Summary: We performed a 2-year extension of our previous 2-year randomized controlled trial of the effects of hydrochlorothiazide on bone mineral density. The improvements in bone density seen in the first 2 years were sustained throughout the extension study. Thiazides provide a further option in the prevention of postmenopausal bone loss. INTRODUCTION: Thiazide diuretics reduce urinary calcium excretion and therefore might prevent osteoporosis. Previously we reported a 2-year randomized controlled trial of hydrochlorothiazide treatment in 185 postmenopausal women that showed positive benefits of hydrochlorothiazide on bone density. Here, we report the results of a 2-year extension to that study. METHODS: Of 185 healthy postmenopausal women, 122 agreed to continue in a double-blinded 2-year extension taking 50 mg hydrochlorothiazide or placebo daily. Measurements of bone density occurred every 6 months and of calcium metabolism at 2 and 4 years. RESULTS: The improvements in bone density seen in the first 2 years of the trial were sustained throughout the extension. There were significant between-groups differences in the change in bone density over 4 years at the total body (0.9%, P<0.001), legs (1.0%, P=0.002), mid-forearm (1.1%, P=0.03), and ultradistal forearm (1.4%, P=0.04). At the lumbar spine (0.9%, P=0.76) and femoral neck (0.4%, P=0.53) the between-groups differences did not reach statistical significance. CONCLUSIONS: Hydrochlorothiazide produces small positive benefits on cortical bone density that are sustained for at least the first 4 years of treatment. They provide a further option in the prevention of postmenopausal bone loss, especially for women with hypertension or a history of kidney stones.