PTH and Calcitonin

The CaR regulates numerous biological processes, including the expression of various genes (e.g., PTH) the secretion of hormones (PTH and calcitonin), cytokines (MCP-1), and calcium (e.g., into breast milk) the activities of channels (potassium channels) and transporters (aquaporin-2) cellular shape, motility (of macrophages), and migration cellular adhesion (of hematopoietic stem cells) and cellular proliferation (of colonocytes), differentiation (of keratinocytes), and apoptosis (of H-500 ley dig cancer cells) [3]. 

Calcitriol functions in concert with parathyroid hormone (PTH) and calcitonin to regulate serum calcium and phosphorous levels. 

Four primary factors influencing calcium and phosphate homeostasis are diet, vitamin D and its metabolites, PTH, and calcitonin. Table 37-1 lists other hormones known to... 

Figure 42-2. Some effects of vitamin D (D), parathyroid hormone (PTH), and calcitonin (CT) on calcium and phosphorus metabolism. Vitamin D increases absorption of calcium from both gut and bone, while PTH increases reabsorption from bone. Both vitamin D and parathyroid hormone reduce urinary excretion ot calcium. (Reproduced, with permission, from Katzung BG [editor] Basic Clinical Pharmacology, 8th ed. McGraw-Hill, 2001.)...

An increase in trabecular bone mass by as much as 50% has been demonstrated in patients treated with low doses of PTH, but it comes at the expense of the cortical bone (1,11,25). Treatment with high doses of PTH is correlated with stimulation of bone resorption (20). Cyclical therapy with PTH and calcitonin has been shown to improve BMD in the spine without adverse effects in the cortical bone (11). When given in combination with estrogen, PTH promoted the formation of well-mineralized trabecular bone. 

The secretion of calcitonin, like that of PTH, is probably governed solely by blood calcium concentration, since there is no evidence for the existence of a trophic hormone that stimulates its release. The dual control system represented by PTH and calcitonin exerts rigorous control over the plasma calcium concentration and is much more efficient than PTH would be acting alone. Calcitonin is somewhat quicker acting than PTH and may be involved in rapid adjustments when the plasma calcium concentration might otherwise overshoot . It has been suggested that while PTH is really the main regulator for plasma, calcitonin is somehow concerned with the balance between bone formation and resorption. 

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. 

Calcitonin is a polypeptide hormone that (along with PTH and the vitamin D derivative, 1,25-dihydroxycholecalciferol) plays a central role in regulating serum ionized calcium (Ca2+) and inorganic phosphate (Pi) levels. The adult human body contains up to 2 kg of calcium, of which 98 per cent is present in the skeleton (i.e. bone). Up to 85 per cent of the 1 kg of phosphorus present in the body is also found in the skeleton (the so-called mineral fraction of bone is largely composed of Ca3(P04)2, which acts as a body reservoir for both calcium and phosphorus). Calcium concentrations in human serum approximate to 0.1 mg ml-1 and are regulated very tightly (serum phosphate levels are more variable). 

Calcitriol and parathyroid hormone, on the one hand, and calcitonin on the other, ensure a more or less constant level of Ca "" in the blood plasma and in the extracellular space (80-110 mg 2.0-2.6 mM). The peptide parathyroid hormone (PTH 84 AA) and the steroid calcitriol (see p. 374) promote direct or indirect processes that raise the Ca "" level in blood. Calcitriol increases Ca "" resorption in the intestines and kidneys by inducing transporters. Parathyroid hormone supports these processes by stimulating calcitriol biosynthesis in the kidneys (see p. 330). In addition, it directly promotes resorption of Ca "" in the kidneys (see p. 328) and Ca "" release from bone (see B). The PTH antagonist calcitonin (32 AA) counteracts these processes. 

The main features of hypocalcemia are neuromuscular—tetany, paresthesias, laryngospasm, muscle cramps, and convulsions. The major causes of hypocalcemia in the adult are hypoparathyroidism, vitamin D deficiency, chronic kidney disease, and malabsorption. Neonatal hypocalcemia is a common disorder that usually resolves without therapy. The roles of PTH, vitamin D, and calcitonin in the neonatal syndrome are under active investigation. Large infusions of citrated blood can produce hypocalcemia by the formation of citrate-calcium complexes. Calcium and vitamin D (or its metabolites) form the mainstay of treatment of hypocalcemia. 

Q2 The hormones that are normally involved in the control of calcium balance are parathyroid hormone (PTH) from the parathyroid gland calcitonin, which is secreted by the thyroid gland and 1,25-dihydroxycholecalciferol (1,25-DHCC, or calcitriol), which is produced in the kidneys. Calcitonin reduces the level of plasma calcium by attenuating its release from bone and by increasing its excretion. The PTH and 1,25-DHCC increase the level of plasma calcium by two mechanisms (1) a combination of an increase in calcium absorption by the gut and an increase in the release of calcium from bone and (2) a reduction in both bone formation and calcium excretion. The three hormones act together to maintain the physiological level of calcium and normal bone turnover. Over 95% of body calcium is located in bone as hydroxyapatite. 

