Calcium is a valuable but demanding building material. In bone, it helps form the structure that supports the body throughout life. In the walls of arteries, however, its deposition can contribute to stiffening them. Keeping calcium involved in the right places and processes requires a remarkably precise regulatory system. Vitamin K is part of that system, and some of its forms, particularly vitamin K2, have attracted growing scientific interest.
A family with two branches: Vitamin K is not a single molecule but a family of compounds. Vitamin K1, or phylloquinone, comes mainly from plants and is abundant in leafy green vegetables.
Vitamin K2 comprises the menaquinones, identified by the abbreviation MK followed by a number, such as MK-4 or MK-7. The number indicates the length of their side chain, determined by the number of isoprenoid units it contains. Many menaquinones are produced by bacteria and are found in fermented foods such as natto, made from fermented soybeans, and in certain aged cheeses.
K1 and K2 belong to the same family, but they do not behave in exactly the same way in the body. K1 is preferentially taken up by the liver, whereas some long-chain menaquinones, such as MK-7, remain in the circulation for longer and reach tissues outside the liver more readily.
There is therefore no absolute division of labour between K1 and K2. Their pharmacokinetic properties and distribution differ, and those differences help explain the particular interest in some forms of K2.
Calcium’s tools: Imagine newly made proteins that do not yet have all the tools they need to perform certain functions. Vitamin K is involved precisely at this stage.
It acts as a cofactor for an enzyme called gamma-glutamyl carboxylase. This enzyme modifies specific glutamic acid residues in proteins, converting them into gamma-carboxyglutamic acid residues, known as Gla. This modification gives the proteins a greater ability to bind calcium.
When vitamin K is insufficient, a larger proportion of these proteins remains uncarboxylated and their functional activity is reduced. Several vitamin K-dependent proteins are involved in blood coagulation, while others, produced outside the liver, are associated with bone metabolism and the regulation of calcification.
The first examples discovered were the clotting factors. This is where the letter K comes from, from Koagulation, the German word for coagulation.
This relationship also explains how vitamin K antagonists such as acenocoumarol and warfarin work. These drugs interfere with the recycling of vitamin K and thereby reduce the activation of certain clotting factors.
There is an important point here. Vitamin K does not transport calcium like a delivery vehicle. It provides certain proteins with the chemical modification they need to perform their functions. The foreman metaphor helps explain this coordinating role, provided that we do not take it literally.
Working alongside vitamin D: Vitamin K2 does not work in isolation. Vitamin D enters the same story at another point in the chain.
Vitamin D obtained through sunlight exposure or the diet must be transformed within the body until it reaches its active hormonal form, calcitriol. One of its functions is to stimulate the production of proteins involved in calcium metabolism, including osteocalcin and matrix Gla protein, or MGP.
Vitamin K then participates in the carboxylation of these proteins, helping them reach their functional form.
This relationship provides a reasonable biochemical explanation for the popularity of supplements combining vitamin D3 and K2. But a biochemical rationale does not, by itself, demonstrate that the combination produces a greater clinical benefit than either vitamin alone.
The distinction matters. It is well established that both vitamins participate in physiological pathways involving calcium-regulating proteins. Whether giving both as supplements produces a meaningful improvement in bone or cardiovascular health is a different clinical question and requires trials designed to measure those outcomes.
Biochemistry suggests a plausible partnership. Clinical research must determine how far that partnership actually extends.
Bones and arteries: Two proteins help explain much of the interest in vitamin K2.
The first is osteocalcin, produced by osteoblasts, the cells responsible for forming bone. Its carboxylation depends on vitamin K and affects its ability to bind calcium and participate in processes related to the mineralisation of the bone matrix.
The second is matrix Gla protein, or MGP. It is produced, among other places, in the arterial wall and participates in mechanisms that limit vascular calcification. Its activity also depends on vitamin K-dependent modifications.
When vitamin K availability is insufficient, the proportion of certain uncarboxylated forms of these proteins increases. Some of them can be measured in the blood and used as indirect markers of the functional status of vitamin K.
This is where the concept known as the calcium paradox comes in. With advancing age, many people lose bone mineral while accumulating calcium in the walls of their arteries. Both processes involve complex mechanisms and cannot simply be reduced to a problem of calcium distribution.
The involvement of vitamin K-dependent proteins provides a biologically plausible explanation for part of this relationship. But a physiological hypothesis is not the same as evidence that taking more vitamin K will prevent osteoporosis or arterial calcification.
That distinction between mechanism and clinical outcome runs through the whole story.
A bone that speaks: For a long time, bone was viewed primarily as a structure that supports the body and protects its organs. Research carried out, among others, by the group led by geneticist Gérard Karsenty helped change that view.
