The Synergy of Vitamins D and K: Finding Health in Balance

The literature surrounding the numerous health benefits of vitamin D is so convincing that it has become routine to test for insufficiency and deficiency and supplement as needed. However, vitamin D does not act alone to provide those benefits. It works in connection with many other important nutrients in the body. New research points to vitamin K as one of vitamin D’s important partners, especially in terms of bone and cardiovascular health. Before we jump into the literature to see the synergy between the two, let’s review the highlights of each vitamin. 

The 411 on Vitamin D 

Unless you are just starting your foray into health and nutrition, you probably already know a lot about vitamin D. For the past decade, study after study has demonstrated the numerous benefits of this vitamin, which is actually a hormone. An umbrella review in 2014 found 74 meta-analyses of observational studies, 87 meta-analyses of randomized controlled trials, and 107 systematic literature reviews that explored the relationship between vitamin D and 137 different health outcomes. This demonstrates the sheer volume of literature out there. Although the umbrella review did not find highly convincing evidence, it did find suggestive evidence for a correlation between vitamin D levels and a variety of health outcomes, especially in specific populations. 

Conditions to which a link with vitamin D has been found include musculoskeletal disorders including osteoporosis, cancer, autoimmune disorders, metabolic disorders, diabetes, heart disease, Alzheimer’s disease, and infectious disease. 

The key areas vitamin D plays a physiological role in are: 
– Promotion of calcium absorption 
– Calcium homeostasis
– Mineralization of bone
– Immune function
– Reduction of inflammation
– Neuromuscular function
– Modulation of cell growth
– Modulation of key genes for body processes 

The classic diseases of vitamin D deficiency are rickets and osteomalacia. Beyond lack of exposure to sunlight or consumption of vitamin D, those with kidney problems or malabsorption issues, especially problems absorbing fat, might have a high risk of deficiency.  

The recommended dietary allowances for vitamin D, per the Food and Nutrition Board, is 15 ug/day for children and adults, with those over the age of 70 needing 20 ug/day and infants needing just 10 ug/day. There is some contention as to the level required to be considered vitamin D deficient. Currently, the Institute of Medicine considers deficient levels under 30 nmol/L, insufficient levels between 30 and 50 nmol/L, and sufficient levels greater than 50 nmol/L. The Endocrine Society states that the serum concentration should be more than 30 ng/ml or 75 nmol/L. 

The 411 on Vitamin K 

Vitamin K is an oft-overlooked vitamin that does much more than just help with blood clotting. There are two main categories of compounds under the distinction of vitamin K: phylloquinone (K1) and menaquinones (K2). The main purpose of vitamin K is to act as a coenzyme for vitamin K-dependent carboxylase, which is involved in synthesizing important proteins in blood clotting, bone metabolism, and other physiological processes. Another important vitamin-K-dependent protein is Matrix Gla-protein, which is found in bone, cartilage, and smooth muscle. Osteocalcin, a protein in bone, also requires vitamin K.  

Although it is a fat-soluble vitamin, it is rapidly metabolized and excreted, so it has much lower tissue storage levels and blood levels than other fat-soluble vitamins. The gut microbiota synthesizes some vitamin K, although the exact amount and usage of it is unclear. The most important physiological functions of vitamin K include: 
– Bone formation
– Blood clotting
– Prevention of arterial calcification
– Regulation of glucose metabolism and insulin sensitivity  

The adequate intake of vitamin K according to the Food and Nutrition Board is 120 ug/day for adult men and 90 ug/day for adult women, with lower ranges for children and teenagers.    

