Actions of Calcitonin

Calcitonin inhibits osteoclasts and decreases blood plasma calcium concentrations (Fig. 10.12). It therefore opposes the action of parathyroid hormone. It is a 32 amino acid hormone secreted by the thyroid C cells. It is related to four bioactive peptides. One is an alternatively spliced product of the calcitonin gene expressed in tissues other than the thyroid (calcitonin gene-related peptide-1, CGRP-1). The other three calcitonin gene-related peptide-2 (CGRP-2), amylin, and adrenomedullin are each encoded by separate genes. 

Loss of the thyroid gland with its calcitonin-producing C cells does not cause osteoporosis, and high levels of calcitonin associated with thyroid carcinoma do not cause osteosclerosis, thick, well mineralized bones distinct from the dense, continuously growing bone that characterizes osteopetrosis (see Sects. 10.2.1 and 10.2.2). These findings indicate that calcitonin does not increase bone deposition, but rather inhibits osteoclast activity 

Daily calcitonin or PTH administration is an effective alternative to bisphosphonates for treating osteoporosis, but much less convenient. Calcitonin and PTH are destroyed by proteases in the intestine and also by proteases in the bloodstream and must be given by daily injection. By contrast, bisphosphonates are not only stable after ingestion, but they also bind to the surface of calcified tissues and are not easily removed. Bisphosphonates can be administered orally, weekly or even monthly. (See Sect. 10.2.3). 

---

Factors controlling calcium homeostasis are calcitonin, parathyroid hormone(PTH), and a vitamin D metabolite. Calcitonin, a polypeptide of 32 amino acid residues, mol wt - SGOO, is synthesized by the thyroid gland. Release is stimulated by small increases in blood Ca " concentration. The sites of action of calcitonin are the bones and kidneys. Calcitonin increases bone calcification, thereby inhibiting resorption. In the kidney, it inhibits Ca " reabsorption and increases Ca " excretion in urine. Calcitonin operates via a cyclic adenosine monophosphate (cAMP) mechanism. 

Gennari C, Fischer JA. Cardiovascular action of calcitonin gene-related peptide in humans. Calcif Tissue Int 1985 37(6) 581 1. 

Raud, J. (1993). Sensory nerve activation as a potential antiinflammatory mechanism. Pharmacol. Toxicol. 72, 30-31. Raud, J., Lundeberg, T., Brodda-Jansen, G., Theodorsson, E. and Hedqvist, P. (1991). Potent anti-inflammatory action of calcitonin gene-related peptide. Biochem. Biophys. Res. Comm. 180, 1429-1435. 

C signal transduction pathway. Secretion of calcitonin is stimulated by hypercalcemia but the effect of the hormone on calcium transport appears to be secondary to increased phosphate uptake by target cells. The number and activity of osteoclasts are decreased, and urinary excretion of hy-droxyproline is decreased, Calcitonin may also inhibit release of calcium from the extracellular fluid calcium pool, but it increases calcium and phosphate excretion by renal tubules. Some tubular cells respond to calcitonin, PTH, and vasopressin, while others respond only to one or two of these hormones. In general, the actions of calcitonin in kidney and in bone are antagonistic to those of PTH. Calcitonin decreases secretion of gastrin and of gastric acid, and inhibits bile flow. 

The known effects of thyrocalcitonin are primarily in bone. Removal of the gut had no effect on the hypocalcemic effect of calcitonin (A6), and neither did nephrectomy (H8). No change in soft tissue calcium content was seen in soft tissues to explain the hypocalcemia (Kl). Calcitonin apparently inhibits bone resorption and thereby decreases calcium entry into the blood. Calcitonin prevents the release of calcium from cultured bone (A5, FIO). In vivo, the release of Ca from prelabeled bone is decreased by calcitonin (Jl). The bone arteriovenous difference in calcium levels is increased by calcitonin (M3). The mode of action of calcitonin is unknown. Calcitonin does not inhibit parathormone (A6, H7, T3), nor is its effect apparently mediated through RNA synthesis (T3). 

Describe the actions of calcitonin and why it is used to treat Paget s disease and osteoporosis. You may need to refer to Chapter 7. 

According to the four-component model for the renal handling of urate, renal uric acid wasting might result from defects either of of presecretory or postsecretory reabsorption, or enhaced secretion of urate in the tubule. Future studies are required in order to delineate the tubular phases that may account for the uricosuric action of calcitonin. 

A hormone secreted by the parafollicular or C cells of the thyroid gland. When the calcium level of the blood rises above normal, calcitonin is secreted, which prohibits further release of calcium from the bones. Thus, the effect of this hormone is opposite to that of the parathyroid hormone which removes calcium from bone. However, it appears that the action of calcitonin occurs mainly do ring the growing years and that it does not have much effect in adulthood. 

Three hormones regulate turnover of calcium in the body (22). 1,25-Dihydroxycholecalciferol is a steroid derivative made by the combined action of the skin, Hver, and kidneys, or furnished by dietary factors with vitamin D activity. The apparent action of this compound is to promote the transcription of genes for proteins that faciUtate transport of calcium and phosphate ions through the plasma membrane. Parathormone (PTH) is a polypeptide hormone secreted by the parathyroid gland, in response to a fall in extracellular Ca(Il). It acts on bones and kidneys in concert with 1,25-dihydroxycholecalciferol to stimulate resorption of bone and reabsorption of calcium from the glomerular filtrate. Calcitonin, the third hormone, is a polypeptide secreted by the thyroid gland in response to a rise in blood Ca(Il) concentration. Its production leads to an increase in bone deposition, increased loss of calcium and phosphate in the urine, and inhibition of the synthesis of 1,25-dihydroxycholecalciferol. 

