Hydrochlorothiazide with salt restriction in nonsurgical hypoparathyroidism: a placebo-controlled single-blinded randomized crossover trial assessing efficacy and safety

Abstract In this single-center, randomized, placebo-controlled, single-blinded, crossover trial (Clinical Trial Registry-India: CTRI/2024/08/090041), we evaluated the efficacy and safety of low-dose hydrochlorothiazide (HCTZ) in adults with nonsurgical hypoparathyroidism (excluding autoimmune and obvious syndromic forms). After stabilization on fixed doses of calcium carbonate and calcitriol under a controlled low-sodium diet, 26 participants received HCTZ (12.5-25 mg/d) or placebo for 7 d, with a 15-d washout before crossover, followed by an optional 4-wk open-label HCTZ extension. The primary outcome was change in serum calcium; secondary outcomes included change in 24-h urinary calcium (UCa), fractional calcium excretion, urinary sodium, and bone turnover markers (β-CTX and P1NP). Compared to baseline (8.61 ± 0.32 mg/dL), serum calcium increased significantly with HCTZ at day 5 (9.01 ± 0.46 mg/dL) and day 8 (9.04 ± 0.52 mg/dL; p < .001), while no significant change occurred with placebo. Hydrochlorothiazide reduced 24-h UCa by −26.3% at day 8 (vs +4.7% with placebo; p < .001). These effects remained robust in sensitivity analyses adjusting for urinary sodium and when expressed per kg body weight. Fractional calcium excretion fell by 29.9% with HCTZ (p < .001). A small but statistically significant decline in serum potassium was observed at day 8 (from 4.18 to 3.95 mEq/L; p < .001), though values remained within the normal range, no participants developed hypokalemia; renal function and intact PTH (iPTH) were stable. During the extension phase, serum calcium levels rose while UCa excretion declined significantly, without any reported adverse effects. These findings indicate that low-dose HCTZ with sodium restriction safely improves calcium homeostasis in nonsurgical hypoparathyroidism—raising serum calcium and reducing calciuria—with good tolerability. Hydrochlorothiazide offers a cost-effective adjunct to standard therapy and warrants further investigation for long-term outcomes.