Although vitamin K insufficiency is not as common as other vitamin insufficiencies, there are populations at greater risk. For example, those who have malabsorption disorders or who take certain blood thinner medications such as warfarin that are vitamin K antagonists have greater risk of insufficiencies. Newborns are also at a high risk, which is why it has become common practice to provide infants with a shot of vitamin K soon after birth. Additionally, the majority of the American population does not consume sufficient quantities of vitamin K, with only 43 percent of men and 62.5 percent of women meeting the adequate intake number, according to data from NHANES 2011-2012 

Synergy of Vitamins D and K  

Researchers are starting to discover an important synergy between vitamins D and K. Some in vitro studies point to vitamin D positively impacting certain bone proteins dependent on vitamin K by increasing their concentrations to induce the formation of bone. Animal and human studies further support these findings through demonstrating that taking vitamin D and vitamin K together have a larger impact than taking vitamin K alone. The inclusion of vitamins D and K with calcium also leads to a bigger effect than taking calcium alone, especially in terms of bone health.  

An important hypothesis to bear in mind is that if vitamin D and K have a synergistic relationship, specifically if vitamin D increases protein concentrations of vitamin K-dependent proteins, then taking high levels of vitamin D supplementation without supporting vitamin K levels through diet or supplementation could lead to an excess of these proteins without sufficient vitamin K to work. This could lead to dysfunction in proteins that play a key role in inhibiting calcification and stimulating bone mineralization.  

When taking high levels of calcium, the balance of vitamin D and K becomes even more important. If there is a balance between vitamin D and K, high levels of calcium intake might not become problematic. However, if there is an imbalance, then the excess calcium might become deposited in the vascular tissue rather than the bone, leading to both osteoporosis and atherosclerosis. 

Let’s see what the literature says about the ways vitamin D and K work together to support health. 

Bone Health  

In a case-control study of 116 Norwegian adults, having low vitamin D and K levels was associated with hip fractures. In the group with low vitamin K1 concentration, the odds of having a hip fracture were three times higher in those who also had a low vitamin D level compared to those with a high vitamin D level. 

A similar study with more participants found that after an 8.2-year follow-up, having low levels of both vitamin D and K led to a 50 percent increased risk of experiencing a hip fracture compared to those with the highest serum levels of the vitamins. The findings remained significant even after adjusting for confounding factors such as BMI, sex, age, smoking, and triglycerides. Having low vitamin K and high vitamin D also had a higher hazard ratio at 1.17, although it was not significant. Having a low vitamin D status but high K had a 0.97 hazard ratio (non-significant), while the group with high levels of vitamin K and high vitamin D was used as a reference. 

In one study over a period of two years on healthy women aged 60 and older, taking combined vitamin D and K led to an increase in BMD, while taking just one of the vitamins did not. In a randomized, double-blind, placebo-controlled trial, 244 participants were put into four different groups: placebo (control), 200 ug/day of vitamin K1, 100 mg calcium with 400 IU vitamin D3, or vitamin K1 with calcium and vitamin D3.  

In this study, all groups experienced a decrease in BMD from baseline in the radius. However, there was a significant increase in bone mineral density (BMD) in the group taking vitamin K plus calcium and vitamin D at 0.8 percent per year. At the ultra-distal radius, there was a significant gain in unadjusted bone mineral content (BMC) in the group with combined supplementation. The placebo group did see a slight rise in the ultra-distal radius in BMD and BMC, but it was not significant. The vitamin D group, combined group, and placebo group saw rises in the femoral trochanter BMC. 

In another study lasting two years, the subjects in the combined therapy group had a BMD increase of 45.2 percent, compared to 9.4 percent in the K2 only group and 23.3 percent in the vitamin D3 only group. Additionally, out of the responders in the combined therapy group, 67.8 percent experienced an increase in BMD of 2 percent or higher. There was also a significant change in BMD after just six months of therapy in the group taking both K2 and D3. During the study, the subjects took K-2 menaquinone-3 (Glakay 45 mg per day), vitamin D3 (10a hydroxycholecalcifrerol Onealfa 1 ug per day), or both. There was also a control group that had dietary therapy only.  

