Calcium and Calcium Alloys 1
Calcium and Calcium Alloys
Stephen E. Hluchan, BCI, Cambridge, MA, 02138, United States
Kenneth Pomerantz, Cornell University Medical College, New York, NY, United States (Chap. 6)
1. Introduction . . . . . . . . . . . . . . . . .
2. Physical and Chemical Properties . .
3. Production . . . . . . . . . . . . . . . . . .
4. Uses . . . . . . . . . . . . . . . . . . . . . .
5. Occupational Health and Safety . . . .
6. Biological Relevance . . . . . . . . . . .
6.1. Introduction . . . . . . . . . . . . . . . . .
6.2. Chemical Properties of Ca Important
in Biological Functions . . . . . . . . . .
6.3. Dietary Considerations; Distribution
in the Body . . . . . . . . . . . . . . . . . .
1. Introduction
Calcium metal was discovered in 1808 inde-
pendently by Sir Humphry Davy and by J. J.
Berzelius and Poutin. Its name derives from
the Latin “calx,” for lime. Calcium belongs to
the alkaline earth elements. Though a metallic
element, it is highly reactive and never found
in its elemental form in nature. Pure Calcium
metal is silvery white. It is oxidized easily and
in air forms a white coating; ignited, the metal
burns with a brilliant white light and a yellow-
red flame.
Calcium is the fifth most abundant ele-
ment in the Earth’s crust and constitutes more
than 3 % of the whole. Calcium is the fourth
most abundant element in the lunar high-
lands. Some important, naturally occurring com-
pounds are the carbonate limestone (CaCO3 ),
gypsum (CaSO4 ·2 H2 O), fluorite (CaF2 ), and
complex silicates.
2. Physical and Chemical Properties
Calcium [7440-70-2], 20 Ca, Ar 40.08; stable iso-
topes 40, 42, 43, 44, 46, 48. Its major properties
are:

c 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10.1002/14356007.a04 515.pub2
1 6.4. Regulation of Plasma Calcium by
1 Hormones . . . . . . . . . . . . . . . . . . 8
2 6.5. Control of Plasma Calcium by Target
3 Organs . . . . . . . . . . . . . . . . . . . . 9
5 6.6. Physiology of Intracellular Calcium
7 Trafficking . . . . . . . . . . . . . . . . . . 10
7 6.7. Physiology of Bone . . . . . . . . . . . . 10
6.8. Disturbances in Plasma Calcium
7 Homeostasis . . . . . . . . . . . . . . . . . 11
6.9. Diseases of Bone . . . . . . . . . . . . . . 11
8 7. References . . . . . . . . . . . . . . . . . . 12
Density (20 ◦ C) 1.55
Melting point 838 ◦ C
Boiling point 1440 ◦ C
Specific heat (0 – 100 ◦ C) 0.624 J g−1 K −1
Heat of fusion 217.7 J/g
Heat of vaporization 4187 J/g
Thermal expansion (0 – 400 ◦ C) 22.3 × 10−6 K−1
Electrical resistivity (0 ◦ C) 3.91 × 10−6 Ω cm
Thermal conductivity (20 ◦ C) 1.26 W cm−1 K−1
Lattice constant (Fcc) 0.5582 nm
Calcium is relatively unstable in moist air,
rapidly forming a hydration coating. It can be
stored in dry air (less than 30 % R.H.) at room
temperature. Calcium reacts spontaneously with
water to form Ca(OH)2 and hydrogen gas; when
finely divided, it will ignite in air, burn at a high
temperature and produce a nitride.
One of the alkaline earth group of metals,
group 2, calcium exists in the face-centered cu-
bic (fcc) form at room temperature, transforms
into a body-centered cubic (bcc) structure at 448
◦
C, and melts at 838 ◦ C.
The predominate stable isotope of calcium is
40
Ca. Calcium exhibits only one valence state,
+2, in all of its reactions. It is slightly less reac-
tive than barium and strontium in the same se-
ries. Calcium is a very ductile metal and can be
formed by casting, extrusion, rolling, etc. Table
1 presents mechanical properties of calcium.
2 Calcium and Calcium Alloys
Table 1. Mechanical properties of calcium metal
cathode. The metal obtained by this method is
Mechanical properties Annealed Cold typically 98 % pure. By further subliming, it can
worked be purified to levels beyond 99 %.
Tensile strength, N/mm2 4800 11500 The major producers of calcium metal are
Yield strength, N/mm2 1370 8500 China, approximately 10 000 – 12 000 t/a, pri-
Elongation, % 51 7
marily at the Shaanxi Zhonghe Special Metal
Modulus of elasticity,
MN/mm2 2.2 – 2.6 Plant, Hanzhong Shaanxi; Russia, 6000 – 8000
Hardness, Rockwell B 16 – 18 t/a, at the Chepetsky Mechanical Plant, Glazov,
Udmurt; the USA, 2000 – 4000 by Minteq Inter-
Calcium is noted for its high reactivity, es- national Inc. at Canaan, Connecticut; Canada, at
pecially the high heat of formation of some of Timminco Ltd; and France, at Pechiney. World
its compounds. This property enables calcium to capacity was approximately 24 000 t/a in 2005.
be used as a reducing agent in the preparation of The USA accounts for about half of the world’s
metals such as chromium, thorium, zirconium, consumption of calcium. Total world capacity
and uranium. Examples are given in Table 2. utilization is close to 80 %.
