# 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.

## Key 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.

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•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.