The DOI matches its Crossref record; 16 of the 16 references it cites were found in a registry or an index.
Effect of Calcium Carbonate on the Absorption of Levothyroxine
Abstract
CONTEXT: The effect of calcium carbonate on the absorption of levothyroxine has not been studied systematically. Such a potential drug interaction merits investigation because concurrent treatment with both drugs is common, particularly in postmenopausal women. OBJECTIVE: To investigate the potential interference of calcium carbonate in the absorption of levothyroxine. DESIGN: Prospective cohort study conducted from November 1998 to June 1999, supplemented with an in vitro study of thyroxine (T(4)) binding to calcium carbonate. SETTING: Veterans Affairs Medical Center in West Los Angeles, Calif. PATIENTS: Twenty patients (age range, 27-78 years; n=11 men) with hypothyroidism who were taking a stable long-term regimen of levothyroxine were included in the study. All patients had serum free T(4) and thyrotropin values in the normal range before beginning the study. INTERVENTION: Subjects were instructed to take 1200 mg/d of elemental calcium as calcium carbonate, ingested with their levothyroxine, for 3 months. MAIN OUTCOME MEASURES: Levels of free T(4), total T(4), total triiodothyronine (T(3)), and thyrotropin, measured in all subjects at baseline (while taking levothyroxine alone), at 2 and 3 months (while taking calcium carbonate and levothyroxine), and 2 months after calcium carbonate discontinuation (while continuing to take levothyroxine). RESULTS: Mean free T(4) and total T(4) levels were significantly reduced during the calcium period and increased after calcium discontinuation. Mean free T(4) levels were 17 pmol/L (1.3 ng/dL) at baseline, 15 pmol/L (1.2 ng/dL) during the calcium period, and 18 pmol/L (1.4 ng/dL) after calcium discontinuation (overall P<.001); mean total T(4) levels were 118 nmol/L (9.2 microg/dL) at baseline, 111 nmol/L (8.6 microg/dL) during the calcium period, and 120 nmol/L (9.3 microg/dL) after calcium discontinuation (overall P=.03). Mean thyrotropin levels increased significantly, from 1.6 mIU/L at baseline to 2.7 mIU/L during the calcium period, and decreased to 1. 4 mIU/L after calcium discontinuation (P=.008). Twenty percent of patients had serum thyrotropin levels higher than the normal range during the calcium period; the highest observed level was 7.8 mIU/L. Mean T(3) levels did not change during the calcium period. The in vitro study of T(4) binding to calcium showed that adsorption of T(4) to calcium carbonate occurs at acidic pH levels. CONCLUSIONS: This study of 20 patients receiving long-term levothyroxine replacement therapy indicates that calcium carbonate reduces T(4) absorption and increases serum thyrotropin levels. Levothyroxine adsorbs to calcium carbonate in an acidic environment, which may reduce its bioavailability. JAMA. 2000;283:2822-2825
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In the citing paper
“Only two of these medications have been studied in a cross-over study design of chronic therapy (132,145), with two other studies also conducted prospectively (140,143).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [132]
In the citing paper
“The list of medications that can alter the absorption of LT4 is extensive and includes calcium carbonate (132-134), PPIs (135), bile acid sequestrants (cholestyramine and colesevelam) (136,137), phosphate binders (138,139), ferrous sulfate (140,141), aluminum-containing antacids (142,143), and sucralfate (144,145).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [132]
In the citing paper
“Hypothyroid patients with normal TSH concentrations were asked to take their LT4 with calcium carbonate for several months. Their serum TSH values increased from a mean of 1.6 mIU/L to 2.7 mIU/L, and returned to 1.4 mIU/L after discontinuation of the calcium (132).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [132]
In the citing paper
“On this ground, Singh et al. (53) reported that both acute and chronic ingestions of calcium carbonate can reduce the in vitro bioavailability of T4 by binding it in a dose-dependent fashion at medium pH 2.”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [53]
In the citing paper
“It is widely acknowledged that direct complexation and chelation play important roles in the malabsorption of LT4 induced by the intake of many drugs, including calcium and iron supplements (72, 73), aluminum-containing antacids (74), bile acid sequestrants (75, 76), and some foods (eg, fiber-rich foods, coffee, and milk) (22, 77, 78).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [73]
In the citing paper
“Calcium carbonate adsorbed T4 dose-dependently at pH 2 but not pH 7.4, thus explaining L-T4 malabsorption (41), and reduced T4 pharmacokinetics (42).”
