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

Abstract

BackgroundThiazide, 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.MethodsUsing 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.ResultsA 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.ConclusionsThiazide users with hyponatremia have a higher risk of fracture than thiazide users without hyponatremia. The fracture-protective effect of thiazide is attenuated by TAH.

The Effects of Osteoporotic and Non-osteoporotic Medications on Fracture Risk and Bone Mineral Density

“…However, their results were subgroup-dependent, as a decreased risk of fractures with thiazide use was found in patients with new-onset stroke or spinal cord injury, but not in community-dwelling individuals or hypertensive patients. Individual cohort studies have suggested that the association between thiazide diuretic use and fracture risk might also depend on the duration of use [ 241 , 242 ] and the presence of hyponatremia [ 243 ]. So far, evidence for the association between the use of thiazide diuretics and fracture risk mainly derives from observational studies.…”

Hyponatriämie im Alter (II) – eine klare Therapie

“…Daraus ergeben sich die Kontrollintervalle [6]. Frakturen treten im Gegensatz zum ursprünglich protektiven Effekt der Thiazide wieder häufiger auf, wenn gleichzeitig eine Hyponatriämie vorliegt [7]. Interessanterweise ist die Kombination von Thiazid mit einem Schleifendiuretikum im Sinne einer sequenziellen Nephronblockade meist unschädlich und damit erlaubt.…”

Antihypertensive drugs demonstrate varying levels of hip fracture risk: A systematic review and meta-analysis

“…Amongst others, a reduced urinary calcium excretion, an increased bone retention of calcium, and a more susceptible gastrointestinal calcium resorption are plausible explanations that act preventive [50][51][52] . In contrast, thiazides are known to induce hyponatremia that is associated with osteoporosis, and as such potentially contradicts the aforementioned protective effect [53] . This may potentially also explain the heterogeneity among our included studies.…”