Full Length Article Effect of eplerenone on markers of bone turnover in patients with primary hyperparathyroidism – The randomized, placebo-controlled EPATH trial Nicolas Verheyen a, ⁎, Martin R. Grübler b,c , Andreas Meinitzer d , Christian Trummer b , Verena Schwetz b , Karin Amrein b , Hans P. Dimai b , Winfried März d,e,f , Cristiana Catena g , Dirk von Lewinski a , Jakob Voelkl h , Ioana Alesutan h , Astrid Fahrleitner-Pammer b , Helmut Brussee a , Stefan Pilz b,i , Andreas Tomaschitz a,f,j a Department of Cardiology, Medical University of Graz, Graz, Austria b Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria c Swiss Cardiovascular Center Bern, Department of Cardiology, Bern University Hospital, Bern, University of Bern, Switzerland d Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria e Synlab Academy, Synlab Services LLC, Mannheim, Germany f Medical Clinic V (Nephrology, Hypertensiology, Endocrinology), Medical Faculty Mannheim, Ruperto Carola University Heidelberg, Mannheim, Germany g Hypertension Unit, Internal Medicine, Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy h Medizinische Klinik mit Schwerpunkt Kardiologie, Campus Virchow-Klinikum, Charité-Universitaetsmedizin Berlin, Berlin, Germany i Department of Health Sciences and the EMGO + Institute, VU University Amsterdam, The Netherlands j Bad Gleichenberg Clinic, Bad Gleichenberg, Austria abstract article info Article history: Received 23 June 2017 Revised 18 August 2017 Accepted 28 August 2017 Available online 14 September 2017 Mineralocorticoid receptor (MR) antagonism may affect bone turnover via direct and indirect pathways involv- ing parathyroid hormone, but randomized controlled trials are lacking. In a pre-specified analysis of the “Eplerenone in primary hyperparathyroidism” placebo-controlled, randomized trial (ISRCTN 33941607), effects of eight weeks MR-blockade with eplerenone on bone turnover markers in 97 patients with primary hyperpara- thyroidism were tested. Mean age was 67.5 ± 9.5 years, and 76 (78.4%) were females. In analysis of covariance with adjustment for baseline values, eplerenone had no significant effect on isoform 5b of the tartrate-resistant acid phosphatase (TRAP), beta-crosslaps, N-terminal propeptide of procollagen type 1 (P1NP), osteocalcin and bone-specific alkaline phosphatase. There was no significant cross-sectional correlation between plasma aldoste- rone concentration or the aldosterone-to-renin ratio and markers of bone turnover in multivariate linear regres- sion models at baseline. These data provide first evidence from a randomized and placebo-controlled trial that short-term MR antagonism may not affect bone turnover, at least in patients with primary hyperparathyroidism. © 2017 Published by Elsevier Inc. Keywords: Bone turnover Mineralocorticoid receptor Eplerenone Primary hyperparathyroidism Randomized controlled trial 1. Introduction MR antagonism reduces cardiovascular outcomes in patients with heart failure with reduced ejection fraction [1,2]. These effects are most likely a consequence of MR blockade in vascular, myocardial and renal cells [3,4]. Experimental and observational studies indicate that MR antagonism may also entail regulation of bone turnover. The MR is functionally expressed in osteoclasts, osteocytes and osteoblasts where aldosterone induces cell proliferation [5,6]. Also effects of gluco- corticoid excess on vertebral bone in rats were, at least in part, mediated via the MR and ameliorated with eplerenone [7]. Another potential mechanism may be the interplay between calcium regulating hor- mones, particularly parathyroid hormone (PTH), and aldosterone. Aldo- sterone-salt infusion in rats resulted in hyperparathyroidism and reduced bone strength. In the same model MR antagonism with spironolactone preserved bone strength, and bone demineralization could be prevented by parathyroidectomy [8,9]. In patients with prima- ry aldosteronism, risk of vertebral fracture is increased and surgical or medical treatment was associated with an improvement in bone miner- al density in several cohorts [10–13]. Also in patients with chronic heart failure, spironolactone therapy was associated with a reduced rate of total fractures in a multivariate model [14]. Taken together, accumulat- ing evidence implies that MR antagonism may directly or indirectly, via parathyroid hormone (PTH), impact on bone health in humans. Howev- er, evidence from randomized, placebo-controlled trials is absent. In the present study, we therefore aimed to test whether administration of Bone 105 (2017) 212–217 ⁎ Corresponding author at: Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria. E-mail address: nicolas.verheyen@medunigraz.at (N. Verheyen). http://dx.doi.org/10.1016/j.bone.2017.08.030 8756-3282/© 2017 Published by Elsevier Inc. Contents lists available at ScienceDirect Bone journal homepage: www.elsevier.com/locate/bone