Osteoclasts calcitonin effect

A peptide hormone rapidly inhibiting osteoclast activity. The relevance of calcitonin in human calcium homeostasis is not well understood. Calcitonin has been used for the treatment of osteoporosis, although due to the availability of more potent drugs with less side effects, and the lack of clear data on the anti-fracture efficacy of calcitonin, its clinical use has been steadily declining. 

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. 

The polypeptide calcitonin is secreted by thyroid C-cells during imminent hypercalcemia. It lowers plasma Ca + levels by inhibiting osteoclast activity. Its uses include hypercalcemia and osteoporosis. Remarkably, calcitonin injection may produce a sustained analgesic effect that is not restricted to bone pain. 

Datta, H.K., Manning, P., Rathod, H., and McNeil, CJ. 1995. Effect of calcitonin, elevated calcium and extracellular matrices on superoxide anion production by rat osteoclasts. Exp. Physiol. 80, 713-719. 

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... 

Clinical PK/PD Calcitonin has a well-established mechanism of action published literature supports that salmon calcitonin, mediated through calcitonin receptors located on osteoclasts, inhibits bone resorption, thereby increasing bone mineral density. Since serum beta-CTx (C-telopeptides of type 1 collagen, corrected for creatinine) is a recognized marker of bone resorption, the effect of administered salmon calcitonin on serum beta-CTx is considered to be an adequate surrogate for pharmacodynamic comparisons. 

Calcitonin inhibits osteoclastic bone resorption, increases the urinary excretion of calcium and phosphate, and reduces serum calcium. It is established in the treatment of disorders of high bone turnover, including Paget s disease and postmenopausal osteoporosis, but is less effective than the bisphosphonates. Calcitonin is less effective than other therapeutic measures in the treatment of acute hypercalcemia. Long-term administration of calcitonin reduces morbidity in cases of osteogenesis imperfecta... 

Therapy is directed at decreasing osteoclastic bone resorption. Bisphosphonates (alendronate, risedronate, pamidronate, and etidronate) and calcitonin are effective in decreasing bone pain, serum ALP, and markers of bone resorption. Patients may occasionally need surgery for skeletal deformity that limits mobility or for arthritic changes, fractures, or nerve compression. 

Bones are constantly dissolved by osteoclasts and remineralized by osteoblasts in response to mechanical forces. Osteoclasts possess an acidic compartment and pass demineralized bone products to the periosteum (Sect. 1). They develop in stress-induced bony microcracks and are activated by differentiation factors secreted by osteoblasts, especially after menopause. Menopausal osteoporosis is controlled by drugs that are a stable form of pyrophosphate (bisphosphonate) or cathepsin K inhibitors (Sect. 2). The calcium ion concentration of blood is raised by parathyroid hormone and a vitamin D derivative called calcitriol. Parathyroid hormone causes kidneys to excrete phosphate, retain calcium, and activate calcitriol production (Sect. 3). Calcitriol induces calcium transporter proteins in osteoclasts and intestinal epithelium, where they move calcium from bone or diet into blood (Sect. 4). The chapter concludes with a discussion of calcitonin which lowers blood calcium concentrations by reversing parathyroid hormone effects on the kidney and inhibiting osteoclast activity (Sect. 5). 

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. 

Bisphosphonates concentrate at sites of active remodeling. Because they are highly negatively charged, bisphosphonates are membrane impermeable but are incorporated into the bone matrix by huid-phase endocytosis. Bisphosphonates remain in the matrix until the bone is remodeled and then are released in the acid environment of the resorption lacunae beneath the osteoclast as the overlying mineral matrix is dissolved. The importance of this process for the antiresorp-tive effect of bisphosphonates is evidenced by the fact that calcitonin blocks the antiresorptive action. 

Calcitonin acts on receptors in bone osteoclasts with a resulting reduction of bone resorption, and it also acts on the renal tubular reabsorption of phosphate. The phosphaturic effects are accompanied by diuresis and increased excretion of other electrolytes. Calcitonin and parathyroid hormone act as a dual negative feedback mechanism in controlling calcium in intra- and extracellular fluids. The range of calcitonin assays suitable for laboratory animals is limited, but the hormone can be measured by two-site radioimmunometric assays (Moukhtar et al. 2005). 

MECHANISM OE ACTION Calcitonin actions are mediated by the calcitonin receptor, a GPCR that couples through multiple G proteins to diverse signal transduction pathways. The hypocalcemic and hypophosphatemic effects of calcitonin result primarily from direct inhibition of osteoclast bone resorption. 

Calcitonin therapy requires the concomitant oral administration of elemental calcium (500 mg/day). Clinical studies have shown that the combination of intranasal calcitonin salmon (200 lU/day), oral calcium supplementation (>1,000 mg/day of elemental calcium), and vitamin D (400 lU/day) has decreased the rate of new fractures by more than 75% and has improved vertebral BMD by as much as 3% annually (3). Calcitonin prevents the abnormal bone turnover characteristic of Paget s disease of the bone and has antiresorptive activity. In the presence of calcitonin, the osteoclast brush borders disappear, and the osteoclasts move away from the bone surface undergoing remodeling (36). Side effects are significantly more pronounced when calcitonin-salmon Is administered by injection and can include nausea, vomiting, anorexia, and flushing. Because calcitonin-salmon Is protein in nature, the possibility of a systemic allergic reaction should be considered. 

In addition to its antiresorptive action via suppression of osteoclast activity, calcitonin-salmon exhibits a potent analgesic effect and has provided considerable relief to those patients suffering from the pain associated with Paget s disease and osteoporosis. This analgesic effect is a result of calcitonin-stimulated endogenous opioid release. The potency of this analgesic effect has been demonstrated to be 30- to 50-fold that of morphine in selected patients. Calcitonin is preferred over estrogen and the bisphosphonates when treatment of both osteoporosis and related bone pain is warranted. 

Contrary to PTH, calcitonin has a lowering action on blood Ca activity. It is synthesized in the parafollicular cells (C cells) in the thyroid. An increased blood Ca activity leads to calcitonin secretion, and within a few minutes both calcium and phosphate concentrations in plasma are lowered. This effect is accomplished by an effect on the bone cells, where calcium is bound as hydroxyapatite. Besides this effect, calcitonin also decreases intestinal uptake and renal reabsorption. Calcitonin inhibits the osteoclasts ( bone eater cells ) and hence reduces the amount of calcium and phosphate released from bone to the extracellular fluid. The effect on the kidneys leads to an increased excretion of calcium, phosphate, sodium, chloride, and water. 

The principal effect of calcitonin is to inhibit bone resorption by osteoclasts and this is reflected in a decreased excretion of hydroxyproline in the urine. Like PTH it acts on the stable calcium pool. Tissue culture preparations of bone, to which PTH has been added, show resorption but, if calcitonin is also added, resorption is inhibited. There is no evidence to support the idea that calcitonin promotes the deposition of bone. 

A polypeptide hormone, consisting of 32 amino acids, produced in the C cells of the thyroid gland. It is involved in calcium homeostasis, its main action being to decrease osteoclastic activity and therefore reduce bone resorption. Calcitonin also has a phosphaturic effect. It is secreted in response to high ionized calcium levels. High serum levels are found in patients with medullary carcinoma of the thyroid. It is usually measured by radioimmunoassay. 

Calcitonin, This decreases osteoclastic activity. It also has a phosphaturic effect. 

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