Calcitonin

Calcitonin (also known as thyrocalcitonin) is a 32-amino acid linear polypeptide is_associated_with::hormone that is produced in is_associated_with::humans primarily by the parafollicular cells (also known as C-cells) of the is_associated_with::thyroid, and in many other animals in the is_associated_with::ultimobranchial body. It acts to reduce blood is_associated_with::calcium (Ca2+), opposing the effects of is_associated_with::parathyroid hormone (PTH).

Calcitonin has been found in is_associated_with::fish, is_associated_with::reptiles, is_associated_with::birds, and is_associated_with::mammals. Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant in the regulation of normal calcium homeostasis. It belongs to the is_associated_with::calcitonin-like protein family.

Biosynthesis and regulation
Calcitonin is formed by the is_associated_with::proteolytic cleavage of a larger is_associated_with::prepropeptide, which is the product of the CALC1 gene. The CALC1 gene belongs to a superfamily of related protein hormone precursors including is_associated_with::islet amyloid precursor protein, is_associated_with::calcitonin gene-related peptide, and the precursor of is_associated_with::adrenomedullin.

Secretion of calcitonin is stimulated by:
 * an increase in serum [Ca2+]
 * is_associated_with::gastrin and is_associated_with::pentagastrin.

Effects
The hormone participates in is_associated_with::calcium (Ca2+) and is_associated_with::phosphorus is_associated_with::metabolism. In many ways, calcitonin counteracts is_associated_with::parathyroid hormone (PTH).

More specifically, calcitonin lowers blood Ca2+ levels in four ways:
 * Inhibits Ca2+ absorption by the is_associated_with::intestines
 * Inhibits is_associated_with::osteoclast activity in is_associated_with::bones
 * Stimulates is_associated_with::osteoblastic activity in is_associated_with::bones.
 * Inhibits renal tubular cell reabsorption of Ca2+ allowing it to be excreted in the is_associated_with::urine

However, effects of calcitonin that mirror those of PTH include the following:
 * Inhibits phosphate reabsorption by the is_associated_with::kidney tubules

In its skeleton-preserving actions, calcitonin protects against calcium loss from skeleton during periods of calcium mobilization, such as is_associated_with::pregnancy and, especially, is_associated_with::lactation.

Other effects are in preventing postprandial is_associated_with::hypercalcemia resulting from absorption of Ca2+. Also, calcitonin inhibits food intake in rats and monkeys, and may have CNS action involving the regulation of feeding and appetite.

Receptor
The is_associated_with::calcitonin receptor, found on is_associated_with::osteoclasts, and in kidney and regions of the brain, is a is_associated_with::G protein-coupled receptor, which is coupled by Gs to is_associated_with::adenylate cyclase and thereby to the generation of cAMP in target cells. It may also affect the ovaries in women and the testes in men.

Discovery
Calcitonin was purified in 1962 by Copp and Cheney. While it was initially considered a secretion of the is_associated_with::parathyroid glands, it was later identified as the secretion of the C-cells of the is_associated_with::thyroid gland.

Pharmacology
Salmon calcitonin is used for the treatment of:
 * Postmenopausal is_associated_with::osteoporosis
 * is_associated_with::Hypercalcaemia
 * Paget's disease
 * is_associated_with::Bone metastases
 * is_associated_with::Phantom limb pain

It has been investigated as a possible non-operative treatment for spinal stenosis.

The following information is from the UK Electronic Medicines Compendium

General characteristics of the active substance
Salmon calcitonin is rapidly absorbed and eliminated. Peak plasma concentrations are attained within the first hour of administration.

Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidney following parenteral administration. The metabolites lack the specific biological activity of calcitonin. Bioavailability following subcutaneous and intramuscular injection in humans is high and similar for the two routes of administration (71% and 66%, respectively).

Calcitonin has short absorption and elimination half-lives of 10–15 minutes and 50–80 minutes, respectively. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically inactive fragments of the molecule. Therefore, the metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevance of this finding is not known. Plasma protein binding is 30% to 40%.

