PHOSPHORUS

28

Physiology, Dietary Sources, and RequirementsJJB Anderson, University of North Carolina, Chapel Hill, NC, USA

r 2013 Elsevier Ltd. All rights reserved.

GlossaryFibroblast growth factor 23 (FGF 23) This newly

recognized hormone is synthesized by bone cells, namely

osteoblasts and osteocytes, to act on the renal tubules to

increase the secretion of phosphate ions into urine.

Hyperphosphatemia Elevated serum phosphate

concentration may contribute to arterial calcification and

chronic renal disease.

Parathyroid hormone (PTH) This hormone has a major

role in the regulation of serum calcium concentration by its

actions on bone and kidney.

Encyclopedia of Human

Phosphate additives Several types of phosphate salts are

used by the food industry to help maintain the physical

properties of foods, including preservation. These additives

are used in baked goods, meats, cola beverages, and other

processed foods.

Vitamin D The hormonal form of this nutrient or skin

biosynthesized molecule aids in calcium and Pi metabolism

by increasing the intestinal absorption of these ions, and

thereby it enhances bone formation.

Introduction

The consumption of a diet sufficient in phosphorus, in the

form of phosphate salts or organophosphate molecules, is

critical for the support of human metabolic functions. Too

much phosphorus, in relation to too little dietary calcium,

may contribute to bone loss, and too little phosphorus along

with too little dietary calcium may not adequately maintain

bone mass, especially in the elderly period of life. Therefore,

under normal dietary conditions, dietary phosphorus is suf-

ficient for numerous metabolic functions; it is only when too

much or too little phosphorus is ingested that skeletal prob-

lems may arise. Much like calcium, elderly subjects need to

consume sufficient amounts of phosphorus, like calcium, in

order to maintain bone mass and density. Excess phosphorus

may contribute to inappropriate elevations of parathyroid

hormone (PTH) and bone loss. It is not yet clear where most

elderly subjects fall along this continuum of intake patterns.

This review delves into the mechanisms by which phosphate

ions impact on calcium metabolism and skeletal integrity.

Calcium–Phosphate Interrelationships

Phosphorus in the form of phosphate ions is essential for

numerous metabolic and structural functions. Phosphate

metabolism is intricately linked to that of calcium because

calcium-regulating hormones, i.e., PTH and 1,25-dihydroxy-

vitamin D, also have direct or indirect effects on phosphate

homeostasis by virtue of their actions on bone, the small

intestine, and the kidneys. Adequate phosphorus and

calcium intakes are needed not only for skeletal growth and

maintenance, but also for many cellular roles, such as energy

production, i.e., adenosine triphosphate (ATP). Phosphate

ions are incorporated in many organic molecules, including

phospholipids, creatine phosphate, nucleotides, and nucleic

acids.

Dietary Sources of Phosphorus

Phosphorus, as phosphates, is especially rich in animal

products, including meats, fish, poultry, eggs, milk, cheese,

and yogurt. Lesser amounts of phosphorus can also be ob-

tained from cereal grains and many vegetables, including

legumes. Because of the abundance of phosphorus in the food

supply, deficiency is highly unlikely except perhaps late in life

when some elderly individuals consume little food. (An ex-

tremely rare deficiency disease, hypophosphatemic rickets,

occurs in infants because of inadequate phosphorus intakes.)

In the USA mean phosphorus intakes approximate

1200–1500 mg per day in adult males and 900–1200 mg per

day in adult females. Daily phosphate intakes have increased

as a result of phosphate additives in processed foods and cola

beverages. Since no federal requirements exist to list quantities

of added phosphates on labels of foods and cola beverages,

the actual additional amounts consumed can only be esti-

mated. Phosphate additives used by the food industry may be

found in baked goods, meats, cheeses, and other dairy prod-

ucts. A conservative estimate is that most adults in the USA

consume an extra 200–350 mg of phosphorus each day from

these sources and cola beverages. Therefore, the total phos-

phorus intakes for men and women are increased accordingly.

