Vitamin K: Calcium Metabolism Modulator for Menopausal Women

Abstract

Vitamin K (VitK) exists in multiple forms, with Vitamin K1 (VitK1) and Vitamin K2 (VitK2) being the most prominent. VitK1 primarily regulates clotting factors in the liver, whereas VitK2 plays a crucial role in activating extrahepatic proteins involved in various physiological processes. VitK plays a pivotal role in various physiological functions, including vascular health, bone metabolism, neuroprotection, hepatoprotection, immune response modulation, dental health, and glucose control. Particularly, activation of the matrix Gla protein and osteocalcin through VitK2 inhibits vascular calcification (VC) and promotes bone mineralization. This review provides an overview of the physiological functions of VitK2, underscoring its role in calcium metabolism modulation and its diverse effects on health. Additionally, this article provides a comprehensive overview of the beneficial functions of VitK, and discusses the significance of adequate dietary intake and oral supplementation of VitK. Particularly, emphasizing on the need for VitK2 supplementation owing to its relatively limited availability in Western diets. VitK2 supplementation effectively counters VC, enhances bone density, and offers neuroprotective, hepatoprotective, and anti-inflammatory benefits. Thus, the supplementation of VitK2, alongside dietary intake, is essential for preventive healthcare, particularly in the prevention of osteoporosis and vascular diseases. Incorporating adequate VitK2 intake highlights its significance in promoting overall well-being. Illustrated summary of the role of VitK in menopausal women.

Graphical Abstract

INTRODUCTION

Vitamin K (VitK) is a fat-soluble vitamin existing in three vitamers: Vitamin K1 (VitK1, phylloquinone), Vitamin K2 (VitK2, menaquinone), and Vitamin K3 (VitK3, menadione). The classification of VitK is based on its side chain [1]. Both VitK1 and VitK2 act as cofactors for gamma-glutamyl carboxylase in the “VitK cycle” but VitK3 was not active at all [1,2].

While VitK1 is concentrated in the liver, regulating the synthesis of clotting factors, VitK2 is found in extrahepatic tissues such as bones and arteries [3]. VitK1 induces the activation of liver-derived VitK-dependent proteins (VKDPs) involved in the coagulation process such as Factors II, VII, IX, and X [3,4]. In contrast, VitK2 differs in its activation of extrahepatic VKDPs, such as osteocalcin (OC) and matrix Gla protein (MGP), a small 84-amino acid protein widely recognized as the most potent inhibitor of vascular calcification (VC) [5].

In turn, VitK2 reduces calcium deposition in the vascular wall and regulates the “calcium paradox” by activating MGP and OC [6]. This results in decreased VC and increased calcium in bone tissue, ultimately modulating the mineralization process in bones and inhibiting the deposition of isosmotic vascular calcium [5,6]. Additionally, VitK2 possesses a variety of functions, prompting the writing of this review to enhance the overall understanding of VitK2-related physiological response.

BENEFICIAL FUNCTIONS OF VITAMIN K

Vascular calcification

The recent discovery of VitK2 is changing the paradigm, shifting the past understanding of VC as a passive, degenerative, irreversible process to a new understanding that it is an actively regulated, continuously preventable and reversible process [7].

In particular, VitK2 acts as a cofactor for γ-carboxylation of dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP) in vascular smooth muscle cells (VSMCs) and chondrocytes [8]. Dephosphorylated carboxylated matrix Gla protein (dp-cMGP) produced in this process undergoes additional phosphorylation by casein [9], an enzyme within osteoblasts, and is transformed into the final active form, phosphorylated matrix Gla protein (p-cMGP). This phosphorylation inhibits connective tissue calcification [10]. Regarding the role of MGP, in-vivo studies have shown that the absence of activated MGP causes VSMCs to differentiate into cells with chondrocyte and osteocyte characteristics, resulting in matrix that promotes calcium crystal deposition [11]. It is known that the activated MGP inhibits the formation of calcium crystals [9,10,11], regulating directly the calcification through alternative calcification inhibitors such as fetuin-A [12] and inhibiting indirectly the differentiation into an osteoblast-like phenotype through fine regulatory factors of VSMCs.

