The Role of Vitamin D3 & K2,The DANCODE Study on Heart Calcification

Vitamin D3 & K2 Quest for Healthier Hearts

Coronary artery calcification (CAC) and, specifically, the progression of CAC serve as robust indicators for acute myocardial infarction and cardiovascular mortality. The potential protective role of vitamin K2 and D3 supplementation in impeding CAC progression has been suggested. This investigation aims to assess the impact of vitamins K2 and D3 on individuals with severe CAC, hypothesizing that their supplementation will decelerate the calcification process.

Vitamin D3 & K2

Method and Analysis

This study employs a multicenter, double-blinded, placebo-controlled design, involving 400 individuals with a CAC score of ≥400, randomized (1:1) to receive vitamin K2 (720 µg/day) and vitamin D3 (25 µg/day) or placebo for a duration of 2 years. Exclusion criteria encompass the use of vitamin K antagonists, coagulation disorders, and prior coronary artery disease. Progression in coronary plaque is evaluated through cardiac CT scans at baseline, 12 months, and 24 months. The primary outcome is the progression in CAC score over the 2-year follow-up, with secondary outcomes including coronary plaque composition and cardiac events. Intention-to-treat analysis is applied to all assessments.

Ethics and Dissemination

No adverse effects related to vitamin K2 usage have been reported thus far. Approval for the protocol has been granted by the Regional Scientific Ethical Committee for Southern Denmark and the Data Protection Agency, adhering to the Declaration of Helsinki. Both positive and negative findings will be disseminated.

Strengths and Limitations

The study’s major strengths lie in its multicenter, double-blinded, randomized design, which allows an examination of the effect of vitamin K2 and vitamin D3 supplementation on CAC progression. Inclusion of both genders and participants with baseline CAC scores ≥400 ensures detectable CAC progression over the 2-year period. However, the study’s unique nature and the 2-year follow-up duration might limit the ability to detect differences.


Vitamin D, also known as calciferol, is a fat-soluble vitamin naturally found in some foods, added to others, and available as a dietary supplement. Endogenously produced through the synthesis triggered by ultraviolet (UV) rays from sunlight on the skin, vitamin D requires two hydroxylations for activation. The first, occurring in the liver, converts it to 25-hydroxyvitamin D [25(OH)D], while the second, primarily in the kidney, forms the active 1,25-dihydroxyvitamin D [1,25(OH)2D], crucial for calcium absorption and maintaining bone health.

Apart from its role in bone health, vitamin D influences various bodily functions, including inflammation reduction, modulation of cell growth, immune function, and glucose metabolism. Genes regulating cell processes are affected by vitamin D, and its receptors are found in many tissues. In foods and supplements, vitamin D exists in two main forms, D2 and D3, both well-absorbed in the small intestine. Serum concentration of 25(OH)D is the primary indicator of vitamin D status, reflecting endogenous production and intake from foods and supplements.

Assessing vitamin D status through serum 25(OH)D concentrations faces challenges due to assay variability. The International Vitamin D Standardization Program aims to standardize these measurements. While serum 25(OH)D is considered for deficiency, 1,25(OH)2D is not a reliable indicator due to its short half-life.

Serum concentrations associated with health outcomes are still under investigation, with different organizations proposing varying thresholds. Vitamin D deficiency can lead to conditions like rickets in children and osteomalacia in adults. The Dietary Reference Intakes (DRIs) provide guidance on vitamin D intake, with values varying by age, sex, and life stage.

Vitamin D Deficiency

Insufficiency arises from low intake, limited sunlight exposure, kidney dysfunction, or absorption issues. Rickets in children and osteomalacia in adults are potential outcomes, with exclusive breastfeeding and specific diets contributing to deficiency. Screening for deficiency is increasing, but its impact on health outcomes is uncertain.

Groups at Risk of Inadequacy

Certain groups, like breastfed infants, older adults, individuals with limited sun exposure, people with dark skin, and those with conditions affecting fat absorption, may require supplements to meet vitamin D needs.

Vitamin D and its Role in Health

While vitamin D’s role in bone health is established, its impact on cancer, cardiovascular disease, and diabetes remains uncertain. Adequate intake is recommended for overall health, especially for older individuals.