Because typical daily calcium intakes of males are 600–800 mg

Nutrition, Volume 4 http://dx.doi.org/10.1016/B978-0-12-375083-9.00225-7

Table 1 Calcium and phosphorus composition of common foods

Food category Phosphorus mg per serving Calcium mg per serving Ca:P ratio (wt:wt)

Milk, eggs, and dairyCheddar cheese, 1 oz 145 204 1.4Mozzarella cheese – part skim, 1 oz 131 183 1.4Vanilla ice milk, 1 cup 161 218 1.4Low-fat yogurt, 1 cup 353 448 1.3Skim milk, 8 oz 247 301 1.2Skim milk – lactose reduced, 8 oz 247 302 1.2Vanilla ice cream, 1 cup 139 169 1.2Vanilla soft-serve ice cream, 1 cup 199 225 1.1Egg substitute, frozen, 1/4 cup 43 44 1.1Chocolate pudding, 5 oz 114 128 1.1Processed American cheese, 1 oz 211 175 0.8Lowfat cottage cheese, 1 cup 300 200 0.7Processed cheese spread, 1 oz 257 129 0.5Instant chocolate pudding, 5 oz 340 147 0.4Soy milk, 8 oz 120 10 0.1

Table 2 Approximate percentage (%) distributions of calcium andphosphate in blood

Serum fraction Calcium (%) Phosphate (%)

Ionic 50–55 55–60Protein-bound 45–50 10–13Complexed 0.3–0.6 30–35

Phosphorus: Physiology, Dietary Sources, and Requirements 29

and of females are 500–650 mg, the Ca:P ratios decrease from

roughly 0.5–0.6 to less than 0.5 when the additive phosphates

are included. As shown later, a chronic low Ca:P dietary ratio

may contribute to a modest nutritional secondary hyperpara-

thyroidism. Table 1 gives representative values of calcium and

phosphorus in selected foods and the calculated Ca:P ratios.

Only dairy foods (except eggs), a few fruits, and a few vege-

tables have Ca:P ratios that exceed 1.0.

Recommended intakes of phosphorus in the US have been

set at 700 mg per day for men and women based on the intake

required to maintain serum phosphorus in the normal range.

Intestinal Absorption of Phosphates

Because phosphate ions are readily absorbed by the small

intestine, i.e., at efficiencies of 65–75% in adults and even

higher in children, a prompt increase in serum inorganic

phosphate (Pi) concentration follows within an hour after

ingestion of a meal begins. (Calcium ions or Ca2þ are much

more slowly absorbed.) The increased serum Pi HPO42�� �

concentration then depresses the serum ionic calcium con-

centration, which in turn stimulates the parathyroid glands to

secrete (and synthesize) PTH. PTH acts on the kidneys to in-

crease urinary phosphate excretion which reduces serum

phosphate and ionic calcium concentrations to their normal

homeostatic set-points. Recent reports suggest that an ele-

vation of serum Pi ionic concentration directly influences PTH

secretion independently of hypocalcemia. These meal-associ-

ated fluctuations in Pi and Ca2þ are part of normal physio-

logical adjustments that occur typically three or more times a

day. Serum phosphate concentrations also display a circadian

rhythm

Pi ions are thought to be absorbed in the small intestine

primarily by transcellular mechanisms that involve cotran-

sport with cations, especially sodium (Naþ ). These mech-

anisms account for the rapid uptake of Pi ions in blood within

an hour after ingestion of a meal. The blood concentration of

Pi is less tightly regulated than the serum calcium concen-

tration. Wider fluctuations in serum Pi concentrations reflect

both dietary intakes and also cellular releases of inorganic

phosphates.

Most Pi absorption in the small intestine occurs in-

dependently of the hormonal form of vitamin D. The reported

role of the of 1,25-dihydroxyvitamin D in intestinal Pi trans-

cellular absorption is somewhat unclear because of the nor-

mally rapid influx of Pi ions after a meal, but this hormone

may enhance the late or slower uptake of Pi ions. Paracellular

passive absorption of Pi ions may also occur, but the evidence

for this is limited.

