Calcium parathyroid hormone effects

Mechanism of Action An antibiotic that forms complexes with DNA, inhibiting DNA-directed RNA synthesis. May inhibit parathyroid hormone effect on osteoclasts and inhibit bone resorption. TherapeuticEffect Lowers serum calcium and phosphate levels. Blocks hypercalcemic action of vitamin Dand action of parathyroid hormone. Decreases serum calcium. 

Brindley, C. W., Williams, E. A., Bronk, J. T., Meadows, T. H Montgomery, R. J., Smith, S. R., and Kelly, P. J. (1988). Parathyroid hormone effects on skeleton exchangeable calcium and bone blood flow. Attt. f. Phtfsioi. 255, H94-H100. 

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). 

Although it is being found that vitamin D metaboUtes play a role ia many different biological functions, metaboHsm primarily occurs to maintain the calcium homeostasis of the body. When calcium semm levels fall below the normal range, 1 a,25-dihydroxy-vitainin is made when calcium levels are at or above this level, 24,25-dihydroxycholecalciferol is made, and 1 a-hydroxylase activity is discontiaued. The calcium homeostasis mechanism iavolves a hypocalcemic stimulus, which iaduces the secretion of parathyroid hormone. This causes phosphate diuresis ia the kidney, which stimulates the 1 a-hydroxylase activity and causes the hydroxylation of 25-hydroxy-vitamin D to 1 a,25-dihydroxycholecalciferol. Parathyroid hormone and 1,25-dihydroxycholecalciferol act at the bone site cooperatively to stimulate calcium mobilization from the bone (see Hormones). Calcium blood levels are also iafluenced by the effects of the metaboUte on intestinal absorption and renal resorption. 

The overall effect in most animals is to stimulate intestinal absorption of calcium with a concomitant increase in semm calcium and a reduction in parathyroid hormone (PTH). Modest hypercalcemia allows the glomerular filtration rate to remain stable and hypercalciuria to occur because of increased filtered load of calcium and reduction of tubular resorption of calcium with reduced PTH. However, with further increases in semm calcium, the glomerular filtration rate decreases, resulting in an even more rapid increase in semm calcium and the subsequent fall in urinary calcium. 

Four small parathyroid glands are embedded on the posterior surface of the thyroid gland as it wraps around the trachea. Parathyroid hormone (PTH, parathormone) is the principal regulator of calcium metabolism. Its overall effects include ... 

Calcium is freely filtered along with other components of the plasma through the nephrons of the kidney. Most of this calcium is reabsorbed into the blood from the proximal tubule of the nephron. However, because the kidneys produce about 1801 of filtrate per day, the amount of calcium filtered is substantial. Therefore, the physiological regulation of even a small percentage of calcium reabsorption may have a significant effect on the amount of calcium in the blood. Parathyroid hormone acts on the Loop of Henle to increase the reabsorption of calcium from this segment of the tubule and... 

Parathyroid hormone stimulates bone resorption by increasing the number and activity of osteoclasts. This demineralization process in the bone releases calcium and phosphate into the blood. Although the action of PTH on the bone appears to increase blood phosphate, its action on the kidney, which increases phosphate excretion in the urine, more than compensates for this increase and the net effect is a decrease in serum phosphate. 

Calcium-phosphorus balance is mediated through a complex interplay of hormones and their effects on bone, GI tract, kidney, and parathyroid gland. As kidney disease progresses, renal activation of vitamin D is impaired, which reduces gut absorption of calcium. Low blood calcium concentration stimulates secretion of parathyroid hormone (PTH). As renal function declines, serum calcium balance can be maintained only at the expense of increased bone resorption, ultimately resulting in renal osteodystrophy (ROD) (Fig. 76-7). 

We have tested the hypothesis that insulin inhibits the stimulatory effect of parathyroid hormone (PTH) on calcium reabsorption in the distal nephron. PTH is known to enhance calcium transport in renal cells, probably by stimulation of adenylate cyclase and subsequent increases in 3 5 cyclic AMP productoin. Since insulin had been observed to inhibit PTH-stimulated increases in kidney cyclic AMP levels in vitro (24) we investigated whether insulin-mediated hypercalciuria was dependent on the presence of PTH in vivo. 

A role for a collagenase, presumably fibroblast-type collagenase, in bone resorption has been indicated by studies employing the Searle A-carboxyl alkyl synthetic collagenase inhibitor CI-1 (compound (197) in Table 8.18) and its less potent stereoisomer CI-2 (compound (198) in Table 8.18) [207]. Cultured embryonic mouse calvaria treated with parathyroid hormone exhibit loss of calcium and show pronounced collagen resorption. CI-1 inhibited the collagen resorption in a dose-dependent manner at significantly lower concentrations than CI-2, but had only a small effect on calcium loss. This inhibitory effect was reversible and not due to inhibitor cytotoxicity. 