Table 2. Heats of formation ∆H f of calcium compounds The process used in Russia is the electrolysis
of molten salts of sodium hydroxide; the same
Compound CAS registry no. ∆H f , kJ/mol
process is believed to be used in China. While
CaBr2 [7789-41-5] − 675.3 electrowinning is the more expensive process, it
CaCl2 [10043-52-4] − 795.5 produces a higher purity metal when properly
CaF2 [7789-75-5] −1215.4
CaH2 [7789-78-8] − 188.8 implemented.
CaI2 [10102-68-8] − 535.1 In the USA and Canada calcium is produced
Ca3 N2 [12013-82-0] − 432.1 by thermal reduction of lime with aluminum.
CaO [1305-78-8] − 636.0
CaO2 [1305-79-9] − 659.4
The reactants, high-calcium lime of small par-
Ca3 P2 [1305-99-3] − 504.5 ticle size and aluminum powder, are compacted
CaS [20548-54-3] − 482.7 into briquettes to ensure intimate contact of the
reactants. The briquettes are charged into a high-
The low density and relatively low electrical temperature alloy retort. The open ends of the
resistivity make calcium one of the most efficient retort protrude from the furnace and are cooled
electrical conductors on a mass basis. At 20 ◦ C, by water jackets to condense the calcium va-
calcium conducts 16.7 % more electricity than por. The retorts are then sealed and the reaction
aluminum, and at 100 ◦ C, it conducts 21.6 % vessel is evacuated to 0.1 Pa or less; it is then
more electricity through one centimeter length heated to 1200 ◦ C. The reaction proceeds for ap-
and one gram mass of the respective metal. Com- proximately 8 h, the vacuum is broken, and the
pared to copper, calcium conducts 150 % higher condensed, 23 – 34 kg pieces of calcium metal,
current density at 20 ◦ C, and 197 % higher at known as crowns, and calcium aluminate residue
100 ◦ C. Calcium metal is not used as a conductor are removed The aluminum reduces the lime
on Earth simply because it reacts spontaneously producing calcium metal vapor. The calcium
when it comes in contact with oxygen, but in the then is removed from the reaction by condensa-
vacuum environment of space, calcium becomes tion, thus allowing the reaction to continue in the
attractive. desired direction. Limestone CaCO3 is quarried
and calcined to form calcium oxide. The cal-
cium oxide is then ground and dry-blended with
3. Production the desired amount of finely divided aluminum.
This mixture is compacted into briquettes for
The electrowinning of metals, the electrochemi- reactants then placed in horizontal tubes, i.e.,
cal production of metals from their compounds, retorts, made of heat-resistant steel and heated
is the oldest industrial electrolytic process. Al- to 1100 – 1200 ◦ C at a pressure less than 13 Pa.
kaline earth metals were first extracted by the The commercial-grade metal resulting from this
English chemist Humphrey Davy, using electrol- process is suitable for most industrial applica-
ysis of molten salts of sodium hydroxide. In the tions such as steelmaking.
electrolytic cell, calcium metal collects at the

A further vacuum distillation step is required
to obtain high-purity calcium metal, used in
more specialized refining applications such as
the production of neodymium for magnetic al-
loys. This second operation reduces the level
of contaminants. Commercial-grade calcium is
placed at the bottom of a large vertical retort
made of heat-resistant steel; the vessel has a
water-cooled condenser at the top. The retort is
sealed and evacuated to a pressure of less than
6.6 Pa; the bottom is heated to 900 – 925 ◦ C.
Calcium distills to the condensing section and
leaves behind less volatile impurities. Table 3
shows the purity after the first and second pu-
rification steps.
Table 3. Chemical analysis of typical commercial and redistilled
calcium
Element Commercial
grade, wt %
Mg 0.50
N 0.08
Al 0.30
Fe 0.008
Mn 0.01
Co n.a.
Li n.a.
Be n.a.
Cr n.a.
B n.a.
Ca and Mg 99.5
4. Uses
Steelmaking. The major use of calcium is
to improve the quality of steel (→ Steel). For
decades, calcium-containing ferroalloys have
been used as tap-stream additions to the molten
metal, or calcium compounds were injected
through a refractory lance by using argon as car-
rier gas. Although the benefits of using pure cal-
cium metal were known, they were difficult to
obtain; calcium is highly volatile, boiling well
below steelmaking temperatures.
