Calcitonin's fantastic voyage: from hormone to marker of a genetic disorder.

The story of thyroid calcitonin is an illuminating example of the voyage of hormone from a therapeutic tool for bone disease to a tumour marker to screen for subclinical forms of cancer. Identified as a new thyroid hormone implicated in calcium metabolism, its pharmacological action offered a new therapeutic tool for the management of bone disease. By measuring the circulating calcitonin, a range of values was obtained for oncologists because the evolution of a newly identified form of thyroid cancer--medullary (MTC)--was poorly understood. Researchers' interest shifted from calcitonin physiological action to its use as tumour marker able to diagnose MTC, especially in genetically predisposed families. Then, oncologists and geneticists combined their efforts to identify genetic mutation(s) implicated in MTC, an example of the decoding that is demanded of contemporary laboratory-based medicine to recognise a pathological entity.

Calcitonin: discovery, development, and clinical application.

In 1954, when I gave a talk on calcium homeostasis at the first Gordon Conference on Bones and Teeth, it was recognized that the level of ionic calcium in the plasma and body fluids must be maintained with precision, since it is critically important for a number of vital processes. However, very little was known of the mechanisms involved and I decided to make this the focus of my research career. With the assistance of a number of first-year medical students working during the summer, we developed a precise method for measuring calcium, demonstrated the remarkable constancy of plasma calcium in normal human subjects, and found that normal calcium levels were restored quickly after being artificially raised or lowered. We focussed on parathyroid hormone (PTH), which plays a key role in controlling hypocalcemia by stimulating osteolysis. While studying the control of its secretion in 1961, we discovered a second calcium-regulating hormone (calcitonin) which was released by hypercalcemia and lowered plasma calcium by inhibiting osteolysis. It is a straight-chain peptide with 32 amino acids and a 7-membered disulfide ring at the N terminal. It is produced by C cells which arise from the neural crest and is considered a neuropeptide hormone. It is produced in the thyroid of mammals and the ultimobranchial glands of lower vertebrates. We were involved in the isolation of salmon calcitonin, which is the form most widely used in therapy because of its high potency. In addition to inhibiting bone resorption, it is a powerful analgesic agent with a potency in certain circumstances which is 30-50 times that of morphine. It is widely used clinically for the treatment of Paget's disease, hypercalcemia, osteoporosis, and relief of bone pain. World sales in 1992 exceeded US$900 million, of which 85% was for osteoporosis.