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Vitamin D3 and K2 with Calcium

Vitamin D3, Vitamin K2, and Calcium

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Meta Information

ID:d3-k2-with-calcium
Name:
Schema Version:2.4_uniform_evidence_2026_06_18

Created

2026-05-21T22:30:00Z

Model

phase-a-upgrade-claude-sonnet-4.6

Interactions

Target id:
/dietary/high-fat-meal
Target name:
Meal Containing Fat
Severity:
moderate
Interaction type:
requirement
Nature:
temporal
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamins D3 and K2 are fat-soluble, and their absorption from the gut is significantly enhanced when consumed with dietary fats.
Actionable advice:
This supplement is best taken with a meal that contains healthy fats like olive oil, avocado, or nuts.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
Since vitamin A precursors are fat-soluble, we noted that carotenoids are more easily absorbed from food if prepared in such a way that the food matrix containing provitamin A (β-carotene) is sufficiently fat rich.
Label source:
PubMed: The effect of food preparation on the bioavailability of carotenoids from carrots using intrinsic labelling. (PMID 21923982)
Action type:
informational_none
Target id:
/intervention/warfarin
Target name:
Warfarin (Coumadin)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin K is essential for blood clotting and directly counteracts the anticoagulant effect of warfarin, potentially leading to treatment failure and dangerous blood clots.
Actionable advice:
This supplement should be strictly avoided while taking warfarin unless specifically directed and monitored by a physician.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
6 Aluminum Lake 10 mg: Dye-free 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S.
Label source:
Action type:
avoid
Target id:
/class/chelating-antibiotics
Target name:
Chelating Antibiotics (Tetracyclines, Quinolones)
Severity:
major
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
4
Hours after target:
2
Description:
Calcium binds to tetracycline and quinolone antibiotics in the gut, forming an insoluble complex that prevents the antibiotic from being absorbed and working effectively.
Actionable advice:
This supplement should be taken at least 2 hours before or 4-6 hours after these types of antibiotics.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
Most antacids, except sodium bicarbonate, may decrease drug absorption by adsorption or chelation of other drugs.
Label source:
PubMed: Antacids revisited: a review of their clinical pharmacology and recommended therapeutic use. (PMID 10400401)
Action type:
separate
Target id:
/intervention/levothyroxine
Target name:
Levothyroxine
Severity:
major
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
4
Hours after target:
4
Description:
Calcium can bind to levothyroxine in the gastrointestinal tract, significantly reducing its absorption and effectiveness.
Actionable advice:
Doses of this supplement and levothyroxine should be separated by at least 4 hours.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
Inform patients that agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine.
Label source:
FDA label: Levothyroxine (Synthroid)
Action type:
separate
Target id:
/condition/hypercalcemia
Target name:
Hypercalcemia (High Blood Calcium)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
This supplement directly increases calcium levels and is absolutely contraindicated in individuals who already have high blood calcium.
Actionable advice:
This supplement should not be taken with a diagnosis of hypercalcemia.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
Recent interest in vitamin D has led to a substantial increase in the use of vitamin D supplements. Vitamin D intoxication may be a concern as hypervitaminosis D can result in irreversible calcification of soft tissues so that it is important to detect early markers of vitamin D intoxication. Our aim was to assess the simultaneous presence of biochemical markers of vitamin D toxicity (i.e. hypervitaminosis D, hypercalcemia) and determine the concentrations of 25-OH-vitamin D at which the risk of hypercalcemia, and thus toxicity, might begin.
Label source:
PubMed: Prevalence of hypercalcemia related to hypervitaminosis D in clinical practice. (PMID 26995293)
Action type:
avoid
Target id:
/condition/renal-impairment
Target name:
Renal Impairment
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Impaired kidneys cannot effectively clear excess calcium, and high vitamin D can worsen this, leading to dangerous mineral deposits and hypercalcemia.
Actionable advice:
This supplement should be avoided with significant kidney disease unless under strict medical supervision.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
Where indicated, and until clear guidelines are established, we suggest using low doses of vitamin D with cautious monitoring of calcium and renal function.
Label source:
PubMed: Vitamin D-induced hypercalcaemia and acute kidney injury in sarcoidosis. (PMID 36690393)
Action type:
avoid
Target id:
/intervention/digoxin
Target name:
Digoxin
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
High blood calcium levels, a potential side effect of this supplement, can increase the risk of serious heart rhythm problems (toxicity) from digoxin.
Actionable advice:
High doses should be avoided and calcium levels should be monitored closely when taking digoxin.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
5.3 Misidentification of Digoxin Toxicity Some signs and symptoms (anorexia, nausea, vomiting, and certain arrhythmias) can equally result from digoxin toxicity as from congestive heart failure.
Label source:
Action type:
avoid
Target id:
/intervention/bisphosphonates
Target name:
Bisphosphonates
Severity:
major
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
Calcium supplements can significantly reduce the absorption of oral bisphosphonates, medications used to treat osteoporosis.
Actionable advice:
This supplement should be taken at least 2 hours after an oral bisphosphonate medication.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate; and to take calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations at a different time of the day
Label source:
FDA label: Risedronate (Actonel)
Action type:
separate
Target id:
/class/bile-acid-sequestrants
Target name:
Bile Acid Sequestrants & Binders
Severity:
major
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
4
Hours after target:
1
Description:
These medications can bind to fat-soluble vitamins (D and K) in the gut, preventing their absorption.
Actionable advice:
This supplement should be taken at least 1 hour before or 4-6 hours after bile acid sequestrants.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
Because cholestyramine binds bile acids, QUESTRAN may interfere with normal fat digestion and absorption and thus may prevent absorption of fat-soluble vitamins such as A, D, E and K.
Label source:
Action type:
separate
Target id:
/class/thiazide-diuretics
Target name:
Thiazide Diuretics
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Thiazide diuretics decrease the urinary excretion of calcium. Combining them with this supplement can lead to dangerously high blood calcium levels (hypercalcemia).
Actionable advice:
This is best used with caution, and it is a good idea to monitor serum calcium levels regularly when taking thiazide diuretics.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
Greater urine calcium reductions after thiazide treatment are observed among those with higher baseline urine calcium, and higher thiazide dose led to a larger reduction.
Label source:
PubMed: Baseline Urinary Calcium and the Efficacy of Thiazide Diuretics for Kidney Stone Prevention. (PMID 41894644)
Action type:
monitor
Target id:
/intervention/iron-bisglycinate
Target name:
Iron Supplements
Severity:
moderate
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
Calcium and iron compete for the same absorption pathway in the gut, and taking them together can reduce the absorption of iron.
Actionable advice:
Doses of this supplement and iron supplements should be separated by at least 2 hours.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
The practical nutritional implications of the inhibitory effect of calcium are considerable since addition of milk, milkshake or cheese to common meals such as pizza or hamburger meals reduced iron absorption by 50-60%.
Label source:
PubMed: Calcium and iron absorption: mechanism of action and nutritional importance. (PMID 1600930)
Action type:
separate
Target id:
/intervention/magnesium
Target name:
Magnesium Supplements
Severity:
moderate
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
High doses of calcium can compete with magnesium for absorption in the gut, potentially reducing magnesium uptake.
Actionable advice:
Doses of this supplement and magnesium should be separated by at least 2 hours.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Exact phrase from label:
Intestinal interactions between Mg and calcium or phosphate have been demonstrated in both humans and animals. The nature of these interactions cannot be readily explained by data currently available.
Label source:
PubMed: The Journal of nutrition (1991)
Exact phrase from label:
In the uptake medium (extracellular), magnesium was a noncompetitive inhibitor of saturable calcium transport, consistent with a regulatory role in calcium uptake by binding to the transporter at a locus other than that for calcium.
Label source:
PubMed: The American journal of physiology (1989)
Exact phrase from label:
Saturable uptake of calcium is carrier mediated, since it is inhibited competitively by strontium and noncompetitively by magnesium.
Label source:
PubMed: Mineral and electrolyte metabolism (1990)
Action type:
separate
Target id:
/intervention/zinc
Target name:
Zinc Supplements
Severity:
moderate
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