Phosphate Homeostatic Mechanisms

The blood concentrations of Pi ions are higher early in life

and then decline gradually until late life. Normal ranges for

adults are from 2.7–4.5 mg dl�1 (0.87–1.45 mmol l�1). The

percentage distribution of the blood fractions of phosphorus

compared to those of calcium are given in Table 2. The

homeostatic control of this narrow concentration range of

Pi is maintained by several hormones, including PTH,

1,25(OH)2vitamin D, calcitonin, insulin, glucagons, and

others, but the control is never as rigorous as that of serum

ionic calcium. In contrast to calcium balance that is primarily

regulated in the small intestine by 1,25(OH)2vitamin D, Pi

balance is mainly regulated by the phosphaturic effect of PTH

on the kidney, primarily the proximal convoluted tubule. In

this sense, Pi regulation is less critical than that of calcium,

which may result from the presence of multiple stores of

this ion distributed throughout the body, i.e., bone, blood,

intracellular compartments. Compared to the highly tight

30 Phosphorus: Physiology, Dietary Sources, and Requirements

regulation of serum ionic calcium, serum phosphate con-

centration is less tightly regulated

A major regulator of Pi is PTH which has several roles: it

blocks renal tubular Pi reabsorption following glomerular

filtration; it increases bone resorption of Pi (and calcium

ions); and it enhances intestinal Pi absorption (and calcium

absorption) via the vitamin D hormone, 1,25(OH)2vitamin D.

Other hormones have more modest effects on serum Pi

concentration.

New understandings are emerging on the role of a new

phosphotonin hormone that helps to lower the serum phos-

phate concentration when elevated. The actions of fibroblast

growth factor 23 (FGF 23), secreted by bone cells, reduce both

renal tubular reabsorption and intestinal phosphate ab-

sorption of phosphate ions which may lessen the need for

PTH, the hormone generally considered most critical for the

renal elimination of excessive serum phosphate ions. The roles

of these two hormones in the reduction of serum phosphate

need to be considered in terms of net calcium retention and

the maintenance of BMD by human subjects. FGF 23 also

reduces the renal production of 1,25(OH)2vitamin D and,

therefore, it impacts intestinal calcium absorption. An elevated

FGF 23 concentration has been associated with cardiovascular

diseases, and if this is the case, especially in elderly subjects,

then concentration of this hormone may prove to be a useful

biomarker in assessing CVD and osteoporosis risk.

Functional Roles of Phosphates

Several major roles of Pi ions have been briefly noted, i.e.,

intracellular phosphate groups for cellular energetics and

biochemical molecules as well as for the skeleton and teeth

(structures). Other important functions also exist. For ex-

ample, in bone tissue phosphates are critical components of

hydroxyapatite crystals and they are also considered triggers

for mineralization after phosphorylation of Type I collagen in

forming bone. Serum phosphates, HPO42� and H2PO4

�, also

provide buffering capacity that helps regulate blood pH and

also cellular pH.

Considerable cellular regulation occurs through the phos-

phorylation or dephosphorylation of Pi ions under the control

of phosphatase enzymes, including protein kinases. These cell

regulartory roles of Pi ions coexist with regulatory functions

involving calcium ions, but Pi ions are much more widely

distributed within cells and cell organelles than Ca ions.

Insulin affects Pi ions by increasing their intracellular up-

take, though temporarily, for the prompt phosphorylation of

glucose. Insulin may also influence the use of Pi ions when

insulin-like growth factor-I (IGF-I) acts to increase tissue

growth or other functions. The broad uses of Pi ions in

structural components, energetics, nucleic acids, cell regu-

lation, and buffering leaves an overall generalization that these

versatile yet critical ions support life.

Phosphate in Health and Disease

Phosphate balance in adults remains zero or slightly positive,

because of the effective homeostatic action of PTH on its target

organs that link the maintenance of serum concentrations of

both phosphate and calcium ions. In late life, however, in-

testinal phosphate absorption decreases and the serum phos-

phate concentration declines (but remain typically within the

normal range), which reflect a slightly negative balance as long

as renal function remains normal. These declines, which may

partly be related to lower phosphorus consumption by the

elderly, may contribute to disease, especially to increased bone

loss or more severe osteoporosis. Typically these changes in Pi

balance are also accompanied by similar changes in calcium

balance. Too little dietary phosphorus, along with too little

dietary calcium, may be determinants of low bone mass and

density and, hence, increased bone fragility. The usual scenario

invoked to explain osteoporosis in old age, however, is that

too little dietary calcium in the presence of adequate dietary

phosphorus stimulates an increase in PTH secretion and,

hence, bone loss (Figure 1).

