Effect of eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism: a randomized, double-blind, placebo-controlled trial

Abstract

Background: Increasing evidence suggests the bidirectional interplay between parathyroid hormone and aldosterone as an important mechanism behind the increased risk of cardiovascular damage and bone disease observed in primary hyperparathyroidism. Our primary object is to assess the efficacy of the mineralocorticoid receptor-blocker eplerenone to reduce parathyroid hormone secretion in patients with parathyroid hormone excess.

Methods/design: Overall, 110 adult male and female patients with primary hyperparathyroidism will be randomly assigned to eplerenone (25 mg once daily for 4 weeks and 4 weeks with 50 mg once daily after dose titration] or placebo, over eight weeks. Each participant will undergo detailed clinical assessment, including anthropometric evaluation, 24-h ambulatory arterial blood pressure monitoring, echocardiography, kidney function and detailed laboratory determination of biomarkers of bone metabolism and cardiovascular disease.The study comprises the following exploratory endpoints: mean change from baseline to week eight in (1) parathyroid hormone(1-84) as the primary endpoint and (2) 24-h systolic and diastolic ambulatory blood pressure levels, NT-pro-BNP, biomarkers of bone metabolism, 24-h urinary protein/albumin excretion and echocardiographic parameters reflecting systolic and diastolic function as well as cardiac dimensions, as secondary endpoints.

Discussion: In view of the reciprocal interaction between aldosterone and parathyroid hormone and the potentially ensuing target organ damage, the EPATH trial is designed to determine whether eplerenone, compared to placebo, will effectively impact on parathyroid hormone secretion and improve cardiovascular, renal and bone health in patients with primary hyperparathyroidism.

Trial registration: ISRCTN33941607.

Figure 1

Flow chart for the EPATH trial.

Figure 2

Overview of the bidirectional interplay between aldosterone and PTH. Calcium influx is crucial for activating the synthesis of renin in juxta glomerular cells and aldosterone in zona glomerulosa cells. Renal renin synthesis is mainly controlled by tubular sodium concentration, arterial blood pressure and the sympathetic nervous system. PTH is suggested to stimulate renin synthesis by increasing calcium levels in JG cells. Extracellular potassium, adrenocorticotropic hormone and angiotensin II are major stimulators of aldosterone synthesis in the adrenal glands. Both factors interact with voltage-gated calcium channels and depolarize the zona glomerulosa cells, which results in elevated intracellular calcium levels. PTH might directly stimulate aldosterone synthesis by binding to the PTH1R and adrenocorticotropic hormone receptor. In addition, PTH is suggested to increase sensibilization of angiotensin II, which by itself reduces cellular calcium extrusion through activating Na+/Ca–exchangers in zona glomerulosa cells. Aldosterone in turn facilitates renal and fecal calcium loss resulting in further PTH secretion.