Calcium is important in steel chemistry be-
cause it is a strong oxide and sulfide former;
furthermore, it has the uncommon ability to al-
ter the oxides and sulfides to give liquid lime
aluminates and underformed sulfides. Treatment
with calcium modifies the melting point of in-
clusions, which rapidly float out of the steel;
in addition, treatment alters the morphology of
any remaining inclusions, rendering them spher-
ical in shape, very small, and finely dispersed.
Calcium and Calcium Alloys 3
The result is a fundamental quality improve-
ment, especially in castability and the mechani-
cal properties: formability, drawing, impact, ten-
sile, machinability, resistance to cracking and
tearing, and improved surface and internal clean-
liness. Calcium also improves resistance to hy-
drogen-induced cracking in line pipe associated
with high-sulfur oil and gas pipelines.
In the early 1970s, calcium wire feeding tech-
nology was introduced. A steel-clad calcium
wire is fed through a delivery system which pro-
pels the wire well below the surface of the molten
steel. The steel cladding protects the calcium un-
til it reaches a depth where the ferrostatic pres-
sure suppresses vaporization.
The use of metallic calcium to refine steel
became common in Japan and the USA in the
Redistilled 1980s. Cored-wire injection technology was ap-
grade, wt % plied in ladle metallurgy, tundish, and mold
0.50 injection for continuous casting. This led to
0.02 the adoption of calcium injection for improved
0.001 castability and superior product quality in thin
0.001
0.002 slab casting. This casting technology, which can
0.0002 produce continuous 50 – 70 mm steel slabs, was
0.0001 developed by SMS and MDH in Germany dur-
0.0001
0.0002
ing the mid-1980. Nucor, USA, established the
0.0001 first commercial-scale thin-slab caster in 1989.
99.9 Thin-slab casting employs a specially de-
signed nozzle that is susceptible to alumina
buildup, develops progressive blockage, serious
clogging, and leads to termination of the cast-
ing process. Calcium has proved the most ef-
fective method to prevent these problems. With
appropriate sequential process steps, treatment
with calcium allows inclusion-shape control and
gives much cleaner steel.
For large-tonnage use and ladle treatment, a
wire-lance system combines the advantages of
wire feeding, gas control of fluid dynamics, and
treatment with pure calcium. This has resulted
in the efficient production of improved-quality
ultraclean steels.
Maintenance-Free Automotive Battery. In
the maintenance-free automotive battery (→
Batteries, Chap. 4.2.2), calcium improves elec-
trical performance and battery life. The anti-
mony – lead alloy used in the conventional lead
– acid battery is replaced with a 0.1 % Ca – Pb
grid alloy. The calcium in “calcium batteries”
refers to the lead alloy used in the production
of the grids for plate making. The alloy is typ-
4 Calcium and Calcium Alloys
ically still 99 % lead with alloying metals. Cal-
cium alloy grids afford low water loss and low
self-discharge.
Calcium improves the conductivity and cur-
rent capability of the cell; it significantly reduces
gassing, permitting the cell to be closed, thus
preventing water loss and extending life. The
hydrogen overvoltage increases with calcium –
lead alloy grids, so at a given rate of overcharge
at the same temperature, an antimonial battery
will consume more water than a calcium battery.
The resulting battery will not require water addi-
tion, i.e., maintenance, during its operating life
under normal operating conditions. Their lower
internal resistance provides a higher charge-rate
acceptance and a small increase in performance.
The life and performance of calcium – lead bat-
teries is enhanced by tight control of the man-
ufacturing process and the specifications of the
grid alloy for the positive plate.
Calcium – lead alloy grids were prone to ex-
pansion and cracking that lead to premature bat-
tery failure. The use of calcium alloys and roll-
hardening the positive grid reduced the problem.
A calcium – aluminum alloy forms a eutectic
with lead, and rapid solidification of the alloy
makes continuous grid making possible.
Lead – calcium alloys have replaced lead –
antimony alloys in a number of casting appli-
cations. These alloys contain 0.03 – 0.15 % Ca.
Aluminum is added to calcium – lead and cal-
cium – tin – lead alloys as a stabilizer for cal-
cium. Adding tin to lead or lead alloys increases
hardness and strength, but lead – tin alloys are
more commonly used in type metals and sol-
ders for their good melting, casting, and wetting
properties. Tin gives the alloy the ability to wet
and bond with metals such as steel and copper;
unalloyed lead has poor wetting characteristics.
Magnet Materials. High-energy-density
magnetic materials are produced using calcium
(→ Magnetic Materials). Samarium – cobalt
magnets with energy products of between 8
and 16 × 104 T·A/m have found applications
in miniature transducers and other devices re-
quiring high energy or volume restrictions. The
reaction is:
3 Sm2 O3 +10 Co3 O4 +49 Ca (g) →6 SmCo5 +49 CaO
The production of neodymium – iron –
boron magnets involves the use of calcium metal
as a reductant. This is an important development
because these magnets have energy products ap-
proaching 40 × 104 T·A/m, over twice that of
samarium – cobalt. In addition, the availabil-
ity of the raw materials is significantly greater
than for samarium – cobalt; both the quantity
and stability of raw material supply limited the
growth of samarium – cobalt magnets. There-
fore, neodymium – iron – boron magnet mate-
rials are less expensive to produce.