Four human conditions that involve abnormal Pi homeo-

stasis need explanation.

Ageing and Renal Function

The serum concentration of Pi increases with a physiological

decline in renal function associated with aging and also with

renal disease when glomerular filtration rate (GFR) falls below

30 ml min�1. Healthy individuals excrete about 67% of their

absorbed phosphate via the urine, and the remainder via the

gut as endogenous secretions. As the glomerular filtration

capacity of the kidneys declines, the serum Pi concentration

increases and more Pi is retained by the body. PTH secretions

increase but the typical serum PTH concentrations, though

elevated, remain within the upper limits of the normal range,

at least for a decade or so. Thereafter, however, serum Pi and

PTH both continue to climb as renal function declines and

increased rates of bone turnover lead to measurable bone loss.

This situation is probably affecting millions in the US each

year as they enter the 50s and proceed into the 60s; in the USA

many of these individuals are overweight or obese and have

the metabolic syndrome which may negatively impact renal

function. As the syndrome worsens, many of these individuals

will progress to chronic renal failure and renal secondary

hyperparathyroidism (see section on Nutritional secondary

hyperparathyroidism).

Nutritional Secondary Hyperparathyroidism

This mild condition has not been fully assessed in any lon-

gitudinal studies lasting as long as one year. The initiating

event is a chronic low calcium and high phosphorus intake

(low Ca:high P ratio) that leads to a chronic elevation of

serum PTH. Elevations in PTH stimulate osteoclastic bone

resorption and declines in bone mass and density. This con-

dition has only been studied experimentally using human

subjects for 28 days, but the chronic rises in PTH and vitamin

D hormone suggest that even a lowering of the Ca:Pi ratio

below 0.5, in this study to B0.25, resulted in adverse effects.

Longer studies are needed to determine if bone losses occur

under this chronic dietary regimen.

Dietary intake1400 mg

Pi

Intestinal

Intestinal

absorption

secretion

1100 mg

200 mg

Gut

Stool500 mg

1400 mg = 500 + 900 mg(Input) = (Output)

Net balance = 0

Bloodplasma

Pi

~4 mg dl−1

6100 mg

Urine900 mg

Kidneys

7000 mgBone

Influx5000 mg

5000 mgEfflux

Figure 1 Phosphorus homeostasis and balance. The intestine, kidneys, and bone are organs involved in phosphate homeostasis. Fluxes ofphosphate ions between blood and these organs are shown. Note the high fluxes in and out of bone each day. To convert phosphorus valuesfrom g to mmol, multiply by 32.29; from mg dl�1 to mmol l�1, multiply by 0.3229. Steps enhanced by parathyroid hormone. Reproduced withpermission from Anderson JJB, Sell ML, Garner SC, and Calvo MS (2001) Phosphorus. In: Bowman BA and Russell R (eds.) Present Knowledgein Nutrition, 8th edn., p. 282. Washington, DC: International Life Sciences Institute Press.

Phosphorus: Physiology, Dietary Sources, and Requirements 31

Renal Secondary Hyperparathyroidism

The true secondary hyperparathyroidism of chronic renal

failure (CRF) has been extremely difficult to treat by clinicians

because of high Pi and PTH concentrations. Traditional

treatment includes the use of binders (chemical) to prevent Pi

absorption from the small intestine. In recent years a calcium-

sensing receptor (CaR) in the parathyroid glands has been

identified and drugs are being developed that will trick the

CaR into thinking that serum calcium is normal, rather than

depressed, thereby reducing PTH secretion. A reduction in

PTH then helps in the conservation of bone tissue, since bone

loss is such a severe problem of CRF patients.

