Purpose Loop diuretics, such as furosemide (F), are commonly used in patients with congestive heart failure, where chronic, inappropriate (relative to dietary Na+) elevations in plasma aldosterone (ALDO) are expected, together with a wasting of soft tissues and bone. We hypothesized aldosteronism is accompanied by increased urinary excretion of Ca2+ and Mg2+ that ultimately leads to bone loss and this scenario would be aggravated with F while spironolactone, an ALDO receptor antagonist, would attenuate this loss.
Methods We monitored: 24 hour urinary Ca2+ and Mg2+ excretion; plasma ionized [Ca2+]o and [Mg2+]o and plasma K+; and bone mineral density of femur. The following groups (n = 5) were studied: age-/gender-matched, untreated and F-treated controls; 4 weeks aldosterone/salt treatment (ALDOST, 0.75 μg/h+dietary 1% NaCl/0.4% KCl); 4 weeks ALDOST + F (40 mg/kg in prepared food); and 4 weeks ALDOST + F + spironolactone (Spi; 200 mg/kg/day in divided doses by twice-daily gavage).
Results ALDOST markedly increased (p < .05) urinary Ca2+ and Mg2+ excretion (4969 ± 1078 and 3856 ± 440 μg/24 h, respectively) vs. controls (896 ± 138 and 970 ± 137 μg/24 h); F co-treatment further increased (p < .05) urinary Ca2+ and Mg2+ excretion (6976 ± 648 and 6199 ± 759 μg/24 h, respectively) while Spi co-treatment attenuated (p < .05) these exaggerated losses (4003 ± 515 and 3915 ± 972 μg/24 h). Plasma [Ca2+]o was reduced (p < .05) at week 4 ALDOST + F and in 5 of 5 rats was accompanied by hypokalemia (< 3.4 mmol/L), with each of these responses rescued by Spi co-treatment. Parathyroid hormone (PTH) was increased (p < .05) in ALDOST compared to controls (30 ± 4 vs. 11 ± 3 pmol/mL, respectively) while bone mineral density of femur was decreased (p < .05) at week 4 of ALDOST and ALDOST + F, which was not the case with Spi co-treatment (0.153 ± 0.006, 0.151 ± 0.006 vs. 0.165 ± 0.003 g/cm2, respectively).
Conclusions Hypercalciuria and hypermagnesuria with ALDOST lead to a fall in plasma ionized concentrations of these divalent cations and the elaboration of PTH with secondary hyperparathyroidism accounting for bone resorption. F exaggerates these losses while co-treatment with Spi attenuates Ca2+ and Mg2+ excretion to prevent bone loss. The management of CHF with diuretics should take into consideration their effects on Ca2+ and Mg2+ homeostasis, including their propensity to either promote or prevent bone loss.
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