Kidney Dysfunction and Arterial Stiffness. Am. J. Hypertens. 2018, 31, 988–994.
  99. Dal Canto, E.; Beulens, J.W.J.; Elders, P.; Rutters, F.; Stehouwer, C.D.A.; Van Der Heijden, A.A.; Van Ballegooijen, A.J. The Association of Vitamin D and Vitamin K Status with Subclinical MeasuRes. of Cardiovascular Health and All-Cause Mortality in Older Adults: The Hoorn Study. J. Nutr. 2020, 150, 3171–3179.
  100. Roumeliotis, S.; Roumeliotis, A.; Stamou, A.; Leivaditis, K.; Kantartzi, K.; Panagoutsos, S.; Liakopoulos, V. The Association of dp-ucMGP with Cardiovascular Morbidity and Decreased Renal Function in Diabetic Chronic Kidney Disease. Int. J. Mol. Sci. 2020, 21, 6035.
  101. Shea, M.K.; Barger, K.; Booth, S.L.; Matuszek, G.; Cushman, M.; Benjamin, E.J.; Kritchevsky, S.B.; Weiner, D.E. Vitamin K status, cardiovascular disease, and all-cause mortality: A participant-level meta-analysis of 3 US cohorts. Am. J. Clin. Nutr. 2020, 111, 1170–1177.
  102. Wessinger, C.; Hafer-Macko, C.; Ryan, A.S. Vitamin K Intake in Chronic Stroke: Implications for Dietary Recommendations. Nutrients 2020, 12, 3059.
  103. Haugsgjerd, T.R.; Egeland, G.M.; Nygård, O.K.; Vinknes, K.J.; Sulo, G.; Lysne, V.; Igland, J.; Tell, G.S. Association of dietary vitamin K and risk of coronary heart disease in middle-age adults: The Hordaland Health Study Cohort. BMJ Open 2020, 10, e035953.
  104. Caluwé, R.; Verbeke, F.; De Vriese, A.S. Evaluation of vitamin K status and rationale for vitamin K supplementation in dialysis patients. Nephrol. Dial. Transplant. 2020, 35, 23–33.
  105. Liu, Y.-P.; Gu, Y.-M.; Thijs, L.; Knapen, M.H.J.; Salvi, E.; Citterio, L.; Petit, T.; Carpini, S.D.; Zhang, Z.; Jacobs, L.; et al. Inactive Matrix Gla Protein Is Causally Related to Adverse Health Outcomes: A Mendelian Randomization Study in a Flemish Population. Hypertension 2015, 65, 463–470.
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