Abnormal Bone Formation in Arterial Walls

A pathologic role for phosphate ions in the initiation of bone

matrix formation and subsequent mineralization associated

with established atherosclerotic plaque has recently been un-

covered. The arterial walls and heart valves have long been

known to develop true bone at these inappropriate loci, but the

mechanism remains elusive. Excessive calcium ions are also

taken up to help bone generation at these abnormal sites. In-

appropriate arterial bone, which occurs mainly in older adults,

may increase the risk of cardiovascular diseases and death.

Conclusions

The general view of dietary phosphorus, supplied in foods as

phosphates, is that too much relative to calcium skews the Ca:P

ratio to much less than 0.5. An another view, however, has

been emerging that suggests that many elderly subjects,

especially women, have very low phosphorus intakes in add-

ition to low calcium intakes and that they may benefit

from increased consumption of both calcium and phosphate

from foods and supplements. In dietary trials designed to re-

duce fractures, especially nonvertebral fractures, of elderly

women and men, calcium plus vitamin D have been the

treatments, but at least one trial that used calcium phosphate

plus vitamin D has shown significant reduction in fractures

over 18 and 36 months of follow-up. Further studies are nee-

ded to target the role of phosphate ions in reducing fractures

among the elderly.

Further Reading

Anderson JJB, Sell ML, Garner SC, and Calvo MS (2001) Phosphorus. In: BowmanBA and Russell R (eds.) Present Knowledge in Nutrition, 8th edn. Washington,DC: International Life Sciences Institute Press.

Bergwitz C and Juppner H (2010) Regulation of phosphate homeostasis by PTH,vitamin D, and FGF 23. Annual Review of Medicine 61: 91–104.

Brot C, Jorgensen N, Jensen LB, and Sorensen OH (1999) Relationships betweenbone mineral density, serum vitamin D metabolites and calcium: Phosphorusintake in healthy perimenopausal women. Journal of Internal Medicine 245:509–516.

Calvo MS, Kumar R, and Heath HH III (1990) Persistently elevated parathyroidhormone secretion and action in young women after four weeks of ingestinghigh phosphorus, low calcium diets. Journal of Clinical Endocrinology andMetabolism 70: 1340–1344.

Calvo MS and Park YM (1996) Changing phosphorus content of the U.S.diet: Potential for adverse effects on bone. Journal of Nutrition 126:1168S–1180S.

32 Phosphorus: Physiology, Dietary Sources, and Requirements

Demer LL and Tintut Y (2008) Vascular calcification: Pathobiology of a multifaceteddisease. Circulation 117: 2938–2948.

Garner SC (1996) Parathyroid hormone. In: Anderson JJB and Garner SC (eds.)Calcium and Phosphorus in Health and Disease, pp. 157–175. Boca Raton, FL:CRC Press.

Harnack L, Stang J, and Story M (1999) Soft drink consumption among USchildren and adolescents: Nutritional consequences. Journal of the AmericanDietetic Association 99: 436–441.

Institute of Medicine (1997) Food and Nutrition Board. Dietary Reference Intakes:Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. Washington, DC:National Academy Press.

Lau WL, Festing MH, and Giacelli CM (2010) Phosphate and vascular calcification:Emerging role of the sodium-dependent phosphate co-transporter PiT-1.Thrombosis and Haemostasis 104: 464–470.

Quarles LD (2008) Endocrine functions of bone in mineral metabolism regulation.Journal of Clinical Investigation 118: 3820–3828.

Ritter CS, Martin DR, Lu Y, Slatopolsky E, and Brown AJ (2002) Reversal ofsecondary hyperparathyroidism by phosphate restriction restores parathyroidcalcium-sensing receptor expression and function. Journal of Bone and MineralResearch 17: 2206–2213.

Slatopolsky E, Dusso A, and Brown A (1999) The role of phosphorus in thedevelopment of secondary hyperparathyroidism and parathyroid cell proliferationin chronic renal failure. American Journal of Medical Sciences 317: 370–376.

Uribarri J and Calvo MS (2003) Hidden sources of phosphorus in the typicalAmerican diet: Does it matter in nephrology? Seminars in Dialysis 16:186–188.

Wyshak G (2000) Teenaged girls, carbonated beverage consumption, and bonefractures. Archives of Pediatric and Adolescent Medicine 154: 610–613.