1. Calcium phosphate is minimally soluble in water. In fact, at the pH of body fluids and the concentrations of calcium and phosphate ions found in extracellular fluids, the critical solubility product is approached and sometimes exceeded. Any calcium phosphate precipitation is prevented by various soluble and extracellular matrix-bound inhibitor systems that buffer the critical (and “metastable”) concentrations of calcium and phosphate ions in blood and tissues, respectively.

2. The irritability, contractility, and conductivity of skeletal and smooth muscles and the irritability and conductivity of nerves are exquisitely sensitive and inversely proportional to the concentration of calcium. (The relationship between the calcium level and cardiac muscle is an equally sensitive but direct one.) The body goes to great lengths to protect these important systems from the danger of hypocalcemia or hypercalcemia.

3. Absorption of calcium across the gut lining cells, reabsorption of filtered calcium by the renal tubule, and resorption of calcium released from the apatite crystals of bone cannot take place without calcium transport systems. These systems include voltage-gated calcium-channel proteins and calcium-binding transporter proteins that transport calcium ions from the exterior to the interior of gut lining or renal tubule cells. The mechanism by which calcium-binding proteins (CBP) are synthesized and act to transport calcium from the lumen of the distal duodenum (and proximal jejunum) across the lining cells and into the extracellular fluid is principally dependent on 1,25-dihydroxyvitamin D, or 1,25(OH)₂D, which enhances the transcription of messenger ribonucleic acid (mRNA) for the synthesis of CBP polypeptide. PTH plays a role in this process by enhancing 25-hydroxyvitamin D–α-hydroxylase activity in the kidney, which forms 1,25(OH)₂D from 25-hydroxyvitamin D. In addition, PTH helps render the gut lining cells more permeable for calcium transport and helps to lower serum phosphate ion concentration by increasing its secretion by renal tubule cells in urine (a high phosphate ion concentration can interfere with calcium absorption).

1,25-Dihydroxyvitamin D’s potent effects on calcium transport in gut lining cells and the release of calcium from bone is mitigated by its relatively short-acting half-life, thereby emphasizing a constant metabolic need to acquire vitamin D precursors. Provitamin D₂ (ergosterol) is ingested or provitamin D₃ (7-dehydrocholesterol) is synthesized from cholesterol by the liver, and both are stored in the skin. Sunlight at wavelengths of approximately 315 nm (ultraviolet range) activates the provitamins into vitamin D₂ (calciferol) or vitamin D₃ (cholecalciferol), respectively, which are then transported to the liver. Here, they are acted on by a vitamin D, 25-hydroxylase (vitamin D, 25-OH_ase) to form 25-hydroxyvitamin D, or 25(OH)D. (Because both D₂ and D₃ are treated identically and act in similar manners, the numerical designator has been omitted.) The 25(OH)D then travels to the renal tubule and, in response to lowered calcium, high PTH, and low phosphate levels in serum, is transformed by 25-hydroxyvitamin D–α-hydroxylase, or 25(OH)D-1α-OH_ase, into the highly potent metabolite 1,25(OH)₂D. If a surplus of either calcium or phosphate is present (indicated by a high serum concentration of calcium or phosphate, or both, or a low PTH level), an alternate pathway is selected in which the 25(OH)₂D is acted on by 25(OH)D-24-OH_ase and the far less potent 24,25(OH)₂D is synthesized.

In a balanced diet, calcium and phosphate are ingested in adequate amounts. However, adequate calcium can be difficult to obtain in many reasonable diets and has led to fortifying food products with supplementary calcium. On the other hand, phosphate is present in almost all foods and dietary deficiencies are uncommon. Accessory factors promoting absorption of calcium from the gut include an acid pH, a low serum phosphate concentration (to avoid exceeding the critical solubility product mentioned in the first axiom above), and the absence of chelators such as phytate, oxalate, or excessive free fatty acids. Transport across the gut lining cells is controlled principally by the interaction of PTH, which renders the cells more permeable to luminal calcium, and 1,25(OH)₂D, which activates the transport polypeptide CBP.

