Two vitamins which often get discussed in isolation are vitamin D and vitamin K2. There is quite a relationship between these two nutrients and that interrelationship is critical to their function and the health benefits they provide.
Vitamin D is a hormone-based nutrient and its deficiencies across the world are well characterised.
Overview of Functionality
When the levels of vitamin D and K2 are optimal then we should expect to see a combination of benefits such as:-
- Better bone mineral density
- Reduced fracture risk in the bone
- Reduced vascular calcification
- Reduced soft tissue calcification or the impregnation of calcium into the soft tissues.
All of these benefits are supported by a number of biochemical events. Vitamin D in combination with vitamin K2 impacts significantly on vitamin K dependent proteins to function properly for a start. Vitamin D helps to increase the expression of inactive forms of two major proteins such as matrix Gla-protein (ucMGP) and osteocalcin (ucOC). Both these proteins are needed for the management of calcium in the body. These two proteins are activated by both vitamin D and K2 through carboxylation, from the inactive form to generate cMGP and cOC.
We will see what happens when levels of vitamin D and K2 in the body are insufficient, are deficient, imbalanced or there is an excess of one of these nutrients, then there is a profound impact on biochemistry.
There are a number of genes coded for in this process. Vitamin D is an activator of such genes especially in the expression of the Matrix GLA protein and osteocalcin. Vitamin K2 also operates like a hormone and it too can activate genes as well.
So, we have two powerful nutrients operating as hormones.
We can see that the combination of both vitamins is incredibly important in overall bone health, cardiovascular health and the management of calcium generally. Its as much about calcium balance and where calcium is deposited in the body. That deposition is normally in the bone but it can also end up in blood vessels and other soft tissues. The latter then is a pathological state created by an imbalance in these two vitamins.
There are now many studies examining the synergistic properties between vitamin D and K2 and its continually growing. There are at this moment in time, 22 interventional studies looking at bone, cardiovascular performance, various biomarkers of K2 and D performance, with one each on immunity and insulin metabolism. There are 11 observational studies into immune function, mortality and cardiovascular performance as well as biomarkers, bone and osteoarthritis. There are 11 in-vitro studies into bone, and one each on glucose metabolism and oxidative stress and then 6 animal studies also on bone and heart health.
The Dual Roles of Vitamin K2
Vitamin K2 has a dual role in both vascular and skeletal health, but also inflammation and oxidative stress. Generally, the biochemistry is complex but K2 alongside D coordinates calcium from a regulatory perspective under the influence of primarily vitamin K2. At a top level, a number of different proteins are essentially managing the flow of calcium and where it ends up. When K2 functions optimally [and which is outside the liver, because vitamin K1 is the dominant form in that organ operating on anticoagulation proteins], it is operating to prevent the pathological calcification of deposition of calcium where it doesn’t belong. K2 also differentiates cells which reduces cardiovascular risk by keeping the endothelium healthy by reducing calcium deposition and stopping plaques forming. It also stops bone mineral density being reduced which means fractures are minimised as well as kidney function being coordinated and functioning well.
The role of K2 in managing inflammation occurs by modifying and modulating NF Kappa B and interleukin 6 to interrupt signal transduction and modify then immune responses in the body, especially downstream inflammation. The growing area is managing oxidative stress because of its impact on mental health. Vitamin K2 activates 12-lipoxygenase which in turn prevents reactive oxygen species being produced and causing cell death. In an overall sense that is reducing oxidative injury and thus optimising mental health.
Bone Health
Osteocalcin
One study looked at the effect of vitamin K2 on osteocalcin in the presence and absence of vitamin D using isolated human osteoblasts. Osteoblasts are cells involved in building and restructuring our bone. It was found that higher doses of vitamin D3 alone caused production and greater accumulation of osteocalcin in the extracellular matrix. Vitamin K2 on its own had no effect on osteocalcin production etc. However, vitamin K2 enhanced vitamin D3-mediated osteocalcin accumulation in the extracellular matrix to greater levels than when it alone was present. The study emphasises the synergy of both vitamins in stimulating osteocalcin production and its activation.
