Chapter 5. Calcium and Phosphorus
Calcium and phosphorus appear most abundantly in the crystalline matrix of bone.
There are, however, other functions for these two macrominerals. Calcium is a major
membrane stabilizer, regulator and activator of muscle contraction and cell signaling.
Phosphorous is more commonly seen as phosphate in proteins, carbohydrates, fats and nucleic
acids.
CALCIUM
History and Early Insights
The word calcium is derived from the Latin word calx or calcis meaning “lime”,
reflecting early usage of calcium oxide or lime by the Romans. The element calcium was
isolated and named by Sir Humphrey Davy in 1808, who used electrolysis of a mixture of
mercuric acid lime to separate the calcium. One of the first Insights into the biological function
of calcium other than bone structure came through studies by Sydney Ringer who showed that
withdrawing calcium from a bathing solution caused a frog heart to cease beating.
Chemical Properties
Calcium is an alkaline earth metal with an atomic number of 20 and atomic weight of 40.
It has only a +2 oxidation state, a property it shares with magnesium and zinc. In nature
calcium occurs most commonly as limestone (CaCO3), gypsum (CaSO4 x 2H2O) or fluorite
(CaF2). With an ionic radius of 0.99 nm, calcium ions are nearly one and a half times the size of
magnesium ions. Typical of alkaline earth metals, the outer electrons in the calcium ions
occupy s and p orbitals. Loss of the two 4s electrons upon ionization gives calcium a highly
stable closed shell configuration more typical of sodium or potassium ions. Because its lacks 3d
electrons, Ca2+ behaves more like a spherical ion and as such its complexes lack coordinate
covalent bonding and a well defined spatial geometry with regular symmetry and color. Its
coordination number can be greater than 7, indicative of a large ion that can form multiple
metal-ligand interactions. Complexes of calcium with organic molecules tend to be
intermediate in binding strength as compared to transition metals such as zinc. The binding is
selective tending to favor carbonyl and alcohol groups. More unique to calcium ions, not
shared by magnesium or zinc, is the ability to bind to multiple centers at once, thus allowing
calcium to serve as a bridging ion or cross-linking agent , properties that are essential to its role
in membrane rigidity, permeability and viscosity as well as cell signaling in response to
hormone activation.
Solubility considerations
The salts of calcium have moderate solubility in water. Indeed, the concentration of
free ion in the cytosol and extracellular fluid is tightly controlled. This applies to calcium in
intracellular compartments as well as extracellular fluid where free ion concentrations
approaches 10-7 and 10-3 M, respectively. Its important to realize that there are mechanisms in
place to maintain free calcium at concentration that will allow crystallization with phosphates
to form bone or other mineral precipitates on the one hand as well as allow calcium to
penetrate cell membranes as a free ion to access internal sites. This delicate balance between
crystalline and free calcium is maintained by careful control of free calcium ion by transporters,
pumps, channels, and binding proteins. Upsetting the balance is characterized by calcium
deposits in arteries, gall bladder, kidney, etc. all reflecting a loss in controlling the free ion.
Disrupting the delicate balance further leads to cell death through a calcium-induced apoptosis.
Analysis of Calcium
Detection and quantification of calcium in biological fluids have relied on a series of
sensitive and specific tests. Table X.1 shows procedures and their sensitivities.
Procedure
Sensitivity
1.AtomicAbsorption Spectrometry (AAS).
2. Fluorescent Dyes.
3. Green Fluorescent Protein
4. Neutron Activation
5. Bone Mineral Density
6. Radio isotopes
Biochemical Properties
Without question, calcium is the most abundant mineral in the body. The average adult
human has about 1 kg of calcium of which nearly 99% is in bones and teeth. Serum and cells
account for 0.1% and 1% of the body load, respectively. Bone thus serves as a major reservoir of
calcium releasing calcium into the serum in response to low serum levels as well as storing
calcium when in excess. Hydroxyapatite [Ca10(PO4)6(OH)2 ], a calcium-phosphate complex, is
the major building block of vertebrate bones and teeth and most prominent calcium complex in
the system
Supporting endoskeleton is not the only important function of calcium. Calcium takes
both active and passive roles in a series of regulatory roles listed in Table X.1. The passive
functions highlight non-regulatory roles whereas active implies functions that are controlled by
or triggered by the presence of calcium ions. The latter include serving as cofactors for
enzymes and cell signaling agents.
