Increased bone resorption (BR) and increased renal tubular reabsorption of calcium (TRCa) may both be involved in the pathogenesis of hypercalcemia of malignancy (HM). We have evaluated the relative importance of these two mechanisms in 33 patients with HM after extracellular volume expansion and after single infusion of clodronate (C12MDP: 500 mg iv over 8 h). The fasting urine Ca/creatinine ratio was taken as an index of BR (BRI). An index of TRCa was calculated (TRCaI) from a nomogram based on the relationship between urine Ca excretion per unit of glomerular filtration rate and plasma Ca (PCa). Mean (+/- SEM) PCa fell from 3.29 +/- 0.07 to 2.69 +/- 0.05 mmol/l three days after C12MDP (n = 33, p less than 0.001), a response similar to that obtained with repeated daily iv injections of 500 to 1000 mg C12MDP. The pathogenesis of hypercalcemia varied according to the type of neoplasm. BRI was the highest in multiple myeloma and breast tumors. TRCaI was markedly increased in squamous-cells lung, bladder, kidney and liver carcinomas, reaching levels observed in primary hyperparathyroidism. TRCaI was normal in most cases of multiple myeloma. Breast tumors appeared to be heterogeneous with respect to TRCaI. The fall in PCa in response to a single infusion of C12MDP was usually most marked in cancer patients with elevated BRI and normal TRCaI. It was very modest in patients with high TRCaI and slightly elevated BRI. In conclusion, this study confirms that stimulation of bone resorption is not the only mechanism of the maintenance of hypercalcemia of malignancy.(ABSTRACT TRUNCATED AT 250 WORDS)