Investigation of the role of VitK2 in cardiovascular health requires biomarkers that reflect VitK status. Many studies have used the status of VKDPs that require carboxylation as a marker, the most common method being MGP measurement. This measurement reflects the bioactivity of VitK over weeks to months. Since VitK deficiency is investigated through measurement of dp-ucMGP, inactive dp-ucMGP serves as a biomarker in the circulation. This represents an unfavorable VitK status and is associated with increased calcium deposition in the vasculature, causes arterial stiffening through intimal calcification and contributes to atherosclerosis [13].

Other VKDPs associated with cardiovascular health include OC and growth arrest-specific 6 (Gas6) proteins [14]. Carboxylation by VitK2 activates OC, which not only promotes bone growth but also prevents calcification of connective tissue by inhibiting calcium and phosphorus precipitation. The role of OC in relation to cardiovascular health is the regulation of VC through activation of adiponectin, which inhibits osteogenic differentiation of VSMCs [15]. Gas6 protein is strongly expressed in the lung, heart, and kidney and has been shown to regulate calcification of VSMC [16].

The VC inhibitory role of VitK2 has also been recently confirmed in some preclinical in vivo studies. The researchers, to further determine the mechanism of inhibition, performed in vitro studies using VSMCs exposed to β-sodium glycerophosphate [17]. Since the hypertension is a major risk factor for VC, VSMCs isolated from spontaneously hypertensive rats (SHRs) were used as a model of cellular vascular dysfunction [18]. The results, interestingly, showed that menaquinone-4 (MK-4) reduced VC progression and preserved the contractile phenotype of SHR-VSMCs, demonstrating for the first time that treatment with MK-4 alleviated VC through inhibition of VSMC osteoblast transdifferentiation [19].

The role of VitK2 in vascular health has been demonstrated in several previous studies, and an inverse relationship between its intake and the occurrence of VC or subsequent cardiovascular events was clearly observed [20]. Additional clinical studies have been performed. In the Rotterdam Cohort, supplementation with VitK2 (menaquinone, 25 µg/day) led to a significant reduction in the risk of VC (52%), coronary artery disease (36%), and cardiac death (57%) [21]. The Prospective Study of Cancer and Nutrition in Europe (PROST-EPIC) cohort study reported that higher VitK2 intake reduced the risk of peripheral artery disease and coronary heart disease [22,23]. Another study showed that high dietary menaquinone intake, but probably not phylloquinone, is associated with reduced coronary calcification. Other studies have shown that VitK2 intake reduces coronary calcification and lowers arterial stiffness [24].

Regarding the function of Vitamin D (VitD), since the MGP gene promoter contains a VitD response element, VitD binding increases MGP expression by 2–3 times [25]. Studies that conducted cell-level experiments to test this theory reported that VitD has a positive effect on VitK-dependent metabolism such as MGP. In an in-vivo rat experiment with a high-concentration active VitD diet for 20 weeks [26]. However, inactive MGP increased, VitK decreased, and renal calcification increased [27]. Additionally, a large-scale randomized clinical trial has also reported that VitD supplementation does not have a positive effect on preventing cardiovascular disease [28]. These results are presumed to be because interaction with VitD increases calcium and phosphorus in the kidney and aorta [29]. Methods to overcome this include supplementation of VitK to alleviate the negative effects of excess VitD on calcification, which was demonstrated through reductions in calcium and phosphorus content in the aorta and kidneys [30]. Full activation of VitK optimizes upregulation of MGP by VitD. This suggests that supplementation with both VitK and VitD has a positive effect on progressive VC, cardiovascular disease, and death.

Osteoporosis

Osteoporosis, the most common bone disease in older men and women, is a metabolic bone disease caused by an imbalance between bone formation and resorption [31], and it is the most common skeletal disease that can affect elderly men and women [32]. It brings loss of bone mass and quality, weakening of skeletal structure, and increased risk of fractures [33]. VC is defined as an ectopic deposition of mineral matrix in the blood vessel wall, commonly occurs in aging and primary chronic diseases (hypertension, diabetes, and chronic kidney disease), and acts as an important risk factor for cardiovascular disease and mortality [34]. It serves as a significant risk factor for cardiovascular diseases and mortality [35]. In the past, osteoporosis and VC were thought to be independent and only related to aging, but many studies have shown a close connection between bone and vascular health [36,37,38].

