eplerenone and Hyperparathyroidism--Primary

The following review presents recent diagnostic and therapeutic developments in the field of endocrinology. With the development of strontium ranelate and teriparatide (human recombinant parathyroid hormone) two new drugs are now available for the treatment of postmenopausal osteoporosis. In addition, the therapeutic use of the calcimimetic agent cinacalcet in the treatment of primary and secondary hyperparathyroidism is discussed. The recent introduction of a novel, long-acting testosterone formulation (testosterone undecanoate) which only requires one intramuscular injection every 3 months, together with the already available hydroalcoholic testosterone gels, appear to be promising alternatives to the previous standard substitution therapy for male hypogonadism. Recently, the mineralocorticoid hormone aldosterone has gained much interest due to its central pathophysiological role in secondary hypertension and its potential deleterious role as a cardiovascular risk factor in nonepithelial target tissues. In this context, the therapeutic potential of a new selective mineralocorticoid receptor antagonist, eplerenone, will be ventilated. In addition, (18)F-DOPA positron emission tomography ((18)F-DOPA-PET), a new functional imaging modality for the diagnostic localization of chromaffin tumors, will be presented and the role of the somatostatin receptor radionuclide therapy with (90)Y-[DOTA](0)-Tyr(3)-octreotide ((90)Y-DOTATOC) for the treatment of advanced neuroendocrine tumors discussed. Furthermore, the ongoing controversy about the diagnosis and treatment of subclinical hypothyroidism will be summarized.

Topics: Adrenal Gland Neoplasms; Adult; Bone Density Conservation Agents; Chronic Kidney Disease-Mineral and Bone Disorder; Cinacalcet; Clinical Trials as Topic; Endocrinology; Eplerenone; Female; Humans; Hyperaldosteronism; Hyperparathyroidism; Hyperparathyroidism, Primary; Hyperparathyroidism, Secondary; Hypogonadism; Hypothyroidism; Male; Naphthalenes; Neuroendocrine Tumors; Organometallic Compounds; Osteoporosis, Postmenopausal; Pheochromocytoma; Positron-Emission Tomography; Pregnancy; Radiography, Abdominal; Spironolactone; Teriparatide; Testosterone; Testosterone Congeners; Thiophenes; Time Factors; Tomography, X-Ray Computed

Human physiology and epidemiology studies have demonstrated complex interactions between the renin-angiotensin-aldosterone system, parathyroid hormone and calcium homeostasis. Several of these studies have suggested that aldosterone inhibition may lower parathyroid hormone (PTH) levels. The objective of this study was to assess the effect of 4 weeks of maximally tolerated mineralocorticoid receptor antagonist therapy with eplerenone on PTH levels in patients with primary hyperparathyroidism (P-HPT) when compared to amiloride and placebo. We also investigated the synergistic effect of these interventions when combined with cinacalcet for an additional 2 weeks.. Randomized, double-blinded, three parallel-group, placebo-controlled trial.. Patients with P-HPT.. Most patients were women (83%) and White (76%). Maximally tolerated doses of eplerenone and amiloride induced significant reductions in blood pressure and increases in renin and aldosterone production; however, despite these physiologic changes, neither intervention induced significant changes in PTH or calcium levels when compared to the placebo. Both eplerenone and amiloride therapy induced significant reductions in procollagen type 1 N-terminal propeptide levels when compared to placebo. When cinacalcet therapy was added, PTH and calcium levels were markedly reduced in all groups; however, there was no significant difference in PTH or serum calcium reductions between groups.. Although maximally tolerated therapy with eplerenone and amiloride induced expected changes in renin, aldosterone and blood pressure, there were no meaningful changes in PTH or serum calcium levels in P-HPT patients. These results suggest that inhibition of aldosterone action does not have a clinically meaningful role in medical therapy for P-HPT.

Topics: Aldosterone; Amiloride; Calcium; Cinacalcet; Eplerenone; Female; Humans; Hyperparathyroidism, Primary; Male; Parathyroid Hormone; Renin

Mineralocorticoid receptor (MR) antagonism may affect bone turnover via direct and indirect pathways involving 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 hyperparathyroidism were tested. Mean age was 67.5±9.5years, 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 aldosterone concentration or the aldosterone-to-renin ratio and markers of bone turnover in multivariate linear regression 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.

