Intestinal Calcium Absorption

The efficiency of dietary calcium absorption depends on two major factors: its interaction with other dietary constituents and physiological/pathological factors. Dietary factors that reduce the total amount of

DIET 1000 mg

125 mg

FECES 825 mg


9825 mg


9825 mg

500 mg 500 mg

000 mg

500 mg 500 mg


000 mg

, URINE 175 mg

Figure 1 Daily calcium turnover.

calcium absorbed by the intestine include phosphate, oxalate, phytate, fiber, and very low calcium intakes, whereas those that increase absorption include protein (or specific amino acids, lysine and arginine) and lactose in infants. The physiological/ pathological factors that decrease intestinal calcium absorption include low serum 1,25(OH)2 vitamin D (the form of the vitamin that effects calcium absorption), chronic renal insufficiency, hypoparathyroid-ism, aging, and vitamin D deficiency, whereas increased absorption is observed during growth, pregnancy, primary hyperparathyroidism, sarcoido-sis, and estrogen and growth hormone administration. The interindividual variability in intestinal calcium absorption is very high for reasons that are not entirely clear. On tightly controlled diets, a homogenous group of subjects can have intestinal calcium absorptions ranging from 10 to 50%.

Dietary calcium is complexed to food constituents such as proteins, phosphate, and oxalate, from which it needs to be released prior to absorption. The role of gastric acid (or the lack thereof induced by commonly used proton pump inhibiting drugs) in intestinal calcium absorption is not well established, although achlorhydria can impair absorption in the fasted state.

Calcium crosses the intestinal mucosa by both active and passive transport. The active process is saturable, transcellular, and occurs throughout the small intestine. The transcellular pathway is a multistep process, starting with the entry of luminal calcium into the enterocyte (possibly via a calcium channel) and translocation of calcium from the microvillus border of the apical plasma membrane to the basolateral membrane followed by extrusion out of the enterocyte. Calbindin, a calcium binding protein that is regulated by the hormonal form of vitamin D, 1,25(OH)2D3, affects every step in the movement of calcium through the enterocyte, including entry into the cell, movement in the cell interior, and transfer into the lamina propria. Although details of the movement of calcium through intestinal cells are still under investigation, it appears that the vitamin D-dependent calcium binding protein calbindin-D9k and the plasma membrane calcium-pumping ATPase 1b (PMCAlb) are critical transport molecules in the cytoplasm and basolateral membrane, respectively. The active transport pathway is predominant at lower levels of calcium intake, and it becomes more efficient in calcium deficiency or when intakes are low and also when calcium requirements are high during infancy, adolescence, and pregnancy. It becomes less efficient in vitamin D-deficient individuals and in elderly women after menopause.

The passive transport pathway is nonsaturable and paracellular. It occurs throughout the small intestine and is unaffected by calcium status or parathyroid hormone (PTH). It is relatively independent of 1,25(OH)2D3, although this metabolite has been found by some investigators to increase the permeability of the paracellular pathway. A substantial amount of calcium is absorbed by passive transport in the ileum due to the relatively slow passage of food through this section of the intestine. The amount of calcium absorbed by passive transport will be proportional to the intake and bioavailability of calcium consumed.

Fractional calcium absorption increases in response to low intake but varies throughout life. It is highest during infancy (60%) and puberty (25-35%), stable at approximately 25% in adults, and then declines with age (by approximately 2% per decade after menopause). There is little difference in calcium absorption efficiency between Caucasians and African Americans. The lower urinary calcium and better calcium conservation in African Americans probably contributes to their higher bone mineral density.


The skeleton acts as the storage site for calcium. Bone calcium exists primarily in the form of hydro-xyapatite (Ca10(PO4)6(OH)2), and this mineral comprises 40% of bone weight. In the short term, the release of calcium from bone serves to maintain serum calcium concentrations. In the longer term, however, persistent use of skeletal calcium for this purpose without adequate replenishment will result in loss of bone density. The storage of very small amounts of calcium in intracellular organelles and its subsequent release into cytosol acts as an intracellular signal for a variety of functions.

Between 60 and 80% of the variance in peak bone mass is explained by genetics, including polymorphisms in the vitamin D-receptor gene and in genes responsible for insulin-like growth factor-1 (IGF-1) and collagen production.

Metabolism and Excretion Regulation by Hormones

The concentration of ionized calcium in serum is closely regulated because it has profound effects on the function of nerves and muscles, blood clotting, and hormone secretion. The principal regulators of calcium homeostasis in humans and most terrestrial vertebrates are PTH and the active form of vitamin D, 1,25(OH)2 vitamin D3 (Figure 2).

