The Absorption of Calcium and Phosphate

The Absorption of Calcium and Phosphate 1. Studies in Intact Animals and in Man 

The most striking feature of the balance experiments in rachitic children and in experimental animals is the increased excretion of calcium in the feces when the diet is deficient or completely lacking in vitamin D. An extra output of phosphate in the feces in vitamin D deficiency is also observed, but the difference is not always so striking. 

It is no surprise that the interpretation of some of the early studies, e.g., that by Orr et al. (1923), was that vitamin D increases the absorption of calcium and phosphate. 

The following quotation from Hess (1929) is useful to illustrate the position in those years. 

Now and again doubt arose Key s (1895) and other experiments did not go very deeply into the problem, and new studies were performed. Nicolaysen was the first to explore the problem fully (1934) and to reach a conclusive result. As the poorly founded postulate of active re-excretion and secretory function of the colon is again being given consideration, a brief summary of Nicolaysen s (1934) experiments will not be out of place. The argument was comparatively simple, namely that the endogenous fraction of the fecal calcium could not be studied except on a diet free of calcium. 

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The enteral absorption of calcium and phosphate after birth depends on a number of factors, including the amounts ingested, the types of foods eaten and the level of vitamin D. Under optimal circumstances, the amounts of calcium and phosphate incorporated into the body per kilogram per day following birth are only about one-third of those accumulated in utero. Since the growth of the baby s body mass is faster than the absorption of calcium and phosphate, the infant must normally borrow from and redistribute his existing bone... 

The physiological role of vitamin D is to maintain calcium homeostasis. Phosphate metabolism is also affected. Vitamin D accomplishes its role by enhancing the absorption of calcium and phosphate from tte small intestines, promoting their mobilization from bone, and decreasing their excretion by the kidney. Also involved are parathyroid hormone and edeitonin. 

This active vitamin D metabolite (1,25 dihydroxycholecalciferol) is an important cofactor for intestinal calcium absorption, which involves calbindins (calcium binding proteins) in the intestine and kidney. Calcitriol is produced in the kidneys by the conversion of 25-hydroxycholecalciferol (calcidiol) and its formation is stimulated by a reduction of plasma calcium and/or phosphate and increased production of parathyroid hormone and prolactin (Figure 6.3). Calcitriol also inhibits the release of calcitonin and, together with PTH, increases the absorption of calcium and phosphate from the gastrointestinal tract and the kidneys. Growth hormone, glucocorticoids, estrogens, testosterone, and the thyroid hormones also influence calcium metabolism. 

Monsen, E. R., and Cook, J. D. (1976). Food iron absorption in human subjects. IV. The effects of calcium and phosphate salts on the absorption of nonheme iron. Am.. Clin. Nutr. 29, 1142-1148. 

Calcium and phosphate enter the body from the intestine. The average American diet provides 600-1000 mg of calcium per day, of which approximately 100-250 mg is absorbed. This figure represents net absorption, because both absorption (principally in the duodenum and upper jejunum) and secretion (principally in the ileum) occur. The amount of phosphorus in the American diet is about the same as that of calcium. However, the efficiency of absorption (principally in the jejunum) is greater, ranging from 70% to 90%, depending on intake. In the steady state, renal excretion of calcium and phosphate balances intestinal absorption. In general, over 98% of filtered calcium and 85% of filtered phosphate is reabsorbed by the kidney. The movement of calcium and phosphate across the intestinal and renal epithelia is closely regulated. Intrinsic disease of the intestine (eg, nontropical sprue) or kidney (eg, chronic renal failure) disrupts bone mineral homeostasis. 

Three hormones serve as the principal regulators of calcium and phosphate homeostasis parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and the steroid vitamin D (Figure 42-2). Vitamin D is a prohormone rather than a true hormone, because it must be further metabolized to gain biologic activity. PTH stimulates the production of the active metabolite of vitamin D, l,25(OH)2D. l,25(OH)2D, on the other hand, suppresses the production of PTH. l,25(OH)2D stimulates the intestinal absorption of calcium and phosphate. l,25(OH)2D and PTH promote both bone formation and resorption in part by stimulating the proliferation and differentiation of osteoblasts and osteoclasts. Both... 