The energy density is sufficient to permit
the replacement of armature windings in mo-
tors, transducers, and generators with permanent
magnets. The weight of an automotive starting
motor was reduced from 3.6 to 1.8 kg; the size
and cost of the motor were commensurately re-
duced as well. This technology is finding exten-
sive applications in automotive, computer pe-
ripheral, medical, home appliance, and military
markets.
There are two methods of producing
the neodymium – iron – boron raw material, a
neodymium – iron alloy. One is the calcium
thermal reduction method:
NdF3 or NdCl3 +Ca+Fe→NdFe+byproducts
or
Nd2 O3 +Ca+Fe→NdFe+byproducts
The second method is by electrolysis:
NdCl2 +electricity→Nd2 +Cl2(v)
or
NdF3 +Nd2 O3 +electricity→Nd+byproducts
The calcium thermal reduction process is pre-
ferred. It has the greatest flexibility in produc-
ing the basic neodymium – iron and alloy varia-
tions. The byproducts are not toxic as they are in
the electrolytic process. The calcium process is
less capital intensive and readily scaled in pro-
duction volume to meet market demands.
Iron Making. Injection of calcium wire has
been adopted by many foundries for iron treat-
ment. Again, the calcium is used for desulfur-
ization, inoculation spherodizing, and alloying.
Calcium ferroalloys are used in the produc-
tion of nodular iron castings. In magnesium
ferrosilicon, calcium reduces the reactivity, en-
hances nucleation, and improves morphology.
The ratio of calcium to magnesium varies from

0.15 to 0.50. Pieces of the ferroalloy are placed
in a protected pocket cut in the refractory lin-
ing of the ladle prior to tap. The molten iron is
then poured into the ladle where it reacts with
the alloy. The treated, nodularized iron is then
cast into molds.
In the in-mold process, granularized ferroal-
loy is placed in a special reaction chamber
formed in the channels of the mold. This per-
mits the reaction to occur when the iron is cast;
it enhances the effectivity of the ferroalloy and
results in improved castings. The process can be
automated for high productivity.
Other Applications of Calcium and Cal-
cium Compounds. Alloys of calcium also are
used to deoxidize magnesium, to strengthen lead
electrodes, and to produce special aluminum
alloys. Calcium is also used to improve the
mechanical properties of lead (→ Lead Alloys).
A proprietary process for improving the integrity
and formability of the lead used in yacht keels
was developed in Australia.
In the debismuthizing of lead by the Kroll-
Betterton process, calcium metal is combined
with bismuth which then floats out in a dross:
3 Pb3 Ca+2 Bi→Bi2 Ca3 +9 Pb
Lead ores are thus refined to commercial soft
lead with 0.02 % or less Bi (→ Lead).
Calcium metal is reacted with zirconium fluo-
ride to refine zirconium; the high heat of reaction
melts the zirconium. The zirconium ingot pro-
duced by this method is remelted under vacuum
for purification. The resulting metal is leached
with acetic acid to remove the lime produced as
a byproduct of the reaction.
Uranium fluoride or oxide can be reduced
with calcium. To produce thorium and uranium,
the oxides are mixed with a stoichiometric ex-
cess of calcium and reduced under an atmo-
sphere of argon. Auergesellschaft during World
War II made the uranium metal for the atomic
bomb project by using metallic calcium to re-
duce uranium oxide to uranium metal. In 1945
the Russians dismantled and took the calcium
plant to Russia for refining uranium. Calcium
produced in China was used in obtaining nuclear
materials as well.
Calcium metal is readily hydrided for use as
a portable source of hydrogen gas. It also is used
in the production of the B-complex vitamin cal-
cium pantothenate [137-08-6].
Calcium and Calcium Alloys 5
Precipitated calcium carbonate is used to re-
place wood pulp in paper and as an antacid.
Many calcium compounds are used in
the foodstuffs, pharmaceuticals and medi-
cal industries. Calcium lactate Ca(C3 H5 O3 )2 ·
5 H2 O, calcium diphosphate (phosphate of
lime), CaHPO4 · H2 O, and tricalcium phosphate
Ca3 (PO4 )2 are used to supply calcium and phos-
phorus to foods. The last-named also finds appli-
cation as a polishing agent in dentifrices and as
an antacid. Calcium lactobionate, a white pow-
der, provides a suspending agent in pharmaceu-
ticals.
Calcium monophosphate, CaH4 P2 O8 ·H2 O is
used as a leavening agent in baking. Anhydrous
monocalcium phosphate CaH4 (PO4 )2 is used in
pre-mixed flour mixes.
