Hypophosphatemia is defined as a serum phosphate level of less than 2.5 mg/dL (0.8 mmol/L) in adults. The normal level for serum phosphate in neonates and children is considerably higher, up to 7 mg/dL for infants. 

Phosphate is critical for a remarkably wide array of cellular processes. It is one of the major components of the skeleton, providing mineral strength to bone. Phosphate is an integral component of the nucleic acids that comprise DNA and RNA. Phosphate bonds of adenosine triphosphate (ATP) carry the energy required for all cellular functions. It also functions as a buffer in bone, serum, and urine.

The addition and deletion of phosphate groups to enzymes and proteins are common mechanisms for the regulation of their activity. In view of the sheer breadth of influence of this mineral, the fact that phosphate homeostasis is a highly regulated process is not surprising.

Phosphate in the body

The bulk of total body phosphate resides in bone as part of the mineralized extracellular matrix. This phosphate pool is accessible, although in a somewhat limited fashion. Approximately 300 mg of phosphate per day enters and exits bone tissue. Excessive losses or failure to add phosphate to bone leads to osteomalacia.

Phosphate is a predominantly intracellular anion with a concentration of approximately 100 mmol/L, although determination of the precise intracellular concentration has been difficult. Most intracellular phosphate is either complexed or bound to proteins and lipids. In response to kinases and phosphatases, these phosphate ions attach and detach from different molecules, forming a constantly shifting pool. Intracellular phosphate is essential for most, if not all, cellular processes; however, because the intracellular concentration of phosphate is greater than the extracellular concentration, phosphate entry into cells requires a facilitated transport process.

Several sodium-coupled transport proteins have been identified that enable intracellular uptake of phosphate by taking advantage of the steep extracellular-to-intracellular sodium gradient. Type 1 sodium phosphate cotransporters are expressed predominantly in kidney cells on the apical membranes of proximal tubule cells and, possibly, the distal tubule cells. They are capable of transporting organic ions and stimulating chloride conductance in addition to phosphate. Their role in phosphate homeostasis is not clear. Other sites of expression include the liver and brain.

Type 2 sodium phosphate cotransporters are expressed in the kidneys, bones, and intestines. In epithelial cells, these transporters are responsible for transepithelial transport, ie, absorption of phosphate from intestine and reabsorption of phosphate from renal tubular fluid. Type 2a transporters are expressed in the apical membranes of kidney proximal tubules, are very specific for phosphate, and are regulated by several physiologic mediators of phosphate homeostasis, such as parathyroid hormone (PTH), dopamine, vitamin D, and dietary phosphate. Currently, these transporters are believed (predominantly on the basis of animal studies) to be most critical for maintenance of renal phosphate homeostasis. Impaired expression or function of these transporters is associated with nephrolithiasis.[1, 2]

Type 2b transporters are very similar, but not identical, to type 2a transporters. They are expressed in the small intestine and are up-regulated under conditions of dietary phosphate deprivation and by vitamin D.

Type 2c transporters, initially described as growth-related phosphate transporters, are a third member of the type 2 sodium phosphate cotransporter family. They are expressed exclusively on the S1 segment of the proximal tubule and together with Type 2a transporters are essential for normal phosphate homeostasis.[3] Similarly to type 2a transporters, type 2c transporters are also regulated by diet and PTH. Loss of type 2c function results in hereditary hypophosphatemic rickets with hypercalciuria in human beings, suggesting that these transporters may actually play a significantly more prominent role in regulation of phosphate homeostasis in human beings than in rodents.[4]

Type 3 transporters (Pit1 and Pit2) were initially identified as viral transport proteins. Almost all cells express type 3 sodium phosphate cotransporters; therefore, these transporters were presumed to play a housekeeping role in ensuring adequate phosphate for all cells. Recent studies, however, point toward a more specific role for Pit1 and Pit2, as Pit1 has been implicated in the development of vascular calcifications and abnormalities in Pit2 are associated with the development of choroid plexus calcifications.[5]  The factors that regulate the activity of these transporter proteins are not completely understood. Evidence suggests, however, that these transporters also participate in the regulation of renal and intestinal transepithelial transport[6, 7] and in the regulation of bone mineralization.[8]  

Circulating phosphate exists as either the univalent or divalent hydrogenated species. Because the ionization constant of acid (pK) of phosphate is 6.8, at the normal ambient serum pH of 7.4 the univalent species is 4 times as prevalent as the divalent species. Serum phosphate concentration varies with age, time of day, fasting state, and season. Serum phosphate concentration is higher in children than adults; the reference range is 4-7 mg/dL in children compared with 3-4.5 mg/dL in adults. A diurnal variation exists, with the highest phosphate level occurring near noon.

Serum phosphate concentration is regulated by diet, hormones, and physical factors such as pH, as discussed in the next section. Importantly, because phosphate enters and exits cells under several influences, the serum concentration of phosphate may not reflect true phosphate stores. Often, persons with alcoholism who have severely deficient phosphate stores may present for medical treatment with a normal serum phosphate concentration. Only after refeeding will serum phosphate levels decline, often abruptly plummeting to dangerously low levels.

Phosphate homeostasis

Phosphate is plentiful in the diet. A normal diet provides approximately 1000-2000 mg of phosphate, two thirds of which is absorbed, predominantly in the proximal small intestine. The absorption of phosphate can be increased by increasing vitamin D intake and by ingesting a very low phosphate diet. Under these conditions, the intestine increases expression of sodium-coupled phosphate transporters to enhance phosphate uptake.

