Hypercalcemia in malignancy. The pathogenesis of hypercalcemia in malignancy has been enigmatic until recent years. Since the realization in 1980 that bioassays for parathyroid hormone detected a cross-reacting substance in malignancy, progress has been remarkably rapid. A parathyroid hormone-related protein was purified and identified by molecular cloning as a 141-amino acid peptide with limited homology to parathyroid hormone itself. Nonetheless, both peptides activate the parathyroid hormone receptor to produce hypercalcemia. It is now clear that the parathyroid hormone-related protein is the cause of hypercalcemia in most solid tumors, particularly squamous and renal carcinomas. New assays for the hormone as well as the related peptide have greatly simplified the differential diagnosis of hypercalcemia. At the same time, new agents for the treatment of hypercalcemia are becoming available, most notably the bisphosphonate drugs. 