Incident Diuretic Use and Subsequent Risk of Bone Fractures: A Large Nationwide Observational Study of US Veterans.

Objective: To investigate the association of incident use of diuretics with subsequent risk of incident bone fractures.

Patients And Methods: In a nationwide cohort of 863,339 US veterans receiving care from the VA health care system between October 1, 2004, and September 30, 2006, with follow-up through June 30, 2018, we examined the association of incident diuretic use (overall, and separately by thiazide, loop, and potassium-sparing diuretics) with subsequent risk of incident bone fractures using multivariable Cox regression models while minimizing confounding by indication using a target trial emulation approach.

Results: Patients were 63.3±12.9 years old; 93.5% (n=807,180) were male; and 27.1% (n=233,996) were diabetic. Their baseline estimated glomerular filtration rate was 84.4±16.5 mL/min per 1.73 m. Among 863,339 patients, 424,386 (49.2%) newly initiated diuretics, of which 77.4% (n=328,524), 22.5% (n=95,457), and 0.1% (n=405) were thiazide, loop, and potassium-sparing diuretic users, respectively. After multivariable adjustments, incident diuretic use (vs non-use) was significantly associated with higher risk of incident fracture (adjusted HR [aHR], 1.14; 95% CI, 1.11 to 1.16). The association was most pronounced for loop diuretics (aHR, 1.39; 95% CI, 1.35 to 1.44) but less evident for thiazide diuretics (aHR, 1.08; 95% CI, 1.06 to 1.10) and was not significant for potassium-sparing diuretics (aHR, 0.97; 95% CI, 0.62 to 1.52). The diuretic-fracture association was more evident in younger (vs older) patients, those with (vs without) corticosteroid use, and those with lower (vs higher) serum sodium levels.

Conclusion: Incident use of diuretics, particularly loop diuretics, was independently associated with higher risk of incident bone fractures. Our findings suggest distinct pathophysiologic contributions of diuretics to bone metabolism and the need for careful attention to skeletal outcomes when initiating diuretics.