INTRODUCTION — The maintenance of calcium and phosphate homeostasis involves intestinal, bone, and renal handling of these ions.

Within the plasma, calcium circulates in different forms. Of the plasma calcium, approximately 40 percent is bound to albumin; 15 percent is complexed with citrate, sulfate, or phosphate; and 45 percent exists as the physiologically important ionized (or free) calcium. As routinely measured in the laboratory, the plasma calcium concentration includes all of the calcium in the plasma (free and bound). In general, measuring the total plasma calcium concentration is sufficient since changes in this parameter are usually associated with parallel changes in the ionized concentration. Exceptions to this commonly occur in patients with hypoalbuminemia, acid-base disorders, and chronic kidney disease. Issues surrounding the measurement of total and ionized calcium are presented elsewhere in detail. (See "Relation between total and ionized serum calcium concentrations".)

In comparison with calcium, plasma phosphorus exists in both organic and inorganic forms, including phospholipids, ester phosphates, and inorganic phosphates. Inorganic phosphates are completely ionized, circulating primarily as HPO₄^2- or H₂PO₄^- in a ratio of 4:1 at a plasma pH of 7.40.

Only a small fraction of the total body calcium and phosphate is located in the plasma. However, it is the plasma concentrations of ionized calcium and inorganic phosphate that are under hormonal control. Calcium balance is mediated primarily by parathyroid hormone (PTH) and calcitriol (1,25-dihydroxyvitamin D), which affect intestinal absorption, bone formation and resorption, and urinary excretion [1-4]. Phosphorus balance is also primarily regulated by PTH but may also respond to fibroblast growth factor 23 (FGF-23) and its cofactor, klotho, which together and separately promote renal excretion of phosphorus [5,6]. The physiologic roles of other hormones (such as calcitonin and estrogens) in the regulation of calcium and phosphate balance are incompletely understood [7].

CALCIUM HANDLING

Gastrointestinal calcium handling — Dietary calcium is absorbed by two mechanisms [7]:

●An active, transcellular pathway via the transient receptor potential vanilloid 6 (TRPV6) channel on the apical membrane of the duodenum and proximal jejunum [7]

●Paracellular calcium transport that occurs throughout the length of the intestine [8]

In contrast to the complete absorption of dietary sodium, potassium, and chloride in the gastrointestinal tract, the absorption of calcium and phosphate is incomplete due to two factors: Activated vitamin D (ie, calcitriol) is required for intestinal calcium absorption (see 'Effect of vitamin D on calcium' below), and calcium combines with certain anions in the intestinal lumen to form insoluble salts (such as calcium phosphate and calcium oxalate) that are not absorbed. As an example, a normal adult may ingest 1000 mg of calcium per day, of which approximately 400 to 500 mg may be absorbed. In addition, 300 mg of calcium are lost into the stool via digestive secretions. Thus, of 1000 mg of ingested calcium, the net absorption is only 100 to 200 mg [1]. In the steady state, this quantity of calcium is excreted in the urine.

Emerging evidence suggests that the calcium sensing receptor (CaSR) also regulates calcium transport across the gastrointestinal epithelia [9].

Bone calcium handling — Most of the body calcium, as well as much of the body phosphate, exists in bone as hydroxyapatite (Ca₁₀[PO₄]₆[OH]₂). Bone is a calcium reservoir that is involved in maintaining a normal plasma ionized calcium concentration; this process depends upon the activity of osteoblasts and osteoclasts, which are regulated by many hormones and proteins, including parathyroid hormone (PTH) and calcitriol. (See 'Regulation of plasma calcium concentrations' below and "Normal skeletal development and regulation of bone formation and resorption", section on 'Systemic and local regulators of bone cells'.)

