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PLoS One. 2018 Dec 7;13(12):e0208712. doi: 10.1371/journal.pone.0208712. eCollection 2018.

Thiazide-associated hyponatremia attenuates the fracture-protective effect of thiazide: A population-based study.

Yang LJ1, Wu PH1,2, Huang TH1, Lin MY1,3,4, Tsai JC1,3.

Author information

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Master of Public Health Degree Program, College of Public Health, National Taiwan University, Taipei, Taiwan.



Thiazide, a first-line therapy for hypertension, lowers blood pressure, increases bone mineral density, and reduces the risk of fractures. However, hyponatremia, an adverse effect of thiazide, is associated with increased risk of osteoporosis and fractures. It is currently unclear whether thiazide-associated hyponatremia (TAH) outweighs the protective effects of thiazide.


Using data from Taiwan's National Health Insurance Research Database, we identified patients who were prescribed thiazide between 1998 and 2010. Those diagnosed with hyponatremia within three years after initiation of thiazide were selected for the TAH group. Thiazide users without hyponatremia were selected for the control group. The association between TAH and fracture risk was further evaluated using multivariable Cox regression models adjusted for comorbidities and medications. Subjects were followed up from the index date until the appearance of a fracture, death, or the end of a 3-year period.


A total of 1212 patients were included in the TAH group, matched with 4848 patients in the control group. The incidence rate of fracture was higher in the TAH group than in the control group (31.4 versus 20.6 per 1000 person-years). TAH was associated with a higher risk of total fractures (adjusted hazard ratio [aHR]: 1.47, 95% confidence interval [CI] = 1.15-1.88), vertebra fractures (aHR: 1.84, 95% CI = 1.12-3.01), and hip fractures (aHR: 1.66, 95% CI = 1.12-2.46) after controlling for comorbidities and other medications.


Thiazide users with hyponatremia have a higher risk of fracture than thiazide users without hyponatremia. The fracture-protective effect of thiazide is attenuated by TAH.

Conflict of interest statement

The authors have declared that no competing interests exist.

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