Regulation of intestinal phosphate transport overall is poorly understood. Although studies had suggested that the majority of small intestine phosphate uptake is accomplished through sodium-independent, unregulated pathways, subsequent investigations have suggested that regulated, sodium-dependent mechanisms may play a greater role in overall intestinal phosphate handling than was previously appreciated. Furthermore, intestinal cells may have a role in renal phosphate handling through elaboration of circulating phosphaturic substances in response to sensing a phosphate load.[9]  Recent studies have confirmed that the ability of intestinal phosphate transport to influence renal phosphate transport is PTH-dependent; however, the signal to the parathyroid gland remains unknown.[10]

Absorption of phosphate can be blocked by commonly used over-the-counter aluminum-, calcium-, and magnesium-containing antacids. Mild-to-moderate use of such phosphate binders generally poses no threat to phosphate homeostasis because dietary ingestion greatly exceeds body needs. However, very heavy use of these antacids can cause significant phosphate deficits. Stool losses of phosphate are minor (ie, 100-300 mg/d from sloughed intestinal cells and gastrointestinal secretions). However, these losses can be increased dramatically in persons with diseases that cause severe diarrhea or intestinal malabsorption.

Bone loses approximately 300 mg of phosphate per day, but that is generally balanced by an uptake of 300 mg. Bone metabolism of phosphate is influenced by factors that determine bone formation and destruction, ie, PTH, vitamin D, sex hormones, acid-base balance, and generalized inflammation.

The excess ingested phosphate is excreted by the kidneys to maintain phosphate balance. The major site of renal regulation of phosphate excretion is the early proximal renal tubule with some contribution by the distal convoluted tubule.[11]  In the proximal tubule, phosphate reabsorption by type 2 sodium phosphate cotransporters is regulated by dietary phosphate, PTH, and vitamin D. High dietary phosphate intake and elevated PTH levels decrease proximal renal tubule phosphate absorption, thus enhancing renal excretion.

Conversely, low dietary phosphate intake, low PTH levels, and high vitamin D levels enhance renal proximal tubule phosphate absorption. To some extent, phosphate regulates its own regulators. High phosphate concentrations in the blood down-regulate the expression of some phosphate transporters, decrease vitamin D production, and increase PTH secretion by the parathyroid gland.

Distal tubule phosphate handling is less well understood. PTH increases phosphate absorption in the distal tubule, but the mechanisms by which this occurs are unknown.  Renal phosphate excretion can also be increased by the administration of loop diuretics.

PTH and vitamin D were previously the only recognized regulators of phosphate metabolism. However, several novel regulators of mineral homeostasis have been identified through studies of serum factors associated with phosphate wasting syndromes such as oncogenic osteomalacia and the hereditary forms of hypophosphatemic rickets, have been discovered.

The first to be discovered was a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), a neutral endopeptidase mutated in the syndrome of X-linked hypophosphatemic rickets. The characteristics of this syndrome (ie, hypophosphatemia, renal phosphate wasting, low 1,25-dihydroxyvitamin D levels) and the fact that PHEX was identified as an endopeptidase suggested the possibility that PHEX might be responsible for the catabolism of a non-PTH circulating factor that regulated proximal tubule phosphate transport and vitamin D metabolism. A potential substrate for PHEX was subsequently identified as fibroblast growth factor 23 (FGF23).

Several lines of evidence support a phosphaturic role for FGF23.[12] Another syndrome of hereditary hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, is characterized by a mutation in the FGF23 gene that renders the protein resistant to proteolytic cleavage and, thus, presumably more available for inhibition of renal phosphate transport. Administration of recombinant FGF23 produces phosphaturia, and FGF23 knockout mice exhibit hyperphosphatemia.

The syndrome of oncogenic osteomalacia, characterized by acquired hypophosphatemic rickets and renal phosphate wasting in association with specific tumors, is associated with overexpression of FGF23. Interestingly, in this syndrome, overexpression of FGF23 is accompanied by 2 other phosphaturic agents, matrix extracellular phosphoglycoprotein (MEPE) and frizzled related protein-4. The roles of these 2 latter proteins and their relationship with FGF23 and PHEX are unknown.

The physiologic role of FGF23 in the regulation of phosphate homeostasis is still under investigation. FGF23 is produced in several types of tissue, including heart, liver, thyroid/parathyroid, small intestine, and bone tissue. The source of circulating FGF23 has not been conclusively established; however, the highest mRNA expression for FGF23 in mice is in bone.[13, 14] FGF23 production by osteoblasts is stimulated by 1,25 vitamin D.[13] Conversely, individuals with X-linked hypophosphatemic rickets show inappropriately depressed levels of 1,25 vitamin D due to FGF23-mediated suppression of 1-alpha hydroxylase activity.

Studies in patients with chronic kidney disease and end-stage renal disease found that FGF23 levels rose with decreasing creatinine clearance rates and increasing plasma phosphorus levels,long before elevations in serum PTH levels are detected. Klotho, a transmembrane protein synthesized in the kidney (predominantly in the distal nephron), is an essential cofactor for the effects of FGF23 on renal proximal tubule cells.[15] Inactivation or deletion of Klotho expression results in hyperphosphatemia and accelerated aging.

The relationship between these 2 functions of Klotho remains unknown. However, Klotho has demonstrable antioxidant, antifibrotic, and pro-survival effects throughout the body.[16]

A study also demonstrated that FGF23 levels rapidly decreased after kidney transplantation suggesting that FGF23 is cleared by the kidney.[17] Thus, residual FGF23 could contribute to the hypophosphatemia frequently seen in posttransplant patients. In healthy young men without renal disease, phosphate intake did not significantly increase FGF23 levels, suggesting that FGF23 may not play a role in acute phosphate homeostasis.[18]

One other family of phosphate-regulating factors is the stanniocalcins (STC1 and STC2). In fish, where it was first described, STC1 inhibits calcium entry into the organism through the gills and intestines. However, in mammals, STC1 stimulates phosphate reabsorption in the small intestine and renal proximal tubules and STC2 inhibits the promoter activity of the type 2 sodium phosphate cotransporter, while the effects on calcium homeostasis are of lesser magnitude. Very little is known about the clinical significance of these newly described mineral-regulating agents or about potential interactions with either the PTH-vitamin D axis or with the phosphatonin-PHEX system.


Any of the following three pathogenic mechanisms can cause hypophosphatemia:

Inadequate intake

Inadequate phosphate intake alone is an uncommon cause of hypophosphatemia. The ease of intestinal absorption of phosphate coupled with the ubiquitous presence of phosphate in almost all ingested food substances ensures that daily phosphate requirements are more than met by even a less-than-ideal diet.