From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [41]
In the citing paper
“For instance, a 3-month supplementation of 1,200 mg/d calcium carbonate reversibly increased TSH in 13/20 patients (65%), with TSH >4.0 mU/L in four (20%) (41). Overall, TSH increased from 1.60 ± 0.22 to 2.71 ± 0.43 mU/L (+69%).”
From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [41]
In the citing paper
“The ingestion of calcium carbonate supplements is associated with lower total T4 (TT4) levels and elevated TSH levels, relative to baseline [ 65 – 67 ].”
From Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults (2022) · cites this paper as [66]
In the citing paper
“Indeed, LT4 can bind to calcium carbonate – potentially reducing the bioavailability [ 66 ].”
From Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults (2022) · cites this paper as [66]
Citations
Cites
Levothyroxine Therapy in Patients with Thyroid Disease
Mandel, S. J., Brent, G. A., & Larsen, P. R. (1993) · Annals of Internal Medicine · doi:10.7326/0003-4819-119-6-199309150-00009 · Cited by 324
Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism
Campbell, N. R. C., Hasinoff, B. B., Stalts, H., Rao, B., & Wong, N. C. W. (1992) · Annals of Internal Medicine · doi:10.7326/0003-4819-117-12-1010 · Cited by 231
Tanis, B. C., Westendorp, R. G. J., & Smelt, A. H. M. (1996) · Clinical Endocrinology · doi:10.1046/j.1365-2265.1996.739560.x · Cited by 177
Delayed Intestinal Absorption of Levothyroxine
BENVENGA, S., BARTOLONE, L., SQUADRITO, S., GIUDICE, F. L., & TRIMARCHI, F. (1995) · Thyroid · doi:10.1089/thy.1995.5.249 · Cited by 156
The influence of cholestyramine on thyroxine absorption
Northcutt, R. C. (1969) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.1969.03160100047012 · Cited by 144
Localization of human thyroxine absorption
HAYS, M. T. (1991) · Thyroid · doi:10.1089/thy.1991.1.241 · Cited by 138
Liel, Y., Harman-Boehm, I., & Shany, S. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.2.8636317 · Cited by 129
Absorption of oral thyroxine in man
HAYS, M. T. (1968) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-28-6-749 · Cited by 111
Sucralfate causes malabsorption of L-thyroxine
Sherman, S. I., Tielens, E. T., & Ladenson, P. W. (1994) · The American Journal of Medicine · doi:10.1016/0002-9343(94)90093-0 · Cited by 105
Kung, A. W. C., & Yeung, S. S. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.3.8772604 · Cited by 100
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“Only two of these medications have been studied in a cross-over study design of chronic therapy (132,145), with two other studies also conducted prospectively (140,143).”
Roberts, C. G., & Ladenson, P. W. (2004) · The Lancet · doi:10.1016/s0140-6736(04)15696-1 · Cited by 567
Orloff, L. A., Wiseman, S. M., Bernet, V. J., Fahey, T. J., Shaha, A. R., Shindo, M. L., Snyder, S. M., Stack, B. C., Sunwoo, J. B., & Wang, M. B. (2018) · Thyroid · doi:10.1089/thy.2017.0309 · Cited by 523
Thyroxine in Goiter, Helicobacter pylori Infection, and Chronic Gastritis
Centanni, M., Gargano, L., Canettieri, G., Viceconti, N., Franchi, A., Fave, G. D., & Annibale, B. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa043903 · Cited by 329
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Metadata
- Authors
- Singh, N.
- Affiliations
- VA West Los Angeles Medical Center (US)
- Corresponding author
- Singh, Nalini
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2000-06-07
- Volume
- 283
- Issue
- 21
- Pages
- 2822
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2107234914
- Cited by
- 219
- References
- 16
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 4 · 2021: 9 · 2020: 9 · 2019: 6 · 2018: 11 · 2017: 11 · 2016: 7 · 2015: 13 · 2014: 7 · 2013: 5 · 2012: 9
- FWCI
- 5.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- levothyroxine, calcium carbonate, drug interactions, drug absorption, hypothyroidism, free thyroxine, thyroxine binding, thyroid-stimulating hormone, triiodothyronine, postmenopausal women, antithyroid drug therapy, veterans, thyroid function monitoring
- MeSH terms
- Absorption, Adult, Aged, Biological Availability, Calcium Carbonate, Drug Interactions, Female, Humans, Hypothyroidism, Male, Middle Aged, Prospective Studies, Thyrotropin, Thyroxine, Triiodothyronine, Cohort Studies
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