++
Calcium and phosphate are regulated by a web of interacting signals. For this reason we describe the regulation of both substances together. Control systems have 2 purposes: (1) on a short-term basis to keep the plasma level of calcium within a range that does not perturb excitable cell function and (2) on a longer-term basis to ensure that there is enough total calcium and phosphate in the body to maintain bone integrity. The key hormones that directly control calcium and phosphate are the active form of vitamin D (1,25-(OH)2D), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23). These hormones regulate 3 crucial processes: (1) the input of calcium and phosphate into the body from the GI tract, (2) the excretion of calcium and phosphate by the kidneys, and (3) the movement of both substances between plasma and bone. These hormones also regulate the production of each other.
++
The term vitamin D in common use denotes any member of a family of closely related molecules that are derived from cholesterol. One member, called vitamin D3 (cholecalciferol), is synthesized in the skin by the action of ultraviolet radiation on precursors synthesized in the body. Another member, vitamin D2 (ergocalciferol), is ingested in food derived from plants. Vitamin D supplements may contain either one. Although not identical structurally, vitamins D2 and D3 are equivalent in terms of their physiological roles in the body and can be considered to be the same vitamin. Until hydroxylated at the first and 25th positions, vitamin D has no significant biological activity. It travels in the blood and becomes hydroxylated at the 25th position by the liver and then hydroxylated again at the first position by proximal tubular cells within the kidneys to yield the active form, which is now, strictly speaking, a hormone. When the precursor is cholecalciferol (vitamin D3), the active hormone is also called calcitriol. For the rest of this text, we will use calcitriol to denote the active hormone that is recognized by specific receptors in target tissues.
++

The hydroxylation step occurring in the kidneys that produces calcitriol is the key control point in its production. That step is regulated by PTH and FGF23. Specifically, PTH stimulates this step (produces more calcitriol), whereas FGF23 inhibits it.
++
The major action of calcitriol on effector systems is to stimulate transcellular absorption of calcium, and to a lesser extent, phosphate, by the duodenum. (It may also increase passive calcium absorption in the lower small intestine by effects on tight junctions.) As well, it stimulates the renal-tubular reabsorption of both calcium and phosphate. Its primary mode of action is to increase the genetic expression of the protein components in the transport pathways. These actions serve functionally to increase or preserve the supply of the main building blocks for the synthesis of hydroxyapatite in bone, that is, calcitriol is effectively a bone-promoting hormone. Calcitriol also has some complicated actions on bone cells, best characterized as permissive for normal bone turnover. The influences of calcitriol on bone and the kidney are far less important than its actions on the GI tract to stimulate absorption of calcium (and phosphate).
++
In terms of the other hormones, calcitriol inhibits the synthesis of PTH in the parathyroid glands. Since PTH stimulates calcitriol production, this action completes a classic negative feedback loop that maintains normal levels of both hormones. Calcitriol also stimulates production of FGF23.
++
Vitmain D controls the supply of calcium; PTH controls plasma calcium concentration.
++
The major event in calcitriol deficiency is decreased calcium absorption from the GI tract, resulting in decreased availability of calcium for bone formation or reformation. In children, the newly formed bone protein matrix fails to be calcified normally because of the low availability of calcium, leading to the disease rickets.3
+
++
++
++
The parathyroid glands are small (pea sized or less) nodules of tissue embedded within the thyroid gland in the neck. Normally a person has 4 parathyroid glands. They secrete PTH (parathyroid hormone), an 84-amino-peptide hormone. The GI tract, kidneys, and bone are all subject to direct or indirect control by PTH. All of its normal activity is contained in the first 34 amino acids, and synthetic PTH can be made containing only this component. The PTH half-life in the plasma is very short (< 10 min), mostly due to rapid degradation in the liver,4 with renal filtration and uptake playing a secondary role. PTH secretion is controlled on a moment-to-moment basis by the calcium concentration of the ECF bathing the cells of the parathyroid glands. Decreased plasma calcium concentration stimulates PTH secretion, and increased plasma concentration inhibits secretion. Extracellular calcium acts directly on the parathyroid glands by binding to a novel class of calcium receptors coupled to G-protein-linked signaling cascades that inhibit the secretion of PTH. Low extracellular calcium stimulates PTH secretion by removing a tonic inhibition. This is a sensitive control system designed to keep free plasma calcium at about 1 mM.
++
Another regulator is plasma phosphate. Elevated phosphate stimulates PTH secretion by stimulating the capacity of the parathyroid gland to synthesize PTH, so that chronically high levels of phosphate lead to elevated PTH. A third regulator, as mentioned previously, is calcitriol, which inhibits PTH synthesis. On a moment-to-moment basis, calcium is the primary acute regulator.