Renal calcium handling — Only ionized (free, non-protein-bound) calcium is filtered by the glomerulus. Approximately 97 to 99 percent of the filtered calcium is reabsorbed in subsequent segments of the nephron [10]; approximately 70 percent is reabsorbed passively in conjunction with sodium reabsorption in the proximal tubule, and approximately 20 percent is reabsorbed in the thick ascending loop of Henle (TALH) through a passive, paracellular mechanism mediated by the tight junction protein, claudin-16 (in conjunction with claudin-19 and interacting with claudin-14), which acts as a channel for divalent cation reabsorption [11]. The major driving force for this transport event is a lumen-positive potential that is generated by the backflux of potassium (and, to a lesser extent, sodium) from cells of the TALH to the lumen (figure 1) [11].

Reabsorption of the remaining 10 to 15 percent of calcium occurs in the distal nephron through a transcellular mechanism [4]. In contrast to the passive reabsorption occurring in more proximal nephron segments, distal calcium handling is active and is responsible for physiologic calcium regulation as well as the dysregulation observed in many disease states. Calcium enters tubular cells via the transient receptor potential vanilloid 5 (TRPV5) channel, which is expressed on the apical membrane of both distal convoluted tubule and connecting tubule cells [4,12,13]. Once inside the cell, calcium binds to the calbindin-D28k protein, which assists in calcium trafficking to the basolateral surface [4]. There, calcium is finally extruded into the circulation via two channels, NCX1 (a 3Na/Ca exchanger) and PMCA1b (a Ca-ATPase) (figure 2) [4].

Emerging studies also suggest that intracellular calcium content may regulate transcellular calcium transport through so-called store operated calcium channels (SOCC) [14].

REGULATION OF PLASMA CALCIUM CONCENTRATIONS — The serum calcium concentration is regulated by multiple hormonal pathways including parathyroid hormone (PTH), vitamin D, fibroblast growth factor 23 (FGF-23), calcitonin, and estrogen. Although these mediators will be discussed individually, they interact with each other to regulate the plasma calcium concentration.

Parathyroid hormone — PTH is a polypeptide secreted by the parathyroid glands in response to decreases in plasma ionized calcium (figure 3) [2]. This change is sensed by the calcium-sensing receptor (CaSR) on parathyroid cells and leads to the appropriate changes in PTH secretion [3,15]. Polymorphisms of the CaSR may underlie a significant portion of the variability observed in the plasma calcium concentrations in normal individuals [16]. In addition, inactivating mutations in this receptor lead to hypercalcemia because a higher-than-normal plasma calcium concentration is required to activate the CaSR and thereby suppress PTH release in such patients [17,18]. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia" and "Parathyroid hormone secretion and action".)

PTH acts to increase the plasma calcium in three ways (algorithm 1):

●Increased intestinal absorption – PTH promotes renal formation of calcitriol (1,25-dihydroxyvitamin D), the major active vitamin D metabolite, which enhances intestinal calcium and phosphate absorption (see 'Effect of vitamin D on calcium' below). The synthesis of calcitriol is discussed in detail elsewhere. (See 'Gastrointestinal calcium handling' above and "Parathyroid hormone secretion and action", section on 'Synthesis of calcitriol' and "Overview of vitamin D", section on 'Renal'.)

●Bone resorption – PTH mobilizes skeletal calcium in two ways. First, PTH mobilizes readily available calcium stores, which are in equilibrium with the extracellular fluid. Second, PTH activates bone resorption by binding to PTH receptors on osteoblasts, which, in turn, increase osteoclast number and activity and result in bone resorption. Evidence also points to direct PTH binding to osteoclasts, which may also contribute to bone resorption [19]. (See 'Bone calcium handling' above and "Parathyroid hormone secretion and action", section on 'Skeletal actions of PTH'.)

●Renal reabsorption – PTH quickly increases calcium reabsorption in the distal nephron by activating adenylyl cyclase, thereby increasing cyclic adenosine monophosphate (AMP) levels that stimulate protein kinase A; protein kinase A, in turn, phosphorylates and activates the transient receptor potential vanilloid 5 (TRPV5) [20], resulting in increased transcellular calcium transport [4]. Additional evidence suggests that phosphorylated claudin-16 interacts with TRPV5 to increase calcium reabsorption in the distal convoluted tubule and that this phosphorylation is also regulated by PTH [21]. PTH also increases the expression of the calcium transport proteins, TRPV5, calbindin-D28k, NCX1, and PMCA1b, in the distal nephron [4], which also enhances renal calcium reabsorption [22].

