Purpose Congestive heart failure (CHF), whose origins are rooted in a salt-avid state mediated by effector hormones of the renin-angiotensin-aldosterone system, is accompanied by tissue wasting, including bone. We hypothesized that aldosteronism is accompanied by hypercalciuria and hypermagnesuria that over time leads to bone wasting and which could be rescued by co-treatment with hydrochlorothiazide (Hctz) and spironolactone (Spi).
Methods In rats, we monitored 24 h 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 Hctz-treated controls; 4 weeks aldosterone/salt treatment (ALDOST, 0.75 μg/h and dietary 1% NaCl/0.4% KCl); 4 weeks ALDOST + Hctz (50 mg/kg in prepared food); and 4 weeks ALDOST + Hctz + Spi (200 mg/kg day in divided doses by twice-daily gavage).
Results ALDOST increased (p < .05) urinary Ca2+ and Mg2+ excretion 4- and 2-fold, respectively; Hctz co-treatment attenuated (p < .05) Ca2+ without affecting augmented Mg2+ excretion while Hctz + Spi normalized Ca2+ and reduced Mg2+ (p < .05) excretion. Compared to controls, plasma [Ca2+]o at 4 weeks ALDOST was reduced (0.89 ± 0.02 vs. 0.83 ± 0.03 mmol/dL; p < .05), but remained unchanged or greater than controls with Hctz and Hctz+Spi (0.88 ± 0.04 and 0.97 ± 0.03 mmol/dL, respectively). Plasma [Mg2+]o fell (p < .05) with ALDOST + Hctz (0.23 ± 0.01 vs. 0.34 ± 0.01 mmol/dL), which was prevented with Spi co-treatment (0.33 ± 0.01 mmol/dL). Hypokalemia (2.9 ± 0.2 mEq/dL) occurred in rats with ALDOST + Hctz, but not with Spi co-treatment. At 4 weeks ALDOST and compared to controls, parathyroid hormone (PTH) was increased (30 ± 4 vs. 11 ± 3 pmol/mL; p < .05) while bone mineral density of femur was reduced (0.153 ± 0.006 vs. 0.170 ± 0.002 g/cm2; p < .05). Co-treatments with either Hctz or Hctz + Spi each prevented bone loss.
Conclusions The hypercalciuria and hypermagnesuria that accompany aldosteronism account for a decline in their plasma ionized concentrations and stimulation of PTH release with secondary hyperparathyroidism responsible for bone resorption. Prevention of bone loss in aldosteronism can be attained with Hctz while both mono- and divalent cation homeostasis and bone integrity can best be maintained with Hctz + Spi co-treatment.