Results from several studies have suggested that bone loss in osteoporosis may promote and increase cardiovascular risk levels and the risk of vascular atherosclerosis. Various hypotheses have been established to further clarify the series of relationships between bone and vascular systems, called bone-vascular crosstalk [39,40,41]. According to the Study of Women's Health Across the Nation (SWAN), Multi-Ethnic Study of Atherosclerosis (MESA), and Rotterdam Study, loss of bone mineral density (BMD) is associated with the development and progression of aortic calcification as well as increased cardiovascular disease mortality [42,43,44]. The Framingham Heart study showed decreased BMD and increased risk of femoral fracture in healthy postmenopausal women with aortic calcification [45]. The MicroRNAs in Patients on Chronic Hemodialysis (MINOS) Study demonstrated a direct correlation between VC and bone fracture risk by showing an increased major risk of bone fracture in men with aortic calcification [46].

Although several studies have highlighted the importance of VitK2 in maintaining bone health [47], the exact function of VitK2 in bone metabolism has not been clearly understood until now. In response, several randomized controlled trials (RCTs) have been conducted in recent years to determine the effectiveness of VitK2 supplementation in both healthy and osteoporotic patients with the purpose of preventing bone loss and fractures.

OC, a secretory small peptide, is synthesized by osteoblasts and has two forms: carboxylated OC (cOC) and uncarboxylated OC (ucOC) [48,49]. When the mineralization process is induced, cOC remains trapped in the bone matrix and, upon bone breakdown, is released into the blood as ucOC. Serum levels of cOC, ucOC and their ratios are [49], therefore, considered important biomarkers of bone turnover status in all populations, regardless of the presence or absence of osteoporosis [50]. In RCTs, treatment with VitK2 (45 µg/day) improved the bone mineralization process by inducing a significant decrease in ucOC along with a significant increase in cOC [51]. In an additional study, cOC serum concentrations increased in both men and women receiving daily VitK2 administration [52].

The effect of VitK2 on bone metabolism, in addition to clinical evidence reported from RCTs, has also been investigated in preclinical animal studies. In a mouse model of osteoporosis by ovariectomy, Rangel and colleagues [53] showed how the VitK2 compound improved BMD and bone formation markers and reduced bone resorption markers. Recently, an osteogenic rat model reported similar results showing increased bone formation and cOC serum levels after VitK2 treatment [54]. Based on the results from the in-vivo model, several in-vitro studies were performed to further understand the molecular mechanism by which VitK2 acts in the bone system. These studies have well established that VitK2 mainly acts on osteoblasts, assisting their proliferation and differentiation and improving bone matrix deposition function through the OC γ-carboxylation-independent pathway [55]. However, including the involvement of MGP in promoting osteoblast proliferation and activity through the Wnt/β-catenin signaling pathway, VitK2 has been shown to enhance bone mineralization and reduce bone resorption in another independent manner [56,57]. In addition, MK-4 promoted osteogenic conversion of human amniotic fluid-derived mesenchymal stem cells (hAFMSC), inhibited osteoclast differentiation of human monocytes (hMC), and promoted the formation of three-dimensional bone aggregates, which is potentially useful for tissue engineering applications in bone regenerative medicine [57].

Upon examining the results of the conducted RCTs, in a clinical trial of 219 osteoporotic postmenopausal women, found that 1 year of supplementation with VitK2 (100 µg/day) significantly increased total BMD [58]. Additionally, in 244 healthy postmenopausal women, 3-year administration of MK-7 (180 mcg/day) was associated with reduced bone loss and reduced risk of vertebral fractures [59]. Also, a meta-analysis involving 6,759 postmenopausal women in good healthindicated enhanced BMD and a reduced occurrence of fractures in individuals with osteoporosis following supplementation with VitK2 [60].

Neuroprotection

Neurodegeneration, the atrophy of nerve cells and gradual decline in function, is one of the most common disorders associated with aging. Treatment of this disease is generally symptomatic, and the effectiveness of drugs often decreases after a certain period of time. In studies to compensate for this shortcoming, it was reported that VitK, a relatively low-toxic compound, has the effect of preventing various neurological disorders such as neuroinflammation, Parkinson's disease, Alzheimer's disease, and multiple sclerosis [61].