Experimental studies of osteocalcin helped show that bone can also function as an endocrine organ, releasing signals capable of influencing other tissues. In animal models, osteocalcin has been linked to mechanisms involved in energy metabolism and has also been associated with reproductive functions, brain function and the response to stress.
This is a fascinating field, but it deserves some distance. A substantial part of this knowledge comes from animal models and cannot be transferred directly to human physiology. Human studies and other experimental models provide additional evidence, but the clinical significance of many of these functions is still being defined.
The story of osteocalcin has broadened our understanding of bone. It does not, by itself, turn vitamin K2 into a proven treatment for all of these processes.
What we know and what remains uncertain: When discussing vitamin K2, it helps to separate three levels of evidence. First comes the biochemical mechanism. Then come changes in biological markers, such as osteocalcin carboxylation. Finally come the outcomes that matter to patients, such as fractures, bone mineral density, arterial calcification or cardiovascular events.
At this last level, the evidence is considerably less conclusive.
A meta-analysis of 16 randomised trials involving 6,425 participants found an improvement in lumbar spine bone mineral density, but no significant reduction in fractures in the overall analysis. Some secondary analyses were more favourable, although their interpretation depends on the characteristics and quality of the studies included.
One particularly informative trial followed 142 postmenopausal women with osteopenia for three years. They received either MK-7 or a placebo, in addition to calcium and vitamin D. MK-7 clearly increased osteocalcin carboxylation. After three years, however, it produced no differences from placebo in bone mineral density, bone turnover markers or bone microarchitecture.
This result captures the problem particularly well. Changing a biological marker shows that an intervention is acting on a particular pathway. It does not necessarily show that the change improves health.
The arteries tell a similar story. A meta-analysis of 14 randomised trials involving 1,533 participants found a small favourable signal regarding the progression of coronary calcification, together with a reduction in certain markers of undercarboxylated MGP. However, the authors stressed the need for better-designed trials to establish whether this translates into a clinical benefit.
The findings are also not consistent across populations. In people with chronic kidney disease, the K4Kidneys trial, involving 159 participants, found that one year of vitamin K2 supplementation did not improve arterial stiffness or other measures of vascular health.
The cautious conclusion is therefore not that K2 is uninteresting. It is that we know considerably more about its biological function than we know about the health benefit of supplementing people who already have an adequate vitamin K intake.
The injection that saves lives: There is one moment in the lives of almost all of us when vitamin K plays a decisive role, although few people remember it. Soon after birth, newborns receive a preventive dose of vitamin K1 by intramuscular injection.
The reason is straightforward. Newborns have limited vitamin K stores, and breast milk contains relatively small amounts. During the first days of life, moreover, the gut microbiota does not yet make a major contribution to the body’s vitamin K supply.
Without prophylaxis, this situation can favour vitamin K deficiency bleeding, which in its most severe forms can involve the brain. Intramuscular vitamin K reduces this risk very substantially.
In Spain, the Spanish Association of Paediatrics recommends 1 mg of intramuscular vitamin K for healthy full-term newborns, generally during the first hours of life. This prophylaxis prevents both classic and late vitamin K deficiency bleeding and is more effective than oral regimens for preventing both forms.
This is a very different clinical story from the one surrounding K2 supplements for bone or arterial health. In newborns, vitamin K is not given because of a promising hypothesis. It is given because prevention of a potentially serious complication is well established.
Few interventions illustrate so clearly the distance between a biological possibility and a preventive measure supported by clinical evidence.
Good sense at the table: All of this calls for prudence rather than enthusiasm.
A varied diet, rich in leafy green vegetables and other sources of vitamin K, provides a sensible foundation for adequate intake. The European Food Safety Authority sets an adequate intake of 70 micrograms of vitamin K per day for adults. This reference applies to vitamin K as a whole and does not establish a separate recommendation for K2.
There is also an important precaution. People taking vitamin K antagonists such as acenocoumarol or warfarin should consult their doctor before using vitamin K supplements. They should also avoid abrupt changes in their usual intake of vitamin K-rich foods, because such changes can alter the anticoagulant effect and require treatment adjustment.
Direct oral anticoagulants such as apixaban and rivaroxaban work through different mechanisms and do not depend on the vitamin K cycle.
K2 does not build bone by itself or clean arteries. Its role is more discreet and, for that very reason, interesting. It provides certain proteins with an essential chemical tool that allows them to perform their functions properly.
Science has described that work with considerable precision. What remains to be established is how much additional benefit increasing K2 availability through supplementation provides to people who already receive enough vitamin K.
Perhaps the foreman does not need more work. Perhaps the first step is simply to make sure that he has the tools he needs.
Today’s research is tomorrow’s therapy