Vitamin K-7 needed to keep Calcium out of soft tissues - Dec 2025
Vitamin D and Vitamin K: Synergistic Roles and Emerging Evidence for Combined Supplementation
Journal of Mid-life Health 16(4):pg 505-508, Oct–Dec 2025. DOI: 10.4103/jmh.jmh_169_25
Khandelwal, Ankur; Ahmed, Kashif Akhtar1; Dikshit, Priyadarshi2 Author Information
The synergistic role of Vitamin D (VD) and Vitamin K (VK) in maintaining skeletal and cardiovascular health has garnered increasing scientific interest. While VD is well known for its role in calcium metabolism, VK, particularly its K2 isoform, ensures that calcium is deposited in bones and not in soft tissues. Recent evidence suggests that the interplay between these two fat-soluble vitamins may have significant implications for bone health, vascular integrity, and chronic disease prevention. This editorial explores current research on their combined supplementation, potential therapeutic benefits, and the caution warranted in clinical practice.
INTRODUCTION
For decades, Vitamin D (VD) has occupied center stage in discussions around bone metabolism, immune function, and chronic disease prevention. However, emerging data have turned the spotlight toward vitamin K (VK), a lesser-known but equally vital nutrient, especially in the context of VD supplementation. Together, these vitamins may offer synergistic benefits that exceed the sum of their individual actions. While VD is well known for its role in calcium metabolism, VK, particularly its K2 isoform, ensures that calcium is deposited in bones and not in soft tissues. Understanding this interaction is critical, especially as VD supplementation becomes more prevalent globally.
DISTINCT ROLES, COMPLEMENTARY FUNCTION
VD, primarily in its active form calcitriol (1,25(OH)2D3), facilitates the absorption of calcium from the intestine. It also modulates immune responses and influences cell differentiation. Conversely, VK, particularly K2 isoform (menaquinone), is essential for the carboxylation of VK-dependent proteins such as osteocalcin and matrix Gla protein (MGP). When carboxylated, these proteins appear to have the ability to chelate and import calcium from the blood to the bone, thereby reducing the risk of osteoporosis. Carboxylated osteocalcin binds with hydroxyapatite to promote bone mineralization and increase bone strength. Further, activated MGP also inhibits vascular and soft-tissue calcification.[1,2]
VD enhances calcium absorption; however, without adequate VK, this can lead to improper calcium utilization and ectopic calcification, particularly within arterial walls. Studies linking VD supplementation to increased vascular calcification in the absence of sufficient VK have led experts to caution against high-dose VD supplementation unless VK status is also adequate.[3,4]
EVIDENCE FOR VITAMIN D AND VITAMIN K SYNERGISM
Bone health
A meta-analysis of eight randomized controlled trials (RCTs) involving 971 subjects found that the combination of VK and VD significantly increased total bone mineral density (BMD) and decreased levels of undercarboxylated osteocalcin. Simultaneously, subgroup analysis showed that VK2 or VK (not specified) supplement was <500 μg/day, which, when combined with VD, significantly increased the total BMD compared with the control group fed a normal diet or the group with no treatment.[5]
Rønn et al. conducted a double-blinded RCT involving 142 postmenopausal women with osteopenia, who received either VK2 (375 μg/day) or a placebo for 3 years. Both groups also received VD3 (38 μg/day) and calcium (800 mg/day). The study found that VK2 supplementation increased the carboxylation of osteocalcin compared to the placebo group, which received only VD3 and calcium. However, changes in bone turnover biomarkers, BMD, and bone microarchitecture were similar between the subgroups with and without VK supplementation.[6]
A recent meta-analysis by Ma et al., including 16 RCTs, evaluated VK2 supplementation in postmenopausal women with and without osteoporosis (excluding studies with VK1). The analysis focused on changes in BMD, fracture risk, and osteocalcin levels. VK2 improved lumbar spine BMD in 10 studies, but significant benefits were seen only when combined with VD, calcium, or bisphosphonates. It also reduced fracture risk (based on five studies) and lowered uncarboxylated osteocalcin levels, with no change in carboxylated osteocalcin.[7]
Wang et al. conducted a prospective study on 71 osteoporotic patients undergoing endoscopic lumbar interbody fusion to assess the impact of combined VK2 and VD3 supplementation. Patients receiving VK2 (45 mg/day), VD3 (250 IU/day), and calcium showed significantly higher fusion rates at 6 months (91.67% vs. 74.29%, P = 0.044) compared to controls receiving only VD3 and calcium. Serum procollagen type I N-terminal propeptide levels were also significantly higher at 3 months in the supplemented group (P = 0.001). Although BMD changes were not statistically different, a positive trend was observed. Clinical improvements were similar in both groups. Overall, the combination may enhance early fusion outcomes.[8]
Cardiovascular health
A prospective study from the Longitudinal Aging Study Amsterdam investigated the joint impact of low VD and VK status on blood pressure and incident hypertension in Dutch adults aged 55–65 years. Among 402 participants, low levels of both vitamins were associated with significantly higher systolic (↑4.8 mm Hg) and diastolic (↑3.1 mm Hg) blood pressure compared to those with sufficient levels. In 231 participants without hypertension at baseline, 62% developed hypertension over a median 6.4-year follow-up. Those with low VD and VK had a 62% higher risk of incident hypertension (hazard ratio = 1.62). These findings suggest that combined deficiencies may adversely affect vascular health.[9]
