We have assessed the early effects of three diphosphonates on calcium and skeletal homeostasis in 68 patients with Paget's disease of bone treated with daily intravenous infusions for five consecutive days. Both clodronate (300 mg/day) and aminohexane diphosphonate (AHDP; 50 mg/day) induced a fall in serum and urine calcium, and secondary hyperparathyroidism. In contrast, these changes were not observed with etidronate (300-700 mg/day) despite similar effects on bone resorption, as judged by urinary excretion of hydroxyproline with each of the three disphosphonates. Histological studies during the early phase of treatment indicated that etidronate, but not clodronate or AHDP, acutely impaired the accretion of calcium into bone, thereby offsetting a hypocalcaemic response. All three diphosphonates induced significant increases in plasma phosphate and tubular reabsorption of phosphate (TmP/GFR). The increase induced by etidronate remained significantly higher than pretreatment values for one month, whereas those induced by clodronate and AHDP were less marked and ill-sustained, and followed by significant decreases in both measurements. These data indicate that the effects of different diphosphonates on serum calcium homeostasis are heterogeneous, depending not only on the prevailing rate of bone resorption, but also on the rate of bone formation, and the effect of each diphosphonate on bone and mineral accretion.