---
title: The drug given to stop stones coming back did not beat placebo — at any of three doses
publication: Medical Insights Korea
section: news
category: Kidney Stones
canonical_url: https://medicalinsightskorea.com/news/thiazide-kidney-stone-prevention-nostone
author: Catherine Cho
published: 2026-09-13T09:00:00+09:00
modified: 2026-09-13T09:00:00+09:00
content_type: reporting
license: Quotation permitted with attribution to Medical Insights Korea and a link to the canonical URL.
---

# The drug given to stop stones coming back did not beat placebo — at any of three doses

NOSTONE randomised 416 recurrent stone formers to hydrochlorothiazide at 12.5, 25 or 50 mg or placebo. Recurrence was 59, 59, 56 and 49 percent, in that order, with no dose-response and more harm on the drug.

## Answer

In the NOSTONE trial, 416 patients with recurrent calcium-containing kidney stones were randomised to hydrochlorothiazide 12.5 mg, 25 mg or 50 mg once daily or to placebo and followed for a median of 2.9 years, and a primary end-point event — symptomatic or radiologic recurrence — occurred in 59 percent of the placebo group, 59 percent of the 12.5 mg group, 56 percent of the 25 mg group and 49 percent of the 50 mg group, with no relation between dose and recurrence (P = 0.66) and with hypokalaemia, gout, new-onset diabetes, skin allergy and a plasma creatinine above 150 percent of baseline all more common on hydrochlorothiazide than on placebo.

## Key takeaways

- NOSTONE randomised 416 patients with recurrent calcium-containing kidney stones to hydrochlorothiazide 12.5 mg, 25 mg or 50 mg daily or placebo, with a median follow-up of 2.9 years.
- Recurrence occurred in 60 of 102 placebo patients (59 percent), 62 of 105 on 12.5 mg (59 percent), 61 of 108 on 25 mg (56 percent) and 49 of 101 on 50 mg (49 percent).
- There was no relation between hydrochlorothiazide dose and the occurrence of a primary end-point event, with a P value of 0.66.
- Hypokalaemia, gout, new-onset diabetes mellitus, skin allergy and a plasma creatinine exceeding 150 percent of baseline were all more common on hydrochlorothiazide than on placebo.
- A 2025 network meta-analysis of nine randomised trials in 999 patients concluded that thiazide and thiazide-like diuretics should not be routinely prescribed for stone prevention on current evidence, despite three regimens separating from placebo.
- A 2026 analysis of 634 patients with paired 24-hour urine collections found that thiazides reduce urine calcium most in those whose baseline urine calcium is highest.
- The 2024 European Association of Urology guideline continues to recommend extensive metabolic screening with two 24-hour urine collections in high-risk calcium-stone formers before targeted therapy.

## Full article

Thiazide diuretics have been the standard medical answer to recurrent calcium stones for decades. They lower urine calcium, urine calcium drives calcium stones, and the logic has been strong enough that guidelines recommended them on evidence nobody described as good. In 2023 the trial that had not been done was done.

### What NOSTONE found

Published in the New England Journal of Medicine, NOSTONE randomised 416 patients with recurrent calcium-containing kidney stones, double-blind, to hydrochlorothiazide at 12.5 mg, 25 mg or 50 mg once daily, or to placebo once daily. The primary end point was a composite of symptomatic or radiologic recurrence, radiologic recurrence being a new stone on imaging or the growth of one already visible at baseline. Median follow-up was 2.9 years.

**NOSTONE: primary end-point events by group**

| Group | Events | Rate | Rate ratio vs placebo (95% CI) |
| --- | --- | --- | --- |
| Placebo | 60 of 102 | 59% | — |
| Hydrochlorothiazide 12.5 mg | 62 of 105 | 59% | 1.33 (0.92–1.93) |
| Hydrochlorothiazide 25 mg | 61 of 108 | 56% | 1.24 (0.86–1.79) |
| Hydrochlorothiazide 50 mg | 49 of 101 | 49% | 0.92 (0.63–1.36) |

The trial was designed around a dose-response question, and the dose-response was absent: P = 0.66 for the relation between dose and event. Read down the rate ratio column and the pattern is not a drug working weakly. Two of the three doses have point estimates above 1.

**59% vs 59%** — kidney-stone recurrence on placebo and on hydrochlorothiazide 12.5 mg over a median 2.9 years in NOSTONE  
_Source: Dhayat NA et al., New England Journal of Medicine, 2023_

And the drug was not free. Hypokalaemia, gout, new-onset diabetes mellitus, skin allergy and a plasma creatinine exceeding 150 percent of baseline were each more common among patients taking hydrochlorothiazide than among those taking placebo. A preventive treatment that does not prevent still causes.