PTH is a single-chain polypeptide that is released from the parathyroid when there is a decrease in the calcium concentration in extracellular fluid. The calcium-sensing

Serum Ca++ f Serum Pi

Figure 2 Hormonal regulation of calcium metabolism.

receptor (acting as the thermostat for calcium) is found on the parathyroid gland, where it detects small perturbations in serum ionized calcium. The decline in serum calcium induces an increase in PTH secretion. PTH has the effect of restoring extracellular calcium concentrations by stimulating the resorption of bone to release calcium, by increasing the renal reabsorption of calcium, and by enhancing the renal conversion of 25(OH)D3 to the active, hormonal form of the vitamin, 1,25(OH)2 vitamin D3. The active form of vitamin D then increases the synthesis of intestinal calcium binding protein (CaBP), leading to more efficient intestinal calcium absorption. PTH release is inhibited when serum calcium and 1,25(OH)2 vitamin D3 increase or when serum phosphate is decreased. The highly regulated interactions among PTH, calcium, 1,25(OH)2 vitamin D3, and phosphate maintain blood calcium levels remarkably constant despite significant changes in calcium intake or absorption, bone metabolism, or renal functions. The extracellular calcium concentration is the most important regulator of PTH secretion and occurs on a minute-by-minute basis. Acute PTH administration leads to release of the rapidly turning over pool of calcium near the bone surface. Chronic administration of PTH increases osteoclast cell number and activity. Interestingly and paradoxically, intermittent PTH administration is anabolic, increasing formation of trabecular bone. In the kidney, PTH has three major functions: It increases calcium reabsorption, inhibits phosphate reabsorption, and enhances the synthesis of the active form of vitamin D. All of these actions are designed to defend against hypocalcemia.

There are two sources of vitamin D: the diet (where it is found as the fortificant vitamin D2 or natural D3) or synthesis in skin during exposure to ultraviolet radiation (sunlight). The vitamin enters the circulation and is transported on a vitamin D binding protein to the liver, where it is hydroxylated to 25(OH) cholecalciferol, which leaves the liver, is bound again to the binding protein in the circulation, and enters the kidney where it is hydroxylated again to 1,25(OH)2D3, the most active metabolite of the vitamin. The primary biological effect of 1,25(OH)2D3 is to defend against hypocalcemia by increasing the efficiency of intestinal calcium absorption and by stimulating bone resorption. 1,25(OH)2D3 interacts with the vitamin D receptor on the osteoblasts, and via RANKL/RANK it stimulates the maturation of osteoclasts that function to dissolve bone, releasing calcium into the extracellular space. The recently discovered RANK ligand, a member of the tumor necrosis factor superfamily, and its two receptors (RANK and osteoprotegerin) are pivotal regulators of osteoclastic bone resorption, both in vivo and in vitro. More of the active metabolite is produced during calcium deficiency or after a low calcium intake in order to restore serum calcium by increasing intestinal calcium absorption, renal calcium reabsorption, and bone turnover.

Serum vitamin D concentrations decline in winter and are generally related to vitamin D intake and sunlight exposure. When serum 25(OH)D3 concentrations decline below 110nmol/l, PTH levels increase, contributing to the bone loss that occurs in vitamin D deficiency and that is evident in northern Europe, the United States, Japan, and Canada during winter months. Rickets is becoming a more recognized health problem, particularly in infants of African American mothers who are not taking vitamin D supplements or consuming adequate amounts of vitamin D-fortified milk and who are exclusively breast-feeding their infants. In the US national nutrition survey conducted in the 1990s, 42% of African American women had low 25(OH) vitamin D concentrations in plasma. Thus, vitamin D deficiency is more prevalent than once believed, and it is particularly a risk for the elderly due to their reduced capacity for synthesizing vitamin D precursors in their skin, in those who are infirm and/or in nursing homes or living at more northern or southern latitudes, or in other situations in which the skin is not exposed to sunlight. The result of vitamin D deficiency is normal serum calcium and elevated PTH and alkaline phosphatase. The secondary hyperpar-athyroidism causes increased osteoclastic activity, calcium loss from bone, and ultimately bone loss.

Several other hormones also affect calcium metabolism. Notably, estrogens are necessary for the maintenance of balance between bone resorption and accretion.

The decrease in serum estrogen concentrations at approximately the time of menopause is the primary factor contributing to the elevated rate of bone resorption that occurs at this stage of life and that is the primary contributory factor to osteoporosis. Estrogen treatment will reduce bone resorption within a few weeks and subsequently lead to higher serum concentrations of PTH and 1,25(OH)2D3 and improved intestinal absorption and renal reabsorption of calcium. Testosterone also inhibits bone resorption, and lack of this hormone can cause osteoporosis in men. Glucocorticoids, sometimes used to treat conditions such as osteoid arthritis, inflammatory bowel disease, and asthma, inhibit both osteoclastic and osteoblastic activity, impair collagen and cartilage synthesis, and reduce calcium absorption. Consequently, excessive bone loss often results from glucocorticoid treatment or occurs when excessive amounts of the hormone are secreted, such as in Cushing's disease. Oral calcium supplements should be considered for patients receiving exogenous glucocorticoids. Thyroid hormones stimulate bone resorption so that bone abnormalities occur in both hyper- and hypothyroidism. Growth hormone stimulates cartilage formation, the formation of 1,25(OH)2D, and intestinal calcium absorption. Insulin stimulates collagen production by osteoblasts and impairs the renal reabsorption of calcium.

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