Relationship Between Changes in Serum Urate and Bone Mineral Density During Treatment with Thiazide Diuretics: Secondary Analysis from a Randomized Controlled Trial

In observational studies, serum urate concentrations associate with bone mineral density (BMD) and reduced risk of fractures. Thiazide diuretics slow the bone loss in healthy older adults, are associated with reduced incidence of fracture and also increase serum urate. We hypothesized that changes in serum urate are associated with changes in BMD during treatment with thiazide diuretics. We analysed data from a double-blind randomized controlled trial of hydrochlorothiazide (50 mg per day) and placebo in normal post-menopausal women. The relationship between change in serum urate and change in BMD after 2 years of treatment was examined using Spearman correlation and multiple linear regression models. Total body BMD increased in the hydrochlorothiazide group by 0.52 % and reduced in the placebo group by 0.29 % over 2 years (between group difference P = 0.0034). Serum urate increased in the hydrochlorothiazide group by 0.038 mmol/L and reduced in the placebo group by 0.004 mmol/L (between group difference P < 0.0001). At Year 2, there was a positive relationship between the change in serum urate and change in total body BMD for entire study population (r = 0.32, P = 0.0002) and for the hydrochlorothiazide group (r = 0.29, P = 0.023). The association between change in serum urate and change in total body BMD persisted after adjusting for treatment allocation, and change in weight, serum calcium, urinary calcium and serum creatinine (P _{change in serum urate} = 0.043). These data raise the possibility that the effects of hydrochlorothiazide on BMD may be mediated, in part, by changes in serum urate concentrations.