Calcium sulfite CaSO3 · 2 H2 O provides a
bleach for paper pulp and textiles. As a bleach,
it is a disinfectant.
Calcium silicate CaO · SiO2 is used as a re-
inforcing agent in rubber. This compound also
helps manipulate the viscosity of liquids, com-
mercially as a filler in paints and coatings. In
coatings it modifies the reflectivity resulting in
reduce sheen, a matte surface. Calcium metasili-
cate CaO·SiO3 (wollastonite) is used as a bright-
ener for paints and paper coatings, a filler for
plastics, a coating for welding rods, and for elec-
trical insulators, tile, and ceramics.
Calcium acetate Ca(C2 H3 O2 ) · 2 H2 O,
(known as lime acetate and vinegar salts) is
employed in liming rosin and the manufacture
of metallic soaps and synthetic resins.
Limestone is an essential element in Portland
cements. Oyster shells (CaCO3 ) are a commer-
cially important source of calcium for animal
feeds.
5. Occupational Health and Safety
Calcium metal reacts with water and acids to
form hydrogen gas, calcium oxide and calcium
hydroxide; the reaction is exothermic. If calcium
metal contacts moisture in the eyes, on the skin,
or in the respiratory tract, severe corrosive irrita-
tion may result. Inhalation of dust or fume may
cause severe respiratory irritation, cough, diffi-
culty in breathing, and chemical pneumonitis.
Contact with skin causes irritation and possible
corrosion damage.
6 Calcium and Calcium Alloys
The substance is severely irritating to the eyes
and may injure eye tissue if not promptly re-
moved.
Ingestion may cause acute irritation or burns
to the mouth, throat, and stomach; calcium may
cause vomiting. Pre-existing chronic respiratory,
skin, or eye diseases may be aggravated.
The symptoms of inhalation include severe
irritation of respiratory tract. Skin and eye con-
tact symptoms are severe irritation.
There are no known adverse health effects
resulting from long-term exposure to calcium
metal
First Aid. Inhalation: Remove to fresh air. If
breathing is difficult, give oxygen. Seek imme-
diate medical attention.
Skin contact: Remove calcium metal imme-
diately with a dry cloth. Wash the area with large
amounts of water until all the chemical is re-
moved.
Eye contact: Immediately flush eyes with
running water for 15 min. Lift upper and lower
eyelids occasionally. Get immediately medical
attention.
Ingestion: If victim is conscious, give large
amounts of water to dilute the alkali. Do not in-
duce vomiting. Never give anything by mouth to
an unconscious person.
Note to physician: All treatment should be
based on observed signs and symptoms of dis-
tress in the patient. Consideration should be
given to the possibility that overexposure to ma-
terials other than calcium metal may have oc-
curred.
Firefighting Measures. Extinguishing
method: Do not use water, foam, or halogenated
hydrocarbons such as Halon or carbon tetrachlo-
ride to extinguish fire. Use only graphite powder,
soda ash, powdered sodium chloride, or an ap-
propriate metal-fire-extinguishing dry powder,
such as Met-L-X. For large fires, withdraw from
the area and let the fire burn.
Firefighting procedures: Firefighters should
wear self-contained breathing apparatus with
full face piece operated in the pressure-demand
or positive-pressure mode. Firefighters should
move containers from the fire area if this can be
done without risk. Do not use water or foam. Use
dry powder only.
Fire and explosion hazards: Water reacts dan-
gerously with calcium metal and is not recom-
mended as an extinguishing agent for fires that
involve it. If water must be used, prevent it from
coming into direct contact with calcium metal. If
contact is unavoidable, apply the water in flood-
ing amounts to safely absorb the heat that will
be generated.
Hazard: Calcium metal is extremely danger-
ous when wet. Calcium metal forms calcium
hydroxide and hydrogen gas resulting in an ex-
plosion hazard when wet. Calcium metal forms
CaO, quicklime, when it burns. It reacts with
wet extinguishing agents such as water, halo-
gens, and possibly carbon dioxide.
Accidental Release Measures. Do not
touch spilled calcium metal. Wear protective
apparel. Do not smoke or place flame or igni-
tion sources near spill area. Do not allow water
to touch spilled calcium metal or to get inside
containers. Use a cover, a plastic sheet for ex-
ample, to prevent water or rain from dissolving
spilled calcium metal or to prevent its spread-
ing. Isolate hazard area and keep nonessential
personnel away from spill or leak site. Shovel
small dry spills into a dry container and cover
it tightly. Move containers away from spill to a
safe area. Take up small spills with sand or an
absorbent and contain as described above. Dike
the flow of large calcium metal and water spills
with soil, sandbags, or concrete. Keep the waste
from entering drains and open sewers. Wear full
protective gear.
Handling and Storage. Storage: Store cal-
cium metal in a sealed container away from wa-
ter, acids, or organic compounds. Protect con-
tainers against physical damage. Calcium metal
will generate heat upon contacting water.
