Renin-angiotensin system inhibitors and risk of fractures: a prospective cohort study and meta-analysis of published observational cohort studies
Eur J Epidemiol
Renin-angiotensin system inhibitors and risk of fractures: a prospective cohort study and meta-analysis of published observational cohort studies
Setor K. Kunutsor 0 1 2 3 4
Ashley W. Blom 0 1 2 3 4
Michael R. Whitehouse 0 1 2 3 4
Patrick G. Kehoe 0 1 2 3 4
Jari A. Laukkanen 0 1 2 3 4
0 Dementia Research Group, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol , Learning and Research Building (Level 1) , Southmead Hospital , Southmead Road, Bristol , UK
1 Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol , Learning and Research Building (Level 1) , Southmead Hospital , Southmead Road, Bristol BS10 5NB , UK
2 & Setor K. Kunutsor
3 Internal Medicine, Central Finland Central Hospital , Jyva ̈skyla ̈ , Finland
4 Institute of Public Health and Clinical Nutrition, University of Eastern Finland , Kuopio , Finland
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 widelyused 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 nonusers 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.
Renin-angiotensin system; Angiotensin converting enzyme; Angiotensin receptor blocker; Cohort study; Fracture
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Patrick G. Kehoe and Jari A. Laukkanen have contributed equally to
this work.
Introduction
Aging of the population is associated with an increase in
age-related chronic conditions such as fractures
(particularly osteoporotic fractures). These are one of the most
common causes of disability worldwide and associated
with high health care costs [
1, 2
]. Complications of fracture
include morbidity, pain, limited function, reduction in
health-related quality of life, as well as mortality [3].
Mortality rates in the first year following hip fracture have
been reported to range from 10 to 50% [
4, 5
]. The
prevention of fractures is therefore of public health
importance.
The majority of older people with osteoporosis have
comorbidities such as hypertension and cardiovascular
disease. Two major risk factors for osteoporotic fractures are
reduced bone mass and falls, and these have a close
relationship with hypertension [
6
]. Elevated blood pressure or
diagnosed hypertension has been shown to be closely
associated with osteoporosis, decreased bone mineral
density (BMD), falls, as well as fractures [
6–10
].
Epidemiological evidence and studies in animal models
suggest that high blood pressure is associated with vitamin D
deficiency and abnormalities in calcium metabolism
[
11, 12
], which are known to be involved in the
pathophysiology of osteoporosis, falls, and fractures [13]. It
therefore appears that medications that lower blood
pressure may have a beneficial effect on bone tissue. Indeed,
blood pressure lowering medications such as thiazides and
b-blockers have consistently been shown to be associated
with the reduced risk of fractures [
14–17
]. Furthermore, the
renin-angiotensin system (RAS), that plays a vital role in
regulating blood pressure and electrolyte balance [18], and
the activation of which is an important contributor to
systemic hypertension [
19
], also has effects on bone tissue.
This is via the detrimental effects of angiotensin II, a
primary mediator of numerous RAS functions, on the bone
[
20
]. Studies have shown that RAS activation induces
osteoporosis as well as reduces blood ionized calcium
levels [
20, 21
]. The RAS inhibiting
drug (...truncated)