Calcium Resorption

Around 99% of calcium is contained in the bones, whereas the other 1% resides in the extracellular fluid. Of this extracellular calcium, approximately 40% is bound to albumin, and the remainder is in the ionized, physiologically active form. Normal calcium levels are maintained by three primary factors parathyroid hormone, 1,25-dihydroxyvitamin D, and calcitonin. Parathyroid hormone increases renal tubular calcium resorption and promotes bone resorption. The active form of vitamin D, 1,25-dihydroxyvitamin D, regulates absorption of calcium from the GI tract. Calcitonin serves as an inhibitory factor by suppressing osteoclast activity and stimulating calcium deposition into the bones. 

Mechanism of Action A bisphosphate that binds to bone and inhibits osteoclast-mediated calcium resorption. Therapeutic Effect Lowers serum calcium concentrations. 

Gallium nitrate is used clinically, at lower doses than for treating tumors, to treat hypercalcemia associated with bone cancers. " It incorporates into bone at very low levels and prevents calcium resorption, leading also to higher phosphate and collagen levels, and hence sturdier bone stmcture. ... 

Three effiects of parathyroid hormone The presence of parathyroid hormone in the plasma is required for the maintenance of I-hydroxylase activity in the kidney. The increase in PTH levels induces an increase in the activity of the hydroxylase, resulting in an increase in the production of l,25-(OH)D3 and an increase in the plasma levels of l,25-[OH)Di. In addition, PTH works in tandem with 1,25-(OH)2Dj in stimulating the osteodasts to dissolve bones and in increasing the efficiency of calcium resorption by the kidneys. Both PTH and l,25-(OH)2D3 are required for these latter two effects, i H is not required for the effect of the vitamin on the intestines. 

CaJciiim sensor protein also occurs in the kidney Specificaliy, the calcium sensor occurs in the thick ascending loop, where the N-terminal half juts Out into the extracellular fluid (not into the lumen of the tubule, but in the space between tubules). When extracellular Ca ions increase in concentration, the thick ascending loop decreases its rale of calcium resorption (Chattopadhyay d (j/., 1996 Pearce and Thakkar, 1997 Pearce ef uf., 1996), The regulatory scenario in the kidney represents a mode of regulating the body s calcium balance that appears completely independent of vitamin D, The overall scenario is that, as extracellular Ca " increases, the parathyroid gland decreases its release of PTH, and the kidney reduces its reabsorption of calcium ions from the developing urine. 

Three effects of l,25-(OH)2Di l,25-Dihydrox)rvitamin D3, in increased concentrations, has three effects that act to restore plasma calcium to the normal value of about 1.5 mM (1) activation of the vitamin D-dependent calcium transport system of the enterocyte, (2) activation of the osteoclasts, and (3) enhancement of calcium resorption by the kidney. Osteoclasts are cells that reside on the outside and inside surfaces of bones. They dissolve the bone, releasing the constituent calcium and phosphate ions into the circulation. l,25-(OH)2D3 can induce an increase in the activity of the osteoclasts. 

Gallium nitrate is approved for treating cancer-related hypercalcemia. It showed antitumor activity fur putienb with lymphoma in phase II trials. - Gallium nitrate probably works in hypercalcemia by inhibiting calcium resorption from bone, although the precise mechanism is unknown. Major side effects include hypocalcemia and nephrotoxicity. On continuous infusion, the drug exhibits biphasic elimination with an a half-life of 8.3 to 26 minutes and a half-life of 6.3 to 95 hours. Between 69 and 91% of the dnsc was recovered in the urine. ... 

Clinically, the animals do not show signs until 24-48 or more hours after ingestion of the bait. The affected animals are depressed, have reduced urine production, and the urine is of low specific gravity. Severely poisoned animals have hematemesis, azotemia, and cardiac arrhythmias. Animals with renal impairment are more susceptible to cholecalciferol poisoning than those with normal renal function. Cholecalciferol poisoning requires protracted treatment, which may require as long as 3 weeks in severe intoxications. Appropriate treatment consists of fluid therapy to assist the kidneys in removing the excess calcium, corticosteroids to minimize inflammation, and calcitonin to enhance calcium resorption into the bone. Pamidronate disodium is the new antidote for this poison. 

Thiazide diuretics increase urinary calcium resorption. A 10-year retrospective study of 83,728 women demonstrated fewer fractures among patients currently taking thiazides." A prospective trial demonstrated maintenance of BMD at the spine and hip over a 3-year period with low-dose hydrochlorothiazide, with a greater effect seen in women." Prescribing thiazide diuretics solely for osteoporosis is not recommended, but is a reasonable choice for the patient with osteoporosis who requires a diuretic. 