Enzyme Cofactors
Calcium is a cofactor for a number of enzymes that catalyze specific reactions. Table X.2
provides of list of some of the more prominent ones and their location within the system as
well as their biochemical function.
Table X.1. Non-structural roles of calcium in biology
Passive Functions
Enzyme cofactor (lipases, hydrolases)
Blood clotting cascade
Active Functions
Relaxation and constriction of blood vessels
Cell aggregation
Muscle protein contraction
Cellular protein turnover
Hormone secretion
Nervous impulse transmission
Intracellular trafficking
Cell signaling
Genetic expression
Apoptosis
Table x.4. Enzymes dependent on calcium for function
Enzyme
Location
Function
Phospholipase A2
Lipase
Thermolysin
Trypsin
intestine
intestine
bacteria
duodenum
acylphospholipid hydrolysis
triacylglycerol hydrolysis
protein hydrolysis
protein digestion
Calcium-Binding Proteins
In addition to enzymes, there are binding protein specifically designed to transport or
store calcium ion or take part as calcium-dependent regulators. These protein tend to serve as
buffers between the free ion
Table x.3. Calcium-binding proteins
Protein
Function
annexins
calbindin
calmodulin
calpains
gla proteins
calcium ATPase
troponin C
parvalbumin
calnexin
cell adhesion
calcium absorption
enzyme regulator
protease activators
blood clotting
cellular calcium efflux
muscle calcium action
calcium ion buffer
glycoprotein folding
Annexins: A family of mainly intracellular proteins, annexins are found in fungi, plants and
animals but are notably absent in bacteria. They function in binding phospholipids in the cell
membrane and in so doing determine the overall architecture of the cell. Annexins also take
part in dynamic changes at the membrane surface such as formation of vesicles for import.
Calcium ions are needed for the connecting points with the phospholipids bilayer, which is
reciprocated by having the annexins makeup the basic structure of the calcium channel in the
membrane.
Calbindin: Transport of calcium ions through the cytosol occurs mainly while attached to
calbindin. The level of calbindin in the cell, therefore, determine the amount of intestinal
calcium absorbed . Synthesis of calbindin is under the control of vitamin D, which suggests a
primary action of the vitamin in calcium absorption is to provide more calbindin for transcellular
movement of calcium ions.
Calmodulin: Calcium ions are known to stimulate biological processes. The ion does not act
alone, but as a complex with proteins. Calmodulin is basically a calcium ion sensing protein
which when saturated can bind as many of four calcium ions. In executing its action,
calmodulin provide calcium ions to enzymes that have the capacity to modulate the calcium ion
levels in the cells. Generally calmodulin is considered a specific type of subunit in the
multisubunit complex.
Calpains: Calcium ions are known to stimulate the activity of certain protease enzymes. Early
recognition of this action led to the discovery of a series of calcium-binding proteins that were
the activating factor. Calpains have since been shown through genetic sequence similarity to
be a family of calcium-dependent activating proteins that target protease enzymes with the
amino acid cysteine at the active site and hence are classified as cysteinyl proteases. Its
important to note that calpains regulate the activity of these enzymes and do not take part in
the catalytic activity directly.
Gla Proteins: A unique function of vitamin K is the synthesis, through a post-translational
modification, of proteins that contain an addition –COOH group attached to select glutamate
residues (Fig. X.1). With the modification the glutamate is referred to as carboxylglutamate,
abbreviated gla, The tandem carboxyl groups in gla are ideally suited to engage calcium ions.
Gla proteins, therefore, make up the vitamin K dependent and calcium-dependent component
of the blood clotting mechanism and otherwise.
Calcium ATPase: ATPases represent a large class of membrane-bound enzymes that serve as
pumps for moving ions across cell membranes against concentration gradients. Calcium ions
require these energy driven pumps to drive calcium ions out of a cell following a response to a
signaling agent such as a hormone. The action effectively shuts off the response by restoring
the very low calcium concentration within the cytosol. Failure to do so could cause cell death
through apoptosis.
Troponin C: Troponin C and the other troponins mediate calcium action in muscle contraction.
The protein along with tropomyosin is localized within the actin filament. Troponin C has three
subunits, one of which Troponin I (TnI) inhibits muscle contraction by blocking the ATPase
enzyme. When calcium is present the inhibition is suppressed, which allows the enzyme to
provide the energy for the muscle to contract.