Handling: Avoid damaging container.
Exposure Controls and Personal Protec-
tion. Ventilation: Provide adequate exhaust ven-
tilation to meet exposure limit requirements. An
exhaust filter system may be required to avoid
environmental contamination.
Respiratory protection: Calcium metal does
not have established exposure limits. Wear a
positive pressure air-supplied respirator in situa-
tions where there may be a potential for airborne
exposure.
Hand protection: Impervious gloves.
Eye protection: Chemical goggles and/or face
shield.

Other protection: Wear rubber apron or other
impervious clothing to prevent contact with skin.
6. Biological Relevance
6.1. Introduction
Calcium is indispensable for life; it is required
for maintenance of structure and metabolism.
Examples of the structural role of calcium in-
clude the elaborate structure of coral [8], the se-
creted shells of mollusks, and the internal skele-
tons of vertebrates. Calcium is also necessary
for many biological functions, the most promi-
nent being muscle contraction, nerve conduc-
tion, and regulation of blood clotting. To control
these functions, all organisms have mechanisms
for maintaining critical intracellular calcium lev-
els. Organisms with a circulatory system also
have mechanisms to control extra-cellular cal-
cium levels as well as calcium uptake and ex-
cretion. The role of calcium in biological sys-
tems has been the subject of a number of books
[9, 10]. This chapter focuses on the molecular,
metabolic and structural aspects of calcium in
vertebrate biology.
6.2. Chemical Properties of Ca
Important in Biological Functions
Calcium has two properties that render it indis-
pensable for life. First, Ca ions complex with or-
ganic compounds, particularly proteins, thereby
affecting their function. Second, Ca salts display
a wide range of solubility, making it possible for
vertebrates to possess a skeleton.
Calcium – Protein/Lipid Interactions.
Calcium mediates many biological functions
through its ability to bind specifically to pro-
teins and lipids. Calcium binds to proteins by
three principal mechanisms. First, it can directly
bind the carboxyl groups of glutamic and aspar-
tic acid residues to alter enzyme function. Sec-
ond, it can interact with specific phosphorylated
serine, tyrosine, or threonine residues. Third,
specific amino acids that have undergone vi-
tamin K-dependent γ-carboxylation effectively
chelate Ca. Proteins may use one or more of
these mechanisms to bind Ca. For example,
Calcium and Calcium Alloys 7
the digestive protein trypsin has a locus of glu-
tamic and aspartic residues that bind Ca, and
this changes the conformation of the enzyme to
enhance its activity [11, 12]. Osteocalcin (a bone
matrix protein) possesses a sequence with three
γ-carboxyglutamic acid residues that enable it to
bind Ca minerals [13]. The bone matrix proteins
osteopontin and bone sialoprotein are rich in as-
partic acid, glutamic acid, and phosphorylated
serine and/or threonine residues, which per-
mit them to bind calcium phosphate crystals
[14 – 18]. Calcium-dependent enzymes can be
activated by two principal mechanisms. Many
enzymes are activated by binding Ca directly.
Other calcium-dependent enzymes do not bind
Ca, but are activated by noncovalent associa-
tion with calcium-binding proteins. Calcium-
binding proteins which fulfill this co-enzyme
function include calmodulin, annexin, and cal-
cineurin.
To optimize the ability of proteins to bind
calcium, the relevant amino acid residues are lo-
calized in specific domains which may be con-
served between species and throughout evolu-
tion. An example domain is known as “EF-
hand”, which is a single helix – loop – helix
structure that binds Ca within the 12-amino acid
loop [19]. The proteins possessing EF hand mo-
tifs have undergone significant and turbulent
molecular evolution. Starting as an archety-
pal protein containing one EF hand, the genes
coding these proteins have undergone dupli-
cations, deletions, and retroversions to yield a
family of calcium-binding proteins with a wide
array of functions and a variable number of
EF hands [19 – 25]. A representative calcium-
binding protein of this type is calmodulin, which
has four EF hands that recapitulate the canoni-
cal EF hand sequence observed in slime molds,
paramecium, plants, and mammals, including
humans [22, 26]. Calcium also complexes with
cell membrane phospholipids, which can anchor
cell surface-associated proteins on the basis of
electrostatic interaction between Ca ion and the
negatively charged head groups of cell mem-
brane phospholipids.
Solubility Range of Calcium Salts. Primary
calcium phosphate Ca(H2 PO4 )2 is extremely
soluble. Secondary calcium phosphate CaHPO4
has a solubility of about 2.0 mM and makes up
8 Calcium and Calcium Alloys
about 85 % of the Ca in extracellular fluid. Ter-
tiary calcium phosphate Ca3 (PO4 )2 has a solu-
bility of about 100 µM, and most of it is found
in bone in the form of hydroxyapatite [27]. Ul-
timately, the control of Ca crystallization is de-
termined by these different solubilities and by
biological factors, such as calcium-binding and
phospholipid vesicles, which can regulate cal-
cium crystal formation.