High doses of calcium can interfere with the absorption of zinc by competing for the same intestinal transporters.
Actionable advice:
Doses of this supplement and zinc should be separated by at least 2 hours.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Exact phrase from label:
Zinc absorption was reduced significantly by 50% when the calcium supplement was given with the meal.
Label source:
PubMed: The American journal of clinical nutrition (1997)
Exact phrase from label:
The decrease in zinc absorption following the ingestion of zinc with different forms of calcium suggests that an antagonistic competition occurred between the minerals and that elemental calcium is the inhibiting factor.
Label source:
PubMed: European journal of clinical nutrition (1994)
Exact phrase from label:
Kinetic parameters showed higher K(m) values with 4 or 15 mM Ca(+2) but unchanged J(max), suggesting competitive inhibition. The Ca(+2) channel blocking agents, La(+3), Ba(+2), verapamil, and diltiazem, inhibited Zn(+2) uptake, whereas calcitriol, trans 1,2 cyclohexanediol, cis/trans 1,3 cyclohexanediol, and the L-type Ca(+2) channel agonist, Bay K8644, induced Zn(+2) uptake.
Label source:
PubMed: The Journal of nutritional biochemistry (2001)
Action type:
separate
Target id:
/class/corticosteroids
Target name:
Corticosteroids
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Long-term use of corticosteroids can impair vitamin D metabolism and reduce calcium absorption, increasing the risk of osteoporosis.
Actionable advice:
If on long-term corticosteroids, consult your doctor about the need for this supplement.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
5.6 Decrease in Bone Density Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function.
Label source:
Action type:
informational_none
Target id:
/class/anticonvulsants
Target name:
Enzyme-Inducing Anticonvulsant Medications
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Certain anticonvulsants (e.g., phenytoin, phenobarbital) increase the liver's breakdown of vitamin D, potentially leading to deficiency.
Actionable advice:
Vitamin D levels should be monitored closely if these medications are taken, and dose adjustments may be necessary.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
• Have had liver problems from taking phenytoin.
Label source:
Action type:
adjust_with_prescriber
Target id:
/condition/history-of-kidney-stones
Target name:
History of Calcium Oxalate Kidney Stones
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Supplemental calcium, particularly without adequate fluid intake, can increase the risk of forming new calcium-based kidney stones in susceptible individuals.
Actionable advice:
It is important to talk to a doctor before using this supplement with a history of kidney stones.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
The treatment group ingested an average of 2100 mg of dietary calcium per day and after 7 years of follow-up, these patients developed a 17% increase in the risk of stone formation compared to the placebo group. calcium supplementation, mostly if given between meals, might increase urinary calcium excretion without the beneficial effect on oxalate, thus increasing the risk for stone formation.
Label source:
Primary literature: https://pmc.ncbi.nlm.nih.gov/articles/PMC8707627/
Action type:
informational_none
Target id:
/biomarker/serum-calcium
Target name:
Serum Calcium
Severity:
moderate
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Long-term or high-dose supplementation directly affects blood calcium levels, which should be monitored to prevent hypercalcemia.
Actionable advice:
Periodically check your serum calcium levels with your doctor while taking this supplement.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Exact phrase from label:
In these trials, vitamin D supplementation often resulted in modest increases in serum calcium levels, but rarely caused hypercalcemia.
Label source:
PubMed: Current opinion in investigational drugs (London, England : 2000) (2010)
Exact phrase from label:
Hypercalcemia occurred in 40% (n = 21) of patients; 2 patients experienced an iCa >1.49 nmol/L.
Label source:
PubMed: Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition (2020)
Exact phrase from label:
Persons at risk for developing milk-alkali syndrome, such as thiazide users and persons with renal failure, should be identified and monitored for alkalosis and hypercalcemia when using calcium supplements.
Label source:
PubMed: Journal of the American Academy of Nurse Practitioners (1997)
Action type:
monitor
Target id:
/biomarker/vitamin-d
Target name:
25-OH Vitamin D
Severity:
moderate
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
This supplement directly raises Vitamin D levels; regular testing is needed to ensure you are in the optimal range and to avoid toxicity.
Actionable advice:
25(OH)D levels should be monitored to guide appropriate dosing and prevent excess.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