Topics: Aged; Biomarkers; Bone Remodeling; Cohort Studies; Eplerenone; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Primary; Male; Placebos; Renin-Angiotensin System; Spironolactone; Treatment Outcome

Accumulating evidence points toward mutual interaction between parathyroid hormone (PTH) and aldosterone as potential mechanism for increasing cardiovascular risk in primary hyperparathyroidism (pHPT).. The Eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism (EPATH) trial is a single-center, randomized, double-blind, parallel-group, placebo-controlled trial. The primary aim is to evaluate the effects of the mineralocorticoid receptor antagonist eplerenone on plasma intact PTH (iPTH) concentration in patients with pHPT. Secondary end points comprised surrogate parameters of cardiovascular health [24-h ambulatory SBP and DBP and echocardiographic parameters related to systolic/diastolic function as well as to cardiac dimensions].. We enrolled 110 study participants with pHPT, 25-hydroxyvitamin D at least 20 ng/ml and estimated glomerular filtration rate more than 50 ml/min per 1.73 m. Patients were 1 : 1 randomly assigned to receive either 25 mg eplerenone once daily (up-titration after 4 weeks to 50 mg/day) or matching placebo for a treatment period of 8 weeks.The study was completed by 97 participants [mean (SD) age: 67.5 ± 9.5 years; 78.4% women). The mean treatment effect (95% confidence interval) for iPTH was 1.0 (0.9-1.1; P = 0.777) pg/ml. Mean 24-h ambulatory SBP and DBP decreased significantly [mean change (95% confidence interval) -6.3 (-9.4 to -3.3) and -3.7 (-5.7 to -1.7) mmHg, respectively; P < 0.001]. No differences were seen in any further secondary outcomes or frequency of adverse events.. In pHPT, treatment with eplerenone compared with placebo had no effect on circulating iPTH levels. Eplerenone treatment was well tolerated and safe and followed by significant decrease of ambulatory blood pressure.

Topics: Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Diastole; Double-Blind Method; Echocardiography; Eplerenone; Female; Humans; Hyperparathyroidism, Primary; Hypertension; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Parathyroid Hormone; Spironolactone; Systole; Vitamin D

The high prevalence of arterial hypertension in primary hyperparathyroidism (pHPT) is largely unexplained. Apart from parathyroid hormone (PTH), the mineral hormones fibroblast growth factor (FGF)-23 and aldosterone-to-renin ratio (ARR) are upregulated in pHPT. We aimed to determine whether nocturnal blood pressure (BP) is related with PTH, FGF-23 or ARR in a relatively large sample of pHPT patients.. Cross-sectional data of the single-center "Eplerenone in Primary Hyperparathyroidism" trial were used. All patients with a biochemical diagnosis of pHPT who had both available 24-h ambulatory BP monitoring and valid laboratory data were included.. Full data were available in 136 patients (mean age 67 ± 10 years, 78% women). Median PTH was 99 (interquartile range: 82-124) pg/ml and mean calcium was 2.63 ± 0.15 mmol/l. ARR, but not PTH or FGF-23, was significantly and directly related with nocturnal SBP (Pearson's r = 0.241, P < 0.01) and DBP (r = 0.328, P < 0.01). In multivariate regression analyses, with adjustment for age, sex, PTH, FGF-23, traditional cardiovascular risk factors, antihypertensive medication and parameters of calcium metabolism ARR remained significantly and directly related with nocturnal BP (SBP: adjusted β-coefficient = 0.289, P < 0.01; DBP: β = 0.399, P < 0.01). The relationship between ARR and nocturnal SBP was exclusively present in patients with PTH levels above the median of 99 pg/ml.. ARR, but not FGF-23 or PTH, was independently and directly related with nocturnal BP parameters in patients with pHPT, and this relationship was dependent on pHPT disease severity. Inappropriately, elevated aldosterone may partially explain the high prevalence of arterial hypertension in pHPT.

Topics: Aged; Aldosterone; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium; Circadian Rhythm; Cross-Sectional Studies; Diastole; Eplerenone; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperparathyroidism, Primary; Hypertension; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Parathyroid Hormone; Randomized Controlled Trials as Topic; Renin; Risk Factors; Sex Factors; Spironolactone; Systole