Hypophosphatemia is most often caused by long-term, relatively low phosphate intake in the setting of a sudden increase in intracellular phosphate requirements such as occurs with refeeding. Intestinal malabsorption can contribute to inadequate phosphate intake, especially if coupled with a poor diet. Although generally not essential for adequate phosphate absorption, vitamin D deficiency can contribute to hypophosphatemia by failing to stimulate phosphate absorption in cases of poor dietary ingestion. Case reports also document patients developing hypophosphatemia due to excessive use of antacids, particularly calcium-, magnesium-, or aluminum-containing antacids.

Increased excretion

Increased excretion of phosphate is a more common mechanism for the development of hypophosphatemia. The most common cause of increased renal phosphate excretion is hyperparathyroidism due to the ability of PTH to inhibit proximal renal tubule phosphate transport. However, frank hypophosphatemia is not universal and is most often mild.

Increased excretion of phosphate can also be induced by forced saline diuresis due to the inhibitory effect of saline diuresis on all proximal renal tubule transport processes. Again, the degree of hypophosphatemia is generally minimal. Vitamin D deficiency not only impairs intestinal absorption, but also decreases renal absorption of phosphate.

Several genetic and acquired syndromes of phosphate wasting and associated skeletal abnormalities have been described. These include syndromes characterized by isolated proximal tubule phosphate wasting, such as the congenital or acquired rickets syndromes described previously, and Fanconi syndrome, in which phosphate wasting represents one component of a generalized proximal tubule dysfunction. Congenital Fanconi syndromes include Wilson disease and cystinosis, while acquired Fanconi syndrome can be seen with several medications, paraproteinemias, connective tissue disorders, and heavy metals.[19, 20, 21]

Shift from extracellular to intracellular space

This pathogenetic mechanism alone is an uncommon cause of hypophosphatemia, but it can exacerbate hypophosphatemia produced by other mechanisms. Clinical situations in which this mechanism is the major cause of hypophosphatemia are the treatment of diabetic ketoacidosis, refeeding, short-term increases in cellular demand (eg, hungry bones syndrome), and acute respiratory alkalosis.



United States

Exact figures are difficult to determine, mainly because phosphate measurements are often not obtained with routine laboratory studies and are determined only when the care provider has a high index of suspicion for hypophosphatemia. In the general population of hospitalized patients, hypophosphatemia is observed in 1-5% of individuals and is usually mild and asymptomatic. The percentage rises steeply in patients with alcoholism, diabetic ketoacidosis, or sepsis, in whom studies have reported frequency rates of up to 40-80%.

Hypophosphatemia has been reported in a significant number of patients following partial hepatectomy for transplantation (up to 55%), attributed to an increase in cell utilization due to regeneration of liver tissue.[22] Hypophosphatemia in this setting is associated with a favorable prognosis. Hypophosphatemia is also seen in approximately one third of hematopoietic cell transplantation, but, in this setting, it correlates highly with mortality.[23]

Hypophosphatemia occurs in a significant percentage of kidney transplant recipients (50-80%), in particular immediately after transplantation. In many patients it can persist for the life of the transplant. Hypophosphatemia has also been reported in association with the metabolic syndrome.[24]


The morbidity of hypophosphatemia is highly dependent on cause, duration, and severity.

Mild and transient hypophosphatemia is generally asymptomatic and is not accompanied by long-term complications.

Chronic hypophosphatemia that accompanies chronic phosphate deficiency can result in significant bone disease. This is seen most commonly in osteomalacia due to vitamin D deficiency, long-term antacid abuse, hereditary phosphate wasting syndromes, malnutrition, and tumor-induced osteomalacia. Frequently in these conditions, the hypophosphatemia is accompanied by significant bone pain, fracture rate, nephrocalcinosis, and renal insufficiency. In childhood phosphate wasting syndromes, long-term treatment with phosphate replacement frequently results in renal insufficiency and hyperparathyroidism.

Acute severe hypophosphatemia can manifest as widespread organ dysfunction. Hypophosphatemia in the ICU setting is associated with respiratory insufficiency due to impaired diaphragmatic contractility and depressed cardiac output due to decreased myocardial contractility that reverse with correction of the electrolyte abnormality.

Severe hypophosphatemia is also associated with rhabdomyolysis, cardiac arrhythmias, altered mental status, seizures, hemolysis, impaired hepatic function, and depressed white cell function. The newest recommendation for the use of aggressive insulin therapy in the ICU setting has the potential for increasing the frequency and severity of and the morbidity of hypophosphatemia. Another factor increasing the frequency and severity of hypophosphatemia is the widespread use of continuous therapies for the treatment of acute renal failure.

Because it has been theorized that hypophosphatemia in the early stages of sepsis may contribute to the development of new arrhythmias, Schwartz et al hypothesized that intravenous phosphorus replacement may reduce the incidence of arrhythmias in critically ill patients. In a study of 34 adult septic patients with hypophosphatemia, IV phosphorus replacement was associated with a significantly reduced incidence of arrhythmias when compared with 16 patients from previously published data (38% vs. 63%, P = 0.04).[25]

Saito et al noted that hypophosphatemia is a common complication in severely disabled individuals, related to frequent bacterial infections, refeeding following malnutrition, and valproate treatment for epilepsy. Because severe hypophosphatemia is life-threatening, serum phosphate levels should be closely monitored, according to the authors. In a study of 19 severely disabled patients, there were 25 episodes of hypophosphatemia. The causes included febrile illnesses (N = 17), refeeding syndrome (N = 4), and Fanconi syndrome (N = 3); one episode was not identifiable. Significantly increased C-reactive protein levels and reduced sodium levels were present during hypophosphatemia episodes.[26]

Race- and sex-related demographics

Hypophosphatemia has no race predilection except for the syndrome of X-linked hypophosphatemic rickets, which predominates in Caucasian populations.