A prospective study from the Hoorn cohort among Dutch Caucasian adults examined the combined impact of low VD and VK status on cardiovascular health and mortality. Among 601 older adults, those deficient in both vitamins had significantly increased left ventricular mass index, indicating adverse cardiac remodeling and a 64% higher risk of all-cause mortality compared to those with adequate levels. VD and VK status were assessed using serum 25(OH) D and plasma desphospho-uncarboxylated matrix-gla protein (dp-ucMGP), respectively. The study suggests a synergistic detrimental effect of concurrent deficiencies on cardiovascular structure and survival. These associations were linked to mechanisms such as activation of the renin–angiotensin–aldosterone system, increased arterial stiffness and pulse pressure, reduced BMD, higher fracture risk, and enhanced vascular calcification. The study highlights the potential importance of monitoring and addressing both VD and VK status in older populations.[10]
A prospective study from the Prevention of REnal and Vascular ENd-Stage Disease cohort investigated the association of plasma VD and VK levels with mortality and cardiovascular outcomes in 4,742 participants. VD was assessed via 25(OH) D and VK via dp-ucMGP levels. Over a median 14.2-year follow-up, 620 participants died, including 142 from cardiovascular causes. Individuals with combined low VD (<50 nmol/L) and VK (dp-ucMGP ≥361 pmol/L) status had a 46% higher risk of all-cause mortality compared to those with adequate levels of both. Similar, though nonsignificant, trends were observed for cardiovascular mortality and events. The findings highlight the potential importance of maintaining sufficient VD and VK status to reduce mortality risk.[11]
The Aortic Valve Decalcification multicenter double-blind RCT investigated whether VK2 and VD supplementation reduces coronary artery calcification (CAC) progression in 304 participants without prior ischemic heart disease. Over 2 years, both groups showed CAC progression, with no significant overall difference (P = 0.089). However, in high-risk patients (CAC scores ≥400 arbitrary units), the intervention group had significantly less CAC progression (P = 0.047). No significant changes were found in noncalcified plaque volume. Notably, the intervention group experienced fewer adverse cardiovascular events (1.9% vs. 6.7%, P = 0.048), suggesting potential benefit in select high-risk individuals.[12]
CLINICAL IMPLICATIONS
Given these findings, clinicians may need to reconsider prescribing VD in isolation, especially in elderly, osteoporotic, or cardiovascular-risk populations.
VD without VK may lead to increased calcium in the blood without ensuring its proper deposition in bones
Combined supplementation may offer a protective cardiovascular profile while also improving skeletal health.
Importantly, VK2 appears to be more beneficial than K1 in this context, given its longer half-life, extrahepatic activity, and better tissue distribution. MK-7 has higher efficacy due to its higher bioavailability and longer half-life than other VK homologs.[13]
DIETARY SOURCES
VD: cutaneous synthesis via sunlight exposure (major source); fortified dairy, fatty fish, sun-exposed mushrooms, and egg yolks (minor sources)[14]
VK1 (Phylloquinone): Green leafy vegetables[15]
VK2-MK4 (menaquinones): Some meats, eggs, and cheeses[15]
VK2-MK7 (menaquinones): Fermented foods (natto), certain cheeses[15]
Long-chain menaquinones (e.g., MK-10–MK-13): Colon bacteria.[15]
SUGGESTED DOSE FOR SUPPLEMENTATION {MK-7: 100–300 μg/day}
While no formal guidelines currently recommend combined supplementation, several experts suggest the following doses to prevent and treat VD and VK deficiencies in adults.
VD3: 1000–2000 IU/day (Adjust based on serum 25(OH) D levels)[16,17]
VK2 (MK-7): 100–300 μg/day (Especially in those taking VD).[18]
Caution: Patients on VK antagonists (e.g., warfarin) should consult their physician before supplementation.
AREAS OF ONGOING RESEARCH
Diabetes and insulin sensitivity: Recent studies have shown that circulating levels of VD and VK are reduced in individuals with type 2 diabetes mellitus, showing significant correlations with blood glucose levels and insulin resistance, while combined supplementation with VD3 and VK2 has been found to significantly reduce blood glucose levels[19,20]
Cancer and inflammation: VD and VK both possess anti-inflammatory and anti-proliferative properties. Their synergistic roles in cancer prevention are under investigation[21,22]
COVID-19 and Immune Function: Interest in both VD and VK surged during the COVID-19 pandemic. Observational studies have shown that deficiencies in both vitamins are independently associated with greater COVID-19 disease severity, suggesting a potential synergistic interplay between them.[23,24] A recent study has demonstrated that a daily dose of 2000 IU of VD3 and 240 μg of VK2 over 24 weeks could help improve symptoms of long COVID by reducing the total number of symptoms secondary to the reduction of the hyper-inflammatory state. VD3 and VK2 supplementation was also effective in reducing gut permeability and fungal translocation, both of which are important factors in the pathophysiology of long COVID.[25]
CONCLUSION
The interplay between VD and VK offers a compelling example of nutrient synergy. While each is indispensable on its own, their combination seems to provide enhanced benefits for bone and cardiovascular health, especially in aging populations. As evidence mounts, the medical community must shift from viewing VD in isolation to considering the broader nutritional context. Incorporating both vitamins into preventive and therapeutic strategies could mark a significant advance in functional nutrition and integrative medicine. Until large-scale, multicenter trials yield definitive recommendations, clinicians should assess individual vitamin status and consider personalized supplementation, particularly in high-risk groups.
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