Several studies have shown that VitK is involved in the production of sphingolipids, components of the neurocortex and cell membranes, and activates Gas6 protein [61,62]. Activation of this protein accelerates cell development, and interaction with its receptor prevents neuron death [63]. In addition, VitK has properties that can be used in the prevention of neurodegenerative diseases such as Alzheimer's disease [64], significantly improves nutritional and metabolic status in autism patients, and also has a neuroprotective function against the neurotoxic effects of mercury [65,66].

Detailed observations of VKDP in the brain showed that the activity of enzymes in the sphingolipid biosynthetic pathway, such as 3-keto-hydro sphingosine synthases (3-KDS) and sulfotransferases, is related to VitK concentration. Furthermore, VitK-dependent Gas6 has been shown to affect cell proliferation and apoptosis resistance, protect gonadotrophin-releasing neurons (GnRH), promote hippocampal neuron survival, and preserve cortical neurons from β-amyloid plaques by preventing apoptosis. Apolipoprotein E4 (apoE4), a risk factor for Alzheimer's disease, has also been shown to be associated with low VitK levels. The role of VitK, which acts on extracellular signal-regulated kinase and cyclic adenosine monophosphate response elementbinding (CREB) proteins through stimulation of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated kinase (MAPK) signaling pathways, is associated with survival-promoting. The effect of VitK on the transcription factor CREB, which regulates the activity of neurotrophins associated with synaptic plasticity, is of particular interest [67].

VitK has the effect of alleviating various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and neuroinflammation. It prevents Parkinson's disease by interfering with α-syn fibrillation and contributes to reducing neuroinflammation by reducing the formation of TNF-α and IL-1β. VitK also correlated with increased nitrate/nitrite, decreased IL-6, decreased apoptotic cell density, and decreased glutamate transporter 1 mRNA expression. It helps prevent and alleviate Alzheimer's disease by increasing apoE4 and sphingolipid production and reducing Aβ production and H₂O₂ cytotoxicity, reactive oxygen species and apoptosis, and helps prevent multiple sclerosis by reducing cell infiltrating inflammation and major histocompatibility complex class II and inducible nitric oxide synthase expression [68].

Hepatoprotection

The prevention and treatment of liver diseases are very important since they are diverse, common, and often have a long-term course. The most common cause of chronic liver disease in Korea is hepatitis B virus, and chronic liver disease increases the risk of cirrhosis or hepatocellular carcinoma (HCC) [69]. Despite advances in treatment approach, the most important factor determining the long-term prognosis of patients with HCC is recurrence, and HCC has a high recurrence rate. Several studies have been conducted to overcome this, many of which were based on the hypothesis that VitK is effective in preventing recurrence and occurrence of HCC.

A study conducted to evaluate the chemopreventive effect of VitK2 on recurrence and survival after treatment of HCC patients randomly assigned hepatitis C virus antibody-positive HCC patients to an experimental group receiving orally menatetrenone containing 45 mg of VitK2 and control group and recurrence and survival rates were analyzed. The experimental group received oral administration of 45 mg of menatetrenone per day. The disease recurrence and survival rates of patients were analyzed. The results showed that the cumulative recurrence-free rates of the experimental and control groups were 92.3% and 71.7% at 12 months, 48.6% and 35.9% at 24 months, and 38.8% and 9.9% at 36 months. In the control group, these rates were 71.7%, 35.9%, and 9.9%, respectively. Confirming that VitK2 suppresses recurrence of HCC. The cumulative survival rates, however, were not statistically significantly different between the two groups [70].

The cytotoxic effect of VitK2 on HCC cells was observed in several in-vitro and in-vivo experiments [71]. The inhibitory action of VitK2 against HCC cell proliferation is associated with increasing expression of the cell-cycle regulatory protein p21 [72], suppressing the expression of hepatoma-derived growth factor [73], and G1 cell-cycle arrest through protein kinase A activation [74]. As such, VitK2 inhibits HCC cell growth through multiple pathways, which is a useful strategy for HCC treatment.