++
PTH exerts at least 5 distinct effects on calcium and phosphate homeostasis (summarized in Figure 10–2 showing the response to hypocalcemia.
++
PTH increases plasma calcium and decreases plasma phosphate.
++
PTH actions on bone acutely increase the movement of calcium and phosphate from the labile pool in bone into the ECF. The mechanism of action is not clear, but the effect is to raise the set point for plasma calcium between plasma and bone fluid, that is, net efflux continues until plasma calcium rises to a new level.
PTH stimulates the bone remodeling process. Normally remodeling results in no net change in total bone calcium, but when PTH remains elevated, the result is erosion of bone hydroxyapatite.
PTH stimulates the hydroxylation step in the kidneys that generates calcitriol. The increased calcitriol stimulates calcium uptake from the GI tract and ensures that enough new calcium enters the body to replace losses in the urine.
PTH increases renal tubular calcium reabsorption, mainly by an action on the distal convoluted tubule. At this location, it acts rapidly through activation of kinases that phosphorylate regulatory proteins on a short-term basis. It also acts, on a slower time scale to increase synthesis of all the components of the transport pathway. The increased uptake of calcium from the tubular lumen increases basolateral extrusion (by a combination of Ca-ATPase activity and Na-Ca antiporter activity). The overall effect is to decrease urinary calcium excretion and retain body calcium.
PTH reduces the proximal tubular reabsorption of phosphate, thereby increasing urinary phosphate excretion and decreasing extracellular phosphate concentration.
++
The adaptive value of the first 4 effects results in a higher extracellular calcium concentration and thus compensates for the lower calcium concentration that originally stimulated PTH secretion. When PTH acts on bone, both calcium and phosphate are released into the blood. Similarly, calcitriol enhances the intestinal absorption of both calcium and phosphate, so that the processes that restore calcium to its normal level are simultaneously acting to increase the plasma phosphate above normal. But this is an unwanted action because of the tendency to form insoluble precipitates of calcium phosphate. Under the influence of PTH, plasma phosphate does not actually increase, because of PTH's inhibition of tubular phosphate reabsorption. Indeed, this effect is so potent that plasma phosphate may actually decrease when PTH levels are elevated.
++
There are nuances to the actions of PTH on bone that have important clinical implications. The response of bone to PTH depends on the pattern of its plasma concentration over time. PTH can either promote resorption of hydroxyapatite (its usual action), or if administered intermittently, promote deposition. Primary hyperparathyroidism, resulting from a primary defect in the parathyroid glands (eg, a hormone-secreting tumor), generates a continuous excess hormone level and causes enhanced bone resorption. This leads to bone thinning and the formation of completely calcium-free areas or cysts. In this condition plasma calcium often increases and plasma phosphate decreases; the latter caused by increased urinary phosphate excretion. A seeming paradox is that urinary calcium excretion is increased despite the fact that tubular calcium reabsorption is enhanced by PTH. The reason is that the elevated plasma calcium concentration induced by the effects of PTH causes the filtered load of calcium to increase even more than it increases the reabsorptive rate. Because the filtered load is so great, there is also an increased amount not reabsorbed, (ie, excreted). This result nicely illustrates the necessity of taking both filtration and reabsorption (and secretion, if relevant) into account when analyzing excretory changes of any substance. And as mentioned earlier, the high urinary calcium content promotes the formation of stones.
++
In contrast to what happens with the continuous presence of elevated PTH that accelerates bone resorption and release of calcium, intermittent rises (produced by infusions once per day) actually increase deposition of calcium in bone. Intermittent infusion of PTH is used therapeutically to increase bone density in osteoporosis patients.
++
Fibroblast growth factor 23 (FGF23) is a peptide hormone synthesized by osteoblasts and osteocytes in bone. It is primarily a negative regulator of phosphate, but has indirect actions on calcium. FGF23 secretion is increased in response to elevated levels of phosphate. It is also stimulated by calcitriol. In the kidney there are FGF23 receptors that are located in the distal tubule. Distal tubule cells contain the membrane protein Klotho, which is a co-receptor required in order for target cells to bind FGF23. FGF23 has 2 actions in the kidney: (1) it decreases reabsorption of phosphate (an action similar to that of PTH) and (2) it decreases production of calcitriol (an action opposite to that of PTH). Since these actions occur in the proximal, not distal tubule, it is suggested that distal tubule cells, upon binding FGF23, signal nearby proximal tubule cells by a paracrine messenger.