Effect of vitamin D on the intestine 1,25-diOH D3 stimulates intestinal absorption of calcium and phosphate. 1,25-diOH D3 enters the intestinal cell and binds to a cytosolic receptor. The 1,25-diOH D3-receptor complex then moves to the nucleus where it selectively interacts with the cellular DNA. As a result, calcium uptake is enhanced by an increased synthesis of a specific calcium-binding protein. Thus, the mechanism of action of 1,25-diOH D3 is typical of steroid hormones (see p. 238). 

Phosphates are important because they affect the absorption of calcium and other elements. The absorption of inorganic phosphorus depends on the amount of calcium, iron, strontium, and aluminum present in the diet. Chapman and Pugsley (1971) have suggested that a diet containing more phosphorus than calcium is as detrimental as a simple calcium deficiency. The ratio of calcium to phosphorus in bone is 2 to 1. It has been recommended that in early infancy, the ratio should be 1.5 to 1 in older infants, 1.2 to 1 and for adults, 1 to 1. The estimated annual per capita intake in the United States is 1 g Ca and 2.9 g P, thus giving a ratio of 0.35. The danger in raising phosphorus levels is that calcium may become unavailable. 

Q4 The parathyroids produce a peptide hormone, PTH, which controls the level of calcium in the body. A sensor on the surface of the parathyroid cells monitors blood calcium concentration and PTH is secreted in response to a fall in plasma calcium ion concentration. An increase in the level of PTH leads to hypercalcaemia (raised blood calcium) conversely, a reduction in the level of PTH leads to hypocalcaemia. PTH acts on the kidney to reduce reabsorption of phosphate and at the same time to increase reabsorption of calcium. In addition, it promotes the release of calcium and phosphate into the blood by activating osteoclasts, which break down the inorganic matrix of bone. PTH also increases the absorption of calcium by the mucosal cells of the intestine. The latter is a rather slow, indirect action mediated by PTH stimulation of calcitriol secretion by the kidney. 

VITAMIN D DEFICIENCY Vitamin D deficiency is associated with inadequate absorption of calcium and phosphate. The resulting decrease in Ca stimulates PTH secretion, which acts to restore plasma Ca + at the expense of bone. Plasma phosphate concentration will remain low due to the phosphaturic effect of PTH. In children, the failure to mineralize newly formed bone results in rickets, a growth disorder in which the long bones may be bowed due to inadequate calcification. 

It was felt that the conclusion to be reached was now substantiated by a system of varied experiments. The conclusion was that vitamin D in the intestine primarily influences the absorption of calcium, and that the effect observed on the absorption of phosphate is only secondary to that upon calcium. 

Wolhach and Bessey explain rickets as due to deficient absorption of calcium and phosphate and conclude that there is no reason to believe that the cells and matrices concerned in hone growth and maintenance are defective in rickets or are directly acted upon by the vitamin D. ... 

General metabolic significance. Vitamin D stimulates intestinal absorption of calcium and phosphate, renal reabsorption of these ions, deposition and mobilization of minerals in the hard tissue, controlling normal calcium and phosphate blood level by means of these processes. Molecular mechanism of the vitamin D effects most frequently conform to the effect of steroid hormones (induction of protein biosynthesis). 

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). 

Vitamin D consists of a group of similar steroid substances, all being metabolized to the active form of vitamin D, calcitriol or l,25(OH)2D3. Vitamin D is necessary for normal absorption of calcium and phosphate from both the intestine and the skeleton. Vitamin D deficiency results in low concentrations of these ions in the extracellular fluid and decreased mineralization of the osteoid in the skeleton. Therefore vitamin D deficiency causes development of rachitis in children and osteomalacia in adults. The circulating levels of calcitriol is influenced by hormonal control. Furthermore, a hormonal control is suggested to work by direct action on the enterocytes. 

Calcitriol increases the intestinal absorption of calcium and phosphate by stimulating the active system for transport of calcium. It also stimulates the synthesis of the calcium-binding protein in the mucosa cells. Calcitriol is more than five times as active as 25(OH)D3 with respect to its effect on the intestinal calcium absorption and more than 100 times as effective as an absorber of Ca ftom the skeleton. The concentration of calcitriol in plasma is about 70 pmol/liter, which is about 1000 times lower than the concentration of 25(OH)D3. 

Both are equally effective In man, and the latter Is often placed In the class of hormones since calciferol Is formed by the action of sunlight on 7-dehydrocholesterol In the skin (Frleden and Llpner, 1971) Vitamin D Increases bone sensitivity to parathyroid hormones and promotes Intestinal absorption of calcium and phosphate ... 