Characteristics in patients
There is a relationship between the subcutaneous dose of calcitonin and peak plasma concentrations. Following parenteral administration of 100 IU calcitonin, peak plasma concentration lies between about 200 and 400 pg/ml. Higher blood levels may be associated with increased incidence of nausea, vomiting, and secretory diarrhea.

Preclinical safety data
Conventional long-term toxicity, reproduction, mutagenicity, and carcinogenicity studies have been performed in laboratory animals. Salmon calcitonin is devoid of embryotoxic, teratogenic, and mutagenic potential.

An increased incidence of pituitary adenomas has been reported in rats given synthetic salmon calcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance. Salmon calcitonin does not cross the placental barrier.

In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin is secreted into the milk.

Pharmaceutical manufacture
Calcitonin was extracted from the ultimobranchial glands (thyroid-like glands) of fish, particularly salmon. Salmon calcitonin resembles human calcitonin, but is more active. At present, it is produced either by is_associated_with::recombinant DNA technology or by chemical is_associated_with::peptide synthesis. The pharmacological properties of the synthetic and recombinant peptides have been demonstrated to be qualitatively and quantitatively equivalent.

Treatments
Calcitonin can be used therapeutically for the treatment of is_associated_with::hypercalcemia or is_associated_with::osteoporosis.

Oral calcitonin may have a chondroprotective role in osteoarthritis (OA), according to data in rats presented in December, 2005, at the 10th World Congress of the Osteoarthritis Research Society International (OARSI) in Boston, Massachusetts. Although calcitonin is a known antiresorptive agent, its disease-modifying effects on chondrocytes and cartilage metabolisms have not been well established until now.

This new study, however, may help to explain how calcitonin affects osteoarthritis. “Calcitonin acts both directly on osteoclasts, resulting in inhibition of bone resorption and following attenuation of is_associated_with::subchondral bone turnover, and directly on chondrocytes, attenuating cartilage degradation and stimulating cartilage formation,” says researcher Morten Karsdal, MSC, PhD, of the department of pharmacology at Nordic Bioscience in Herlev, Denmark. “Therefore, calcitonin may be a future efficacious drug for OA.”

Subcutaneous injections of calcitonin in patients suffering from is_associated_with::mania resulted in significant decreases in irritability, euphoria and hyperactivity and hence calcitonin holds promise for treating is_associated_with::bipolar disorder. However no further work on this potential application of calcitonin has been reported.

Diagnostics
It may be used diagnostically as a is_associated_with::tumor marker for is_associated_with::medullary thyroid cancer, in which high calcitonin levels may be present and elevated levels after surgery may indicate recurrence. It may even be used on is_associated_with::biopsy samples from suspicious lesions (e.g., is_associated_with::lymph nodes that are swollen) to establish whether they are is_associated_with::metastasis of the original cancer.

Cutoffs for calcitonin to distinguish cases with medullary thyroid cancer have been suggested to be as follows, with a higher value increasing the suspicion of medullary thyroid cancer: When over 3 years of age, adult cutoffs may be used
 * females: 5 ng/L or pg/mL
 * males: 12 ng/L or pg/mL
 * children under 6 months of age: 40 ng/L or pg/mL
 * children between 6 months and 3 years of age: 15 ng/L or pg/mL

Increased levels of calcitonin have also been reported for various other conditions. They include: C-cell hyperplasia, Nonthyroidal oat cell carcinoma, Nonthyroidal small cell carcinoma and other nonthyroidal malignancies, acute and chronic renal failure, hypercalcemia, hypergastrinemia and other gastrointestinal disorders, and pulmonary disease.

Structure
Calcitonin is a polypeptide hormone of 32 amino acids, with a molecular weight of 3454.93 daltons. Its structure comprises a single alpha helix. Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called is_associated_with::calcitonin gene-related peptide (CGRP), beta type.

The following are the amino acid sequences of salmon and human calcitonin: Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro
 * salmon:
 * human:

Compared to salmon calcitonin, human calcitonin differs at 16 residues.