The mechanism by which PTH enhances calcium reabsorption in the thick ascending loop of Henle (TALH) is not clearly defined. However, one study has found that PTH 1 receptor (PTH1R) signaling directly and indirectly regulates the paracellular calcium transport pathway by inhibiting claudin-14 expression in the TALH [23]. In animals lacking the PTH receptor in the TALH, claudin-14 protein expression markedly increases, leading to reduced calcium reabsorption. Conversely, blocking expression of claudin-14 by gene deletion reverses the hypercalciuria and hypocalcemia of parathyroid-deficient animals. The mechanism of distal calcium reabsorption is presented above. (See 'Renal calcium handling' above.)

Small elevations in the plasma calcium concentration act as negative feedback in these processes by binding to the CaSR on parathyroid glands, thereby decreasing PTH secretion. In addition, an increase in calcitriol inhibits production and secretion of PTH by the parathyroid gland. (See "Parathyroid hormone secretion and action", section on 'Regulation' and 'Regulation of vitamin D' below.)

Vitamin D — Vitamin D3 (cholecalciferol) is a fat-soluble steroid that humans obtain primarily through synthesis in the skin from 7-dehydrocholesterol in the presence of ultraviolet light (figure 4). Cholecalciferol is hydroxylated in the 25 position by the hepatic enzyme, 25-hydroxylase, resulting in the formation of 25-hydroxyvitamin D, which is also known as calcidiol. (See "Overview of vitamin D".)

Calcidiol then enters the circulation (bound by vitamin D-binding protein), is filtered by the glomerulus, and is then reabsorbed by the tubule. Studies in vitamin D-deficient animals suggest that the proximal tubule is the important site of calcitriol synthesis. However, studies in the normal human kidney under conditions of vitamin D sufficiency indicate that the distal nephron is the predominant site of 1-alpha-hydroxylase expression [24]. Here, calcidiol enters one of two pathways: the 1-alpha-hydroxylase pathway that produces the most active form of vitamin D (calcitriol [1,25-dihydroxyvitamin D]) or the 24-alpha-hydroxylase pathway to form the inactive metabolite, 24,25-dihydroxyvitamin D [25]. (See "Overview of vitamin D", section on 'Renal'.)

Calcitriol can also be synthesized in activated macrophages and thymic-derived lymphocytes, an effect that appears to be mediated by interferon gamma [26]. This extrarenal production of calcitriol may be important in granulomatous diseases (such as active pulmonary sarcoidosis and tuberculosis) and in lymphomas, in which overproduction of calcitriol can lead to hypercalcemia and hypercalciuria via increased intestinal calcium absorption. (See "Hypercalcemia in granulomatous diseases" and "Etiology of hypercalcemia", section on 'Hypervitaminosis D'.)

Effect of vitamin D on calcium — Calcitriol increases the plasma calcium concentration through effects on the gastrointestinal tract, bone, and the kidney (figure 4):

●Increased intestinal absorption – The main effect of calcitriol is to enhance apical intestinal calcium absorption by increasing the expression of transient receptor potential vanilloid 6 (TRPV6) and basolateral efflux via increased expression of PMCA1b [7]. (See 'Gastrointestinal calcium handling' above.)

●Bone resorption – The mechanism by which calcitriol impacts bone resorption in humans is unclear. In animals that are in negative calcium balance (such as with very low dietary calcium intake), calcitriol increases calcium release from skeletal stores by binding to osteoblasts and osteocytes and by increasing levels of pyrophosphate, a potent mineralization inhibitor [27]. (See 'Bone calcium handling' above.)

●Renal reabsorption – Calcitriol increases reabsorption of calcium in the distal convoluted tubule and the collecting tubule by increasing expression of TRPV5 and calbindin-D28k. (See 'Renal calcium handling' above.)

The physiologic implications of calcitriol deficiency in normal adults are uncertain, although deficiency in children can lead to rickets. In adult patients with chronic kidney disease, however, calcitriol deficiency appears to be an important risk factor for secondary hyperparathyroidism [28]. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Clinical manifestations' and "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Decreased calcitriol activity'.)