Hypophosphatemia has no sex predilection except for the syndrome of X-linked hypophosphatemic rickets, which is seen in male children


Hypophosphatemia can occur in persons of any age. Acquired hypophosphatemia tends to occur in late adolescence to adulthood. Cases occurring in late adolescence are often related to eating disorders. With aging, hypophosphatemia is often related to alcoholism, tumors, malabsorption, or vitamin D deficiency.

The genetic syndromes of phosphate wasting manifest in infancy or childhood. These syndromes include the following:

Acquired hypophosphatemia tends to occur in late adolescence to adulthood. Cases occurring in late adolescence are often related to eating disorders. With aging, hypophosphatemia is often related to alcoholism, tumors, malabsorption, malnutrition, or vitamin D deficiency. Hypophosphatemia has been reported in up to 15% of geriatric patients undergoing refeeding.[27] Hypophosphatemia has also been reported in up to 35% of adult patients undergoing open heart surgery and is associated with prolonged mechanical ventilation, increased use of cardiovascular drugs, and prolonged hospitalization.[28]


Most patients with hypophosphatemia are asymptomatic. The history alone rarely alerts the physician to the possibility of hypophosphatemia. In cases of oncogenic osteomalacia or in some of the genetic causes of phosphate wasting, patients complain of bone pain and fractures. Otherwise, physicians must have a high index of suspicion and must be aware of the clinical conditions that might be complicated by hypophosphatemia.[29]

Symptoms of hypophosphatemia are nonspecific and highly dependent on cause, duration, and severity. Mild hypophosphatemia (ie, 2-2.5 mg/dL), whether acute or chronic, is generally asymptomatic. Patients with severe and/or chronic hypophosphatemia are more likely to be symptomatic. Weakness, bone pain, rhabdomyolysis, and altered mental status are the most common presenting features of persons with symptomatic hypophosphatemia.

Occasionally, patients with mild hypophosphatemia may complain of weakness. Whether the weakness is secondary to hypophosphatemia or is due to the underlying disorder causing the hypophosphatemia is not clear, however.

Acute mild hypophosphatemia commonly occurs with the treatment of diabetic ketoacidosis because of the sudden large doses of insulin used to treat the uncontrolled diabetes. However, mild hypophosphatemia is asymptomatic and rapidly reversed.

Mild hypophosphatemia can also occur after renal transplantation and can last years without any discernible symptoms.

Primary hyperparathyroidism is also associated with mild hypophosphatemia; however, the symptoms of hypercalcemia appear to be more prominent than those of mild hypophosphatemia.

Moderate degrees of hypophosphatemia are commonly observed in patients with the refeeding syndromes. Most commonly, these individuals have a history of long-standing alcohol use and chronic malnutrition, resulting in the development of total body phosphate depletion. When these patients are admitted to the hospital, their serum phosphate level is most often within the reference range. However, feeding stimulates insulin release, leading to a shift of phosphate from the extracellular to the intracellular compartment.

At times, the ensuing hypophosphatemia can be profound. Depending on the severity of the hypophosphatemia, the patient may complain of muscle weakness and generalized weakness or may develop the full-blown hypophosphatemic syndrome. In this particular clinical situation, if the practitioner does not have a high index of suspicion, the delirious state can be misinterpreted as delirium tremens.

The acute hypophosphatemic syndrome occurs most commonly in persons with chronic alcoholism, but it can also be observed in refeeding of patients who have eating disorders,[30] patients who have been starved for any reason, or patients who are receiving parenteral nutrition with inadequate quantities of phosphate replacement.[31]

Hypophosphatemia has been reported as a presenting feature in some patients with cannabinoid hyperemesis syndrome.[32]

Patients with chronic phosphate wasting syndromes frequently present with bone pain, muscle weakness, and skeletal disorders. In the genetic syndromes of renal phosphate wasting or acquired oncogenic osteomalacia, the serum phosphate level is generally moderately depressed. Symptoms are predominantly muscle weakness and bone pain or fractures.[33]

In short, symptoms alone rarely alert the physician to the possibility of hypophosphatemia. Recognizing that hypophosphatemia can complicate specific clinical conditions allows the physician to make this diagnosis. If considering the diagnosis of hypophosphatemia, the physician should attempt to elicit the following clinical clues to conditions associated with hypophosphatemia:


No physical signs are specific for hypophosphatemia. In fact, physical signs of mild hypophosphatemia are generally absent.

Chronic hypophosphatemia can be associated with short stature and evidence of rickets, with bowing of the legs, when caused by one of the genetically transmitted phosphate wasting disorders. In adults, chronic hypophosphatemia is more commonly associated with bone pain upon palpation.

Severe acute hypophosphatemia can have a variety of signs, including the following:

Myocardial contractility may be impaired from depletion of adenosine triphosphate (ATP), and respiratory failure due to weakness of the diaphragm has been described. The reduction in cardiac output may become clinically significant, leading to congestive heart failure, when the plasma phosphate concentration falls to 1.0 mg/dL (0.32 mmol/L).[36]

Acute hypophosphatemia superimposed upon preexisting severe phosphate depletion can lead to rhabdomyolysis. Although creatine phosphokinase elevations are fairly common in hypophosphatemia, clinically significant rhabdomyolysis has been described almost exclusively in alcoholics and in patients receiving hyperalimentation without phosphate supplementation.


The differential diagnosis of hypophosphatemia is most easily considered according to pathogenetic mechanisms. The following discussion conforms to this approach, but note that hypophosphatemia is frequently the result of more than one mechanism.

Inadequate intake

Inadequate ingestion can result from phosphate deficiency in the diet or from poor intestinal absorption. Hypophosphatemia due to inadequate intake is uncommon but should be strongly considered in certain patient populations, as follows:

Excessive losses

Phosphate wasting can result from genetic or acquired renal disorders. The genetic disorders generally manifest in infancy, when the children exhibit short stature and bone deformities.

