Evidence for a direct effect of thiazides on bone

Thiazide diuretics may induce hypercalcemia which could not be explained by their hypocalciuric effect. It was suggested that thiazides may act directly on bone and enhance release of calcium from the skeleton to blood. The effect of thiazides was studied in 7 thyroparathyroidectomized (TPTX) dogs which were supplemented with thyroid hormone. Bone biopsies were obtained 30 days after TPTX and following double tetracycline labelling. The animals then received 75 mg of hydrochlorothiazide daily. A second bone biopsy was obtained after 90 days of therapy. Maintenance of serum calcium in the normal range required supplementation of 30 g CaCO₃/day before thiazide, but only 10 g/day during thiazide. Urinary hydroxyproline increased significantly, but there was no hypocalciuria. There were significant (p≤0.01) increments in total number of osteocytic lacunae per unit volume total bone, but no change in elliptical ratio and mean area of osteocytic lacunae. Structural parameters of bone, including volumetric density of total bone, volumetric density of osteoid, surface density, and mean trabecular diameter, were not altered. Cellular parameters including surface density of osteoclasts and osteoblasts were initially low, reflecting the state after TPTX and were not significantly affected by thiazides. The drug did not affect appositional rate of bone as well. The data indicate that thiazide, even in the absence of parathyroid hormone, exerts a direct effect on bone associated with enhanced bone resorption. This effect may underlie, at least in part, the elevation in serum calcium during treatment with thiazides.