Calcium plays a critical role in many cellular processes, including hormone secretion, muscle contraction, nerve conduction, exocytosis, and the activation and inactivation of many enzymes. As described in Chapter 3, calcium also serves as an intracellular second messenger by carrying information from the cell membrane into the interior of the cell. It is therefore not surprising that the body very carefully regulates the plasma concentration of free ionized calcium, the physiologically active form of the ion, and maintains plasma ionized calcium concentration within a narrow range.
Phosphate is no less important. Because it is part of the ATP molecule, phosphate plays a critical role in cellular energy metabolism. It also plays crucial roles in the activation and deactivation of enzymes. However, unlike calcium, the plasma phosphate concentration is not strictly regulated, and its levels fluctuate throughout the day, particularly after meals.
Calcium and phosphate homeostasis are intimately tied to each other for two reasons. First, calcium and phosphate are the principal components of hydroxyapatite crystals [Ca10(PO4)6(OH)2)], which by far constitute the major portion of the mineral phase of bone. Second, they are regulated by the same hormones, primarily parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (calcitriol) and, to a lesser extent, the hormone calcitonin. These hormones act on three organ systems—bone, kidneys, and gastrointestinal (GI) tract—to control the levels of calcium and phosphate in plasma. However, the actions of these hormones on calcium and phosphate are typically opposed in that a particular hormone may elevate the level of one ion while lowering that of the other. Figures 52-1 and 52-2 depict the overall daily balance of calcium and phosphate for an individual in a steady state.
FIGURE 52-1 Calcium distribution and balance. Note that all values are examples for a 70-kg human, expressed in terms of elemental calcium. These values can vary depending on factors such as diet.
FIGURE 52-2 Phosphate distribution and balance. Note that all values are examples for a 70-kg human, expressed in elemental phosphorus. These values can vary depending on factors such as diet.
The gut, kidneys, and bone regulate calcium balance
In plasma, calcium exists in three physicochemical forms: (1) as a free ionized species (Ca2+), (2) bound to (more accurately, associated with) anionic sites on serum proteins (especially albumin), and (3) complexed with low-molecular-weight organic anions (e.g., phosphate, citrate, and oxalate). The total concentration of all three forms in the plasma is normally 2.2 to 2.6 mM (8.8 to 10.6 mg/dL). In healthy individuals, ~45% of calcium is free, 45% is bound to protein, and 10% is bound to small anions. The body tightly regulates the ionized form of Ca2+ between 1.0 and 1.3 mM (4.0 and 5.2 mg/dL). The ionized form is the most important with regard to regulating the secretion of PTH and is involved in most of the biological actions of calcium.
Most total-body calcium is located within bone, ~1 kg (see Fig. 52-1). The total amount of calcium in the extracellular pool is only a tiny fraction of this amount, ~1 g or 1000 mg. The typical daily dietary intake of calcium is ~800 to 1200 mg. Dairy products are the major dietary source of calcium. Although the intestines absorb approximately one half the dietary calcium (~500 mg/day), they also secrete calcium for removal from the body (~325 mg/day), and therefore, the net intestinal uptake of calcium is only ~175 mg/day. The second major organ governing calcium homeostasis is bone, which in the steady state deposits ~280 mg/day of calcium and resorbs an equal amount. The third organ system involved, the kidney, filters ~10 times the total extracellular pool of calcium per day, ~10,000 mg/day. The kidneys reabsorb ~99% of this Ca2+, so that the net renal excretion of Ca2+ is ~1% of the filtered load (see Fig. 36-16). In a person in Ca2+ balance, urinary excretion (~175 mg/day) matches net absorption by the GI tract.
The gut, kidneys, and bone also regulate phosphate balance
The concentration of total phosphate in adult plasma—predominantly inorganic phosphate in the form of and —ranges from 0.8 to 1.5 mM, a variation of 80%. It is ~50% higher in children. Laboratories report total plasma phosphate concentration as elemental phosphorus (range in adults, 2.5 to 4.5 mg/dL). Between 85% and 90% of the circulating inorganic phosphate is filterable by the kidneys, either ionized (50%) or complexed to Na+, Ca2+, or Mg2+ (40%); only a small proportion (10% to 15%) is protein bound.
Like calcium, most total-body phosphate is present in bone, which contains ~0.6 kg of elemental phosphorus (see Fig. 52-2). A smaller amount of phosphorus (0.1 kg) resides in the soft tissues, mainly as organic phosphates, such as phospholipids, phosphoproteins, nucleic acids, and nucleotides. An even smaller amount (~500 mg) is present in the extracellular fluid (ECF) as inorganic phosphate. The daily dietary intake of phosphorus is typically 1400 mg, mostly as inorganic phosphate. Again, dairy products are the major source. The net absorption of phosphate by the intestines is ~900 mg/day. In the steady state, bone has relatively small phosphate turnover, ~210 mg/day. The kidneys filter ~14 times the total extracellular pool of phosphate per day (~7000 mg/day) and reabsorb ~6100 mg/day. Hence, the net renal excretion of phosphorus is ~900 mg/day, the same as the net absorption by the GI tract.