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Risk of Ischemic Stroke Associated with Calcium Supplements and Interaction with Oral Bisphosphonates: A Nested
Diana Barreira-Hernández1, Sara Rodríguez-Martín1, Miguel Gil2
1Department of Biomedical Sciences (Pharmacology), University of Alcalá (IRYCIS), 28805 Alcalá de Henares, Spain.
Insights
Calcium supplements (CS) alone increase cardioembolic ischemic stroke (IS) risk, especially with oral bisphosphonates (oBs). Calcium with vitamin D (CaD) showed no significant IS risk. This highlights risks associated with specific supplement combinations.
Area of Science:
- Cardiovascular epidemiology
- Pharmacovigilance
- Nutritional science
Background:
- Conflicting evidence exists regarding the association between calcium supplements (CS) and ischemic stroke (IS).
- Previous studies have not consistently differentiated between calcium alone (CaM) and calcium with vitamin D (CaD), nor between cardioembolic and non-cardioembolic IS subtypes.
- The potential interaction between CS and oral bisphosphonates (oBs) in stroke risk remains underexplored.
Purpose of the Study:
- To investigate the association between calcium supplements (CaM and CaD) and the risk of ischemic stroke (IS), differentiating between cardioembolic and non-cardioembolic subtypes.
- To examine the potential interaction effect of concomitant use of calcium supplements and oral bisphosphonates (oBs) on IS risk.
- To clarify conflicting findings on calcium supplement use and stroke risk.
Main Methods:
- A nested case-control study design was employed, including incident IS cases aged 40-90 and randomly sampled controls matched by age, sex, and index date.
- Conditional logistic regression was used to compute adjusted odds ratios (AOR) and 95% confidence intervals (CI) for current users versus non-users, focusing on new users.
- The study analyzed 13,267 IS cases (4400 cardioembolic, 8867 non-cardioembolic) and 61,378 controls.
Main Results:
- Calcium alone (CaM) use was significantly associated with an increased risk of cardioembolic IS (AOR = 1.88), with risk increasing with duration of use, but not with non-cardioembolic IS (AOR = 1.05).
- Concomitant use of CaM and oral bisphosphonates (oBs) substantially increased cardioembolic IS risk (AOR = 2.54) but showed no effect on non-cardioembolic IS.
- Calcium with vitamin D (CaD) use was not associated with either IS subtype, though a small association with cardioembolic IS was observed when combined with oBs (AOR = 1.35).
Conclusions:
- The findings support the hypothesis that calcium supplements (CS), particularly calcium alone (CaM), increase the risk of cardioembolic ischemic stroke (IS).
- The risk of cardioembolic IS associated with CS is notably amplified when used concurrently with oral bisphosphonates (oBs).
- Calcium with vitamin D (CaD) appears to have a different risk profile, with limited association with IS, even when combined with oBs.
Abstract:
Conflicting results about the association of calcium supplements (CS) with ischemic stroke (IS) have been reported. We tested this hypothesis by differentiating between CS alone (CaM) and CS with vitamin D (CaD) and between cardioembolic and non-cardioembolic IS. We examined the potential interaction with oral bisphosphonates (oBs). A nested case-control study was carried out. We identified incident IS cases aged 40-90 and randomly sampled five controls per case matched by age, sex, and index date. Current users were compared to non-users. An adjusted odds ratios (AOR) and 95% CI were computed through conditional logistic regression. Only new users were considered. We included 13,267 cases (4400 cardioembolic, 8867 non-cardioembolic) and 61,378 controls (20,147 and 41,231, respectively). CaM use was associated with an increased risk of cardioembolic IS (AOR = 1.88; 95% CI: 1.21-2.90) in a duration-dependent manner, while it showed no association with non-cardioembolic IS (AOR = 1.05; 95% CI: 0.74-1.50); its combination with oBs increased the risk of cardioembolic IS considerably (AOR = 2.54; 95% CI: 1.28-5.04), showing no effect on non-cardioembolic. CaD use was not associated with either cardioembolic (AOR = 1.08; 95% CI: 0.88-1.31) or non-cardioembolic IS (AOR = 0.98; 95% CI: 0.84-1.13) but showed a small association with cardioembolic IS when combined with oBs (AOR = 1.35; 95% CI: 1.03-1.76). The results support the hypothesis that CS increases the risk of cardioembolic IS, primarily when used concomitantly with oBs.
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