Parvalbumin: This calcium-binding protein is present in skeletal and heart muscle and brain. In
the brain the parvalbumin is mainly within neurons that respond to the neurotransmitter
gamma-amino butyric acid (GABA). As an extension of the neuronal role, parvalbumin is also
present in endocrine tissue. The function of paralbumin has not been clarified, but its actions
are linked to the ability of the protein to sequester calcium ions internally and hence lower
calcium action on other systems.
Calnexin: This calcium-binding protein is associated with the endoplasmic reticulum. Its
function is to monitor the folding of glycoproteins, acting as chaperone or surveillance factor.
Nutritional Properties
Calcium’s requirement in the diet predictably varies with age, gender, and physiological
state. An adult human male and female between the ages of 19 and 50 requires about 1 gram
of calcium per day. Adults over 50 require 1.2 g per day. As noted in Table X.2, calcium needs
Life Stage
Age
Males
Females
(mg/day)
(mg/day)
____________________________________________________
Infant
0-6 months
210
210
Infant
0-6 months
270
270
Children
1-3 years
500
500
Children
4-8 years
800
800
Children
9-13 years
1,300
1,300
Adolescent
14-18 years
1,300
1,300
Adult
19-50 years
1,000
1,000
Adult
51+ years
1,200
1,200
Pregnant
18 years and younger
1,300
Pregnant
19+ years
1,000
Lactating
18 years and younger
1.300
Lactating
19+ years
1,000
in younger adults increase with pregnancy and lactation. Part of the increase reflects needs of
the mother whose bone growth is still progressing as well as calcium set aside for neonate
consumption. The final stages of bone growth tends to reach a climax early in the second
decade of life. Older adults, both male and female, also show an enhanced need for calcium,
owing perhaps to alterations in bone metabolism with aging and the greater likelihood of bone
loss in senior years.
Source of dietary calcium are listed in Table X.3. Those richest in calcium meet the daily
requirement in about 200 grams of the food item. Included as rich sources are cheese and soy
flower. Dairy products have one third less calcium per weight and fruits provide less than one
third per weight of calcium.
Table x.2. Food Sources of Calcium
Richest: (600-900 milligrams/100 grams)
Cheese
Wheat-soy flower
Molasses
High: (120-350 milligrams/100 grams)
Dairy products: milk, yoghurt, sour cream, ice cream
Low: (<100 milligrams/100 grams)
Fruits
Diet and Bioavailability
Calcium that occurs in plants is mainly bound as calcium oxalate, which tends to make
plants less favorable in supplying calcium in the diet. Its attraction towards phosphate also makes
calcium in plants vulnerable to binding to phytic acid (phytate). These organophosphate complexes
tend to diminish the absorption of calcium at the level of the intestine and within the system.
Dietary Supplements
Supplementing calcium to the diet is common in the populace. The U.S. National Heath
Survey in 1986 found the 14% of the men, 25% of the women, and 7.5 % of children surveyed
admitted taking supplements. A follow up study in 1992 showed that supplements for men
increased the calcium intake, but not significantly. For women the increase was statistically
significant.
Upper Limit
Based on milk alkali syndrome which is a measure of renal insufficiency, the upper limit
for calcium is 2,500 mg per day. This represents calcium that is taken from food, water and
supplements. The UL value is common across the Life Stages.
Calcium Deficiency
As can be expect from its role in mineralization, a calcium deficiency will affect bone
structure and tensile strength. It role in muscle contraction and other intracellular events will
also be compromised when intake is subadequate. Low calcium intake come from the diet or
from impairments in intestinal absorption. Calcium deficiency will impact on bone health and
can result on loss of bone density and osteoporosis. Annually, osteoporosis accounts for
around 1.5 million bone fractures in the U.S.; in Canada, the incidences is around 76,000
fractures.
Excessive Intake
An increased propensity to develop kidney stones and renal failure (alkali disease) is a
concern when calcium is in excess. More likely is the propensity of calcium to interfere with the
absorption, excretion and metabolism of other minerals. Very high levels of calcium, nearly
twice the RDA, can decrease iron and magnesium absorption. These effects are enhanced
when combined with high sodium in the diet, which tends to raise the rate of magnesium
excretion. Zinc absorption is also impaired by high calcium. The effect is more apparent when
dietary zinc intake is marginal. With those who have adequate zinc intake, the effect is
minimal.