Genetic disorders

Genetic disorders that cause phosphate wasting include the following:

X-linked hypophosphatemic rickets is characterized by short stature, radiographic evidence of rickets, and bone pain. Patients with this condition also may have calcification of tendons, cranial abnormalities, and spinal stenosis. In addition to hypophosphatemia, these patients have relatively low levels of 1,25 dihydroxyvitamin D-3, levels that are inappropriately low for the degree of hypophosphatemia.

The defective gene is PHEX, which encodes for a membrane-bound neutral endopeptidase.[39, 40] Present understanding of this disorder is that the inactive neutral endopeptidase is unable to cleave a circulating phosphaturic substance. Data suggest that this circulating substance might be FGF23. This results in impaired phosphate reabsorption by decreasing the sodium-phosphate cotransporter in the kidneys.

Autosomal dominant hypophosphatemic rickets has similar manifestations, with hypophosphatemia, clinical rickets, and inappropriately low levels of 1,25 dihydroxyvitamin D-3. The cause of this disorder is thought to be mutations of FGF23 that result in resistance to degradation, persistently high circulating levels of FGF23, and subsequent phosphaturia.

Hereditary hypophosphatemic rickets with hypercalciuria is a rare disorder characterized by hypophosphatemia, phosphate wasting, hypercalciuria, bone pain, muscle weakness, and high levels of 1,25 dihydroxyvitamin D-3. The cause of this disorder is an inactivating mutation in the type 2c sodium-phosphate cotransporter.

Vitamin D–resistant rickets is an autosomal recessive disorder. In type I, the defect is in renal 1-alpha-hydroxylation. Type II is characterized by end organ resistance to the effects of 1,25 dihydroxyvitamin D-3. These patients present in childhood with hypocalcemia, hypophosphatemia, hyperparathyroidism, rickets, bone pain, muscle weakness, and alopecia. The disease is caused by mutations in the vitamin D receptor that prevent normal responsiveness to circulating vitamin D-3.

Mutations in the type 2a sodium-phosphate cotransporter have been reported in some patients with hypophosphatemia and inappropriate urinary phosphate wasting associated with nephrolithiasis and/or osteoporosis.[1, 41]

Rarely, significant renal phosphate wasting is observed in patients with fibrous dysplasia/McCune-Albright syndrome, disorders that result from mutations in the alpha subunit of the stimulatory G protein. Excess production of FGF23 has been found in some of these patients.[42]

Acquired phosphate-wasting syndromes

Acquired phosphate wasting syndromes are of diverse etiologies, as follows:

Intracellular shift of phosphate

Several physiologic agents stimulate phosphate uptake from the extracellular environment into the cell. This phenomenon can exacerbate the hypophosphatemia caused by the previously described mechanisms and can result in profound hypophosphatemia. However, in some circumstances, the shift alone may be enough to produce hypophosphatemia, albeit of a milder degree.

Acute respiratory alkalosis or hyperventilation produces hypophosphatemia by stimulating a shift of phosphate into the cells. This mechanism is responsible for the hypophosphatemia observed with salicylate overdose, panic attacks, and sepsis. Extreme hyperventilation in normal subjects can lower serum phosphate concentrations to below 1.0 mg/dL (0.32 mmol/L), and it is probably the most common cause of marked hypophosphatemia in hospitalized patients. Less pronounced hypophosphatemia may occur during the increase in ventilation after the successful treatment of severe asthma.[53]

The effects of respiratory alkalosis are exacerbated by concomitant glucose infusions and may persist after hyperventilation ceases. Respiratory alkalosis also may be the precipitating factor in the hypophosphatemia-induced acute rhabdomyolysis that can occur in alcoholic patients.[54]

Other mechanisms are as follows:

Kidney transplantation

Hypophosphatemia is a common complication of kidney transplantation.[56] Tertiary hyperparathyroidism has long been thought to be the etiology, but hypophosphatemia can occur in patients with low parathyroid hormone (PTH) levels and can persist after high PTH levels normalize. Furthermore, even in the setting of normal allograft function, hypophosphatemia, and hyperparathyroidism, calcitriol levels remain inappropriately low following transplantation, suggesting that mechanisms other than PTH contribute to phosphate homeostasis.

FGF23 induces phosphaturia, inhibits calcitriol synthesis, and accumulates in chronic kidney disease. This factor has been suggested as a possible mediator of posttransplantation hypophosphatemia.[57] Dipyridamole enhances renal tubular phosphate reabsorption and has been shown to be effective in posttransplant hypophosphatemia in small studies.

Laboratory Studies

Serum phosphate, calcium, and magnesium

In addition to serum phosphate studies, serum calcium and magnesium studies can be helpful. High calcium levels coupled with low phosphate levels suggest primary hyperparathyroidism, while low calcium levels suggest vitamin D deficiency or malabsorption. Because of the many factors that regulate calcium independently of phosphate, serum calcium concentrations may be within reference ranges in either of these circumstances and thus cannot be used for a definitive diagnosis.

Low magnesium levels are also suggestive of poor nutrition. Serum potassium derangements, especially hypokalemia, may occur with certain hypophosphatemic conditions, such as diabetic ketoacidosis and alcoholism.

Serum albumin

Because almost half of serum albumin is bound to serum calcium, changes in serum albumin levels affect the total calcium concentration. Thus, in hypoalbuminemia, a decrease in albumin of 1 g/dL causes a fall in total calcium of approximately 0.8 mg/dL.

Intact parathyroid hormone and vitamin D levels

Primary hyperparathyroidism is very common, especially in elderly persons. Vitamin D deficiency is also very common, especially in geriatric or chronically ill persons. The excellent assays available for evaluation of parathyroid hormone (PTH) and vitamin D levels have simplified confirmation of the diagnosis of PTH and vitamin D disorders.

A high PTH level in the presence of high calcium and low phosphate levels is very suggestive of primary hyperparathyroidism. If the PTH level is high and the calcium and phosphate levels are low, secondary hyperparathyroidism is probable, perhaps due to intestinal malabsorption. The intestinal malabsorption could be due to isolated vitamin D deficiency or to a primary gastrointestinal disorder.

