The changes of parathyroid hormone (PTH) and of vitamin D metabolites after intravenous administration of the bisphosphonate APD were studied in ten patients with Paget's disease of bone and in ten patients with tumour-induced hypercalcaemia. After APD all patients with Paget's disease became hypocalcaemic and showed an increase in both N-PTH and C-PTH values. Patients with malignancies had a nearly six-fold greater decrease in serum calcium but rises in N-PTH and C-PTH were observed only in those who developed hypocalcaemia. Overall, a clear rise in PTH was found when serum calcium fell below 2.20 mmol/l. Basal 25-hydroxy- and 24,25-dihydroxyvitamin D concentrations were similar in the two groups and showed no change after APD treatment. Circulating 1,25-dihydroxyvitamin D, however, increased in all patients with Paget's disease and in six of the hypercalcaemic patients. It is concluded that the main regulator of PTH secretion is the concentration of calcium per se rather than the magnitude or the rate of its change. The production of 24,25-dihydroxyvitamin D is not affected by wide variations in serum calcium while that of 1,25-dihydroxyvitamin D is sensitive to these changes.