Meta Information
ID:calcium-citrate
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:
/class/chelating-antibiotics
Target name:
Tetracycline & Quinolone Antibiotics
Severity:
major
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
6
Description:
Calcium binds (chelates) to tetracycline and quinolone antibiotics in the gut, forming an insoluble complex that prevents the antibiotic from being absorbed and rendering it ineffective.
Actionable advice:
These antibiotics should be taken at least 2 hours before or 6 hours after calcium.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
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 (Thyroid Hormone)
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 therapeutic effect.
Actionable advice:
Doses of levothyroxine and calcium 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:
Source url:
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:
/intervention/bisphosphonates
Target name:
Bisphosphonates (e.g., Alendronate)
Severity:
major
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
Calcium, like food, severely impairs the absorption of oral bisphosphonates, which can make them ineffective for treating osteoporosis.
Actionable advice:
Bisphosphonates should be taken on an empty stomach, with at least 2 hours before calcium is taken.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
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:
/intervention/iron-bisglycinate
Target name:
Iron Supplements
Severity:
major
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
4
Description:
Calcium competes with and significantly inhibits the intestinal absorption of both heme and non-heme iron.
Actionable advice:
Calcium and iron supplements should be separated by at least 4 hours.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
However, at the latter levels, calcium citrate and calcium phosphate reduced iron absorption significantly by 49% and 62%, respectively.
Label source:
PubMed: Calcium supplementation: effect on iron absorption. (PMID 1984334)
Action type:
separate
Target id:
/class/diuretics
Target name:
Thiazide Diuretics (e.g., HCTZ)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Thiazide diuretics decrease the amount of calcium excreted in the urine, which when combined with calcium supplements can lead to dangerously high blood calcium levels (hypercalcemia).
Actionable advice:
High-dose calcium supplements should be avoided, or used only under strict medical supervision, while taking thiazide diuretics.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism.
Label source:
FDA label: Hydrochlorothiazide (HCTZ)
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 levels of calcium in the blood (hypercalcemia) increase the risk of serious cardiac side effects from digoxin, including arrhythmias.
Actionable advice:
Calcium supplements should be avoided while taking digoxin unless specifically approved and monitored by a doctor.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Advise patients that digoxin is a cardiac glycoside used to treat heart failure and heart arrhythmias.
Label source:
Action type:
avoid
Target id:
/condition/renal-impairment
Target name:
Kidney Disease / Renal Impairment
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Impaired kidneys cannot effectively excrete excess calcium, leading to a high risk of hypercalcemia, soft tissue calcification, and worsening kidney damage.
Actionable advice:
Calcium supplements should not be taken in significant kidney disease, except under the direct guidance of a nephrologist.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Low-turnover bone has also been hypothesized to impair calcium buffering and promote vascular calcification; however, its clinical impact seems limited in the era of widespread calcimimetic use or following parathyroidectomy.
Label source:
PubMed: Parathyroid hormone levels: the lower the better the outcomes. (PMID 42077169)
Action type:
avoid
Target id:
/intervention/vitamin-d
Target name:
Vitamin D3
Severity:
major
Interaction type:
requirement
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin D is essential for producing the hormone calcitriol, which is required for the active transport and absorption of calcium from the intestine.
Actionable advice:
Adequate Vitamin D intake through sun, diet, or supplementation should be maintained for calcium to be effective.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
CONCLUSION: Vitamin D plus calcium is superior to no therapy or calcium alone in the management of corticosteroid-induced osteoporosis.
Label source:
PubMed: The role of vitamin D in corticosteroid-induced osteoporosis: a meta-analytic approach. (PMID 10446876)
Action type:
informational_none
Target id:
/procedure/high-dose-bolus
Target name:
Single Doses >500mg Elemental Calcium
Severity:
major
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
The body's capacity to absorb calcium is saturable; absorption efficiency drops sharply with single doses exceeding 500-600 mg of elemental calcium.
Actionable advice:
Split your total daily calcium dose into smaller doses of 500mg or less, taken several hours apart.
Validation status:
validated_via_clinical_guidance
Evidence tier:
tier_b
Evidence basis:
clinical_guidance_verbatim
Evidence anchors:
Exact phrase from label:
All varieties of calcium supplements are better absorbed when taken in small doses of 500 mg or less, typically with a meal.
Label source:
Clinical guidance: Mayo Clinic — Calcium and calcium supplements
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 compete with zinc for absorption pathways in the small intestine, reducing the bioavailability of zinc.
Actionable advice:
High-dose calcium and zinc 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:
Source url:
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: The effect of calcium carbonate and calcium citrate on the absorption of zinc in healthy female subjects. (PMID 8194505)
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 and magnesium compete for the same intestinal absorption channels, which can reduce the uptake of both minerals when taken together.
Actionable advice:
High-dose calcium and magnesium supplements should be separated by at least 2 hours.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
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)
Source url:
Exact phrase from label:
OBJECTIVE: In view of the widespread use of magnesium (Mg) as a nutritional supplement, we investigated whether Mg would affect the absorption of calcium (Ca) as the intestinal absorption sites for Mg and Ca differ.