Regulation of vitamin D — Plasma calcitriol concentrations are regulated by PTH, the serum calcium and phosphate concentrations, and FGF-23. These issues are presented elsewhere in detail. (See "Overview of vitamin D", section on 'Metabolism'.)

Briefly, in response to reduced calcium concentrations, PTH increases the activity of 1-alpha-hydroxylase, thereby increasing the production of calcitriol (see "Overview of vitamin D", section on 'Metabolism'). An excessive rise in the plasma calcium is prevented, in part, by the increase in the calcitriol concentration:

●Calcitriol exerts a negative influence on the parathyroid gland, thereby decreasing PTH production and release [4,25]. The decrease in PTH leads to reduced renal calcium reabsorption and reduced conversion of calcidiol to calcitriol. (See 'Parathyroid hormone' above.)

●In addition, calcitriol directly inhibits 1-alpha-hydroxylase in the kidney via binding of calcitriol to the vitamin D receptor [29].

●Calcitriol also promotes its own inactivation by increasing transcription of CYP24A1, the gene encoding 24-alpha-hydroxylase.

Conversely, with hypercalcemia and diminished PTH levels, activity of 1-alpha-hydroxylase decreases and activity of 24-alpha-hydroxylase increases, resulting in increased formation of inactive vitamin D. An excessive fall in the plasma calcium is prevented by an increase in PTH and an increase in 1-alpha-hydroxylase activity.

The clinical importance of the interaction between PTH and calcitriol on renal calcium handling is evident in hypoparathyroidism, a disorder in which both PTH and calcitriol levels are reduced [30]. The ensuing decrease in distal calcium reabsorption results in persistent calcium excretion, despite the presence of hypocalcemia. If calcitriol is given in this setting to raise the plasma calcium concentration, there will still be PTH deficiency and persistence of a partial defect in distal calcium reabsorption. As a result, raising the plasma calcium to normal levels with supplemental calcitriol can increase the filtered calcium load and markedly increase hypercalciuria, thereby predisposing to calcium stone formation. (See "Etiology of hypocalcemia in adults", section on 'Hypocalcemia with low PTH (hypoparathyroidism)'.)

FGF-23 also regulates vitamin D metabolism by inhibiting expression of CYP27B1 (the gene encoding 1-alpha-hydroxylase) and promoting expression of CYP24A1 (the gene encoding 24-alpha-hydroxylase), resulting in decreased calcitriol and increased 24,25-dihydroxyvitamin D [31]. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Fibroblast growth factor 23'.)

Direct effects of the plasma calcium — In addition to PTH and calcitriol, calcium ions can directly influence renal calcium handling (as well as sodium and potassium handling) via signaling through the CaSR [32,33]. The CaSR is expressed in all nephron segments:

●In the loop of Henle, signaling through the CaSR increases production of 20-hydroxyeicosatetraenoic acid (20-HETE), which inhibits the apical potassium channel. Inhibition of potassium recycling via this channel reduces sodium chloride reabsorption via the Na-K-2Cl transporter, diminishing the generation of the lumen-positive electrical gradient and therefore passive calcium reabsorption (figure 1). (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Urine calcium excretion'.)

●In the distal nephron, activation of the CaSR inhibits TRPV5 activity and therefore diminishes calcium reabsorption and enhances calcium excretion [34].

●As noted above, calcium reabsorption in the proximal tubule occurs predominantly via a passive transcellular mechanism. The role of the CaSR in regulation of proximal tubular calcium reabsorption is not clear [33]. (See 'Renal calcium handling' above.)

PHOSPHATE HANDLING AND REGULATION

Phosphate handling — Absorption of dietary phosphorus in the small intestine occurs via sodium-dependent and sodium-independent pathways and may involve vitamin D regulation [6,35]. The sodium-dependent transport depends, in part, upon the NaPi-IIb transport protein, but the nature of the sodium-independent pathway (transcellular or paracellular route) is uncertain. Transport through the sodium-independent pathway appears to be unregulated and may explain the robust absorption of dietary phosphate in patients who are vitamin D deficient or in advanced chronic kidney disease [36].