Observational studies link low vitamin D levels to depression, but clinical trials show mixed results, particularly in older adults.

Multiple Sclerosis (MS)

Associations between low vitamin D levels and MS risk exist, but clinical trials don’t support supplementation preventing MS onset.

Type 2 Diabetes

Observational studies suggest a link between low vitamin D levels and diabetes risk, but clinical trials on supplementation’s efficacy are inconclusive.

Weight Loss

While observational studies suggest a connection between low vitamin D status and higher body weights, clinical trials don’t establish a direct cause-and-effect relationship.

Health Risks from Excessive Vitamin D

Excessive intake can lead to toxicity, causing hypercalcemia and adverse health effects. The recommended upper limit is 250 mcg per day.

Medication Interactions

Vitamin D supplements may interact with medications like orlistat, statins, steroids, and thiazide diuretics. Individuals on these medications should discuss their vitamin D intake with healthcare providers.

Vitamin D and Healthy Diets

The 2020–2025 Dietary Guidelines for Americans emphasize meeting nutritional needs through foods, with fortified foods and supplements useful when meeting requirements through food alone is challenging. A healthy dietary pattern includes a variety of foods and limits added sugars, saturated fat, sodium, and alcohol, staying within daily calorie needs. Certain foods are fortified with vitamin D, such as okra, collards, and white beans, and natural sources include fatty fish.

Ischemic heart disease, constituting a significant percentage of total mortality, often remains asymptomatic until myocardial infarction symptoms arise. Subclinical stages manifest as CAC on non-contrast cardiac CT scans. CAC risk elevates with age, with men typically exhibiting higher CAC scores than women. Identifying and treating individuals with severe CAC is crucial for preventing cardiovascular disease.

Vitamin K, particularly phylloquinone (K1) and menaquinone-7 (K2), plays a vital role in coagulation factor activation and inhibiting arterial calcification. Vitamin K2, in particular, activates matrix-Gla proteins (MGP), crucial for preventing vascular calcification. Recent trials, including the AVADEC Trial, explored the impact of high-dose vitamin K2 and D supplementation on CAC progression, revealing potential benefits.


The randomized trial seeks to test the hypothesis that vitamin K2 (720 µg/day) and vitamin D3 (25 µg/day) supplementation, compared to a placebo, will reduce CAC progression in individuals with severe CAC.


The Danish Coronary Decalcification (DANCODE) trial adopts a multicenter, double-blinded, randomized, placebo-controlled approach. Participants are identified through the Danish Heart Registry, meet specific criteria, and are assigned to either the vitamin K2 and D3 supplementation group or the placebo group. The primary endpoint is the change in CAC score over 24 months, with various secondary endpoints and safety assessments.

Sample Size and Randomization

The study plans to include 400 patients, considering the mean CAC progression from the AVADEC trial. Randomization is conducted by the pharmacy at Odense University Hospital, ensuring a balanced allocation.

Statistical Methods Intention-to-treat analysis is applied, presenting the primary endpoint as a continuous variable. Linear mixed models are utilized for primary and secondary endpoints, with sensitivity analyses for missing data.

Patient and Public Involvement

Patients and the public were not directly involved in the study design.


The Steering Committee oversees practical aspects of DSMB monitoring safety. Data registration is conducted through REDCap, with results published in peer-reviewed journals.

Feasibility Approximately 13,000 patients undergo cardiac CT in Western Denmark annually. Invitations to participate in DANCODE are sent to eligible patients, and the study is expected to conclude in March 2026.

The study, approved by ethical committees and authorities, ensures participant safety. Dissemination includes publication in peer-reviewed journals and communication of results to participants and the public.

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CAC, especially its progression, serves as a potent predictor of cardiovascular events. The DANCODE study aims to investigate the impact of vitamin K2 and D3 supplementation on CAC progression, offering potential insights into preventive strategies for cardiovascular diseases. The study’s strengths include its design and participant characteristics, while its limitations include potential shared effects of vitamins K2 and D3 and the absence of baseline vitamin level inclusion.

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