Calcitonin is a naturally occurring mammalian hormone that plays a major role in regulation of calcium levels. It inhibits bone resorption by binding to osteoclast receptors. Compared with mammalian calcitonin, salmon calcitonin has high potency and extended duration of action. Although commercial formulations of calcitonin-salmon actually are synthetic and not derived from salmon, they contain the same amino acid sequence as calcitonin of salmon origin. 

Calcitonin. This hormone, which is also secreted from the thyroid gland, is synthesized by the parafollicular cells (C cells) located between the follicles. The primary effect of calcitonin is to decrease the blood levels of calcium and phosphate. The mechanism of action involves the direct inhibition of osteoclast activity, which decreases bone resorption. This results in less demineralization of the bone and therefore a decrease in the release of calcium and phosphate from the bone into the blood. Calcitonin has no direct effect on bone formation by osteoblasts. 

Three forms of calcitonin are available, salmon, porcine and human calcitonin. Long-term use of porcine calcitonin, being the most antigenic product, can lead to the production of neutralizing antibodies. Synthetic salmon preparations are therefore preferable. Human calcitonin is less immunogenic but it is also less active. Human calcitonin monomer has a half-life of about 10 minutes while the half-life of salmon calcitonin is considerably longer. However these half-lives are not directly related to the duration of action which varies from 30 min to 12 hours after intravenous administration and from 8 hours to 24 hours when administered subcutaneously or intramuscularly. Calcitonin is metabolized in the blood and in tissues like for example the kidneys. 

Peptides are used by most tissues for cell-to-cell communication. As noted in Chapters 6 and 21, they play important roles in the autonomic and central nervous systems. Several peptides exert important direct effects on vascular and other smooth muscles. These peptides include vasoconstrictors (angiotensin II, vasopressin, endothelins, neuropeptide Y, and urotensin) and vasodilators (bradykinin and related kinins, natriuretic peptides, vasoactive intestinal peptide, substance P, neurotensin, calcitonin gene-related peptide, and adrenomedullin). This chapter focuses on the smooth muscle actions of the peptides. 

The diverse actions of AM are mediated by the 7-transmembrane G protein-coupled calcitonin receptor-like receptor (CRLR) which coassembles with subtypes 2 and 3 of a family of receptor-activity-modifying proteins (RAMPs), thus forming a receptor-coreceptor system. Binding of AM to CRLR activates Gs and triggers cAMP formation in vascular smooth muscle cells, and increases nitric oxide production in endothelial cells. Other signaling pathways are also involved. 

BIBN4096BS Antagonist of calcitonin gene-related peptide (CGRP) Blocks some central and peripheral (vasodilator) actions of CGRP Migraine1... 

The changes in calvarial phosphatase activities observed in animals treated with 25-(OH)D3 are totally different from those obtained with either 1.25-(OH)2D3 or 24.25—(OH)2D3. This fact indicates that physiological doses of 25-(OH)D3 may have an effect on cellular activity, independent of the conversion of this metabolite into these dihydroxyderivatives. The various effects of these vitamin D3 metabolites cannot be correlated with changes in serum calcium and/or phosphate concentrations. Among those factors other than serum calcium and phosphate concentrations that may be involved in the mechanism of action of vitamin D3 metabolites on bone phosphatase activities, the parathyroid hormone is of importance. This hormone is known to be a potent activator of bone phosphatases223,224,228. Parathormone increases the content of alkaline, neutral and acid phosphatases in mouse calvaria in vitro. Calcitonin does not prevent the increase of those enzymes while dichloromethylene diphosphonate causes a decrease in acid phosphatase and pyrophosphatase226. ... 

The principal effects of calcitonin are to lower serum calcium and phosphate by actions on bone and kidney. Calcitonin inhibits osteoclastic bone resorption. Although bone formation is not impaired at first after calcitonin administration, with time both formation and resorption of bone are reduced. Thus, the early hope that calcitonin would prove useful in restoring bone mass has not been realized. In the kidney, calcitonin reduces both calcium and phosphate reabsorption as well as reabsorption of other ions, including sodium, potassium, and magnesium. Tissues other than bone... 

Limited data are available on in vitro effects of barium on the endocrine system. Studies done with isolated pancreatic islet cells from mice show barium is transported across the cell membrane and incorporated into organelles, especially the mitochondria and secretory granules (Berggren et al. 1983). Barium was found to increase cytoplasmic calcium consequently, the insulin- releasing action of barium may be mediated by calcium. Barium has also been found capable of stimulating the calcitonin secretion system of the thyroid in pigs (Pento 1979). 

The nasal application of drugs is an area of growing interest (21) and a number of publications has shown that simple molecules as well as more complex species (eg calcitonin, insulin etc) can be well absorbed by this route, either directly or in the presence of so-called absorption enhancers. One problem with such materials could be too rapid clearance of the delivery system from the nasal cavity through the efficient action of the mucociliary system. For this reason Ilium has considered the use of microsphere systems. 

Vitamin D, along with parathyroid hormone and calcitonin, plays a primary role in calcium and phosphorus homeostasis in the body. Intensive research efforts over the past several years have elucidated a role for vitamin D in many other physiological processes as well. The biological actions of this seco-steroid are mediated primarily through the action of its polar metabolite, 1,25-dihydroxy vitamin D3 (l,25(OH)2D3). There is emerging evidence that l,25(OH)2D3 has many more target tissues than those involved in its classical role in the control of mineral metabolism. In addition, some of the actions of l,25(OH)2D3 may be mediated by mechanisms other than the classical steroid-receptor interaction. In this chapter we will provide a brief overview of the multiple actions of vitamin D3 and the pleiotropic mechanisms by which these actions are accomplished. 

---