In addition to its role in the intestinal absorption of calcium, vitamin D also directly influences bone and kidney cells. This interaction with parathormone and calcitonin affects the metabolism of calcium and phosphate in a complex manner which is still not completely understood. 

It is generally accepted that a normal secretion of hydrochloric acid by the stomach is necessary for optimal absorption of calcium and phosphate, better absorption being due to a lowering of the pH of the gastrointestinal tract. The presence of hypochlorhydria or achlorhydria therefore exerts an adverse influence upon calcium and phosphate absorption. 

Effects of Vitamin D Deficiency.—The vitamin regulates the absolute and relative absorption of calcium and phosphate solutes from the intestinal tract, and may be regarded as a calcio-kinetic, or calcium-distributing, vitamin. Avitaminosis D is characterised by —... 

Vitamin D is a family of closely related molecules that prevent rickets, a childhood disease characterized by inadequate intestinal absorption and kidney reabsorption of calcium and phosphate. These inadequacies eventually lead to the demineralization of bones. The symptoms of rickets include bowlegs,... 

Human parathyroid hormone (hPTH) is an 84 amino acid polypeptide that functions as a primary regulator of calcium and phosphate metabolism in bones. It stimulates bone formation by osteoblasts, which display high-affinity cell surface receptors for the hormone. PTH also increases intestinal absorption of calcium. 

Mechanism of Action An antacid that reduces gastric acid by binding with phosphate in the intestine, and then is excreted as aluminum carbonate in feces. Aluminum carbonate may increase the absorption of calcium due to decreased serum phosphate levels. The drug also has astringent and adsorbent properties. Therapeutic Effect Neutralizes or increases gastric pH reduces phosphates in urine, preventing formation of phosphate urinary stones reduces serum phosphate levels decreases fluidity of stools. 

Vitamin D analogs Calcifediol (Calderol) Calcitriol (Rocaltrol) Dihydrotachysterol (DHT, Hytakerol) Ergocalciferol (Calciferol, Drisdol) Generally enhance bone formation by increasing the absorption and retention of calcium and phosphate in the body useful in treating disorders caused by vitamin D deficiency, including hypocalcemia, hypophosphatemia, rickets, and osteomalacia... 

Q7 Calcium is present in both intracellular fluid (ICF) and ECF, but the concentration in the ECF is twice as high as that in the ICF. Calcium is found in both ionized and bound forms, and Ca2+ homeostasis is mainly controlled by parathyroid hormone, which increases absorption of calcium in the intestine and reabsorption in the nephron. Calcitonin also affects ECF calcium concentration by promoting renal excretion when there is an excess of calcium in the body. The normal kidney filters and reabsorbs most of the filtered calcium however, in renal disease this is reduced and blood calcium decreases. Calcium and phosphate imbalance can occur in patients with renal failure, leading to osteomalacia (defective mineralization of bone). Osteomalacia is mainly due to reduced production of 1,25-dihydroxycholecalciferol, an active form of vitamin D metabolized in the kidney. Deficiency of 1,25-dihydroxycholecalciferol reduces the absorption of calcium salts by the intestine. 

Actions are complex. Vitamin D promotes the active transport (absorption) of calcium and therefore of phosphate from the gut, to control, with parathormone, the mineralisation of bone and to... 

Hypoparathyroidism can result from decreased production of PTH or failure of target organs to respond to PTH. In rare cases, it involves the production of genetically defective PTH. PTH provokes the kidney to conserve calcium and to excrete phosphate. Thus, hypoparathyroidism results in low plasma calcium and high plasma phosphate levels. The disease may result in the calcification of soft tissues because of the high plasma phosphate level. Elevated phosphate levels result in an increased rate of precipitation of calcium and phosphate as the calcium phosphate salt. The disease is treated with oral calcium supplements and phosphate-binding antacids to minimize the absorption of dietary phosphate. 

SEDA-22, 172) (1,2). However, hypercalcemia has also been reported in a few patients using no more than the recommended doses (3,4). Calcipotriol exerts its effects on systemic calcium homeostasis by increasing intestinal absorption of calcium and probably phosphate. This results in suppression of parathyroid hormone and 1,25-dihydroxycolecalciferol (5). 

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