Bisphosphonates use is associated with increased coronary artery calcification in the general population: The Rotterdam study

TL;DR

Long-term use of bisphosphonates is linked to increased coronary artery calcification in the general population, with a stronger effect seen over longer durations of use.

Contribution

This study provides new evidence of a dose-response relationship between prolonged bisphosphonate use and coronary artery calcification in a large population-based cohort.

Findings

Long-term bisphosphonate use (>5 years) was associated with larger baseline coronary artery calcification (CAC).

A dose-response relationship was observed, with increased calcification volume across quartiles of bisphosphonate use duration.

The effect was strongest in coronary arteries and weakest in intracranial carotid arteries.

Abstract

Bisphosphonates may influence arterial calcification through mechanisms shared with bone formation. As treatment often extends over several years, assessing the arterial effects requires long-term follow-up. This population-based cohort estimated the long-term association of bisphosphonates with calcification across multiple key arterial sites.

We included 2399 Rotterdam Study participants with baseline CT-assessed calcification in the coronary arteries (CAC), aortic arch (AAC), and extra/intracranial carotid arteries (ECAC and ICAC). Among these, 815 participants underwent repeat CT after a mean of 13.6 years. Pharmacy-linked data provided cumulative information on bisphosphonate use from study entry to follow-up. Multivariable linear and mixed-effects regressions evaluated associations between bisphosphonate use, duration, and the dose-response of duration with calcification volume.

Long-term bisphosphonate use (>5 years) was statistically significantly associated with larger baseline CAC compared with both never use (β [95 % CI]: 0.42 [0.10, 0.73]) and short-term use (p-interaction = 0.02). At follow-up, prolonged use (mean duration: 4.9 years) was also significantly associated with increased CAC. Effect estimates increased across quartiles of duration for CAC, AAC, and ECAC (but not ICAC), with a significant linear trend only for CAC (p-trend < 0.0001), suggesting a dose-response relationship. Across arterial sites, CAC showed the largest effect estimates, ICAC the smallest.

Long-term bisphosphonate use is associated with increased arterial calcification, most notably with increased CAC, with a dose-response relationship further strengthening this observation. Large-scale observational studies are encouraged to use advanced causal inference methods to evaluate this long-term association and provide additional evidence to strengthen the causal interpretation.

Image 1

•Long-term bisphosphonate use was assessed via pharmacy records over 13.6 years.•Repeated CT-assessed arterial calcification was analyzed at multiple anatomical locations.•Prolonged bisphosphonate use is linked to larger coronary artery calcification with a dose-response trend.•The effect varied across arteries, with coronary arteries most affected and intracranial carotids least.•Consistent association across bisphosphonates suggests the effect was not driven by one compound.

Long-term bisphosphonate use was assessed via pharmacy records over 13.6 years.

Repeated CT-assessed arterial calcification was analyzed at multiple anatomical locations.

Prolonged bisphosphonate use is linked to larger coronary artery calcification with a dose-response trend.

The effect varied across arteries, with coronary arteries most affected and intracranial carotids least.

Consistent association across bisphosphonates suggests the effect was not driven by one compound.

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