While the guideline panel stresses the insufficient evidence to support screening with 25(OH)D testing, they also acknowledge the “growing interest by patients and physicians in assessing vitamin D status”. The evidence supporting the recommendations of the guideline is well outlined in the guideline and an accompanying communication article, but a common real-life scenario is that individuals with indications for empiric vitamin D supplementation may ask for a 25(OH)D test before starting supplementation and for a follow-up measurement [1,38,39,40].
Label source:
Action type:
monitor
Target id:
/biomarker/bone-mineral-density
Target name:
Bone Mineral Density
Severity:
moderate
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin D enhances calcium absorption, while Vitamin K2 helps direct the absorbed calcium into bones, working together to support bone density.
Actionable advice:
This combination is designed to synergistically support bone health and calcium metabolism.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
Current evidence supports the notion that joint supplementation of vitamins D and K might be more effective than the consumption of either alone for bone and cardiovascular health.
Label source:
PubMed/primary literature: https://pmc.ncbi.nlm.nih.gov/articles/PMC5613455/
Action type:
monitor
Target id:
/class/acid-suppressors
Target name:
Gastric Acid Suppressors
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Medications that reduce stomach acid (like PPIs) can decrease the absorption of calcium carbonate, a common form of calcium supplement.
Actionable advice:
If using acid-suppressing medication, consider a calcium citrate supplement instead, or discuss with your doctor.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
omeprazole at a dose of 20 mg QD taken for 7 days significantly reduced the absorption of calcium carbonate taken under fasting conditions.
Label source:
Primary literature: https://pmc.ncbi.nlm.nih.gov/articles/PMC4525469/
Action type:
informational_none
Target id:
/dietary/phytate-rich-foods
Target name:
High-Oxalate/Phytate Foods (e.g., Spinach, Beans, Nuts)
Severity:
minor
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
Oxalates and phytates, found in many plant foods, can bind to calcium in the gut, forming insoluble complexes that prevent its absorption.
Actionable advice:
For best absorption, it is best taken at least 2 hours apart from meals very high in spinach, beans, or whole grains.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
There is no dispute that many ANFs negatively alter the absorption of vitamins, minerals, and proteins in addition to inhibiting some enzyme activities, thus negatively affecting the bioavailability of nutrients in the human body. This review discusses the chemical properties, plant bioavailability, and deleterious effects of anti-minerals (phytates and oxalates), glycosides (cyanogenic glycosides and saponins), polyphenols (tannins), and proteinaceous ANFs (enzyme inhibitors and lectins).
Label source:
PubMed: Bacterial Degradation of Antinutrients in Foods: The Genomic Insight. (PMID 39123599)
Action type:
separate
Target id:
/class/viscous-fibers
Target name:
Gel-Forming Viscous Fibers
Severity:
minor
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
Large amounts of dietary fiber, especially from supplements like psyllium, can bind to minerals and slightly decrease calcium absorption.
Actionable advice:
This supplement and high-dose fiber supplements are best separated by at least 2 hours.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Exact phrase from label:
Psyllium husk, a highly viscous fiber, has beneficial effects for health, but has been reported to inhibit absorption of calcium.
Label source:
PubMed: Bioscience, biotechnology, and biochemistry (2004)
Exact phrase from label:
While the absorption with cellulose was slightly higher than in the absence of fiber, and the absorption with psyllium was slightly lower, neither difference was statistically significant. However, the difference between added psyllium and cellulose was statistically significant (P < .05).
Label source:
PubMed: Journal of the American Geriatrics Society (1995)
Exact phrase from label:
This was reduced by 3, 22 and 27% by adding bread, psyllium or pectin to BD, respectively (P < 0.05).
Label source:
PubMed: International journal of food sciences and nutrition (1996)
Action type:
separate
Target id:
/class/calcium-channel-blockers
Target name:
Calcium Channel Blockers
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
There is a theoretical concern that high levels of supplemental calcium could counteract the therapeutic effects of calcium channel blockers, though this is rarely clinically significant.
Actionable advice:
It is a good idea to talk to a doctor before taking high-dose calcium while on a calcium channel blocker.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with NORVASC have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume.
Label source:
Action type:
informational_none