Other studies

An arterial blood gas study should be ordered if respiratory alkalosis is under consideration as a cause of hypophosphatemia.

Serum lactate, CBC with differential, and serum ammonia level, may be useful in selected patients to investigate some of the common causes of hypophosphatemia, such as sepsis and hepatic encephalopathy, which can cause respiratory alkalosis with subsequent hypophosphatemia.

At the current time, FGF23 levels are available only as a non-FDA-approved test and are in limited use. Levels of Klotho, Phex, or other mediators of phosphate wasting are not clinically available.

Tests for phosphate wasting

A 24-hour urine collection for phosphate can be performed if the question of phosphate wasting is unresolved. A fractional excretion of phosphate of greater than 15% in the presence of hypophosphatemia confirms the presence of renal phosphate wasting.

Phosphate wasting and subsequent hypophosphatemia can be due to proximal tubule disorders, such as Fanconi syndrome. To determine if the patient has a generalized proximal renal tubule disorder, urinalysis should be performed and serum bicarbonate, serum glucose, and serum uric acid levels should be measured.

Full-blown Fanconi syndrome consists of renal glycosuria, aminoaciduria, type II renal tubular acidosis, hypouricemia due to hyperuricosuria, and hypophosphatemia due to phosphate wasting. When Fanconi syndrome is present, the urinalysis demonstrates the presence of amino acids (proteinuria) and glucose. If the urine dipstick is positive for glucose at a time when the serum glucose concentration is less than 180 mg/dL, then renal glycosuria or renal glucose wasting is also present. Uric acid levels are also low, often less than 2 mg/dL. Evidence of mild nonanion gap metabolic acidosis is observed on the renal profile.

Imaging Studies

If a phosphate-wasting syndrome is suggested, then bone films to evaluate for osteopenia, osteomalacia, or hyperparathyroidism are indicated. Although plain bone films cannot yield histologic data, looser zones are very suggestive of osteomalacia. Erosions of the distal phalanges and clavicles and circular punched-out lesions in the long bones are highly typical of primary hyperparathyroidism.

Ultrasonographic images of the neck can help, at times, identify a parathyroid adenoma. A technetium Tc 99m sestamibi scan may be more useful. Uptake of the radioactive tracer has the advantage of being able to pick up ectopic parathyroid tissue.

Bone densitometry is also useful for assessing the chronicity and the severity of phosphate wasting. Chronic phosphate deficiencies result in significant decreases in bone density, while mild transient hypophosphatemia does not.

Mesenchymal tumors that can cause oncogenic osteomalacia have been discovered with the use of indium-111 octreotide scanning, computed tomography, or magnetic resonance imaging.

Histologic Findings

Most parathyroid lesions are adenomas. Occasionally, a carcinoma is found. Most of the tumors causing oncogenic osteomalacia are benign (eg, hemangiopericytoma).

Bone Biopsy

Bone biopsy is the only method for defining bone pathology. Hyperparathyroidism and osteomalacia may both have classic radiologic findings, but when the radiograph shows only osteopenia, bone biopsy findings help distinguish between these pathologies. The finding of osteomalacia directs the diagnostic studies toward vitamin D deficiency, malabsorption, or oncogenic osteomalacia. On the other hand, classic findings of hyperparathyroidism prompt the search for parathyroid disease.

Medical Care

Medical care for hypophosphatemia is highly dependent on three factors: cause, severity, and duration. Phosphate distribution varies among patients, so no formulas reliably determine the magnitude of the phosphate deficit. The average patient requires 1000-2000 mg (32-64 mmol) of phosphate per day for 7-10 days to replenish the body stores.

When a treatable cause of the hypophosphatemia is known, then treatment of that underlying cause is of paramount importance and is often curative. Examples include the following:

Oral phosphate supplements, although not curative, are useful for the treatment of the genetic disorders of phosphate wasting and can often normalize phosphate levels and decrease bone pain. Treatment considerations are as follows:

Parenteral phosphate supplementation is generally reserved for patients who have life-threatening hypophosphatemia or nonfunctional gastrointestinal syndromes. Treatment considerations are as follows:

The management of patients with hypophosphatemia can be divided into various subgroups based on the severity of the hypophosphatemia and the need for ventilation, as follows:

Vitamin D supplementation

Vitamin D supplementation is appropriate for patients with vitamin D deficiency. Most patients respond to oral vitamin D-2 supplements, commonly available in over-the-counter multivitamin preparations.

Because the kidneys are responsible for the final 1-alpha hydroxylation of vitamin D, patients with significant renal insufficiency may not be able to metabolize liver-derived 24 hydroxyvitamin D-3 to its active dihydroxy form. These patients benefit from oral 1,25 dihydroxyvitamin D-3 supplements. Because vitamin D enhances calcium and phosphate absorption, frequent monitoring of both is required.

FGF23 Antibody Treatment

Recently, FGF23 antibody treatment has become available for individuals with some genetic forms of hypophosphatemic rickets.[58] This exciting development is still limited in application but holds promise for the broader community of individuals with hypophosphatemia due to high FGF23 levels.

Surgical Care

Patients with primary hyperparathyroidism benefit from parathyroidectomy. For patients in whom parathyroidectomy is not feasible, treatment with the new calcium mimetic agents has shown demonstrable control of hyperparathyroidism. Patients with oncogenic osteomalacia are cured by excision of the tumor that is causing the phosphate wasting and relative vitamin D deficiency.


An endocrinologist might be helpful if the diagnosis of primary hyperparathyroidism is not readily apparent, especially to exclude the possibility of familial hypocalciuric hypercalcemia. In conjunction with a surgeon, an endocrinologist can help assess the patient for the different potential therapies for primary hyperparathyroidism and choose the best individual therapy.

A gastroenterologist may help in establishing a diagnosis of malabsorption and in pinpointing the cause. Input from this consultant can also be very useful in formulating the most effective therapy and patient education.

A nephrologist can help confirm the likelihood of phosphate wasting and can help assess the patient for causes of renal phosphate wasting.