Digestion and Absorption
Digestion
Nearly all of the calcium taken in the diet is locked into a food matrix made up of
protein, complex carbohydrates, and polyphosphate complexes. Salivary amylases combined
with mastication assist in partial release of calcium from glycogen and starch. A greater
portion, however, is liberated by amylases in the proximal intestine. Proteases in the stomach
and duodenum, effect a partial hydrolysis of protein molecules down to small peptides and in
the process liberate calcium as free ions by disrupting the calcium binding sites in the protein.
The moderately strong acidity of the gastric juice (pH 1.7) also helps dissociate the calcium ions
from the peptides and renders salts of calcium such as calcium phosphate more soluble.
Absorption
Calcium absorption efficiency is generally the same for all food. This aspect of calcium
metabolism has received much interest because absorption efficiency tends to wane as a
person grows older. As will be discussed later, insufficient calcium in the diet or poor
absorption of the ion can lead to bone resorption, which weakens bone structure and renders
bone more susceptible to breakage, a typical scenario that is seen in aging individuals.
Among the more pertinent features of calcium absorption is its location in the small
intestine where absorption is more prominent. There is also a clear need for 1,25-dihydroxy
vitamin D3 (calcitriol) in the process. Segments of the intestine take up calcium by at least two
separate and non-overlapping mechanisms, paracellular and transcellular. Paracellular
transport calcium involves the movement of calcium ions between absorbing cells and never
penetrating the membrane. Paracellular is non-saturable and increases linearly with increasing
calcium ions at the absorbing site. Only a small portion of the calcium enters the system by
paracellular transport; but, more importantly, this process is not regulated by 1,25-dihydroxy
vitamin D3. In contrast transcellular transport makes use of the whole cell to move calcium
from the absorbing apical surface to the exporting basal surface. Effective transcellular
movement requires calbindin, the cytosolic calcium-binding protein to chaperone the calcium
ion during its passage. Calbindin levels determine the rate of calcium passage. Consequently,
transcellular absorption is characterized by a saturable uptake curves (see Fig. X) and a rate of
transport that is dependent on the level of calbindin. The latter is met by calcitriol, whose
action in part in to stimulate the synthesis of calbindin.
Role of Calcitriol (1,25-dihydroxy D3) in Calcium Absorption
Calcitriol is the active form of vitamin D3 and along with parathyroid hormone comprise
one of the major regulators of calcium absorption. Calcitriol is synthesized through a series of
reactions whose initiation begins with a uv-dependent transformation of 7-alpha-cholesterol to
choleciferol, vitamin D3. The ensuing synthesis to the active from involves dual hydroxylation
taking place first in the liver and then in the kidney. The final product has three hydroxyl
groups on the molecules and is referred to as a triol. As will be discussed below, calcitriol is
also a major regulator of phosphorus absorption.
A primary action of calcitriol is to raise the level of calbindin mRNA in the cell. Calbindin
levels in the cell control the rate of calcium passage into the system. Raising calbindin protein
therefore has the capacity to stimulate calcium absorption; a reaction that assures effective
transport when the level of calcium in the intestine is low.
Parathyroid Hormone
Parathyroid hormone (PTH) plays an important role in calcium and phosphorus levels in
the blood and the maintenance of a steady state of the two minerals. Its effects are directed
mainly at calcium levels as indicated by the following observations:
1) Lowering blood calcium stimulates bone resorption, restoring blood calcium,
2) Lowering calcium by raising phosphorus stimulates PTH,
3) PTH stimulates calcium absorption efficiency, resulting in a greater percentage of
calcium absorbed into the organism.
Interaction with other nutrients
Absorption of calcium and its internal use by cells can be influenced by components in
the diet. These substances can give symptoms of calcium deficiency and therefore be
accompanied by pathological changes such as bone loss and excessive urinary calcium output.
Table 5.X summarizes some of the dietary factors that can block or delay calcium absorption
and disrupt calcium homeostasis internally.