Much of body phosphate exists in bone as hydroxyapatite (Ca₁₀[PO₄]₆[OH]₂). The utilization of this reservoir as a source to increase the plasma phosphate concentration is similar to its utilization to increase plasma calcium as discussed above, although other hormones such as fibroblast growth factor 23 (FGF-23) may also be involved in mobilizing phosphate from bone. (See 'Bone calcium handling' above.)

In animals with normal serum phosphate levels and adequate phosphate intake, most of the filtered phosphate is reabsorbed by the proximal tubule, whereas approximately 10 to 20 percent is excreted in the urine. Little, if any, phosphate transport occurs beyond the proximal tubule in distal segments of the nephron.

Phosphate reabsorption in the proximal tubule is mediated by three separate transport proteins, each of which is dependent upon concurrent sodium transport: the type IIa sodium phosphate cotransporter (alternatively referred to as Npt2a, NaPi-IIa, or SLC34A1), the type IIc sodium phosphate cotransporter (alternatively referred to as Npt2c, NaPi-IIc, or SLC34A3), and the type III sodium phosphate cotransporter (called Pit-2, Ram-1, or SLC20A2) [37]. Data suggest that NaPi-IIa and NaPi-IIc are the most relevant to phosphate transport in humans [38].

Most of the experimental work on renal phosphate handling has been carried out in genetically manipulated mice, in which 70 to 80 percent of proximal tubule phosphate reabsorption is mediated by Npt2a, with lesser contributions by Npt2c and Pit-2. The abundance and activity of these transporters are mostly determined by interactions with key proteins involved in their attachment to the luminal membrane (scaffolding), transport from the cell cytosol to the membrane (trafficking), or intracellular signaling. Sodium hydrogen exchanger regulatory factor (NHERF1) is likely the most important protein involved in anchoring Npt2a to the luminal membrane to allow for phosphate reabsorption.

Regulation of plasma phosphate concentrations — Although bone release and gut absorption are important in establishing the filtered load of phosphate, it is the renal threshold for phosphate reabsorption in the proximal tubule that is most important in determining the steady state serum phosphate concentration. As an example, in patients with a primary disturbance in proximal tubular phosphate reabsorption, such as those with hereditary NaPi-IIc transport protein deficiency, feeding large amounts of phosphate causes only a minimal increase in steady state serum phosphate levels [39]. In addition, although acute cellular uptake of phosphate may transiently reduce serum levels (such as might occur following acute episodes of respiratory alkalemia) [40], steady state concentrations are most dependent upon rates of renal reabsorption. Phosphate reabsorption depends upon dietary phosphate intake, serum phosphate concentrations, and the activity of parathyroid hormone (PTH), FGF-23 and other phosphatonins, and active vitamin D (calcitriol) [41]. However, it is increasingly clear that the principal control of phosphate handling by the kidney is under the control of the FGF-23/alpha Klotho axis:

●Low dietary phosphate intake or low serum phosphate levels increase both synthesis of Npt2a transporters and insertion of these transporters into the lumen of the proximal tubule, leading to increased proximal tubule reabsorption and almost complete reabsorption of phosphate (figure 5). The sensing mechanism for phosphate in mammalian species remains uncertain [42], although some data suggest that the Raf/MEK/ERK signaling pathway may play a role as a phosphate sensor in some cell types.

●Conversely, PTH and FGF-23, the two dominant phosphaturic hormones, act by reducing the binding of Npt2a to NHERF1. One study has shown that the FGF receptor 1c and the PTH receptor respond to separate and distinct signals but converge on NHERF1 to inhibit PTH- and FGF23-sensitive phosphate transport and down-regulate NPT2A abundance [43]. As a result, there is less trafficking of Npt2a to the luminal membrane and increased retrieval of the transporter from the luminal membrane [44], which increases phosphate excretion and lowers the plasma phosphate concentration. Emerging evidence suggests an important involvement of G protein-coupled receptor kinase 6A (GRK6A) in mediating PTH-sensitive phosphate transport by targeted phosphorylation coupled with NHERF1 conformational changes [45].