Reabsorption of filtered calcium from the proximal tubule obeys the same rules. A diminished PTH level or decreased synthesis of 1,25(OH)₂D leads to decreased tubular reabsorption of calcium, whereas a high level of PTH and an increased level of 1,25(OH)₂D enhance reabsorption. Although both PTH and 1,25(OH)₂D are apparently able to cause resorption of bone, the vitamin D metabolite is at least partly responsible for the normal mineralization of bone.

The mechanism of phosphate absorption is less selective than that of calcium absorption but also appears to be at least partly dependent on the vitamin D metabolites. Because dietary intake of phosphate varies widely and absorption is almost unrestricted, the first axiom might suggest that humans stand poised on the brink of metastatic calcification and ossification because of a high, uncontrollable intake of phosphate. In fact, the renal excretory mechanisms exert a fine-tuned control over phosphate ion levels. In addition, tubular reabsorption of phosphate is exquisitely and inversely responsive to the concentration of PTH. Thus, PTH, which acts to increase tubular reabsorption of calcium, diminishes tubular reabsorption of phosphate, thus avoiding the potential disaster associated with exceeding the critical solubility product.

PTH plays a critical role in regulating levels of calcium and phosphate in serum and extracellular fluid. If the normal calcium concentration is not maintained, the diminished level signals the parathyroid glands to produce more PTH. The release of PTH, which is almost entirely dependent on the calcium level, has six separate functions, five of which are designed to correct the calcium deficit in serum and extracellular fluid. The five functions of PTH are as follows:

1. Increasing the synthesis of 1,25(OH)₂D in the kidney

2. Acting at the level of the gut lining cell (with vitamin D) to increase absorption of calcium

3. Acting at the level of the renal tubule (with vitamin D) to increase tubular reabsorption of filtered calcium

4. Acting at the level of bone (with vitamin D) to increase the population of activated osteoclasts, which destroy not only the hydroxyapatite crystals but also segments of organic bone matrix, thus releasing both calcium and phosphate ions

5. After releasing phosphate ions from bone (see 4), lowering the tubular reabsorption of phosphate to reduce the potential danger of violating the critical solubility product

A brief mention of two other homeostatic systems should be included in this discussion, namely, the body’s response system to hypercalcemia and hyperphosphatemia.

The standard physiologic mechanism that controls hypercalcemia (see first and second axioms above) is twofold: (1) “Turnoff” of the vitamin D/PTH/calciumsparing system, resulting in limited production of 1,25(OH)₂D, greatly diminished PTH elaboration, diminished gut absorption of calcium, diminished resorption of bone, and greatly diminished tubular reabsorption of calcium. (2) Increased elaboration of calcitonin, a hormone of low molecular weight secreted by the parafollicular cells (C cells) of the thyroid gland, which acts to lower the serum calcium concentration. This is achieved principally by diminishing the osteoclast population and activity and, to some extent, by reducing gastrointestinal absorption. However, it should be clearly noted that although the second mechanism may be well developed in avian species and although administration of exogenous, non–species-specific calcitonin may have a profound effect on the skeleton, the natural mechanism in humans appears to be too limited to protect the body from hypercalcemia.

Hyperphosphatemia, or increased concentration of serum phosphate, may lead to metastatic calcification, particularly in renal failure, since the critical solubility product can be exceeded even if calcium levels are normal. An increase in phosphate ions, however, appears to effectively impair the vitamin D/PTH/calciumsparing system. Thus, with increase of phosphate levels in serum and extracellular fluid, synthesis of 1,25(OH)₂D markedly declines. Also, gastrointestinal absorption and tubular reabsorption of calcium, and even bone breakdown, are initially reduced, thus diminishing the concentration of calcium. (If these mechanisms continue for a long period of time, however, they will induce a secondary hyperparathyroidism in response to the lowered serum calcium level.)

The system of calcium and phosphate metabolism is complex, and the variables are multiple. The fundamental axioms and the interactions of the various hormonal and mineral materials discussed here are important in understanding the principles that govern and control the homeostatic mechanisms and the alterations that lead to the rachitic syndrome (see Plates 2-28 and 2-29, and Section 3, Metabolic Diseases, Plates 3-13 to 3-23).