Gallium exerts a hypocalcemic effect by inhibiting calcium resorption from bone, possibly by stabilizing bone matrix, thereby reducing increased bone turnover. It is indicated in the treatment of symptomatic, cancer-related hypercalcemia unresponsive to adequate hydration. 

In patients with hypercalcemia, treatment with a loop diuretic plus saline promotes calcium excretion and helps lower serum calcium. In patients with intact regulatory function, increases in calcium resorption promoted by thiazides have minor impact on serum calcium due to buffering in bone and gut. However, thiazides can unmask hypercalcemia that occurs in diseases that disrupt normal calcium regulation (eg, hyperparathyroidism, sarcoidosis, carcinoma). 

Intracellular calcitriol receptors are widespread in the body. They are found, for example, in the small intestine, the kidneys, the bones, and the parathyroid gland. Calcitriol binds to these receptors and induces at the DNA level the transcription of hormone-sensitive genes. It influences cell differentiation and proliferation, stimulates an increased uptake of calcium ions from the intestine through enhanced formation of calcium-binding proteins, and also controls the release of calcium from the bones. [91] Since the counter-ion of the calcium is mostly phosphate, calcitriol raises consequently the phosphate level in blood as well. While the release of calcium from the bones appears counterproductive, this effect is however over-compensated by the increased intestinal calcium resorption, resulting in an elevated serum concentration. 

Some conflicting statements have been made concerning the relative potencies of compounds possessing of the 24 R)- and 24(iS)-configuration in the vitamin D3 side chains. DeLuca (185) claims that both synthetically derived 24-hydroxyvitamin D3 isomers stimulate intestinal calcium transport almost equally well in the rat and has shown that the 24(S)-isomer has little or no activity in bone calcium resorption or in bone formation, whereas the 24(/ )-isomer is almost as active as 25-hydroxyvitamin D3 in these in vivo tests. However, Atkins (7) claims that both diastereo-isomers of 24,25-dihydroxyvitamin D3 are potent stimulators of bone resorption in tissue culture and there is no significant difference between the (R)- and (5)-forms. Boris (24) recently also showed that both 24 R)-and 24(/S)-isomers of la,24,25-trihydroxyvitamin D3 promote bone mineralization almost equally well in cockerels. Whether the differentiation of the 24(i )- and 24(5)-diastereoisomers in bone formation and resorption occurs only in the absence of the la- and the 25-hydroxy substituents is not known at this time, but it seems unlikely. 

In describing the process of ossification, we emphasized two facts (1) that calcification occurs on a cartilaginous and connective tissue model and (2) that the ossified tissue is continuously remodeled. Thus, one should clearly distinguish the processes of ossification and calcification. Ossification is a form of differentiation involving the elaboration of a matrix, calcium deposition, calcium resorption, and remodeling of the matrix followed by new calcium deposition. Thus, calcium deposition (calcification) and calcium removal (decalcification) are two processes essential to the differentiation of bone tissue. 

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. 

Calcitonin is active in nephrectomized and parathy-roidectomized animals, indicating that the hormone does not act through the kidney or the parathyroid. Thyrocalcitonin causes hypocalcemia even in rats fed a low-calcium diet. Consequently, the hormone does riot seem to influence intestinal absorption of calcium. Calcitonin facilitates calcium retention in bone cultures. It is likely that the hormone acts by interfering with calcium resorption in bone, but the exact mechanism by which the interference takes place is not known. 

The effect of parathyroid hormone upon bone is considered by Albright to be secondary to the increase in urinary phosphate excretion, the depletion of serum phosphate causing accelerated resorption of phosphate from bone which is inevitably accompanied by increased calcium resorption. This author distinguishes between hyperparathyroidism with bone disease and a like condition without bone disease. In the former there is an increase in the resorption of bone with a compensatory increase in bone formation, the osteoblasts and osteoclasts being numerically increased and the phosphatase activity of the serum raised. The latter condition shows normal bone metabolism, and the increased calcium excretion is postulated to come entirely from increased calcium intake and absorption, whereas serum phosphatase activity is normal. 

Vitamin D2 and D3 are hydroxylated first in the liver to the prohormone 25-hydroxycholecalciferol (calcidiol) and subsequently in the kidney to the vitamin D hormone la,25-dihy-droxycholecalciferol (calcitriol). Calcitriol acts as an inductor of proteins in various organs. It promotes calcium resorption in the intestine and... 

A functional parathyroid adenoma would produce excess parathyroid hormone (PTH). PTH stimulates osteodasiic activity and increases renal tubular calcium resorption, leading to hypercalcemia by increasing bone turnover. Vitamin D is metabolized to the active 1,25 dihydroxy form, which interacts with parathyroid hormone to prodiKe hypercalcemia. Impaired renal tubular function in chronic renal disease Oncluding cadmium toxicosis)... 

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