6.3. Dietary Considerations;
Distribution in the Body
The age-adjusted daily calcium requirement is as
follows: 0 – 0.5 years, 400 mg; 0.5 – 1.0 years,
600 mg; 1 – 10 years, 800 mg; 11 – 24 years,
1200 mg; 25 and above, 800 mg. The bulk of
dietary calcium is derived from dairy and grain
products (76 %), the remainder coming from
vegetables, protein foods, fruit, sugar, fats, and
oils [28]. Lactose enhances the calcium absorp-
tion, but fiber and fat, and certain plant con-
stituents reduce its bioavailability. The use of
calcium supplements to compensate for poor di-
etary intake is controversial, since uptake by the
gut is highly regulated. Furthermore, the absorp-
tion of Ca supplements is dependent on their
solubility: the citrate, maleate and lactate salts
have high bioavailability, whereas the oxalate is
poorly absorbed [28].
Phosphorus is an essential dietary ingredient
and a major bone mineral component. Phospho-
rus is present in most foods, and most adults
consume greater than 100 % of required daily
allowances [29].
Vitamin D is essential to normal Ca home-
ostasis and is derived from dietary sources and
from de novo synthesis in peripheral tissues. The
required daily allowance for vitamin D is 10
mg/d; it is found in fortified milk, cod liver oil,
and certain fish [30].
The adult human contains 1.0 – 1.3 kg of Ca,
about 99 % of which is located in the skeleton,
0.5 % in the teeth, and the remainder in soft tis-
sues and extracellular fluids. Within the plasma
compartment, 48 % is found in the free (ionized)
form, 48 % is bound to plasma proteins, and 3 %
is complexed as citrate, phosphate, or bicarbon-
ate. A simplified schematic of whole-body Ca
flux is shown in Figure 1.
Figure 1. Whole body distribution of calcium [31]
Plasma calcium pool is in equilibrium with Ca input (from
the intestine, bone and kidney) and Ca output (urine, sweat
and feces). There is a steady-state balance in Ca flux to and
from bone. While a significant amount of Ca is filtered out
by the kidney, most is reabsorbed, and the net loss is usually
compensated for by intestinal absorption
6.4. Regulation of Plasma Calcium by
Hormones
Cells and tissues have developed mechanisms
for compartmentalizing Ca within extracellular
and intracellular pools, and can regulate the flux
of Ca between these pools very precisely. Hor-
monal regulation of gastrointestinal absorption,
renal absorption, and bone mineral Ca flux pro-
vides a system through which plasma calcium
levels remain within narrow limits. Three major
hormones regulate Ca flux from the gut, kidney
and bone.
Parathyroid hormone (PTH) is a major short-
term regulator of plasma calcium level and is
synthesized by the parathyroid gland. Cell sur-
face receptors for Ca in the parathyroid gland
are activated when plasma calcium level falls,
resulting in PTH secretion [32]. PTH is also se-
creted in response to catacholamines, vitamin
D, and calcitonin. The net effect of PTH is to in-
crease plasma calcium level by interacting with
target cells in the kidney, gut, and bone to stim-
ulate Ca entry into the plasma pool [33].
Vitamin D is responsible for long-term main-
tenance of plasma calcium level. It is derived
from the diet or generated de novo form choles-
terol following exposure of the skin to ultraviolet
 Calcium and Calcium Alloys 9

Figure 2. Intestinal cell calcium transport

Two mechanisms allow for transcellular Ca transport. First, Ca is transported through the apical surface by a Ca transport
protein (calbindin D28K ). It is then transported through the cell bound to Ca-binding proteins, and is extruded into extracellular
milieu along basolateral cell surface by vitamin D-inducible ATP-dependend Ca pump in association with Na/Ca exchanger
and Na/K pump [37]. Second, calibindin-D28K immobilizes Ca on the cell membrane, which invaginates to form vesicles that
carry Ca to basolateral surface. Here, the vesicles fuse with the plasma membrane, discharging Ca into the extracellular milieu
[38]. Two processes also allow for paracellular Ca transport. Ca flows passively down a concentration gradient (from 0.5 to
1.25 mM) through structures between intestinal cells called tight junctions that are semipermeable to Ca. In addition, Ca can
also be “dragged” by solvent water. By the latter two passive processes, Ca is absorbed, albeit with low efficiency [39].

light [34]. Vitamin D undergoes hydroxylation
in the liver to form 25-(OH)-D and then by the
kidney to 1, 25-(OH)2 -D, which is the major ac-
tive metabolite regulating Ca homeostasis. Cir-
culating vitamin D2 has a half-life of about 1.5
d. The major target organs of vitamin D2 include
the gut, kidney, and bone [35].
