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• Gene structure and mRNA

  The human CT gene, located on chromosome 11p15.2- p15.1, consists of six exons and five introns. CT mRNA is coencoded with calcitonin gene-related peptide (CGRP) mRNA in the single gene. In mammals, the synthesis of the mRNAs encoding these two hormones is controlled by tissue-specific alternative splicing. The CT precursor mRNA is synthesized in thyroidal C-cells, whereas the CGRP precursor mRNA is synthesized in neural tissues. The pufferfish ct gene consists of four coding exons. The splicing of exons 1, 2, and 3 yields CT, whereas that of exons 1, 2, and 4 yields CGRP.;

• Receptors

  The calcitonin receptor (CTR) is a member of a subfamily of the seven-transmembrane domain GPCR superfamily that includes several peptide receptors. Porcine CTR cDNA was obtained for the first time in 1991. Subsequent cloning of the gene demonstrated that it is approximately 70 kb in length, and contains at least 14 exons, 12 of which encode procine CTR. Different isoforms of CTR resulting from alternative splicing of the gene have been described in various animal species with differential tissue expression of the transcripts. The human CTR gene has been mapped to chromosome 7q21.3. CTRs have been identified from various vertebrates. Invertebrate CTR has also been sequenced from the protochordate, Ciona intestinalis. Invertebrate CTs and CTR are described in another section. The value of the dissociation constant (Kd) in rats and trout CTR was 0.25 to 3.3 nM.;

• Synthesis and release

  CT synthesis in thyroid C-cells and its release are stimulated principally by increased blood calcium levels. In fish as well as mammals, a calcium-sensing receptor has been cloned. In fasted eels, plasma CT levels were not detectable by the specific sandwich ELISA technique (detection limit: 30 pg/mL). In eels that were fed a high amount of calcium-consomme solution (Ca2+: 1.25M; 1mL/100 g body weight), the plasma CT concentration increased rapidly (CT: below detection level at 0 h to 1118.2 pg/mL at 3 h) corresponding to increased plasma calcium levels. In fish as well as mammals, the trigger for CT secretion appears to be primarily a change in blood calcium levels. Recently, CT was synthesized in the osteoblasts of goldfish scales. The secretion of CT was promoted by melatonin. This regulation was also observed in the calvariae of rats.;

• Agonists and Antagonists

  The relative potency of the agonistic effects are salmon CT=eel CT>human CT<porcine CT. CT family peptide hormones such as CGRP and AMY also have agonist activity. Salmon CT8–32 (VLGKLSQELHKLQTYPRTNTGSGTP) and AC512 (Lys10-Bolton Hunter, R18N30Y32- salmon CT9–32) have antagonist activity.;

• Application in Particular Diseases

  In Osteoporosis:
  • Calcitonin is released from the thyroid gland when serum calcium is elevated. Salmon calcitonin is used clinically because it is more potent and longer lasting than the mammalian form. Calcitonin is reserved as a third-line agent because efficacy is less robust than with the other antiresorptive therapies.
  • Calcitonin is indicated for osteoporosis treatment for women at least 5 years past menopause. Although limited data suggest beneficial effects in men and concomitantly with glucocorticoids, these indications are not FDA approved.
  • Only vertebral fractures have been documented to decrease with intranasal calcitonin therapy. Calcitonin does not consistently affect hip BMD and does not decrease hip fracture risk.
  • Calcitonin may provide pain relief to some patients with acute vertebral fractures. If used, it should be prescribed for short-term treatment (4 weeks) and should not be used in place of other more effective and less expensive analgesics, nor should it preclude the use of more appropriate osteoporosis therapy.
  • The intranasal dose is 200 units daily, alternating nares every other day. Subcutaneous administration of 100 units daily is available but rarely used because of adverse effects and cost.
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