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enz)nne that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, h)rpoth)n oidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

Yamaguchi, M. and Kishi, S. (1995b). Inhibitory effect of zinc-chelating dipeptide on parathyroid hormone-stimulated osteoclast-like cell formation in mouse marrow cultures Involvement of calcium signalling. Peptides 16, 629-633. 

Osteomalacia is the condition in which bone becomes demineralised due to deficiency of vitamin D. In this condition parathyroid hormone (PTH) acts on the bone to maintain serum calcium, resulting in demineralisation. Serum calcium is usually normal or slightly low alkaline phosphatase levels are high, reflecting excessive osteoblast activity, and serum phosphate falls as an effect of PTH on the kidney. The same condition in children results in defects in long bone formation, and is termed rickets. 

Alternatives to steroid hormone therapy for osteoporosis include raloxifene, bisphosphonates, sodium fluoride, vitamin D and calcium supplementation, calcitonin, and parathyroid hormone. Tamoxifen has estrogenic effects on bone and delays bone loss in postmenopausal women. However as a result of estrogenic activity in the uterus, long-term tamoxifen administration has been associated with an increased risk of... 

Mechanism of Action A calcium receptor agonist that increases the sensitivity of the calcium-sensing receptor on the parathyroid gland to extracellular calcium, thus low-eringthe parathyroid hormone (PTH) levels. TiierapeHtic Effect Decreases serum calcium and PTH levels. 

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. ... 

Which one of the following statements concerning vitamin D is correct A. Chronic renal failure requires the oral administra tion of 1,25-dihydroxycholecalciferol. B. It is required in the diet of individuals exposed to sunlight. C. 25-Hydroxycholecalciferol is the active form of the vitamin. D. Vitamin D opposes the effect of parathyroid hor mone. E. A deficiency in vitamin D results in an increased secretion of calcitonin. Correct answer = A. Renal failure results in the decreased ability to form the active form of the vitamin, which must be supplied. The vitamin is not required in individuals exposed to sunlight. 1,25-dihydroxycholecalciferol is the active form of the vitamin. Vitamin D and parathyroid hormone both increase serum calcium. A deficiency of vitamin D decreases the secretion of calcitonin. 

Other target organs for the action of 1,25-dihydroxyvitamin D include the kidneys, bone, muscle,vwand skin. The hormone promotes reabsorption of both Ca2+ and inorganic phosphate by kidney tubules. In bone it binds to a specific receptor where it promotes the mobilization of calcium ions. This effect may result in part from stimulation of calcium-activated ATPase of the outer membrane of bone cells. Dissolution of bone also requires the presence of parathyroid hormone (PTH), the 83-residue hormone secreted by the parathyroid gland. In women past the age of menopause and in elderly men the production of 1,25-dihydroxyvitamin D decreases.w This may be a cause of the serious bone loss (osteoporosis) frequently observed. Treatment with 1,25-dihydroxyvitamin D3 or a synthetic analog seems to be helpful to such individuals. /Xy See also Chapter 30, Section A,5. 

Parathyroid Hormone. The role of the parathyroid gland and PTH in controlling calcium metabolism was previously discussed. A prolonged or continuous increase in the secretion of PTH increases blood calcium levels by several methods, including increased resorption of calcium from bone. High levels of PTH accelerate bone breakdown (catabolic effect) to mobilize calcium for other physiologic needs. 

Osteoporosis Generalized bone demineralization often associated with effects of aging and hormonal changes in postmenopausal women Calcium supplements, vitamin D, calcitonin, bisphosphonates, intermittent parathyroid hormone, estrogen, or SERMs (raloxifene] (see Chapter 30]... 

FIG. 15 Effect of lycopene on resorption of the calcium phosphate substrate coating of osteologic multitest slides in the presence of osteoclasts (Rao et al., 2003). (Lycopene I -Effect on osteoclasts Lycopene inhibits basal and parathyroid hormone-stimulated osteoclast formation and mineral resorption mediated by reactive oxygen species in ray bone marrow cultures. Reprint from Journal of Medicinal Food. 2003 6, pp. 69-78 by permission of Mary Ann Liebert, Inc., Publishers.)... 

Some mechanisms contributing to bone mineral homeostasis. Calcium and phosphorus concentrations in the serum are controlled principally by two hormones, l,25(OH)2D3(D) and parathyroid hormone (PTH), through their action on absorption from the gut and from bone and on excretion in the urine. Both hormones increase input of calcium and phosphorus from bone into the serum vitamin D also increases absorption from the gut. Vitamin D decreases urinary excretion of both calcium and phosphorus, while PTH reduces calcium but increases phosphorus excretion. Calcitonin (CT) is a less critical hormone for calcium homeostasis, but in pharmacologic concentrations CT can reduce serum calcium and phosphorus by inhibiting bone resorption and stimulating their renal excretion. Feedback effects are not shown. 

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