Previous to its widespread use as a cancer biomarker, including its role in raising suspicion of medullary thyroid cancer (MTC), calcitonin had an interesting history.
In the Journal of Musculoskeletal Neuronal Interactions, Srinivasan and colleagues detailed the early history of calcitonin. It was first discovered as a blood-calcium lowering hormone in 1961. It has been used to treat metabolic bone disease ever since.
“Due to its ability to inhibit osteoclast activity, calcitonin reduces the risk of vertebral refracture, and it is also a powerful analgesic agent with proven efficacy in managing acute back pain caused by recent vertebral compression fractures,” Srinivasan et al wrote.
The popularity of calcitonin skyrocketed; by 1992, worldwide sales of therapeutic calcitonin had reached more than $900 million. However, the rise of a new medication class, bisphosphonates, pushed calcitonin to the side. Scientists were deeply impressed by the clinical properties of etidronate, a bisphosphonate, for treating hyperglycemia, Paget’s disease, and post-menopausal osteoporosis.
It was later discovered that bisphosphonates are not such a miracle drug after all, since their long-term use is associated with osteonecrosis of the jaw and atypical femoral fractures. As a result, physicians started to have second thoughts on whether bisphosphonates were indeed superior to calcitonin as a bone disease medication.
Calcitonin as a Biomarker
The history of calcitonin as a drug has further twists and turns; however, we will now focus on its role as a cancer biomarker.
Human calcitonin is secreted primarily by the parafollicular C cells of the thyroid gland. However, other tissues—such as the thymus, parathyroid glands, lungs, small intestine, and the liver—are also capable of secreting calcitonin. The prohormones of calcitonin (and any other hormones) are not secreted into the bloodstream in healthy individuals.
“[Procalcitonin] in the serum serves as a helpful biomarker in cases of bacterial-mediated septic states,” Kiriakopoulos and colleagues wrote in Therapeutic Advances in Endocrinology and Metabolism. “More specifically, the production of [procalcitonin] in medullary thyroid carcinoma (MTC) is mediated by the thyroid C-cells, whereas in cases of acute bacterial infection, the most probable sites are the neuroendocrine cells of lungs and intestine.”
In summary, the presence of procalcitonin has been associated with MTC and sepsis, since normal individuals have very low serum levels of procalcitonin.
Read more about MTC etiology
It is worth providing a brief definition of MTC here for the sake of clarification. As Giovanella and colleagues explained in Du Gruyter, “Medullary thyroid carcinoma (MTC) is caused by a malignant transformation in the parafollicular C-cells of the thyroid, where calcitonin (CT) is released.”
In other words, an excess of calcitonin is released in MTC due to the malignant transformation in the parafollicular C-cells of the thyroid. This is why calcitonin is used as a biomarker for MTC. In addition, scientists have proposed procalcitonin as a complementary/alternative biomarker for MTC.
Calcitonin and Precalcitonin Performance
Giovanella and colleagues investigated the performance of calcitonin and procalcitonin in the differential diagnosis between MTC and non-MTC thyroid diseases, as well as their value in the differential diagnosis between active and inactive MTC.
The research team collected serum samples from 16 patients with active MTC and 23 patients with inactive MTC. Laboratory studies were conducted on the samples.
Read more about MTC diagnosis
“[Calcitonin] and [procalcitonin] assays were highly sensitive and specific MTC markers; in the few cases with false-positive [calcitonin] results, a negative [procalcitonin] measurement safely excluded active MTC,” they wrote.
These preliminary findings give further weight to the use of calcitonin and procalcitonin in the effort to diagnose MTC. At the very least, it gives further reasons for continued research into the diagnostic value of calcitonin and procalcitonin in MTC and other diseases.
An Alternative Treatment Approach
We now return briefly to the use of calcitonin as a bone metabolic disease drug. Unfortunately, its association with cancer and the introduction of newer and better drugs have largely removed it as a first-line therapy for any disease. However, calcitonin is sometimes still used as a backup medication should first-line medications fail.
We now know that calcitonin may also play a role in treating acute and chronic neuropathic pain. For example, studies have demonstrated it might be able to play a role in treating phantom limb pain. Various studies have demonstrated the potential of calcitonin to help treat a range of diseases, including diabetic neuropathy, lumbar spinal canal stenosis, post-operative pain, and trigeminal neuralgia. Alas, currently more established drugs for treating neuropathic pain do already exist, once again pushing calcitonin to the sidelines.
However, Srinivasan and colleagues speculated that the development of calcitonin as an oral drug may renew interest in its bone healing properties.
“Although calcitonin will be used less for its original purpose of increasing [bone mineral density] and reducing fracture risk, its unique analgesic efficacy means that there may still be a future for this old friend,” they wrote.
Giovanella L, Fontana M, Keller F, Verburg FA, Ceriani L. Clinical performance of calcitonin and procalcitonin Elecsys® immunoassays in patients with medullary thyroid carcinoma. Clin Chem Lab Med. 2020;59(4):743-747. doi:10.1515/cclm-2020-1424
Srinivasan A, Wong FK, Karponis D. Calcitonin: a useful old friend. J Musculoskelet Neuronal Interact. 2020;20(4):600-609.
Kiriakopoulos A, Giannakis P, Menenakos E. Calcitonin: current concepts and differential diagnosis. Ther Adv Endocrinol Metab. 2022;13:20420188221099344. Published online May 21, 2022. doi:10.1177/20420188221099344