In a randomized, single-blind, 2-arm, placebo-controlled trial that lasted for 14 weeks, making lifestyle changes combined with taking a nutraceutical supplement containing RIAA, berberine, vitamin D3, and vitamin K1 led to better markers for bone health in healthy postmenopausal women. The researchers instructed all participants to switch to a modified low-glycemic load diet in a Mediterranean pattern with no limits on caloric intake as well as adopt an exercise regimen that consisted of 150 minutes per week of aerobic activity. The study started with a 2-week lead-in during which all participants took a placebo twice a day. In week 3, participants were randomized into either continuing the placebo or taking a tablet consisting of 200 mg hop rho iso-alpha acids, 100 mg berberine sulfate trihydrate, 500 IU vitamin D3, and 500 ug vitamin K1. They continued the lifestyle changes and no one was given calcium supplementation.  

At baseline, the participants had elevated serum OC (an osteoblast product and a biomarker for bone turnover). Both groups were vitamin D sufficient, with levels above 75 nmol/L. The treated participants saw a mean reduction of 34 percent in serum OC at 10 weeks and 31 percent at 14 weeks compared to their baseline measurements, while the placebo arm had a 19 percent increase at 14 weeks. The placebo group also saw a decrease of serum vitamin D levels, while the treated group had an increase of 8 percent and 13 percent at weeks 10 and 14 respectively. Additionally, the treatment group experienced a significant increase in serum IGF-I (a biomarker for bone formation) at 10 and 14 weeks.   

Sufficient vitamin D and K can also help improve osteoarthritis in the knee. Researchers reviewed data in two knee osteoarthritis cohorts to see the relationship between vitamins D and K and knee function. In the Health ABC Knee OA sub-study, the group with sufficient levels of circulating K1 (at or above 1.0 mol/L) and vitamin D (at or above 50 nmol/L of 25(OH)D) had improved physical performance battery scores and had a faster gait speed during the baseline and follow up compared to the groups who had sufficient levels of just one of the vitamins or low levels of both. Another study, the OAI, confirmed this finding. In this study, those who consumed adequate intake of both according to the IOM recommendations at baseline had a faster gait speed and chair stand completion time than those who were insufficient in one or both of the vitamins.  

Heart Health  

The synergy between vitamin K and D also plays a role in maintaining the health of your heart. In one study looking at just over 1,000 Czech men and women aged between 25 and 75 years, researchers found a correlation between lower levels of both vitamin D and K levels and increased aortic pulse wave velocity (aPWV), which estimates risk for cardiovascular problems and predicts morbidity and mortality.  

After dividing the groups into 16 subgroups, the researchers found that the highest aPWV levels were in those with low status of both vitamins. When looking at just vitamin D, there was only a significant difference in those who also had low vitamin K status. There was an adjusted odds ratio of 6.83 for having a high aPWV in those who had low vitamin status. In those with high vitamin D status, there was a small, nonsignificant increase in those with a low vitamin K status compared to those with high vitamin K status. Conversely, those with low vitamin D status had 15 times higher relative risk of an increased aPWV if they also had low vitamin K.  

In one prospective cohort study, low vitamin D and K had an association with higher systolic and diastolic blood pressure. The researchers looked at data from the second Longitudinal Aging Study Amsterdam (LASA) with a sample of 231 participants aged between 55 and 65 years at baseline. About 19 percent of the sample fell into the low vitamin D and low vitamin K group (dp-ucMGP greater or equal to 323 pmol/L and 25(OH)D less than 50 nmol/L). This group correlated with the group that had the highest blood pressure.  

After adjusting for sex and age, those with low levels of vitamins K and D had an increased systolic blood pressure reading by 6.5 mmHg compared with the high vitamin D and K group. Even after adjusting for other confounders, the results were significant, with a 4.8 mmHg increase. For diastolic blood pressure, the group with low levels of both vitamins had a 4.2 mmHg increase, which was significant, and an adjusted increase of 3.1 mmHg, which was also significant. The group that had high vitamin D and low vitamin K also had a significantly higher diastolic blood pressure at 2.8 mmHg compared to the reference group. There was also an increase in the incidence of hypertension after the follow up period of six years. Those in the low vitamins D and K group had a hazard ratio of 1.69 for developing hypertension compared to the control group. However, upon adjusting for additional confounders, it dropped to 1.62, which did not remain significant.  

