Diuretics and bone loss in rats with aldosteronism

OBJECTIVES We hypothesized that the increased urinary Ca2+ and Mg2+ excretion and bone loss that accompanies aldosteronism is aggravated with furosemide and is attenuated by spironolactone. BACKGROUND Furosemide, a loop diuretic, is commonly used in patients with congestive heart failure (CHF), in which chronic, inappropriate (dietary Na+) elevations in plasma aldosterone (ALDO) and a catabolic state that includes bone wasting are expected. METHODS In age- and gender-matched, untreated controls, four weeks of aldosterone/salt treatment (ALDO/salt, 0.75 mu g/h + 1% NaCl/0.4% KCl in drinking water), four weeks of ALDO/salt + furosemide (40 mg/kg in prepared food), and four weeks of ALDO/salt + furosemide + spironolactone (200 mg/kg/day in divided doses by twice-daily gavage), we monitored: 24-h urinary Ca2+ and Mg2+ excretion; plasma-ionized [Ca2+]o and [Mg2+]o, K+, and parathyroid hormone (PTH); and bone mineral density (BMD) in the femur. RESULTS The ALDO/salt increased (p < 0.05) urinary Ca2+ and Mg2+ excretion (4,969 +/- 1,078 and 3,856 +/- 440 mu g/24 h, respectively) compared with controls (896 +/- 138 and 970 +/- 137 mu g/24 h, respectively); furosemide co-treatment further increased (p < 0.05) urinary Ca2+ and Mg2+ excretion (6,976 +/- 648 and 6,199 +/- 759 mu g/24 h, respectively), whereas spironolactone co-treatment attenuated (p < 0.05) these incremental losses (4,003 +/- 515 and 3,915 +/- 972 mu g/24 h). Plasma [Ca-2 +/-]o was reduced (p < 0.05) at week 4 ALDO/salt + furosemide and was accompanied by hypokalemia (< 3.4 mmol/l) that were rescued by spironolactone. Plasma PTH was increased (p < 0.05) compared with controls (30 +/- 4 vs. 11 +/- 3 pg/ml, respectively), whereas BMD was decreased (p < 0.05) with ALDO/salt and ALDO/salt + furosemide, but not with spironolactone co-treatment. CONCLUSIONS In aldosteronism, hypercalciuria and hypermagnesuria and accompanying decrease in plasma-ionized [Ca2+]o and [Me2+]o lead to hyperparathyroidism that accounts for bone wasting. Furosemide exaggerates these losses, whereas its combination with spironolactone attenuates these responses to prevent bone loss. (J Am Coll Cardiol 2005;46:142-6) (c) 2005 by the American College of Cardiology Foundation.