A surgeon is required for parathyroidectomy or for removal of a tumor causing oncogenic osteomalacia.

A psychiatrist should be requested for patients with a self-imposed eating disorder such as anorexia or bulimia. These common disorders can be fatal and are often difficult to treat. Psychiatric intervention often requires years to effect a remission.


A regular diet generally provides all of the phosphate required for the day and more. For patients with phosphate wasting, high-phosphate diets (including dairy products, meats, and beans) should be encouraged, along with phosphate supplements. Cow’s milk, an excellent and accessible source of phosphate, contains 1 mg (0.032 mmol) of elemental phosphate per milliliter. Consumption of vitamin D–supplemented foods should also be encouraged.


For transient mild hypophosphatemia, no activity restrictions are necessary. For chronic phosphate wasting syndromes, the degree of bone disease is the best guide for assessing activity. Severe osteomalacia puts patients at high risk for fracture. Notably, these patients often have accompanying proximal muscle weakness and muscle pain that in and of themselves restrict activity. These patients with established osteomalacia should avoid high-impact activities and should practice fall precautions.

Medication Summary

The goals of pharmacotherapy are to increase serum phosphate levels, to reduce morbidity, and to prevent complications.

Potassium acid phosphate (Neutra-Phos-K)

Clinical Context:  PO preparations are available as sodium or potassium phosphate in cap or liquid form. Neutra-Phos packets contain 250 mg of phosphorus/packet. Tabs contain 250, 125.6, or 114 mg apiece. Liquid preparations are available as 250 mg/75 mL.

Potassium phosphates, IV

Clinical Context:  Contains 3 mmol/mL of phosphorus and 4.4 mEq/mL of potassium.

Sodium phosphates, IV

Clinical Context:  Contains 3 mmol/mL of phosphorus and 4 mEq/mL of sodium.

Class Summary

Phosphate salts are used to increase serum phosphate levels. Phosphorus is involved in many biochemical functions in the body and significant metabolic and enzyme reactions in almost all organs and tissues; it exerts a modifying influence on the steady state of calcium levels, a buffering effect on acid-base equilibrium, and a primary role in the renal excretion of hydrogen ion. For severe hypophosphatemia (< 1 mg/dL), use parenteral preparations of phosphate for repletion. IV preparations are available as sodium or potassium phosphate. Response to IV serum phosphorus supplementation is highly variable and can be associated with hyperphosphatemia and hypocalcemia. Infusion rate and choice of initial dosage is based on severity of hypophosphatemia and presence of symptoms. Closely monitor serum phosphate and calcium levels. For less severe hypophosphatemia (1-2 mg/dL), PO phosphate salt preparations can be used.

Ergocalciferol (vitamin D-2)

Clinical Context:  Requires conversion to active 1,25 dihydroxy cholecalciferol in kidneys. Administered PO.

Calcitriol (Calcijex, Rocaltrol)

Clinical Context:  Active form of vitamin D, 1,25 dihydroxyvitamin D-3. Use in patients with renal failure who are unable to convert inactive prohormone forms to active metabolite. Available in PO and parenteral form.

Doxercalciferol (Hectorol)

Clinical Context:  Requires hydroxylation in liver to be converted to an active vitamin D metabolite. May cause less toxicity than calcitriol with regard to calcium homeostasis. Predominantly used to treat secondary hyperparathyroidism of renal failure

Paricalcitol (Zemplar)

Clinical Context:  Vitamin D-3 analogue available in parenteral form and predominantly used to treat secondary hyperparathyroidism of renal failure, especially when calcitriol treatment has resulted in hypercalcemia. Appears to have a lesser effect on calcium and phosphorus metabolism than calcitriol. For this reason, it is not as useful as calcitriol for the treatment of hypophosphatemia.

Class Summary

Vitamin D enhances intestinal and renal absorption of phosphate. Can be administered in addition to phosphate supplements to increase serum phosphate and total body phosphate stores.

Cinacalcet (Sensipar)

Clinical Context:  This drug is available in oral form and has to be taken daily for desired effect. To monitor efficacy, the drug should be taken at the same time every day and the intact parathyroid hormone (iPTH) level should also be taken at the same time every time it is checked. The clinician needs to monitor also for the development of hypocalcemia.

Class Summary

This category of drug activates the calcium sensing receptor on parathyroid gland cells, thus diminishing the release of parathyroid hormone. These agents are useful for the control of hyperparathyroidism in patients who are unwilling to undergo surgery or who are suboptimal candidates for surgery.

Further Outpatient Care

For transient hypophosphatemia, no further evaluation is required. In some clinical situations, periodic determination of serum phosphate concentration may be required, for example, in phenytoin-induced vitamin D deficiency.

If a patient undergoes parathyroidectomy for hyperparathyroidism, calcium and phosphate levels should be monitored postoperatively to assess the adequacy of the procedure and to ensure that the remaining parathyroid tissue is adequate to maintain mineral balance. In the vast majority of cases of primary hyperparathyroidism, calcium and phosphate levels normalize virtually immediately postoperatively and remain stable thereafter.

For phosphate wasting syndromes, periodic monitoring of bone density and bone films can help in assessing the degree of end organ damage.

For hypophosphatemia due to eating disorders, continued outpatient counseling and monitoring for signs of malnutrition are required.

Further Inpatient Care

Follow-up phosphate determinations are helpful in establishing whether the patient has had a transient reversible episode of hypophosphatemia or a more chronic condition. Even in cases of established phosphate deficiency, most individuals respond readily to oral or parenteral phosphate repletion, and phosphate levels normalize within a few days. In contrast, phosphate wasting syndromes characteristically are refractory to vigorous supplementation.

If evidence of vitamin D deficiency is found, then the cause should be determined and corrected if possible. Management may include the following:

Phosphate deficiency may also result from eating disorders. In appropriate clinical circumstances, this possibility should be explored with the patient and counseling should be provided if necessary. An inability to eat an adequate diet because of socioeconomic circumstances, dental inadequacies, or swallowing difficulties should be investigated and addressed.

