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Calcium (Ca) is present largely (99%) in the skeleton as the hydroxyapatite crystal of calcium phosphate [Ca10(PO4)10(OH)2]. Only the 1% to 2% that resides in recently deposited and rapidly exchangeable surface bone, blood, and extracellular fluid is readily mobilized. Calcium serves as an inter- and intracellular messenger and is necessary for neuronal and neuromuscular communication, muscular contraction, cardiac rhythmicity, enzyme function, clotting, protein synthesis and secretion, and cellular proliferation. Intracellularly, calcium is a second messenger that propagates signals that control cellular activities such as gene transcription, cell division, growth, movement, and function. Total serum calcium is composed of about 50% ionized calcium (Ca2+), the physiologically active form, about 40% calcium bound to albumin and globulins where it is inert, and 10% is complexed to citrate, lactate, bicarbonate, phosphate, or sulfate. Systemic acidosis decreases calcium binding to albumin thus increasing serum Ca2+ levels, while alkalosis increases calcium binding to albumin and lowers Ca2+ values.

Serum Ca2+ levels are maintained within narrow limits by a complex integration of the plasma membrane Ca2+ sensing receptor (CaSR); parathyroid hormone (PTH) and its receptor (PTH/PTH-related protein [PTHrP]-R-PTHR1; calcitonin, the product of the thyroidal parafollicular (C) cell and its receptor; and the vitamin D hormone system acting upon the intestinal tract, bone, and kidney (Fig. 542-1).1-3 As the serum Ca2+ concentration increases, the CaSR on the chief cell of the parathyroid gland (PTG) is activated and decreases PTH synthesis and release. Activation of the CaSR in the distal renal tubule decreases reabsorption of calcium and increases its urinary excretion. PTH stimulates osteoclastic bone reabsorption and increases renal tubular synthesis of 1,25 dihydroxyvitamin D3 (calcitriol) and intestinal absorption of calcium.

Figure 542-1.

Regulation of calcium and phosphate homeostasis. In response to calcitriol [1,25(OH)2D3] and parathyroid hormone (PTH), calcium is absorbed from the intestinal tract, kidney tubule, and bone. Calcitonin inhibits resorption of bone calcium. The Ca2+-sensing receptor (CaSR) modulates the activity of the parathyroid glands and the renal tubules. PTH, hypocalcemia, and hypophosphatemia stimulate renal tubular synthesis of calcitriol. PTH inhibits renal tubular reabsorption of phosphate, as does fibroblast growth factor-23 (FGF23), a phosphatonin secreted by osteoblasts. FGF23 also inhibits renal tubular synthesis of calcitriol. VDR, Vitamin D nuclear receptor.

Ca2+ enters cells through transmembrane calcium channels. Intracellularly, Ca2+ is bound to calbindin and calmodulin. Ca2+ leaves the cell through adenosine triphosphate (ATP)-driven Ca2+ pumps and by exchange for sodium (Na+) through H+-ATPase and Na+-Ca2+ exchangers. In the intestinal tract, calcium is absorbed in the duodenum, jejunum, ileum, and colon through the enterocyte’s calcium transport protein 1 (TRPV6), whose synthesis is stimulated by calcitriol. Ca2+ is released from the enterocyte ...

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