Bone Microarchitecture
The microarchitecture of bone is about the microcrystalline architecture which involves a host of different nutrients like calcium, magnesium and phosphorous.
Vitamin K2 performance was explored in 148 healthy postmenopausal women in terms of managing the microarchitecture (microstructure) of the tibia in an interventional trial.
This was a double-blind, randomised and controlled study. It looked at supplementation with calcium (800mg/day) and with vitamin D (38micrograms/day), K2 MK-7 (375 micrograms/day) in combination. One group had calcium with vitamin D, another had K2, calcium and vitamin D. The study was over 12 months. In essence, vitamin K2 preserves the trabecular bone structure, preserves bone mineral density and also reduces uncarboxylated osteocalcin.
Here, K2 MK-7 prevents age-related deterioration of trabecular bone microarchitecture at the tibia in postmenopausal women. It means the bone keeps its strength and vitality as a result.
Bone Quality
A meta-analysis of various randomised controlled trials shows that a combination of vitamins K2 and D can significantly increase the total bone mineral density.
In this research the impact of vitamin K1 versus K2 plus vitamin D was assessed. It showed that there was a minor level of activity from K1 which is understandable because as mentioned before, in the liver rather than at the bone. Vitamin K2 is focused very specifically on bone mineral density. It also significantly decreases undercarboxylated osteocalcin with a more favourable effect than expected when vitamin K2 was present. In other words it increases the activity of osteocalcin so having a more favourable effect in the presence of vitamin K2.
Heart Health
Arterial Calcification
An animal study in rats shows there is an interplay between vitamins K and D . This study analyses the mineral accumulation of calcium in the abdominal aorta in rats on warfarin. Warfarin is a drug that causes a deficiency in vitamin K2. It also is apparent that when K2 is deficient and vitamin D is in excess there is an acceleration of the calcification of soft tissue, specifically the blood vessels. With the increased levels of calcification comes a reduction in survival rate of the rats because of this issue. So, vitamin K2 is important here in reducing this pathological condition.
Matrix Gla Protein (MGP)
In a biochemical study, the effect of vitamin D3 on MGP has confirmed the demand for K2 to activate MGP. MGP is a protein that is activated and expressed to protect the vasculature from calcification.
It is known that vitamin D3 activates the expression of the gene coding for MGP. When sufficient amounts of vitamin K2 are present, then MGP is carboxylated and then effectively binds calcium in the vascular system so decreasing the risk for vascular mineralization and hardening of the arteries.
It means that more vitamin K2 is required if MGP levels are to be maintained and then in an activated form.
Mortality
If the combined levels of vitamin D and K are low, then this status can be related to a higher mortality risk. To confirm this result, a prospective study was conducted on 4,742 subjects from the general population. The researchers were looking at levels of vitamin D, levels of Matrix Gla protein as a measure of vitamin K2 levels. They looked at all-cause mortality, cardiovascular events and mortality, the levels of Dp-ucMGP (dephosphorylated uncarboxylated matrix Gla protein). The follow-up time for the study was 15 years.
A high vitamin K2 and D status means that all-cause survival is the highest of all the those groups. Low vitamin D but high K status was next, then high D but low K2 but the worst case was low D and K2 status. It means that K2 has a more profound effect on mortality than expected.
Blood Pressure
A combination of low vitamin D and K2 status is associated with an increased blood pressure and a trend for a greater hypertension risk. This was noted in an observational trial with 402 mean and women between the ages of 55 and 65 years. The follow-up was between 4 and 6 years. The vitamin K status was measured from levels of Dp-ucMGP values.
The mechanism for this result is clear. When vitamin D and specifically when K2 levels fall, there is an increase in calcification of the arteries losing their flexibility and increasing their hardness. That results in this increased level of blood pressure in both diastolic and systolic values as well as a long-term increased risk of hypertension.