### What the wider evidence says two years on

A network meta-analysis published in World Journal of Urology in 2025 pooled nine randomised trials totalling 999 patients. Three regimens did separate from placebo on recurrence: chlorthalidone 50 mg daily with an odds ratio of 0.18 (95% CI 0.04 to 0.88), hydrochlorothiazide 50 mg daily at 0.52 (0.29 to 0.93), and trichlormethiazide 4 mg daily at 0.26 (0.10 to 0.68).

That reads like a rescue until the rest is included. No dose-dependent effect appeared when hydrochlorothiazide 50 mg was compared with 12.5 mg or 25 mg, or chlorthalidone 50 mg with 25 mg. Trichlormethiazide 4 mg produced more adverse effects than placebo with an odds ratio of 49.96 and a confidence interval running from 1.78 to 1,402.80 — an interval that width is a warning about the evidence, not a measurement of the harm. The authors' conclusion was that current evidence does not support routine prescribing of these drugs for stone prevention and that head-to-head trials are urgently needed.

### The line of defence that is left

If thiazides work by lowering urine calcium, then a trial that enrols recurrent stone formers regardless of their urine calcium is testing the drug on people it was never mechanistically expected to help. That argument has a 2026 measurement behind it.

Writing in the Journal of Urology, a group examined 634 patients who had a 24-hour urine collection for stone disease, were newly prescribed a thiazide, and completed a second collection between 30 and 180 days later. Higher baseline urine calcium was associated with greater absolute and percentage reductions in 24-hour urine calcium, and higher thiazide doses with greater reductions still.

> **What that study did and did not show**  
> It showed the biochemical step: thiazides move urine calcium furthest in the people whose urine calcium starts highest. It did not show the clinical step. Adjusted incidences of clinical stone events did not differ significantly across baseline calcium groups once a thiazide had been prescribed. The signal that baseline urine calcium matters came from the untreated: among people with no thiazide exposure, stone events rose with baseline urine calcium. So the case for selecting patients by 24-hour urine is a case about who is at risk, and remains a hypothesis about who benefits.

### What this means for a Korean stone patient

The 2024 European Association of Urology guideline update did not abandon metabolic evaluation after NOSTONE; it made the case for it sharper. Every stone should be analysed, every patient should have baseline metabolic screening, and calcium-stone formers at high risk of relapse should have extensive screening with two 24-hour urine collections before targeted therapy. On the trial evidence, the 24-hour urine is now the more defensible half of that pairing and the tablet is the less.

How often the two are ordered together in Korean practice is not something any study cited here measures, and it is the gap worth naming rather than filling with an assumption. Korea has national claims data detailed enough to answer it — the same source that has already been used to count every lithotripsy and every scan — and no published analysis has asked how many Korean patients on preventive therapy ever had the urine test that is supposed to select them for it.

For the patient in front of a urologist, the practical reading is narrower than the headline. A thiazide is not a proven way to stop calcium stones returning. It remains a reasonable option in a patient with genuinely high urine calcium who has been counselled about hypokalaemia, gout and glucose, and it is a poor default for a recurrent stone former whose urine has never been measured.

## Sources

- Dhayat NA, Bonny O, Roth B, Christe A, Ritter A, Mohebbi N, Faller N, Pellegrini L, et al. Hydrochlorothiazide and prevention of kidney-stone recurrence. New England Journal of Medicine 2023;388(9):781-791. doi:10.1056/nejmoa2209275. PMID:36856614. https://doi.org/10.1056/nejmoa2209275
- Oliveira AV, Sampaio ALN, Mascarenhas RW, Pinto LOAD, Andriolo RB. Thiazide and thiazide-like diuretics for kidney stones recurrence: a systematic review and network meta-analysis of randomised controlled trials. World Journal of Urology 2025;44(1):41. doi:10.1007/s00345-025-06137-8. PMID:41396435. https://doi.org/10.1007/s00345-025-06137-8
- Hsi RS, Yan PL, Crivelli JJ, Ferraro PM, Curhan GC, Best S, Asplin JR, Shahinian V, et al. Baseline urinary calcium and the efficacy of thiazide diuretics for kidney stone prevention. Journal of Urology 2026;216(2):230-240. doi:10.1097/ju.0000000000005042. PMID:41894644. https://doi.org/10.1097/ju.0000000000005042
- Skolarikos A, Somani B, Neisius A, Jung H, Petřík A, Tailly T, Davis N, Tzelves L, et al. Metabolic evaluation and recurrence prevention for urinary stone patients: an EAU guidelines update. European Urology 2024;86(4):343-363. doi:10.1016/j.eururo.2024.05.029. PMID:39069389. https://doi.org/10.1016/j.eururo.2024.05.029

## Citation

Catherine Cho (2026). "The drug given to stop stones coming back did not beat placebo — at any of three doses". Medical Insights Korea. https://medicalinsightskorea.com/news/thiazide-kidney-stone-prevention-nostone

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