Bone Loss in Rats with Aldosteronism

Objective: We hypothesized that aldosteronism is accompanied by hypercalciuria and hypermagnesuria that lead to bone loss, which could be rescued by hydrochlorothiazide and spironolactone.

Methods: We monitored 24-hour urinary Ca and Mg excretion; plasma ionized [Ca]o and [Mg]o and plasma K; and bone mineral density of the femur. The following groups (n=5 in each group) were studied: age- and gender-matched, untreated controls; controls + 4 weeks hydrochlorothiazide; 4 weeks aldosterone/salt treatment (ALDOST, 0.75 mug/h and dietary 1% NaCl/0.4% KCl); 4 weeks ALDOST+hydrochlorothiazide (50 mg/kg in prepared food); and 4 weeks ALDOST+hydrochlorothiazide+spironolactone (200 mg/kg day in divided doses by twice-daily gavage).

Results: ALDOST increased (P<0.05) urinary Ca and Mg excretion four- and twofold, respectively; hydrochlorothiazide co-treatment attenuated (P<0.05) Ca excretion in controls and during ALDOST without affecting augmented Mg excretion whereas hydrochlorothiazide+spironolactone normalized Ca and reduced Mg excretion (P<0.05). Compared with controls, plasma [Ca]o at 4 weeks of ALDOST was reduced (0.89+/-0.02 versus 0.83+/-0.03 mmol/L; P<0.05) but remained no different from levels in controls with hydrochlorothiazide and hydrochlorothiazide+spironolactone (0.88+/-0.04 and 0.97+/-0.03 mmol/L, respectively). Plasma [Mg]o fell (P<0.05) with ALDOST+hydrochlorothiazide (0.23+/-0.01 versus 0.34+/-0.01 mmol/L) and was prevented with spironolactone co-treatment (0.33+/-0.01 mmol/ dL). Hypokalemia (2.9+/-0.2 mmol/L) occurred in rats with ALDOST+hydrochlorothiazide but not with spironolactone co-treatment. At 4 weeks of ALDOST, plasma parathyroid hormone was increased (30+/-4 versus 11+/-3 pg/mL; P<0.05) and bone mineral density was reduced (0.153+/-0.006 versus 0.170+/-0.002 g/cm; P<0.05). Co-treatments with either hydrochlorothiazide or hydrochlorothiazide+spironolactone each prevented bone loss.

Conclusions: Hypercalciuria and hypermagnesuria accompany aldosteronism and account for a decline in their plasma ionized concentrations and secondary hyperparathyroidism with bone resorption. Attenuation of bone loss in aldosteronism can be achieved with hydrochlorothiazide; however, mono- and divalent cation homeostasis, together with bone integrity, are each preserved with the combination hydrochlorothiazide+spironolactone.