Table 5.X. Dietary Factors with the Potential to Influence Calcium Homeostasis
Factor
Minerals
Magnesium deficiency
Phosphorus excess
Sodium
Non-Minerals
Protein
Oxalic acid
Phytic acid
Caffeine
Effect on
hypocalcemia
absorption
excretion
excretion
absorption
absorption
absorption and excretion
Magnesium, phosphorus and sodium profoundly influence calcium uptake and
excretion. Magnesium deficiency, not excess, triggers bone resorption by lowering blood
calcium levels. The deficiency must be rather severe for blood calcium levels to decline. In
humans, however, a mild deficiency will suffice. Excess intake of phosphorus is detrimental to
calcium absorption, betraying a close interaction between the two bone minerals. As noted
below (Table 5.x) phosphorus-rich foods such as dairy products, soft drinks and meats can
exacerbate a mild calcium deficiency. Sodium ions in excess also affect calcium absorption, but
exert a more detrimental effect through enhancing calcium excretion. Sodium has only a
minimal effect on bone loss, however.
Non-mineral components in the diet also impinge on the absorption and excretion of
calcium. Calcium chelators such as oxalic acid and phytic acid have the capacity to bind free
calcium and prohibit is transport across the intestinal membrane. Foods rich in oxalic acid
include spinach, beans, and potatoes. Phytic acid, a chelator and a potent binder of calcium
ions, is a major source of phosphorus from plant foods. Grains and nuts in the diet are perhaps
the greatest sources of phytic acid. Thus, vegetarians are at risk of calcium insufficiency
because of the high level of phytic acid in these foods. A more detailed explanation of phytic
acid is given below. Caffeine is most detrimental to individuals whose intake of calcium is subadequate. A susceptible population includes postmenopausal and lactating women. Caffeine
appears to operate at the level of calcium excretion resulting in excessive urinary loss. It can
also affect calcium absorption, but a direct connection between caffeine and accelerated bone
loss has not been established.
PHOSPHORUS
History and Early Insights
The element phosphorus derives its name from two Greek words phôs (light) and
phorus (bearer) whose literal translation means “bearer of light”. The term traces back to the
discovery by Hennig Brand, a German chemist, who in 1669, while attempting to make gold by
heating urine, observed the formation of a white substance in the mix. In the presence of air,
the substance glowed in the dark. Unbeknown to Brand, the light reflected an oxidation
reaction between elemental phosphorus and oxygen, a spontaneous event tantamount to
setting the phosphorus on fire. Robert Boyle, the great English chemist, was the first to
combine phosphorus with sulfur-coated wooden sticks, the forerunner of wooden matches.
Insights into the biological role of phosphorus came in 1769 with the discovery by Jonathan
Gann and Carl Scheele that the matrix of bone was composed largely of calcium and
phosphate. Other than bone, phosphorus was found in serum and urine and in time was
shown to be a component of nucleic acids. Although the tendency in nutrition is to consider
phosphorus as the nutrient, in the biological sphere the phosphorus is always phosphate.
Chemical Properties
Phosphorus is a Group V non-metal configured as [Ar]3s23p33 with oxidation states of +3
and +5 resulting from the loss of 3s2 and (3s2 +3p3) electrons respectively. Because it is highly
reactive in air, phosphorus is never found in a free state, but rather as oxy-anions, mainly
phosphates and organic esters of phosphate. Phosphates have the potential to form
polyphosphates through a heat-induced polymerization that results in the loss of a water
molecule and an anhydride bond between the phosphate groups. Compounds with linked
polyphosphate groups such as ATP are sources of high energy for that reason.
Analysis
Test of phosphate in living tissues and fluids rely on the Fisk-Saborrow test.
Biochemical Properties
As noted with calcium, most of the phosphorus in an adult human (between 500 and
700 grams) is present in bones and teeth. About 15 percent appears in phosphate-bound lipids
and nucleic acids. Only about 0.1% is present as plasma phosphorous, which, due to pH
considerations is the dibasic HPO4= salt of phosphoric acid. The phosphate ions in the blood
and cells acts as a buffer that stabilizes pH. Phosphate-bound metabolic intermediates in
metabolic pathways makeup a large but highly unstable pool of phosphate in the cell. Organic
esters of phosphate are extremely abundant in living systems, most notably sugar esters in
metabolic pathways and diesters in DNA, RNA. Diesters of phosphate also make their
appearance in acylglycerol phosphates that comprise the major lipids in cell membrane.
Divalent cations such as Ca2+, Mg2+, Mn2+ and Zn2+ tend to bind weakly to organophosphate
complexes and in so doing compete with one another for phosphate binding groups on
proteins. Adding a phosphate group to a sugar effectively traps the sugar within the cytosol
and seals its fate for destruction via the glycolytic or hexose monophosphate shunt pathways.