Hypocalcemia is the predominant factor that stimulates PTH release, causing secondary phosphaturia. A direct phosphate sensor in the parathyroid gland has been proposed, but none have been identified. (See "Parathyroid hormone secretion and action", section on 'Regulation'.)

The mechanisms by which increases in phosphate intake or total body content lead to changes in phosphatonins (eg, FGF-23) and active vitamin D (calcitriol) are largely unknown.

The mechanism by which high dietary phosphate intake and high serum phosphate levels may stimulate FGF-23 release from bone also remains uncertain [41].

SUMMARY

●Within the plasma, calcium circulates in different forms. Of the plasma calcium, approximately 40 percent is bound to albumin; 15 percent is complexed with citrate, sulfate, or phosphate; and 45 percent exists as the physiologically important ionized (or free) calcium. In comparison with calcium, plasma phosphorus exists in both organic and inorganic forms, including phospholipids, ester phosphates, and inorganic phosphates. Inorganic phosphates are completely ionized, circulating primarily as HPO₄^2- or H₂PO₄^- in a ratio of 4:1 at a plasma pH of 7.40. Only a small fraction of the total body calcium and phosphate is located in the plasma. However, it is the plasma concentrations of ionized calcium and inorganic phosphate that are under hormonal control. (See 'Introduction' above.)

●Calcium handling occurs in the gastrointestinal tract, the bone, and the kidney (see 'Calcium handling' above):

•Gastrointestinal calcium absorption is incomplete. In addition, approximately 300 mg of calcium are lost into the stool via digestive secretions. Thus, of 1000 mg of ingested calcium, the net absorption is only 100 to 200 mg. In the steady state, this quantity of calcium is excreted in the urine. (See 'Gastrointestinal calcium handling' above.)

•Most of the body calcium, as well as much of the body phosphate, exists in bone as hydroxyapatite (Ca₁₀[PO₄]₆[OH]₂). Bone is a calcium reservoir that is involved in maintaining a normal plasma ionized calcium concentration. (See 'Bone calcium handling' above.)

•Ionized (free, non-protein-bound) calcium is filtered by the glomerulus. It is approximated that 97 to 99 percent of the filtered calcium is reabsorbed in subsequent segments of the nephron. (See 'Renal calcium handling' above.)

●The serum calcium concentration is regulated by multiple hormonal pathways including parathyroid hormone (PTH), vitamin D, fibroblast growth factor 23 (FGF-23), calcitonin, and estrogen. These mediators interact with each other to regulate the plasma calcium concentration. (See 'Parathyroid hormone' above and 'Vitamin D' above and 'Direct effects of the plasma calcium' above.)

●Absorption of dietary phosphorous in the small intestine occurs via sodium-dependent and sodium-independent pathways and may involve vitamin D regulation. Much of body phosphate exists in bone as hydroxyapatite (Ca₁₀[PO₄]₆[OH]₂). The utilization of this reservoir as a source to increase the plasma phosphate concentration is similar to its utilization to increase plasma calcium, although other hormones such as FGF-23 may also be involved in mobilizing phosphate from bone. With normal serum phosphate levels and adequate phosphate intake, most of the filtered phosphate is reabsorbed by the proximal tubule, whereas approximately 10 to 20 percent is excreted in the urine. Little, if any, phosphate transport occurs beyond the proximal tubule in distal segments of the nephron. (See 'Phosphate handling' above.)

●Although bone release and gut absorption are important in establishing the filtered load of phosphate, it is the renal threshold for phosphate reabsorption in the proximal tubule that is most important in determining the steady state serum phosphate concentration. Phosphate reabsorption depends upon dietary phosphate intake, serum phosphate concentrations, and the activity of PTH, FGF-23 and other phosphatonins, and active vitamin D (calcitriol). (See 'Regulation of plasma phosphate concentrations' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jonathan Hogan, MD, who contributed to an earlier version of this topic review.