Bone calcium mobilization

Hypercalcemia can be treated by (1) administering 0.9% NaCl solution plus furosemide (if necessary) renal excretion (2) the osteoclast inhibitors calcitonin, plicamycin, or clodro-nate (a bisphosphonate) bone calcium mobilization i (3) the Ca +chelators EDTA sodium or sodium citrate as well as (4) glucocorticoids. 

Because of its potent effects on parathyroid hormone, intestinal calcium absorption, and bone calcium mobilization, calcitriol can cause hypercalcemia, often precluding its use in therapeutic doses (32). Hyperphosphatemia is also a persistent problem in patients on chronic hemodialysis and can be aggravated by therapeutic doses of calcitriol. The use of large doses of calcium carbonate or acetate to control phosphate absorption can increase the risk of hypercalcemia from calcitriol (33). 

The bone resorbing activities of la,25(OH)2D2 and la,25(OH)2D4 were almost the same as for la,25(OH)2D3. It is positively related to binding affinity to VDR. The results clearly explain that the calcemic effects of la,25(OH)2D2 and la,25(OH)2D4 are comparable to that of la,25(OH)2D3 as expected from their binding affinity for VDR. Sato et al. reported that bone calcium mobilization of 24-epi-la,25(OH)2D2 and la,25(OH)2D7 in vitamin D deficient rats was about 50% of that by la,25(OH)2D3 by assessing serum calcium changes after intravenous administration [36]. The results of biological activities of la,25-(OH)2D analogues were shown in Table 1 in comparison with those of l,25(OH)2D3. 

Vitamin D functions in the process of calcium mobilization from previously formed bone making it available to the extracellular fluid upon demand by the calcium homeostatic system as described under the regulation of vitamin D metabolism. From the experiments described in the metabolism section it is clear that 1, 25-(0H)2D3, rather than 25-OH-D3 or vitamin D3 functions in the mobilization of calcium from bone under physiologic conditions. The mechanism whereby 1,25-(0H)2D3 initiates mobilization of calcium from bone is not at all understood. In contrast to the response of intestinal calcium transport to 1, 25-(0H)2D3 this process is blocked by the prior administration of actinomycin D suggesting that in fact a transcriptive event is involved in this activation As previously pointed out, bone possesses a specific receptor for 1,25bone cells has not yet been determined however. In vivo the 1,25-(OH)2D3 activation of bone calcium mobilization requires the presence of parathyroid hormone but the nature of... 

It is also clear that the introduction of the la-hydroxy function is an absolutely essential metabolic event for calcium absorption. Nephrec-tomized vitamin D-deficient animals show no increase in intestinal calcium transport or bone calcium mobilization in response to physiological doses of vitamin D3 or 25-hydroxyvitamin D3. On the other hand these animals respond efficiently to la,25-dihydroxyvitamin D3. 

Dj). From the liver 25-OH-D3 is transported to the kidneys where it is converted to l,25-(OH)2-D3, the most active form of vitamin D in increasing calcium absorption, bone calcium mobilization, and increased intestinal phosphate absorption. The active compound 1,25-(OH)2-D3 functions as a hormone, since it is a vital substance made in the body tissues (the kidneys) and transported in the blood to cells within target tissues. This physiological active form of vitamin D3 is then either transported to its various sites of action or converted to its metabolite forms of 24,25-dihydroxycholecalciferol or 1,24,25-trihydroxycholecalciferol (see Fig. V-48). 

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. 

Stimulating activation of vitamin D by 1-a-hydroxylase to cal-citriol (1,25-dihydroxyvitmin D3) to promote calcium absorption in the GI tract and increased calcium mobilization from bone... 

Mechanism of Action A synthetic polypeptide hormone that acts on bone to mobilize calcium also acts on kidney to reduce calcium clearance, increase phosphate excretion. Therapeutic Effect Promotes an increased rate of release of calcium from bone into blood, stimulates new bone formation. 

Falsafi R, Tatakis DN, Hagel-Bradway S, Dziak R. 1991. Effects of inositol trisphosphate on calcium mobilization in bone cells. Calcif Tissue Int 49 333-9. 

With calving, the mother cow tends to stop eating. Hence, the diet may no longer be a reliable source of calcium at the onset of lactation. This leaves the bones as a source of calcium. The body requires a period of adjustment to activate the calcium-mobilizing mechanisms. The prior consumption of high-calcium foods leaves these mechanisms in the nonactivated state. The sudden change from a... 

Calcitriol is the main active metabolite of vitamin D, and synergizes with parathormone in mobilizing bone calcium and Increasing calcium absorption from the intestine. Vitamin D occurs in a number of sterol forms. These include vitamin D3 (cholecaldferol - the form in foods and made in the skin by the action of UV) vitamin Dj (ergocalciferol -also from plants). These forms are 25-hydroxylated in the kidney, and then la-hydroxylated in the kidney (under the control of parathormone), to make the most active form. This is available as calcitriol. Vitamin D facilitates the absorption of calcium and to a lesser extent, phosphorus, from the intestine and promotes deposition into the bones. A deficiency of vitamin D therefore results in bone deficiency disorders, e.g. rickets in children. Therapeutic replacement of vitamin D in cases of severe deficiency requires quantities of the vitamin best provided by one of the synthetic vitamin D analogues (e.g. alfacalcidol and dihydrotachysterol). 

In bone, a CaBP called osteocalcin contains 49 amino acids (M.W. 5500-6000). Its synthesis is stimulated by 1,25-(0H)2D. Osteocalcin contains four residues of y-carboxyglutamic acid, which require vitamin K for their synthesis and are important as binding sites for calcium (Chapter 36). Although vitamin K deficiency reduces the osteocalcin content of bone, it does not cause functional bone defects. For this reason, osteocalcin may function in calcium mobilization rather than deposition. Alternatively, as an effective inhibitor of hydroxyapatite formation, it may prevent overmineralization of bone. 1,25-(OH)2D increases y-glutamyl carboxylase activity in the renal cortex. The relationship between vitamin D and vitamin K needs clarification. 

Osteomalacia is caused by deficiency of vitamin D. Vitamin D regulates calcium homeostasis in the body by facilitating absorption of calcium from the intestine and, together with PTH, by enhancing calcium mobilization from bone and by reducing excretion of calcium by the kidney. Deficiency of vitamin D leads to inadequate absorption of calcium. Low levels of calcium stimulate the release of PTH, which in turn causes release of calcium from bone and failure to mineralize newly formed bone. 

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