The Discovery of Calcitonin

Overview

Calcitonin is a 32-amino-acid peptide hormone secreted by the parafollicular C-cells of the thyroid gland in mammals, and by the ultimobranchial body in non-mammalian vertebrates. It was identified in 1961 by Douglas Harold Copp at the University of British Columbia, who was studying calcium regulation using a perfused thyroid-parathyroid preparation in dogs. When he raised perfusate calcium, he observed a rapid fall in blood calcium distinct from any known action of parathyroid hormone, and he attributed this to a new "hypocalcemic" hormone he named calcitonin.

Independent work by Iain MacIntyre and colleagues at the Hammersmith Hospital in London, and by Philip Munson in the United States, confirmed calcitonin's existence and demonstrated that it originated from the thyroid rather than the parathyroid. Because mammalian calcitonin comes from the thyroid, it was briefly called "thyrocalcitonin" before the shorter name prevailed.

Calcitonin's amino acid sequence was determined in the mid-1960s, and the hormone was quickly synthesized. Salmon calcitonin, in particular, proved remarkably potent in humans and became a widely used therapy for certain bone disorders before newer agents largely replaced it.

Key People

• Douglas Harold Copp (1915–1998): Canadian endocrinologist who discovered calcitonin.
• Iain MacIntyre: British endocrinologist who confirmed and extended the calcitonin work.
• Philip Munson: American physiologist who independently studied hypocalcemic pituitary extracts.
• Claude Arnaud: Contributor to calcitonin structure and clinical studies.

Timeline

• 1961: Copp publishes evidence for a hypocalcemic hormone from the parathyroid-thyroid region.
• 1963: MacIntyre and colleagues show calcitonin originates from the thyroid.
• 1968: Amino acid sequence of several species' calcitonins is determined.
• 1970s: Salmon calcitonin is synthesized and studied for Paget disease, osteoporosis, and hypercalcemia.
• 1984: Calcitonin gene-related peptide (CGRP) is discovered by alternative splicing of the calcitonin gene.
• 2018: Anti-CGRP migraine therapies (erenumab and others) are approved.

Background

Calcitonin acts through its receptor (CTR), a G protein-coupled receptor. In bone, it inhibits osteoclast activity and therefore reduces bone resorption. In the kidney, it has minor effects on calcium and phosphate handling. Calcitonin's physiological importance in normal adult calcium homeostasis is modest — humans without calcitonin (for example, after total thyroidectomy) do not develop obvious calcium abnormalities — but the hormone has clear effects at pharmacological doses and serves as a tumor marker in medullary thyroid carcinoma.

One of the most important downstream discoveries from calcitonin research came in 1984, when the calcitonin gene was shown to produce a second peptide, calcitonin gene-related peptide (CGRP), by tissue-specific alternative splicing. CGRP is a potent vasodilator and central player in migraine pathophysiology, leading to a major new class of migraine therapies.

Modern Relevance

Salmon calcitonin (Miacalcin, Calcimar) has been used for Paget disease of bone, hypercalcemia of malignancy, and osteoporosis. Its clinical use has declined substantially since the 2010s due to safety concerns and the availability of more effective osteoporosis treatments such as bisphosphonates, denosumab, and PTH analogs.

Serum calcitonin remains useful as a tumor marker, particularly in medullary thyroid carcinoma, where C-cells give rise to calcitonin-secreting tumors. Genetic testing for RET proto-oncogene mutations associated with multiple endocrine neoplasia type 2 is typically paired with calcitonin measurement. Meanwhile, CGRP-targeting drugs have revolutionized migraine treatment, turning a spin-off of calcitonin biology into one of the most commercially significant peptide drug classes of the 2020s.

Related Compounds

• Calcitonin
• Salmon calcitonin
• CGRP
• PTH
• Erenumab