Use of renin-angiotensin system inhibitors is associated with reduction of fracture risk in hemodialysis patients

Abstract

Background: Patients with chronic kidney disease, especially those undergoing dialysis treatment and having secondary hyperparathyroidism, have a high risk of bone fracture. The renin-angiotensin system (RAS) is associated with osteoclastic bone resorption. We aimed to examine whether the use of RAS inhibitors reduces the incidence of fracture in hemodialysis patients.

Methods and findings: This was a multicenter, 3-year, prospective, observational study. From 2008 to 2011, maintenance hemodialysis patients with secondary hyperparathyroidism (N = 3,276) treated with angiotensin converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) at baseline were followed for a mean of 2.7 years. The association between the use of ACEI/ARB and hospitalization rate owing to fracture was examined by using Cox regression models. Effect modifications by the severity of secondary hyperparathyroidism (intact parathyroid hormone [iPTH] level), sex, and systolic blood pressure were also examined. The incidence proportion of fracture-related hospitalization was 5.42% throughout the observation period. ACEI/ARB use was associated with a lower rate of fracture-related hospitalization (adjusted hazard ratio, 0.65; 95% confidence interval [CI], 0.45-0.92). This association was not significantly affected by sex (P = 0.56) or systolic blood pressure levels (P = 0.87). The hazard ratios adjusted by iPTH levels were qualitatively different, but not statistically significant (P = 0.11): 0.77 (95% CI, 0.42-1.39), 0.38 (95% CI, 0.20-0.73), 0.59 (95% CI, 0.29-1.21), and 1.29 (95% CI, 0.58-2.42) for the first, second, third and fourth quartiles of iPTH, respectively.

Conclusions: Use of RAS inhibitors is associated with a lower rate of fracture-related hospitalization in hemodialysis patients with secondary hyperparathyroidism.

Trial registration: ClinicalTrials.gov NCT00995163.

Conflict of interest statement

Competing Interests: The MBD-5D study was supported by research grants from Kyowa Hakko Kirin. M. F. has acted as a consultant, received honoraria, and grants (research support) from Kyowa Hakko Kirin. T. A. has acted as a consultant and received grants (research support) from Kyowa Hakko Kirin, besides of being a member of the speakers’ bureau at Kyowa Hakko Kirin. S. F. has acted as a scientific advisor for Kyowa Hakko Kirin, and has received grants (research support) from Kyowa Hakko Kirin. The other authors have no conflicts of interest to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Cumulative proportion of the incidence of hospitalization owing to fractures.

ACEI: angiotensin converting enzyme inhibitor, ARB: angiotensin II receptor blocker.

Fig 2. Crude, case-mix-adjusted, and multivariate-adjusted hazard ratios of hospitalization owing to fractures associated with angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use.

The covariates included in each analytical model for adjustment were as follows: case-mix, age, sex, duration of dialysis, and causes of end-stage kidney disease. In the multivariate-adjusted model, in addition to those in the case-mix model, the following covariates were adjusted; body mass index; Kt/V; comorbidity of cardiovascular disease and/or diabetes mellitus; smoking; history of parathyroidectomy; prescriptions of anti-coagulants, vitamin D receptor activators, and phosphate binders; and serum levels of albumin, calcium, phosphorus, intact parathyroid hormone, alkaline phosphatase, and blood hemoglobin, in addition to systolic and diastolic blood pressure and the use of antihypertensive drugs (β-blockers, calcium channel blockers, diuretics, and others). HR: hazard ratio, ACEI: angiotensin-converting enzyme inhibitor, ARB: angiotensin II receptor blocker.

Fig 3. Multivariate-adjusted hazard ratios of hospitalization owing to fractures associated with angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use considering patients with different levels of parathyroid hormone, sex, or systolic blood pressure.

The hazard ratio was obtained from the Cox regression model adjusted for the distribution of age; sex; duration of dialysis; causes of end-stage kidney disease; body mass index; Kt/V; comorbidity of cardiovascular disease or diabetes mellitus; smoking; history of parathyroidectomy; prescriptions of anti-coagulants, vitamin D receptor activators, and phosphate binders; and serum levels of albumin, calcium, phosphorus, parathyroid hormone, alkaline phosphatase, and blood hemoglobin, in addition to systolic and diastolic blood pressure and the use of antihypertensive drugs (β-blockers, calcium channel blockers, diuretics, and others). P values for interactions were obtained from the likelihood ratio test. CI: confidence interval, HR: hazard ratio, iPTH: intact parathyroid hormone, ACEI: angiotensin-converting enzyme inhibitor, ARB: angiotensin II receptor blocker.