Low-dose hydrochlorothiazide and preservation of bone mineral density in older adults - A randomized, double-blind, placebo-controlled trial

Background: Thiazide may have beneficial effects on bone mineral density and may reduce risk for hip fracture. However, the existence of a causal role remains uncertain because experimental evidence is limited. Objective: To determine the effect of hydrochlorothiazide on rates of bone loss in older adults. Design: Randomized, double-blind, placebo-controlled trial with 3-year follow-up. Setting: A large health maintenance organization in western Washington State. Participants: 320 healthy, normotensive adults (205 women, 115 men) 60 to 79 years of age. Intervention: Random assignment to one of three study groups: 12.5 mg of hydrochlorothiazide per day, 25 mg of hydrochlorothiazide per day, or placebo. Measurements: Bone mineral density using dual-energy x-ray absorptiometry at the total hip, posterior-anterior spine, and total body; blood and urine markers of bone metabolism; incident falls, clinical fractures, and radiographic vertebral fractures. Results: 309 of 320 participants completed the 36-month visit (97%). Adherence to study medication throughout follow-up was high in all participants (81.6% to 89.7%) except men in the high-dose hydrochlorothiazide group (60.5%). According to intention-to-treat analysis, the 36-month differences in percentage change in total hip bone mineral density were 0.79 percentage point (95% CI, -0.12 to 1.71) for the 12.5-mg hydrochlorothiazide group and 0.92 percentage point (CI, -0.001 to 1.85) for the 25-mg group compared with placebo (P = 0.03). Percentage change at the posterior-anterior spine was significantly greater for the 25-mg hydrochlorothiazide group at 6 months (intergroup difference, 1.04 percentage points [CI, 0.22 to 1.86]) compared with placebo (P = 0.005); at 36 months, this difference was 0.82 percentage point (CI, -0.36 to 2.01; P = 0.12). No significant differences were seen in total-body bone mineral density between the treatment groups. Treatment effects were stronger in women than in men. Conclusions: In healthy older adults, low-dose hydrochlorothiazide preserves bone mineral density at the hip and spine. The modest effects observed over 3 years, if accumulated over 10 to 20 years, may explain the one-third reduction in risk for hip fracture associated with thiazide in many epidemiologic studies.