Furthermore, VitK2 induces HCC cell differentiation and apoptosis. In an in-vitro experiment, VitK suppressed malignancy in cancer cells and promoted expression in normal hepatocytes through suppressing connexin 43 expression and increasing connexin 32 activity [75]. In another study, the apoptotic effect of VitK2 was related to the mitochondrial pathway and the extrinsic apoptosis pathway through activation of the tumor-repressor gene p53 [76,77]. In addition, the effect of VitK2 in preventing tumor invasion in HCC cells through suppressing matrix metalloproteinase (MMP) expression was also reported [78].

In addition to studies on HCC, a study investigating the protective effect of VitK2 on liver regeneration using a partial liver resection rat model suggested that VitK2 promoted liver regeneration by significantly increasing serum albumin levels and simultaneously reducing the levels of alanine and aspartate aminotransferases [77]. Another study reported that combined treatment with VitK2 and angiotensin-converting enzyme inhibitor clinically improved liver dysplastic nodules in female patients with cirrhosis [79]. In-vitro experiments have speculated that this liver regenerative effect may be related to the regulation of matrilin-2 and hepatic oval cell proliferation [80]. In addition, a recent study found that VitK2 directly regulates the hepatocellular inflammatory response associated with hyperlipidemia by halting monocyte-hepatocyte adhesion through activating Gas6 carboxylation [81].

Although the mechanisms studied to date are limited to only part of the signaling network regulated by VKDPs and require further study, VitK2 supplementation at recommended doses not only has a positive effect on the prevention and treatment of malignancies, but also promotes liver regeneration and protection. It is clear that it is effective. Therefore, the VitK2 status of liver disease patients should be identified and appropriate strategies or guidelines must be established to improve the deficiency.

Covid/infection

Gastrointestinal symptoms such as abdominal pain, diarrhea, and vomiting were observed in one-third of patients in the early stage of coronavirus disease 2019 (COVID-19), and severe complications include acute respiratory distress syndrome, cardiomyopathy, acute renal failure, acute respiratory distress, sepsis, and severe complications. Complications such as pneumonia were also reported in one-third of them. Various studies on viral infection and clinical management of the disease have shown higher rates of COVID-19 infection in men compared to women.

A rapid rise in proinflammatory interleukin-6 (IL-6) was observed in severely ill COVID-19 patients requiring intensive care unit admission, and COVID-19 infection is known to activate cytokine/chemokine secretion, which is called ‘cytokine storm'. The onset of this phenomenon has a significant impact on the severity of the disease and is considered a negative prognostic indicator for multi-organ dysfunction and death. The anti-inflammatory effect of VitK, which has recently received attention, is mediated through reduction of prostaglandin E2, cyclooxygenase-2, and IL-6. VitK deficiency, which occurs due to intestinal malabsorption or malabsorption due to anticoagulants or long-term antibiotic treatment, has been observed to increase inflammatory cytokines, including IL-6 and C-reactive protein. Research results showed that VitK deficiency causes a cytokine storm through increased proinflammatory IL-6 and promotes inflammatory response by activating both cellular and humoral immunity. This is inflammatory response also contributes to VCs and thrombi, disseminate intravascular coagulation (DIC), which are hallmarks of microvascular damage observedin COVID-19 patients [82].

Indeed, research results confirm that VitK deficiency contributes to the induction of the cytokine storm through the increase of proinflammatory IL-6, activating both cellular and humoral immunity and promoting the inflammatory response. This inflammatory response may also contribute to the characteristic microvascular damage observed in COVID patients, including VC, thrombosis, and disseminated intravascular coagulation [83].

Respiratory failure and thrombosis are also common in severe patients with COVID-19, and VitK activates coagulation factors in the liver and extrahepatic endothelial anticoagulant protein S, which is necessary to prevent thrombosis. In the condition of VitK deficiency, intrahepatic procoagulant factors are activated before envelope proteins. Additionally, based on the fact that VitK activates MGP, which functions as a defense against pulmonary and vascular elastic fiber damage, the hypothesis was established that VitK is involved in the link between COVID-19 and pulmonary and thrombotic diseases [84].

