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

European Journal of Epidemiology, Jul 2017

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.

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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 - 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)


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Setor K. Kunutsor, Ashley W. Blom, Michael R. Whitehouse, Patrick G. Kehoe, Jari A. Laukkanen. Renin-angiotensin system inhibitors and risk of fractures: a prospective cohort study and meta-analysis of published observational cohort studies, European Journal of Epidemiology, 2017, pp. 947-959, Volume 32, Issue 11, DOI: 10.1007/s10654-017-0285-4