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Diuretics and Bone Loss in Rats With Aldosteronism

Peter H. Law, BS^_*, Yao Sun, MD, PhD^_*, Syamal K. Bhattacharya, PhD, Vikram S. Chhokar, MD^_* and Karl T. Weber, MD, FACC^_*,_*

^_* Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee

Manuscript received November 11, 2004; revised manuscript received January 21, 2005, accepted March 17, 2005.

^_* Reprint requests and correspondence: Dr. Karl T. Weber, Division of Cardiovascular Diseases, University of Tennessee Health Science Center, 920 Madison Avenue, Suite 300, Memphis, Tennessee 38163 (Email: KTWeber{at}utmem.edu).

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 µg/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 µg/24 h, respectively) compared with controls (896 ± 138 and 970 ± 137 µg/24 h, respectively); furosemide co-treatment further increased (p < 0.05) urinary Ca²⁺ and Mg²⁺ excretion (6,976 ± 648 and 6,199 ± 759 µg/24 h, respectively), whereas spironolactone co-treatment attenuated (p < 0.05) these incremental losses (4,003 ± 515 and 3,915 ± 972 µg/24 h). Plasma [Ca²⁺]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 [Mg²⁺]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.

Abbreviations and Acronyms   ALDO = aldosterone   BMD = bone mineral density   CHF = congestive heart failure   DOC = deoxycorticosterone   PTH = parathyroid hormone

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