Arterial Stiffness
There is a synergistic effect of low vitamin K and D status on raised arterial stiffness.
In a cross-sectional study, 1,023 men and women from the general population were assessed in terms of their vitamin D and K2 status. The measure was pulse wave velocity. Again, this was explained by calcification of the arterial walls.
It seems that K2 is perhaps more important or significant here because it is needed for maintaining the flexibility of the vasculature. When K2 is low, vitamin D is helping unfortunately to maintain a higher than normal level of calcification and an increase in arterial stiffness.
A major trial, the AVADEC trial (Aortic Valve Decalcification Trial) is setting out to assess the effects on vitamin K2 supplementation in a change on the AVC score, levels of calcification of the coronary arteries including the carotid, aortic, renal, iliac and femoral arteries. The coronary arteries feed the blood vessels of the heart. When they harden and lose their elasticity they become restricted in terms of their blood flow and flexibility increasing the risk of myocardial infarction or heart attack.
The design is randomised, double-blinded, placebo-controlled intervention trial. It involves 389 males. It measured changes in coronary artery calcification (CAC). The intervention was 720 micrograms of MK-7 and 25 micrograms of vitamin D or a placebo daily over 2 years.
The results have yet to be published but was presented at the ESC Congress 2022 in Barcelona.
This study is showing the importance of K2 in terms of preventing aortic valve calcification.
It shows that in the group with the baseline CAC score that supplementation with both K2 and D slowed down the progression of coronary artery plaque development as well as the event rate in a population with a high CAC score.
Immunity
Vitamin D3 is produced as result primarily from sunlight exposure and from dietary intake. Vitamin K2 comes via dietary intake.
Vitamin K2 modulates inflammation as well as activating a host of proteins involved in bone and vascular health such as osteocalcin, MPG, Gas 6, protein C and protein S.
In terms of immunity, a study looked at 135 hospitalized patients with COVID-19. They found the levels of K2 are directly related to the production of interleukin 6 which is a strong inflammatory mediator and in terms of the destructive processes that are started by COVID-19 in the lungs. Interleukin-6 (il-6) is a central component of the destructive inflammatory process associated with COVID-19. In this study, vitamin D was not as significant as K2 which appears to mediate il-6 activity within the elastic fibres. It is limiting and mediating degradation.
It appears that a vitamin K and D deficiency is independently associated with a worse outcome from COVID-19. It means that K2 and D3 are mediating and modulating immune function, but that K2 has a broader effect in terms of protecting the lungs and the degradation of the elastic fibres preventing inflammation and potentially calcification of those lung tissues.
When K2 is deficient, we see an actual increase in the risk for worse outcomes and increase in the risk for a more severe COVID-19 disease outcome.
Summary
There is an extraordinary balancing act between vitamins D3 and K2. We know about the biochemical mechanisms by which vitamin D and K2 activate various proteins in bone health. The optimal levels of both vitamins are interactive and that balance point is absolutely critical. When vitamin D levels are increased in the body, the need for vitamin K2 must also rise to avoid an imbalance. An imbalance means that if an excess of vitamin D is present there can be a deficiency of vitamin K2 which is promoted because of the excess need for that vitamin.
The long-term vitamin D supplementation could promote production of large amounts of vitamin K-dependent proteins, which remain inactive because there is not enough vitamin K to be carboxylated. Its thus about maintaining a ratio.
The imbalance between vitamin D and K promotes an environment where excess calcium is deposited in our vascular tissues instead of our bones. This is a pathological state to be avoided.
A new report; the CRN Health Care Savings Report of 2022 shows that the use of dietary supplements by specific populations reduces the direct and indirect medical costs associated with several common conditions. In terms of vitamin K2, the net avoided costs for reducing cardiovascular disease were close to 9 billion US dollars. This was a cost-benefit ratio related to the investment in terms of vitamin K2 from the perspective of cardiovascular health.
So, long-term supplementation with different nutrients can make an extraordinary difference in terms of savings.
Leave a Reply