In a controlled study, dp-ucMGP, an inactive VitK-dependent MGPs, and Prothrombin induced by VitK absence-II (PIVKA-II) were found to be inversely proportional to extra- and intrahepatic VitK concentrations, and dp-ucMGP was found to be inversely related to COVID-19. It was increased in patients compared to controls, and higher dp-ucMGP was observed especially in patients with poor prognosis. PIVKA-II levels were normal in 82.1% of patients, and dp-ucMGP also correlated with coronary and thoracic aortic calcification scores. In summary, dp-ucMGP was significantly increased in COVID-19 patients, resulting in extrahepatic VitK deficiency, which was associated with poor prognosis. These data suggest that pneumonia-induced extrahepatic VitK depletion disrupts the activation of MGP and endothelial protein S, leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 [85].

VitK deficiency, therefore, may worsen the prognosis in COVID-19 patients through worsening inflammatory response and coagulopathy, and prevention through appropriate supplementation of VitK is very important.

Osteoarthritis

Appropriate treatments to prevent the structural pathology of osteoarthritis (OA), the most common form of arthritis, have not yet been developed. VitK acts as a cofactor for γ-glutamyl carboxylase and plays an important role in the activation of γ-carboxyglutamate (Gla)-containing proteins, thereby reducing tissue calcification. Many studies have been conducted, therefore, based on the hypothesis that VitK is effective in preventing OA, the main cause of which is cartilage calcification.

A case-control study found that plasma VitK levels were lower in patients with knee OA compared to healthy controls and that higher levels correlated with thicker medial cartilage. The study also showed that OA patients with VitK deficiency had higher Western Ontario McMaster Scale (WOMAC) scores, which indicates disease severity. Another study using MGP as a marker of VitK status found that serum dp-ucMGP levels were lower in knee OA than in normal controls, and VitK levels were negatively correlated with arthritis severity [86].

Cohort studies have improved our understanding of the relationship between VitK status and OA. In the Multicenter Osteoarthritis Study (MOST) of 1,180 participants, VitK deficiency was found to be associated with the development of radiographic knee OA and cartilage damage based on VitK levels and knee magnetic resonance imaging images, where lower VitK levels tended to increase the incidence of OA on either side of the knee. This study, which reported a statistically significant modulation of VitD levels, has limitation that it did not consider lifestyle factors and other nutrients that may be involved in OA [87].

In the Health ABC Study, which analyzed the course of plasma VitK deficiency after 3 years, articular cartilage and meniscus damage were observed. Another study linked VitK deficiency to decreased cartilage thickness in the medial, lateral, and knee-hip joints, as confirmed by ultrasound evaluation and progression of OA [88].

Although several studies have reported that VitK prevents and slows the progression of OA, evidence from clinical trials is limited and further researches are required to determine the intake, supplementation dose, and type of VitK that is most effective. Data to date suggest that the best recommendation for preventing OA in older adults is maintaining adequate VitK intake.

Glucose control

Diabetes is an adult disease whose prevalence is gradually increasing in modern society, and many studies reported that VitK supplementation, through activation of OC (VKDP), regulation of adipokine levels, anti-inflammatory action, and lipid-reducing effects, improves insulin sensitivity and glucose tolerance, prevents insulin resistance, and reduces the risk of type 2 diabetes (T2D).

In the Framingham Offspring cohort study, after 12 months of phylloquinone intake, the 2-hour oral glucose tolerance test (OGTT), insulin concentration, and insulin sensitivity index (ISI0, 120) were assessed after adjustment for age, sex, waist circumference, life characteristics, and diet quality, and consumption of phylloquinone has been shown to increase insulin sensitivity and improve sugar levels [89].

Another study reported that phylloquinone supplementation lowered insulin resistance and fasting blood glucose in men but not in women [90]. Several studies have concluded that phylloquinone supplementation reduces the risk of T2D and that menaquinone supplementation has similar efficacy [91].

Results from a series of studies conducted in patients at high risk for T2D show a benefit from intake of two forms of VitK, phylloquinone and menaquinone. The intake required to reduce this risk was lower for menaquinone compared to phylloquinone, and some studies reported that menaquinone was more effective than phylloquinone in activating VKDPs, suggesting that menaquinone is more effective than phylloquinone in reducing the risk of T2D [89,90,91].