In one study, taking a supplement with both vitamin K and D (320 IU vitamin D and 1000 ug of vitamin K1 per day) led to maintained characteristics of the vessel wall in the carotid artery in postmenopausal women, while the control group and the group taking vitamin D alone had significant worsening during the 3-year follow up.  

Metabolic Health  

Another key area of interest in which the benefits of K and D have been identified is metabolic health, specifically in helping to maintain glucose metabolism and inflammation. In one study, women with PCOS who supplemented with 400 IU vitamin D, 180 ug vitamin K, and 1,000 mg calcium for 8 weeks had improved lipid concentrations and markers for insulin metabolism compared to those who were on a placebo. They also had improved markers for makers of oxidative stress, although the markers for inflammation did not change. 

In a randomized, double-blind, placebo-controlled trial in Iran, researchers looked at the impact of vitamin D and K supplementation along with calcium on metabolic health. The inclusion criteria included individuals aged between 40 and 85 years who had a BMI at or above 25 and had a diagnosis of type-2 diabetes. Groups were matched based on age, sex, medication and dosage, and BMI. Then, they were randomly assigned to intervention or placebo. The treatment group received 90 ug of vitamin K (form MK-7), 500 mg calcium, and 5ug vitamin D. There was a compliance rate above 90 percent. After 12 weeks, the group supplementing had a significant reduction in the maximum levels of left CIMT compared to the placebo group, although the treatment had no impact on mean left and right CIMT or maximum CIMT. Supplementation did lead to significant changes in serum levels of calcium, vitamin D, and insulin. There was also a significant increase in HDL-cholesterol and a decrease in hs-CRP and MDA.  

 Additional Health Benefits  

One study that looked at the co-supplementation of vitamin D, K, and calcium found benefits for women with PCOS. In a randomized, double-blind, placebo-controlled trial, one group took 200 IU vitamin D, 500 mg calcium, and 90 ug vitamin K plus or placebo two times per day for a period of eight weeks. The researchers reviewed biomarkers for inflammation, oxidative stress, and hormone levels at the beginning and end of the study. They found a significant reduction in serum free testosterone (-2.1 compared to 0.1 pg/ml) and DHEAS (-0,8 compared to -.1 ug/ml). There was also a significant difference in MDA concentrations and total antioxidant capacity (TAC), with those taking the supplements exhibiting an increase of 75.7 mol/L in TAC compared to the placebo group, which had a decrease of 80 mol/L of TAC. There was also a trend for a stronger decrease in luteinizing hormone in those who took the supplements. There was no significant change in FSH, 17-OH-progesterone, prolactin, glutathione, or inflammation markers. 

In many of these studies, having sufficient levels of both vitamins D and K had the greatest positive impact on health. In some, vitamin K levels had a larger role in the result than vitamin D, demonstrating the importance of not just supplementing with vitamin D but to also ensure you consume sufficient levels of vitamin K or supplement accordingly. 

How to Get Sufficient Vitamins D and K  

Sunlight and Vitamin D 

Upon exposure to sunlight, your body synthesizes vitamin D in the skin. When your skin comes into contact with ultraviolet B radiation from the sun, it converts 7-dehydrocholesterol into previtamin D3. There are two steps to the creation of vitamin d: taking vitamin D into the liver and converting to 25-hydroxyvitamin D or caldidiol. Then, the kidneys convert this into the active form, 1,25-dihydroxyvitamin D or calcitriol. Blood tests for vitamin D typically measure 25-hydroxyvitamin D. 

Factors that could reduce the ability of your skin to absorb sufficient levels of UVB to convert the cholesterol into vitamin D include: 
– Clothing
– Cloud coverage
– Glass
– Melanin content of the skin
– Season
– Shade
– Smog
– Sunscreen
– Time of day  

Generally, sitting in the sun between 10 AM and 3 PM for 5 to 30 minutes at least two times per week with uncovered arms, legs, face, or back should be sufficient for vitamin D synthesis. However, many people do not spend enough time outdoors and must find vitamin D in their diet or take vitamin D supplements. Care also must be taken to balance getting enough sun for vitamin D synthesis and protecting against skin cancer and other possible harm from the UV rays of the sun.  

