The minerals calcium, magnesium, and phosphorus participate in many of the body's most important functions. These interact closely with vitamin D in bone health which is covered in Chapter 20: Vitamins. These elements play prominent roles in energy processes and the transport of metabolites in a host of molecular biochemical reactions. In addition, calcium and phosphorus constitute the principal components of the skeleton in the form of hydroxyapatite, Ca10(PO4)6(OH)2. Magnesium, which is mainly an intracellular cation, is a cofactor in a wide variety of enzymatic reactions. Together, these 3 elements constitute 98% of body minerals by weight and are essential nutrients for life processes.1,2,3
Both calcium and phosphorus appear in the serum and extracellular fluid in low concentrations. Total serum calcium concentration is closely maintained in a narrow range of 2.13 to 2.63 mmol/L (8.5-10.5 mg/dL). Approximately half of the calcium in the serum is bound to albumin at normal levels of the latter; most of the remainder is ionized. The ionized fraction is the physiologically active portion, and in health, the concentration is constant. If hypoalbuminemia should occur, the total calcium concentration decreases, but the ionized portion remains undisturbed.
Calcium is regulated by a number of organs (eg, small intestine, kidney), bone, and various hormones (parathyroid hormone, calcitonin, and 1,25-dihydroxyvitamin D [1,25-(OH)2-D]). The gastrointestinal tract (primarily the duodenum and jejunum) regulates calcium absorption by 2 mechanisms-hormonally regulated active transport via calcium channels (transient receptor potential cation channel subfamily V members 5 and 6 [TRPV5 and TRPV6]) and by passive diffusion. The kidney is an important site of action of parathyroid hormone and is also the site of synthesis of the active hormonal form of vitamin D (1,25-[OH]2-D). Bone accounts for 99% of calcium, 80% of phosphorus, and 60% of magnesium in the body and can readily exchange these minerals with extracellular fluid to maintain homeostasis.
Parathyroid hormone secretion is regulated by ionized calcium via the calcium-sensing receptor (CASR). Parathyroid hormone helps maintain serum calcium levels by causing the release of calcium from bone and also by preventing the reabsorption of phosphorus in the kidneys. Calcitonin, a hormone secreted by the parafollicular cells of the thyroid, inhibits bone resorption and can lower serum calcium and phosphorus levels. However, there is no definite phenotype of calcitonin deficiency or excess and hence its physiologic role in regulation of minerals is unclear.4,5,6
Vitamin D facilitates transcellular calcium intestinal absorption and aspects of bone remodeling. To achieve this effect, it must undergo sequential hydroxylation in the liver to calcidiol and in the kidney to the final product, 1,25-(OH)2-D, also known as calcitriol.7,8 Calcidiol (25-hydroxyvitamin D [25-OH-D]) represents the primary circulatory and storage form of vitamin D. Anticonvulsant drugs, such as phenobarbital and phenytoin, can interfere with vitamin D hydroxylation and metabolism, increasing daily requirements. Although only partially understood, bone formation and calcium metabolism are also regulated via genetic factors. Studies have implicated specific vitamin D receptor genes in calcium absorption and other aspects of bone health in children.9,10,11
Factors other than calcium and vitamin D that are important in maintaining bone health are genetic factors; hormonal factors, especially levels of growth hormone and estrogen; and physical activity. In children, evidence suggests that a combination of adequate mineral intake and weight-bearing physical activity are optimal for bone formation and mineralization.12,13,14,15 Disuse osteoporosis, which may occur in children with chronic illnesses, also leads to marked bone loss.
Serum phosphorus concentration varies and is age- and diet-dependent. The reference range is 1.6 to 2.4 mmol/L (5.0-7.5 mg/dL) for infants, 1.3 to 1.78 mmol/L (4-5.5 mg/dL) for older children, and 0.8 to 1.6 mmol/L (2.5-4.5 mg/dL) for adolescents and adults.4
Less is known about the regulation of phosphorus. Phosphorus is absorbed efficiently in the small intestine, and its absorption is inhibited by aluminum-containing antacids. Phosphorus is filtered and reabsorbed in the kidney, and parathyroid hormone inhibits its renal reabsorption. A significant aspect of phosphorus regulation is renal excretion, such that renal insufficiency leads to decreased renal phosphate excretion and hyperphosphatemia.7
Only a small fraction of total body magnesium is present in serum. The normal serum total magnesium concentration is 1.6 to 2.5 mg/dL. Approximately half of this magnesium is protein bound, principally to albumin. Magnesium homeostasis is maintained partly by controlling intestinal absorption but also by controlling renal excretion. Magnesium appears to be absorbed principally in the ileum by 3 mechanisms: passive diffusion, "solvent drag," and active transport.7 Absorption of magnesium is inversely related to intake and is minimally affected by vitamin D.
Parathyroid hormone decreases renal reabsorption of filtered magnesium. Release of parathyroid hormone is modestly suppressed by increased concentrations of magnesium in extracellular fluid, an action that may be mediated by an increase in calcium in the cytosol of parathyroid cells. Conversely, hypomagnesemia stimulates the release of parathyroid hormone.7,16,17,18,19 Magnesium is required for production and release of parathyroid hormone.