Calcium homeostasis and the pathogenesis and management of hypercalcemic disorders

The maintenance of a normal serum calcium concentration requires a stable equilibrium between mineral in the skeleton and the extracellular fluid and the carefully integrated and balanced actions of parathyroid hormone (PTH), vitamin D, and, to a much lesser extent, calcitonin. The amino acid sequences of bovine, porcine, and part of human PTH have recently been determined. It has been recognized that some of the difficulties encountered in measuring PTH by radioimmunoassay in serum are due to the conversion of the hormone into fragments, to the variable specificity and sensitivity of the antisera used in these determinations, and to the presence of a previously unrecognized precursor in the synthesis of the hormone. Parathyroid hormone appears to stimulate its target tissues (bone and kidney) through the adenyl cyclase mechanism, and it has now been appreciated that factors other than calcium have regulatory control over the secretion of hormone. The metabolism of vitamin D has been elucidated, and the active metabolite, 1,25-dihydroxy-cholecalciferol, has been identified. Production of this compound in the kidneys is under feedback control so that vitamin D takes on the characteristics of a hormone. Future developments involve the synthesis of more active and shorter-acting metabolites of vitamin D, drugs that will be of considerable usefulness to the clinician. Despite many years of research and a number of interesting biochemical, physiologic, and clinical studies, the importance of calcitonin in human physiology has not yet been determined. Nevertheless, its measurement in blood is a useful diagnostic aid in medullary carcinoma of the thyroid. Multiphasic screening programs have disclosed a surprisingly high prevalence of hypercalcemia in a random population. In most instances, the differential diagnosis can be made by carefully collecting a data base and using conventional laboratory procedures. Nevertheless, the assay for PTH has proven useful for diagnosis in some patients, particularly in the preoperative localization of parathyroid adenomas. The path is cleared for the development of more meaningful hormone assays and additional prospective studies on the management of asymptomatic patients with hyperparathyroidism. This review is written at an exciting time when major advances are being made in our understanding of calcium homeostasis, and rapid changes are occurring in the spectrum of hypercalcemic disorders being presented to the physician. Many of these research developments are summarized in relation to the clinical problem.