Phosphate-bound sugars and compounds in general do not easily cross cell membranes
without the aid of specific carrier proteins.
One of the most important non-strucutral roles for phosphate is that of a mediator of
hormonal action and cell signaling. Signaling reponses are controlled by a series enzymes, the
protein kinases, that use ATP as a source of phosphate and thereby activate (or inhibit) target
enzymes and mediators. To be effective the phosphate group forms ester bonds with serine,
threonine and tyrosine residues within the proteins. The action modulates the activity of the
protein (enzyme), in some instances allowing a hormone receptor protein to engage other
signalling molecules and propage the signal internally.
Nutritional Properties
Recommended Intake
Data derived from the National Health Survey estimate that the average diet for both
men and women contains about 62 mg/100 Kcal phosphorus. Its ubiquitous nature in foods
makes it practically impossible to create a phosphorus deficiency in a balanced diet. Table 5.x
shows data taken from the Institute of Medicine. According to Dietary Reference Intakes
(DRI), the recommend dietary allowance (RDA) for phosphorus reaches a peak at between 9
and 18 years of age for both genders. With aging there is a drop
Table 5.X Dietary Reference Intakes for Phosphorus as a Function of Life Stage and Gender
DRI values (mg/day)
RDA
Males
Females
Life Stage
1-3 yr
4-8 yr
9-13 yr
14-18 yr
19-30 yr
31-50 yr
51-70 yr
460
500
1,250
1,250
700
700
700
460
500
1,250
1,250
700
700
700
Pregnancy
<18 yr
19-50 yr
1,250
700
Lactation
<18 yr
19-50 yr
1,250
700
off in the requirement. It is also noted that pregnant and lactation have no influence on the
RDA.
Food Sources
Table 5.X illustrates the phosphorus content of a variety of foods. The data are taken
from the USDA Handbook No. 8 series. From the table one may surmise Of the various food
sources dairy products provide the highest amounts of phosphorus. Vegetables tend to be
Figure 5.X Structure of Phytic Acid (Phytate)
lower than meats and dairy products. Grains such as oats, wheat bran, beans and plant
material in general are also very high, owing to their phytic acid content (Fig. 5.x). The inositol
ring structure of phytate can bind up to six phosphates per molecule and thus is a major
component of phosphate in the diet of animals subsisting on grains.
Table 5.X Phosphorus Content of Selected Foods
Item
Amount
P content (mg)
Macaroni and Cheese
Milk (2% fat)
Ham
Almonds
Oat meal
Cheddar cheese
Broiled shrimp
Cooked ground beef
Tofu
Baked potato
Egg
Whole wheat bread
Peas
Cola beverage
Potato chips
Dark chocolate
White bread
Orange
1 cup
1 cup
3 oz
¼ cup
1 cup
1 oz
2 large
3 oz
½ cup
1
1
1 slice
½ cup
1 can
14
1 oz
1 slice
1
322
248
210
184
178
146
137
135
120
115
86
74
72
46
43
41
30
18
Data taken from U.S. Department of Agriculture
Upper Limit
The upper limit of phosphorus intake in adults is roughly 8 times the RDA. The delicate
balance between phosphorus and calcium presages a potential harm to a system when this
level is reached. The condition of hyperphosphatemia signals a serious adverse effects.
Included as likely are (1) reduced calcium intake (more problematical when intake of calcium is
sub-adequate) and (2) calcification of soft tissues, particularly the kidneys.
Digestion and Absorption
Digestion
Phosphorus in food sources is present mainly as esterified organic phosphate. In
cereals, seeds and grains much of the phosphate is covalently bound as phytic acid and can
only be absorbed after enzymatic breakdown of phytic acid by phytases. The enzyme,
therefore, is a major factor in the digestion of phosphate from phosphate -rich grains.
Ruminants have phytase abundantly available through bacteria in the rumen. Mammals also
have bacterial phytases, but the enzyme is mainly in the colonic bacteria and thus beyond the
phosphate absorption sites in the small intestine. Because the concentration of phytase in
plants is not the same for all plants, it has been advantageous to supplement animal feed with
microbial phytase to aid the digestibility and increase the amount of absorbable phosphate.
