Renin-angiotensin system inhibitors and risk of fractures: a prospective cohort study and meta-analysis of published observational cohort studies

Abstract

The renin-angiotensin system (RAS) represents an important target of antihypertensive medications. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), which are widely-used RAS inhibiting drugs, have been suggested to have beneficial effects on bone tissue. We aimed to assess the associations of use of ACEIs and/or ARBs with the risk of fractures using a population-based prospective cohort and a meta-analysis of published prospective cohort studies. Information on antihypertensive medication use (including both ACEIs and ARBs) were assessed in 1743 men and women of the Kuopio Ischemic Heart Disease prospective cohort study. Hazard ratios (HRs) [95% confidence intervals (CI)] of ACEIs or ARBs use with incident fractures were calculated. A total of 203 composite (hip, humeral, and wrist) fractures occurred during a median follow-up of 14.8 years. In multivariate adjusted analysis, the HR for composite fractures comparing users of ACEIs or ARBs with non-users was 1.00 (0.59-1.69). The corresponding adjusted HR for hip fractures comparing users versus non-users of ACEIs or ARBs was 0.89 (0.32-2.47). Including the current study, a total of 11 observational cohort studies involving 3526,319 participants and >323,355 fractures were included in a meta-analysis. Comparing ACEI users with non-users and ARB users with non-users, the HRs for composite fractures were 1.09 (0.89-1.33) and 0.87 (0.76-1.01) respectively. The corresponding HRs for hip fractures were 0.91 (0.86-0.95) and 0.80 (0.75-0.85) respectively. Use of RAS inhibitors was not associated with long-term risk of composite fractures in both primary and pooled analyses. Pooled evidence however suggests a beneficial effect of RAS blockers on hip fracture risk.

Keywords: Angiotensin converting enzyme; Angiotensin receptor blocker; Cohort study; Fracture; Renin-angiotensin system.

Fig. 1

Hazard ratios for composite fractures risk comparing ACEIs or ARBs use with no use, by several participant level characteristics. Hazard ratios were adjusted for age, sex, BMI, smoking, history of diabetes, systolic blood pressure, prevalent hypertension, prevalent CHD, prevalent heart failure, alcohol consumption, and use of statins, or calcium channel blockers; ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin II receptor blocker, CHD coronary heart disease, CI confidence interval, HR hazard ratio, *, P value for interaction; cut-offs used for age, body mass index, systolic blood pressure, total cholesterol, and physical activity are median values

Fig. 2

Prospective studies of RAS inhibitors and risk of composite fractures. The summary estimates presented were calculated using random effects models; size of data markers are proportional to the inverse of the variance of the relative ratio; ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin II receptor blocker, CI confidence interval (bars), RR relative risk, RAS renin-angiotensin system blockers

Fig. 3

Prospective studies of RAS inhibitors and risk of hip fractures. The summary estimates presented were calculated using random effects models; size of data markers are proportional to the inverse of the variance of the relative ratio; ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin II receptor blocker, CI confidence interval (bars), RR relative risk, RAS renin-angiotensin system blockers