Parathormone Bone resorption

Hyperparathyroidism Excess parathormone causes bone resorption. 

The polypeptide parathormone is released from the parathyroid glands when plasma Ca + level falls. It stimulates osteoclasts to increase bone resorption in the kidneys, it promotes calcium reabsorption, while phosphate excretion is enhanced. As blood phosphate concentration diminishes, the tendency of calcium to precipitate as bone mineral decreases. By stimulating the formation of vit D hormone, parathormone has an indirect effect on the enteral uptake of Ca + and phosphate. In parathormone deficiency, vitamin D can be used as a substitute that unlike parathormone, is effective orally. 

In hypocalcemia, the parathyroid increases its secretion of parathormone, resulting in enhanced liberation of Ca2+. Calcitonin transfers active osteoclasts into a resting state. Calcitonin given therapeutically relieves pain associated with neoplastic bone metastases and vertebral body collapse. Estrogens diminish bone resorption by (a) inhibiting activation of osteoclasts by osteoblasts and (b) promoting apoptosis of osteoclasts. 

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). 

A number of experiments conclusively established that parathormone accelerates bone resorption. Bone resorption is observed after transplantation of parathyroids in contact with parietal bone or in tissue cultures of bone supplemented with parathormone. 

Parathormone also increases DNA, RNA, and protein synthesis in osteoclasts, but decreases such synthetic processes in osteoblasts. These findings are in keeping with the role of the hormone in bone resorption. The intramitochondrial calcium granules in bone cells are also increased after the administration of parathormone. Whether this effect is related to calcium release remains to be shown. The exact molecular sequence that leads to calcium resorption in bone is not known. But it has been established in experiments using bone calvaria and isolated bone cells that parathormone elicits the formation of a second messenger namely, cyclic AMP (see chapter on hormones) through the stimulation of adenylcyclase. 

Postmenopausal bone loss is effectively inhibited by prophylactic administration of estrogen (Recker et al, 1977), but estrogen administration to osteoporotic patients (the conventional treatment) fails to restore lost bone. Estrogen appears to act primarily by putting a brake on bone resorption, i.e., it inhibits the action of parathyroid hormone, the primary stimulus to osteoclastic bone resorption. The mechanism of this inhibition is unknown receptors for estrogen have not been found in bone. A high intake of calcium during the postmenopausal period (up to 1500 mg/d) also is inhibitory (Heaney, 1981), presumably because it raises the level of ionized calcium in the serum sufficiently to suppress parathormone synthesis. 

It might be expected that increased bone resorption through the agency of PTH would also cause an increase in plasma phosphate concentration. In fact this does not occur because the hormone has an independent effect on the kidney, causing a decrease in phosphate reabsorption by the tubules and consequently an increase in its excretion. On the other hand, parathormone increases the reabsorption of calcium by kidney tubules and so reduces excretion, thus conserving the plasma calcium (Figure 30.4). 

Vitamin D is essential for the action of parathormone on osteoclasts whereby bone resorption and a hypercalcaemic response are induced. For this reason parathormone is comparatively inactive in patients with rickets. The mechanism of this synergistic effect is not clear but, since actinomycin D blocks the hypercalcaemic activity of vitamin D, it may be that the vitamin induces the formation of a calcium-binding protein in osteoclasts in a similar manner to its behaviour in the intestine. Certainly excess of vitamin D has effects on bone cells similar to those of PTH in that it mobilizes bone calcium and produces hypercalcaemia. In vitamin D deficiency, production of PTH is greatly increased in an attempt to compensate for the chronic hypocalcaemia. 

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. 

Parathormone, parathyrin a hormone produced by the parathyroid gland, which influences the metabolism of calcium and phosphate. It is a single chain proteohormone with 84 amino acid residues of known primary structure [R.T. Sauer etal. Biochemistry 13 (1974), 1994-1999]. M, 9,402 (porcine). P. influences the cells that degrade bone (osteoclasts) by activation of membrane-bound adenylate cyelase and by increasing the entry of Ca into these cells. The resulting mobilization of Ca causes an increase in blood ealcium. This is necessarily accompanied by the release of free phosphate which is excreted via the kidneys. Thus P. favors phosphate secretion in the distal part of the kidney tubule, and inhibits phosphate resorption in the proximal tubule. P. promotes calcium absorption by the intestine. The action of P. is therefore opposite to that of Calcitonin (see). P. is degraded by the liver, and some is excreted in the urine. Absence of P. leads to a decrease of blood calcium, accompanied by neuromuscular overexcitability (tetany). 

It is far from clear whether the incorporation of the citrate ion into calcified tissues is merely a consequence of the stability and solubility properties of calcium citrates or whether it plays an essential part in the mineralization process. It increases the solubility of apatite and inhibits alkaline phosphatase. Citrate accumulation in bone is influenced by both parathormone and vitamin D. High levels of vitamin D appear to stimulate osteocytes to produce citrate and this may play some part in the subsequent increase in resorption. Despite these observations no clear picture of the role of citrate in mineralization has emerged. 

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