Yeast are rich in phytase, which contributes to the higher bioavailability of phosphate in
levened bread products. However, phytic acid when in a complex with unabsorbed calcium is
resistant to the phytase action.
Absorption and Bioavailability: Role of Calcitriol
Phosphate liberated from its organic components is free to enter the system. Internal
homeostasis is regulated at both the level of absorption and renal excretion. These processes
are parathyroid hormone and calcitriol (1,25-dihydroxycholecalciferol, 1,25-(OH)2D3)
dependent. A decrease in plasma phosphorus (hypophosphatemia), stimulates renal
production of calcitriol, enhancing the level of hormone in the circulation. The calcitriol in turn
has two actions in an attempt to correct the low serum phosphorus: (1) to stimulate directly a
sodium-coupled phosphate-cotransport system in the upper small intestines thus bringing
more phosphate into the system (Fig. 5.x) and indirectly, (2) to mobilizes bone calcium raising
the level of serum calcium (hypercalcemia), which promotes calcium absorption and
suppresses PTH. The concerted action on calcitriol/PTH restores phosphorus to normal plasma
levels.
Calcium-Phosphorus Interactions
Because of its propensity to form crystalline aggregates with calcium, the
recommended intake of phosphorus must pay heed to the calcium level of the diet. Generally a
ratio of 1.3:1, Ca:P, is considered optimal. In quantitative terms, an adult human consuming
1,200 mg of calcium should have 900 mg of phosphorous to maintain the ratio. Indeed, a sharp
deviation from this ratio can upset absorption efficiency and alter the homeostasis of either
mineral. This in turn can trigger homeostatic changes internally that lead to pathologies. The
basis for these undesirable reactions relate to the tendency of the two minerals to precipitate
out of solution when either one is in excess. Pathologies become apparent when
mineralization occurs in soft tissue such as the development of calcium-phosphate deposits as
stones in the gall bladder and kidney.
The effect of phosphorus intake on PTH is illustrated in Figure 5.X. In the study rats
were fed diets with a Ca:P ratio that was either 1.1 (control) or 0.5:1 (high phosphorus) with Ca
being the same in both groups . After 18 days, the group that had higher phosphorus in their
diet had higher levels of PTH in the blood, suggesting that suppressing the amount of calcium
absorbed could raise PTH levels. Homeostatic mechanisms, therefore are designed to maintain
the two minerals at levels that prevent crystallization. An excess of either calcium or
phosphorus can shift the equilibrium precipitation crystals.
Table 5.X shows how variations in the percentage of phosphorus in the diet impinge on
the absorption percentage and blood levels of calcium and phosphorus in animals. As the
amount of phosphorus increases, the percentage of calcium absorbed decreases. Neither the
calcium nor phosphorus in serum is affected by the higher phosphorus influx. There was,
however, a sharp rise in plasma parathyroid hormone (PTH). More important these
observations suggest, raising the phosphorus levels in the diet at a constant level of calcium
intake has the potential to decrease bone mineral density.
Table 5.X. Changes in Calcium Absorption, Serum Phosphorus and Calcium with Phosphorus
Measured
P = 1.05%
Calcium absorption (%)
Serum P (mg/dl)
Serum Ca (mg/dl)
Serum PTH (pg/ml)
BMD of 5th lumbar
21.7  4.5
6.5  0.6
11.4  0.4
61.8  32.8
76.7  2.7
P =1.1%
8.6  5.5
7.2  0.4
11.4  0.4
135.2  48.4
73.0  2.8
P =1.2%
9.0  7.4
7.2  0.4
11.4  0.4
212.2  136.4
73.8  2.7
Data from Koshihara et al, 2004
PTH = parathyroid hormone. BMD = bone mineral density
SUMMARY
Calcium and phosphorus are the two macrominerals in the system. They are most
visible as the elements in crystaline bone where the two combine to form hydroxyapatite, the
building block of bone. Crystallization, however, is only a small part of their overall necessity.
Calcium acts as a hormone regulator, an enzyme cofactor, and is a major factor in cell signaling
and genetic expression. Most of the phosphorus appears as phosphate and as such is a major
structural component of nucleotides such as DNA, RNA, and membrane lipids. The most
familiar form of phosphate is in the structure of ATP where phosphate represents a source of
high energy for the cell, energy that is realized when the pyrophosphate bond in ATP is broken
in conjunction with the action of kinase enzymes.