Even in high latitudes, enjoying the sunshine is a strong predictor of sufficient vitamin D status. Researchers reviewed data from an all-Irish cohort consisting of 5,286 individuals who were over 60 years of age, were ethnically Irish, and had no dementia diagnosis. The researchers took information through a detailed sociodemographic, lifestyle, and health questionnaire that included their exposure to the sun. They determined the UV dose data using data from the Tropospheric Emission Monitoring Internet Service, giving each participant a grid cell based on their residence. There were consistent findings that those who enjoyed sunshine had higher serum 25(OH)D concentrations compared to those who avoided it. In those with higher ambient D-UVB radiation who were not taking supplements had levels higher than 20 nmol/L. The most common characteristics of the group in the insufficient range were those who were in the lowest quartiles of cw-D-UVB, avoided the sun, and did not supplement.  

Thus, even in higher latitudes among an older population, who generally synthesis less vitamin D than younger populations, spending time in the sun still made a big difference in ensuring ample serum vitamin D levels. 

Food Sources of Vitamin D 

Although your body can synthesize vitamin D, most people are deficient due to lifestyle factors and protection against skin cancer. One way to help increase your vitamin D levels is to consume it in your food.  The foods highest in vitamin D2 and D3, in order from greatest to least, are mushrooms, fish like halibut, carp, mackerel, eel, and salmon. Mushrooms are the best source of vitamin D2, while fish is the best source of vitamin D3. The fish species richest in vitamin D3, from greatest to least, are: 
– Halibut
– Carp
– Mackerel
– Eel
– Salmon
– Swordfish
– Trout
– Tuna 

Other foods rich in vitamin D include eggs, milk, and fortified foods, including some varieties of soy and almond milk. 

Although fish is rich in vitamin D3, you also have to be careful of mercury and other toxins. Generally, species higher up in the food chain, such as swordfish, mackerel, and tuna have the highest levels of mercury. It is also best to find wild-caught fish rather than farmed fish. 

Food Sources of Vitamin K  

Foods richest in phylloquinone, from greatest to least, include: 
– Kale
– Collard greens
– Spinach
– Parsley
– Lamb
– Turnip and mustard greens
– Beet greens
– Swiss chard
– Brussels sprouts
– Spring onions
– Broccoli 

Basically, if you eat your greens, you will consume sufficient levels of vitamin K. You can find K-2 or menaquinones in some animal and fermented foods such as cheese. Bacteria in the gut also synthesize K2. 

Tips for Supplementing  

Although vitamin D is very important, too much might become toxic. At high levels, vitamin D has been found to cause calcification of the tissue and vascular system, polyuria, and heart arrhythmia. The tolerable upper limit (TUL) for vitamin D is 100 ug/day for adults, which is the equivalent of 4,000 IU. Children and infants have a lower TUL. There is no defined TUL for vitamin K, per the Food and Nutrition Board, but that does not mean that adverse events cannot happen if you consume excessive levels in supplement form.  

When you supplement with both vitamin K and D, it is important to know what form of the vitamin is in the supplement. It is common to find phytonadione, a synthetic vitamin K1, in supplement form rather than the natural phylloquinone. It is best to try to supplement with phylloquinone when possible. You can also find supplements that have K2. For vitamin D, you have an option of D2 or D3.  

Vitamin K has the potential to interact with certain medications, especially vitamin-K antagonists like Warfarin. It is important to discuss supplementing with vitamin K with your doctor, especially if you are on any type of anticoagulant.  

Concluding Remarks 

So, perhaps when I stated in a previous blog that vitamin K was the new vitamin D, I should have said that vitamin K was vitamin D’s best friend instead. Just as it is important to have sufficient levels of vitamin D for many body processes, it is also important to have sufficient levels of vitamin K. With the two working in synergy, you cannot forget about balance. With too much vitamin D without sufficient vitamin K, you could end up leading to dysfunction rather than benefiting from the advantages associated with vitamin D.



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