Label source:
PubMed: Journal of the American College of Nutrition (1994)
Source url:
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)
Action type:
separate
Target id:
/intervention/vitamin-k2
Target name:
Vitamin K2 (Menaquinone)
Severity:
moderate
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin K2 activates proteins that help direct calcium into bones and teeth and prevent its deposition in arteries and soft tissues, promoting both skeletal and cardiovascular health.
Actionable advice:
Consider taking Vitamin K2 alongside calcium and Vitamin D to support proper calcium utilization.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
Vitamin K2 is transported to extrahepatic tissues, such as bone and the vascular wall, regulating the activity of matrix Gla protein (MGP) and osteocalcin (bone Gla protein)—the main vitamin K-dependent proteins.
Label source:
Primary literature: https://pmc.ncbi.nlm.nih.gov/articles/PMC5613455/
Action type:
informational_none
Target id:
/dietary/phytate-rich-foods
Target name:
Foods High in Oxalates or Phytates
Severity:
moderate
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
Oxalates (in spinach, rhubarb) and phytates (in whole grains, legumes) can bind to calcium in the gut, forming insoluble salts and reducing calcium absorption from supplements taken with these foods.
Actionable advice:
For maximal absorption, calcium supplements are best separated from meals very high in oxalates or phytates by 2 hours.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The heatmap revealed significant interspecific variability in antinutrients, dominated by oxalates and phytates.
Label source:
PubMed: Nutritional, mineral, and bioactive composition of indigenous leafy vegetables from the Congo Basin: A systematic review and meta-analysis. (PMID 42215083)
Action type:
separate
Target id:
/condition/history-of-kidney-stones
Target name:
History of Kidney Stones
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
While citrate can help prevent stone formation, high total calcium intake can increase urinary calcium excretion and may raise the risk of calcium oxalate stones in susceptible individuals.
Actionable advice:
It is important to consult a doctor before taking calcium supplements for those with a history of kidney stones.
Validation status:
validated_via_clinical_guidance
Evidence tier:
tier_b
Evidence basis:
clinical_guidance_verbatim
Evidence anchors:
Exact phrase from label:
High concentrations of calcium and oxalate in the urine are major risk factors for the formation of calcium oxalate stones in the kidneys.
Label source:
Clinical guidance: Linus Pauling Institute — Calcium, Oregon State University
Action type:
informational_none
Target id:
/intervention/strontium
Target name:
Strontium Supplements
Severity:
moderate
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
Strontium and calcium are chemically similar and compete for the same absorption mechanisms in the gut, reducing the uptake of both minerals.
Actionable advice:
Strontium and calcium supplements should be separated by at least 2-4 hours.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Strontium present outside the vesicle inhibited saturable calcium uptake competitively, consistent with binding to the transporter at the same site as calcium.
Label source:
PubMed: The American journal of physiology (1989)
Source url:
Exact phrase from label:
When the calcium concentration was increased, the strontium passive absorption was decreased. The vitamin D3 and its derivatives increased intestinal strontium transport significantly and this increment was not modified by calcium. In our experiment, calcium is competitive with strontium only in passive absorption.
Label source:
PubMed: Comptes rendus des seances de la Societe de biologie et de ses filiales (1976)
Source url:
Exact phrase from label:
In each of these instances it is important to maintain a normal dietary intake of calcium.
Label source:
PubMed: Canadian Medical Association journal (1981)
Action type:
separate
Target id:
/dietary/meal
Target name:
Any Caloric Meal
Severity:
moderate
Interaction type:
requirement
Nature:
temporal
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
While calcium citrate does not require stomach acid for absorption, taking it with food can improve gastrointestinal tolerance and may slightly enhance absorption.
Actionable advice:
It is best taken with a meal or snack to minimize potential stomach upset.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
In conclusion, calcium citrate is more bioavailable than calcium carbonate when given with a meal.
Label source:
PubMed: Pharmacokinetic and pharmacodynamic comparison of two calcium supplements in postmenopausal women. (PMID 11075309)
Action type:
informational_none
Target id:
/class/proton-pump-inhibitors
Target name:
Proton Pump Inhibitors (PPIs)
Severity:
minor
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Unlike calcium carbonate, calcium citrate does not require stomach acid for absorption, making it a preferred form for individuals on acid-suppressing medications like PPIs.
Actionable advice:
Calcium citrate is an effective choice if you are taking a PPI; no timing adjustments are needed.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Absorption
PRILOSEC delayed-release capsules contain an enteric-coated granule formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the granules leave the stomach.
Label source:
Action type:
informational_none
Target id:
/class/calcium-channel-blockers
Target name:
Calcium Channel Blockers (CCBs)
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Theoretically, high doses of supplemental calcium could oppose the therapeutic effect of CCBs, which work by blocking calcium channels, but this is not considered clinically significant at standard doses.
Actionable advice:
Standard doses of calcium as directed are generally fine; no special precautions are typically needed with CCBs.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Patients (76% males, 89% Caucasian, 93% enrolled at US sites, 89% with
a history of angina, 52% without PCI, 4% with PCI and no stent, and 44% with a stent) were randomized to double-blind
treatment with either NORVASC (5-10 mg once daily) or placebo in addition to standard care that included aspirin (89%),
statins (83%), beta-blockers (74%), nitroglycerin (50%), anti-coagulants (40%), and diuretics (32%), but excluded other
calcium channel blockers.
Label source:
Action type:
informational_none