Teeth

The sugar consumption, regarding dental health, increases hypothalamic oxidative stress (ROS) and thus reverses dentinal fluid flow, making teeth vulnerable to oral bacterial flora. Acid produced by oral bacterial flora erodes tooth dentine, causes irreversible loss of the tooth enamel layer, and causes metalloproteinase-based dissolution, resulting in an inflammatory response. The antioxidant effect of VitK acts not only within the mouth but also systemically, reducing inflammatory responses in the mouth and body. In addition, VitK maintains and improves the buffering capacity of saliva by affecting the secretion/flux of calcium and inorganic phosphate. These observations imply that low-sugar and high-VitK diets improve dental health [92].

Dietary intake and oral supplementation

The ways to consume VitK2, which has those various positive effects, include consuming fermented foods. Unlike VitK1, which is found in leafy green vegetables, VitK2 is relatively less abundant in the Western diet, as it is present in large amounts in various fermented foods such as natto and in much smaller amounts in meat and dairy products. Overcoming this requires oral supplementation, and the recommended effective dose of MKs for cardiovascular health is 180–360 µg/day [24].

Since no side effects from excessive intake of VitK have not yet been reported and the World Health Organization (WHO) has not set an upper acceptable level for VitK intake, high intake of VitK through diet and oral supplementation is recommended to maintain bone and vascular health.

CONCLUSION

In conclusion, the multifaceted functions of VitK2 underscore its importance in various aspects of health, ranging from cardiovascular and bone health to neuroprotection, hepatoprotection, glucose control, and dental health (Fig. 1). The emerging understanding of VitK2's role in these domains suggests that it is not only necessary for maintaining optimal health but also for preventing and potentially treating certain conditions.

Fig. 1. Illustrated summary of the role of Vitamin K (VitK) in menopausal women. MGP: matrix Gla protein, CV: cardiovascular, VKDP: VitK-dependent protein, DM: diabetes mellitus, COVID-19: coronavirus disease 2019.

Key findings suggest that VitK2 supplementation can positively impact vascular health by inhibiting VC and reducing the risk of cardiovascular events. Additionally, it plays a crucial role in maintaining bone density and reducing the risk of fractures in individuals with osteoporosis. As evidenced by various studies conducted to date, VitK supplementation ultimately promotes the carboxylation of OC and MGP, increasing BMD and reducing VC. This supports the idea that VitK2 may play a crucial role in maintaining bone and vascular health. In relation to bone diseases, the ability of VitK2 to improve bone quality and reduce the risk of bone density loss and fractures has been elucidated by several clinical studies, confirming OC γ-carboxylation as a key mechanism through which this natural compound can enhance bone health. Additionally, VitK2 acts as a cofactor for the gamma-carboxylation of dp-ucMGP in VSMCs and chondrocytes, while the final phosphorylation of dp-cMGP inhibits connective tissue calcification, thereby reducing arterial sclerosis.

Therefore, VitK2 can regulate the “calcium paradox” by increasing calcium in bone tissue through the activation of OC and MGP, while reducing calcium deposition in vascular walls. Therefore, VitK2 may be recommended as a naturally occurring bioactive compound that can potentially prevent or treat metabolic bone and vascular diseases such as osteoporosis and VC. Especially in postmenopausal women, where osteoporosis and VC are more prevalent due to decreased estrogen levels, consuming VitK through diet and oral supplementation can be greatly beneficial for maintaining bone and vascular health.

Moreover, VitK2 demonstrates neuroprotective effects, potentially mitigating the progression of neurodegenerative diseases. It also shows promise in hepatoprotection, particularly in preventing the recurrence of HCC and promoting liver regeneration. Additionally VitK2 also has positive effect on inflammation including COVID-19. Furthermore, VitK2 supplementation may aid in glucose control, reducing insulin resistance and the risk of T2D. In terms of dental health, VitK's antioxidant properties contribute to maintaining oral health and preventing decay.

Dietary intake of VitK2 can be achieved through consuming fermented foods, although it is less abundant in Western-style diets. Therefore, oral supplementation may be necessary to ensure adequate intake, with recommended dosages ranging from 180–360 µg/day. Importantly, there is no documented evidence of toxicity associated with excessive VitK intake.

In summary, incorporating ample VitK2 through a combination of dietary sources and oral supplementation is crucial for promoting overall health and well-being, emphasizing its importance as a key nutrient in preventive healthcare strategies.