Thiazide Diuretics and Calcium Excretion
Yes, thiazide diuretics inhibit calcium excretion by decreasing urinary calcium loss, which is precisely why they are recommended as first-line pharmacological therapy for preventing recurrent calcium kidney stones in patients with hypercalciuria. 1, 2, 3
Mechanism of Action
Thiazides decrease the excretion of calcium through their effects on renal tubular transport. 3 The FDA label for hydrochlorothiazide explicitly states that "hydrochlorothiazide also decreases the excretion of calcium." 3
The hypocalciuric effect occurs through two potential mechanisms depending on volume status:
- When extracellular fluid volume is reduced (as occurs with higher thiazide doses and sodium restriction for kidney stone treatment), the proximal tubule plays the major role in thiazide-induced hypocalciuria 4
- When extracellular fluid volume is preserved, the distal tubule is predominantly involved in the hypocalciuric effect through NaCl cotransporter inhibition 4
Clinical Evidence and Applications
The American Urological Association specifically recommends thiazide diuretics for patients with high or relatively high urine calcium and recurrent calcium stones (Standard; Evidence Strength: Grade B). 1 This recommendation is based on the drug's ability to reduce urinary calcium excretion, which is a key factor in calcium stone formation. 1
Hydrochlorothiazide reduces urinary calcium excretion effectively at doses of 25 mg orally twice daily or 50 mg orally once daily. 1 The American College of Physicians recommends thiazide diuretics as effective pharmacological monotherapy for preventing recurrent nephrolithiasis when increased fluid intake alone is insufficient. 1
Research confirms this effect: In children with idiopathic hypercalciuria, thiazides reduced urinary calcium excretion and resolved hematuria in all cases without altering serum calcium concentration. 5 A more recent study showed that chlorthalidone reduced urinary calcium from 130 ± 70 mg/g Cr at baseline to 76 ± 52 mg/g Cr with morning dosing. 6
Sex-Related Differences
The hypocalciuric effect may be more pronounced in women. In female rats, bendroflumethiazide decreased urinary calcium excretion by 50%, while it had no effect in male rats. 7 This sex difference is attributed to 2-fold higher expression of the thiazide-sensitive Na+-Cl− cotransporter in the apical membrane of the distal convoluted tubule in females. 7
Important Clinical Caveats
Dietary sodium restriction must be continued when thiazides are prescribed to maximize the hypocalciuric effect and limit potassium wasting. 2 Sodium intake should be limited to 2,300 mg (100 mEq) daily. 2
Monitor for hypokalemia, which is the most common adverse effect. 3 Potassium supplementation may be needed when using thiazides. 2 Periodic determination of serum electrolytes should be performed in all patients. 3
In Bartter syndrome, thiazides should not be routinely administered despite their hypocalciuric effect, as compensatory salt reabsorption in the distal convoluted tubule is critical for volume homeostasis, and thiazides may lead to life-threatening hypovolemia in these salt-wasting patients. 7
Hydrochlorothiazide at 25 mg once daily may be insufficient for stone prevention. A recent study found that HCTZ 25 mg did not significantly reduce urinary calcium regardless of timing of administration (mean 24-hour UCa was 124 ± 38 mg/g Cr at baseline vs 106 ± 40 mg/g Cr with AM dosing). 6 In contrast, chlorthalidone 25 mg was more effective, suggesting that the longer-acting chlorthalidone may be preferable. 6