Phosphate deficiency due to congenital wasting disorders often leads to severe osteomalacia. Bone films are warranted to determine and assess the severity of osteopenia. In some cases, bone biopsy might be helpful in determining optimal treatment.

Acquired phosphate wasting syndromes should prompt a search for the cause, as follows:

Inpatient & Outpatient Medications

Phosphate supplements are available in capsule or powder form. Because intestinal absorption of phosphate is typically excellent, phosphate supplements administered twice a day are generally adequate.

Vitamin D supplements in the form of ergocalciferol (D-2) or 1,25 dihydroxyvitamin D-3 are appropriate for patients with vitamin D deficiency. For patients with renal insufficiency, the active 1,25 form is more appropriate.


Although severe hypophosphatemia can be a medical emergency, parenteral phosphate is available in all hospital formularies and is the treatment of choice for severe hypophosphatemia. Therefore, transfer to another facility is rarely, if ever, needed.


Patients with hypophosphatemia due to eating disorders such as anorexia or bulimia require counseling and dietary therapy.

Patients with hypophosphatemia due to nonpsychiatric eating disorders, such as those elicited by poor socioeconomic status, dental problems, or swallowing difficulties, should receive dietary counseling and monitoring. The patients should be educated about the necessity for a balanced diet and should be encouraged to ingest full nutritional supplements. Continued dietary follow-up care can help prevent further relapses.

Patients who have recurrent hypophosphatemia should be discouraged from ingesting large quantities of antacids because they bind intestinal phosphate and block absorption.


Complications of hypophosphatemia depend on severity and chronicity. Mild transient hypophosphatemia yields no complications. Studies in patients with diabetic ketoacidosis undergoing intensive insulin therapy show that they often develop mild hypophosphatemia during the course of therapy. However, the hypophosphatemia produces no discernible problems, and treatment with supplemental phosphate has no effect on recovery.

Moderate hypophosphatemia can lead to muscle weakness. This complication can be particularly important to recognize in the ICU, where hypophosphatemia can lead to respiratory muscle depression and impaired cardiac output. Treatment of hypophosphatemia in this setting can increase cardiac output and facilitate weaning from the ventilator. Moderate hypophosphatemia can also have consequences on renal function, specifically, mild metabolic acidosis and hypercalciuria.

The acute hypophosphatemic syndrome described in previous sections can have severe complications. Although all of the organ effects are reversible with treatment, the clinical picture is dramatic and potentially fatal if not recognized.

These patients can have seizures, delirium, coma, or focal neurologic findings. They develop heart failure, rhabdomyolysis, acute hemolysis, leukocyte dysfunction, and abnormal results from liver function tests. Heart failure, rhabdomyolysis, and hemolysis can produce acute renal failure because of poor flow and pigment damage. Leukocyte dysfunction increases susceptibility to infection. These patients can also exhibit platelet dysfunction, glucose intolerance, and metabolic acidosis.

Chronic hypophosphatemia due to phosphate wasting produces a predominantly bone pathology. In children, the resulting rickets leads to short stature and significant bony deformities associated with abnormal bone mineralization. Adults develop osteomalacia with accompanying severe bone pain and fractures.


The prognosis for a treatable and usually transient cause of hypophosphatemia is excellent. Discontinuation of antacids in cases of antacid abuse, ingestion of a normal diet in patients with eating disorders, or parathyroidectomy for patients with hyperparathyroidism are all examples of curable hypophosphatemia. In patients with acute liver failure, hypophosphatemia  is associated with a good prognosis, as it may represent cellular use of phosphorus during hepatocyte regeneration.[59, 60]

The prognosis for phosphate wasting syndromes is also largely dependent on the underlying cause. For hyperparathyroidism, parathyroidectomy is curative. For vitamin D deficiency (a combination of poor absorption and renal wasting), replacement of vitamin D is curative. On the other hand, X-linked hypophosphatemic rickets and vitamin – resistant rickets are only partially treatable with present medications and result in lifelong skeletal deformities.

Patient Education

Patients with inadequate ingestion of phosphate-containing foods or with excessive antacid ingestion benefit from dietary education.

Patients with vitamin D deficiency should be educated on the importance of maintaining a normal vitamin D balance.


Eleanor Lederer, MD, FASN, Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Society of Nephrology<br/>Received income in an amount equal to or greater than $250 from: Healthcare Quality Strategies, Inc<br/>Received grant/research funds from Dept of Veterans Affairs for research; Received salary from American Society of Nephrology for asn council position; Received salary from University of Louisville for employment; Received salary from University of Louisville Physicians for employment; Received contract payment from American Physician Institute for Advanced Professional Studies, LLC for independent contractor; Received contract payment from Healthcare Quality Strategies, Inc for independent cont.


Rosemary Ouseph, MD, Professor of Medicine, Director of Kidney Transplant, University of Louisville School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Christie P Thomas, MBBS, FRCP, FASN, FAHA, Professor, Department of Internal Medicine, Division of Nephrology, Departments of Pediatrics and Obstetrics and Gynecology, Medical Director, Kidney and Kidney/Pancreas Transplant Program, University of Iowa Hospitals and Clinics

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FASN, Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Disclosure: Nothing to disclose.

Additional Contributors

James W Lohr, MD, Professor, Department of Internal Medicine, Division of Nephrology, Fellowship Program Director, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Disclosure: Received research grant from: GSK<br/>Partner received salary from Alexion for employment.


Datinder Deo, MD Chief Fellow, Department of Nephrology, University of Louisville Hospitals

Disclosure: Nothing to disclose.

Deepak Mittal, MD Fellow, Department of Nephrology, University of Louisville School of Medicine

Disclosure: Nothing to disclose.

Snehal Patel, MD Fellow, Department of Nephrology, University of Louisville School of Medicine

Snehal Patel, MD is a member of the following medical societies: American College of Physicians, American Society of Nephrology, Kentucky Medical Association, and Renal Physicians Association

Disclosure: Nothing to disclose.


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