Bone is a relatively dynamic organ that undergoes significant turnover that is, hone resorption and deposition it is broken down hy osteoclasts and rebuilt by osteoblasts. Besides an adequate supply of calcium, a close cooperation is required between these two types of cell. Complex signalling pathways achieve proper rates of growth and differentiation these pathways include the action of several hormones, including parathyroid hormone (PTH), vitamin D, growth hormone, steroids and calcitonin, as well as several cytokines. 

Osteoclasts are multinucleated cells found on the endosteal surface of bone, in Haversian systems and periosteal surfaces. PTH activates osteoclasts (indirectly via osteoblasts that possess PTH receptors). Calcitonin is a potent inhibitor of osteoclast activity. Local cytokine factors, including interleukin-1 (IL-1), tumour-necrosis factor (TNF), TGF- 0 and interferon-y (INF-y), are important regulators. Osteoclast resorption of bone releases collagen peptides, pyridinoline cross-links and calcium from the bone matrix, through the action of lysosomal enzymes (collagenases and cathepsins). The collagen breakdown products in serum and urine (e.g. hydroxyproline) can be used as biochemical markers. 

PTH and 1,25-dibydroxyvitamin D are the primary hormones regulating bone and mineral metabolism. Calcitonin has pharmacological actions, but a physiological role has not been established in adults. PTHrP is the principal mediator of hmnoral hypercalcemia of malignancy. 

Family B. Giucagon/ViP/Caicitonin receptor-like Calcitonin, CGRP and CRF receptors PTH and PTHrP receptors... 

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. 

Calcitonin therapy results in decreased bone resorption. Osteoclasts have calcitonin receptors and calcitonin inhibits their activity. Sodium fluoride stimulates bone formation by unknown mechanisms. In women with osteoporosis, fluoride therapy produced an increased bone mineral density but no reduction in the rate of vertebral fractures. Other drugs known as selective estrogen receptor modulators (raloxifene, droloxifene, idoxifene, and levormeloxifene) may provide an alternative to estrogen replacement therapy (Chapter 34). Administration of low doses of PTH [or recombinant PTH( 1 -34)] does not affect serum calcium concentration, promotes bone formation, and increases mineral density. This anabolic action of PTH is probably mediated by decreasing osteoblast apoptosis. 

The concentration of ionized calcium is closely regulated by the interactions of parathyroid hormone (PTH), phosphorus, vitamin D, and calcitonin (Fig. 49-9). Parathyroid hormone increases serum calcium concentrations by stimulating calcium release from bone, reducing renal excretion, and enhancing absorption in the gastrointestinal tract secondary to increased renal production of 1,25-... 

Parathyroid hormone (PTH), vitamin D and calcitonin work in synchrony to regulate calcium homeostasis (not presented in tables). PTH is an 84 amino acid chain secreted by the parathyroid glands in response to low serum calcium. PTH induces bone resorption, which liberates calcium into the bloodstream. These actions are dependent on adequate serum concentrations of 1,25-dihydroxy cholecalciferol (a derivative of vitamin D). Bone resorption is counterregulated by calcitonin, which inhibits osteoclasts (the cells which degrade bone). 

The normal maintenance of blood calcium levels within a narrow range is regulated by two hormones in humans PTH and 1,25 dihydroxy vitamin O3 (1,25(0H)2VitD3). In the absence of these hormones, blood calcium levels fall. The integrated actions of PTH and 1,25(0H)2VitD3 are responsible for maintaining calcium levels in the normal range. Calcitonin s actions in many aspects oppose those... 

Several studies in the older literature address effects of Pb on calcitropic endocrine functions in humans. Earlier discussion addressed effects of Pb on children s l,25-(OH)2-D3 levels, where relatively high PbB concentrations in children (>30 p.g/dl) depressed vitamin D levels. Calcium repletion even in the presence of elevated PbB values appears to abolish the reduction. Mixed results for levels of parathyroid hormone (PTH), calcitonin (CAL), l,25-(OH)2-D3, and 25-hydroxy vitamin D (25-OH-D3) have been noted for lead workers with high PbB values compared to adults in the general population. Kristal-Boneh et al. (1998) saw increases in the two hormones reported, serum PTH and 1,25-(0H)2-D, with increasing PbB (mean = 43 p.g/dl). Mason et al. (1990), by contrast, saw an increase in the dihydroxy vitamin D but no change in 25-OH-D3. 

The antagonistic effects of calcitonin on bone resorption also appear to require the presence of vitamin D. Thus the vitamin is necessary for the action of both PTH, which promotes resorption, and calcitonin, which inhibits it. This is just one more aspect of the complex interplay of mechanisms involving these three substances which ensure the stability of blood calcium and the proper maintenance of the calcified tissues through continuous remodelling. 

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