Chronic antihypertensive therapy with thiazide diuretics in older women and risk of osteoporotic vertebral fractures: A recently much-debated association Running title: Thiazide-related hyponatremia and osteoporotic vertebral fractures

Background An alleged association of chronic use of thiazide diuretics with an increased risk of bone fragility fractures has been highlighted by a relatively recent prospective cohort study (Am J Med. 2016 Dec; 129(12):1299-1306). However, the concept that thiazides exert a beneficial effect on osteoporosis is still a predominant view. This effect would be mediated by the decrease in renal clearance of calcium ions, a pharmacological feature recognized for a long time now to this class of drugs , as opposed to the increase in calcium urinary excretion attributed instead to loop diuretics, i.e. furosemide and similar drugs . The purpose of this retrospective study is to attempt to clarify whether regular use of thiazide diuretics as antihypertensive therapeutics is associated with a significantly increased risk of osteoporotic fractures in female patients, aged over 70 years. Methods In this two-centre retrospective study, we followed up a cohort of female patients with (n= 80) and without (n= 158) thiazide-induced hyponatraemia. Results A total of 48 osteoporotic fractures was recorded during a median followup period of 57.5 months. By means of univariate regression analysis, an association was found between thiazide-induced hyponatraemia and increased risk of vertebral fractures (Odds ratio [OR]: 7.6; 95% confidence interval [CI]: 3.755 15.39; p <0.0001). Multivariate regression analysis, however, showed that age (OR: 1.823; 95% CI: 1.211 to 2.743) and body mass index (OR: 0.156; 95% CI: 0.038 to 0.645) were the only independent predictors of osteoporotic fractures. No association of a history of thiazide-induced hyponatraemia and risk of fracture was noticeable in the final model. Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 28 July 2017 doi:10.20944/preprints201707.0082.v1 © 2017 by the author(s). Distributed under a Creative Commons CC BY license. 2 Conclusions Because a history of thiazide-induced hyponatremia is associated with osteoporotic fracture in univariate but not multivariate analyses, a possible explanation is that confounding factors of older age and low body mass index are responsible for the apparently heightened risk of fragility fractures in hypertensive female patients with thiazide-related hyponatremia.