Calcitonin is a short 32 amino acid peptide
secreted by specialized cells in the thyroid gland.
Calcitonin secretion is stimulated (or inhibited)
by acute increases (or decreases) in plasma cal-
cium concentration. Its plasma half-life is about
10 min. Calcitonin inhibits bone resorption, thus
antagonizing the effect of PTH. The role of cal-
citonin in regulating plasma calcium levels is
minor relative to PTH and vitamin D [36].
6.5. Control of Plasma Calcium by
Target Organs
In the intestine, Ca is absorbed as the free ion
with an efficiency of approximately 30 – 32 %.
Calcium traverses the intestinal lining either by
transcellular flux, which is mediated by calcium-
transport proteins or vesicular transport, or a sec-
ond, passive flux between intestinal cells, known
as paracellular flux (Fig. 2).
The kidneys are the principal regulators of
plasma calcium level, and filter about 10 g of
Ca per day. In the renal glomeruli, Ca is fil-
tered out of the blood into the proximal tubule;
however, 70 % is reabsorbed in this portion of
the kidney by paracellular transport. In addi-
tion, about 20 % of the filtered Ca is reabsorbed
in the thick ascending limb of Henle by para-
cellular transport and calcitonin-induced active
transport. The remaining Ca is absorbed by the
distal convoluted tubes in a PTH- and vitamin D-
dependent manner due to enhanced expression
of calbindin-D28K . The urinary filtrate thus con-
tains approximately 1 % of the filtered Ca load
[39].
Bone contributes to the steady-state plasma
calcium level, which is regulated by PTH and vi-
tamin D. PTH promotes bone resorption by acti-
vating cells within the bone matrix (osteoclasts)
committed to matrix destruction, allowing Ca
access to plasma [29]. However, PTH also pro-
motes bone formation, probably due to its action
on cells lining bone (osteocytes). Vitamin D has
multiple effects on Ca trafficking: it enhances
10 Calcium and Calcium Alloys
deposition of Ca into bone by stimulating the
maturation of primitive bone cells (osteoblasts)
to osteocytes, but also acts in concert with PTH
to stimulate osteoclast activity. Thus, PTH and
vitamin D act together to increase the rate of
bone and mineral turnover without altering net
bone mineral content or mass [40].
6.6. Physiology of Intracellular Calcium
Trafficking
The optimum intracellular calcium concentra-
tion is 0.1 µM, which is 10 000 times less than
the extracellular calcium level. Accordingly,
cells developed mechanisms to control Ca flux
between the extra- and intracellular pools. The
major restriction of extracellular Ca to the intra-
cellular milieu is the plasma membrane which
has a low passive permeability to Ca. How-
ever, the plasma membrane also has Ca chan-
nels which allow Ca entry in response to changes
in voltage, stretching, or hormonal stimulation
[41]. At least one type of channel is tonically ac-
tive and permits Ca to the extracellular milieu, as
described above [42]. In addition, an intracellu-
lar tubular structure known as the smooth endo-
plasmic reticulum (SER) serves as a source of in-
tracellular Ca. A membrane-bound Ca/ATPase
transports cytoplasmic Ca into the SER, which
lowers cytoplasmic calcium level. In contrast,
release of calcium from the SER is mediated by
two receptors, one of which is responsive to hor-
monal stimulation, while the other is activated
by the Ca itself [43]. The cytoplasmic calcium
level is thus a reflection of the state of activa-
tion of the cell. Collectively, calcium-dependent
enzymes control nearly every aspect of cell func-
tion, including nucleotide metabolism, glycogen
metabolism, electrolyte balance, neuromuscular
irritability, neural function, muscle contraction,
and proliferation.
6.7. Physiology of Bone
Bone is a connective tissue that has the ability to
become calcified. Structurally, bone consists of
hydroxyapatite deposited within an organic ma-
trix. Hydroxyapatite is hard, rigid, and brittle,
and is effective mainly in resistance to compres-
sion. However, the organic matrix, over 90 % of
which is collagen type I, is flexible and tension
resistant. Thus, bone has the tensile strength of
cast iron, but has only one-third the weight and
is ten times as flexible. Bone is organized into
two general types of structures. Compact bone
which forms the shafts of the long bones and the
outer surface of nearly all other bones, is highly
calcified (80 – 90 %). Trabecular bone forms the
ends of the shafts of the long bones and most of
the bones in the spine, and is 15 – 20 % calcified
[44].
Cellular Basis of Bone Formation and
Turnover. Bone undergoes continuous remod-
eling due to the activity of bone-forming cells
(osteoblasts, osteocytes), and bone-resorbing
cells (osteoclasts). Osteoblasts secrete connec-
tive tissue proteins to form unmineralized bone
matrix. Mature osteoblasts, known as osteo-
cytes, lie within small cavities that are com-
pletely surrounded by bone, and are responsible
for bone deposition. These cells are activated by
vitamin D, calcitonin, platelet-derived growth
factor, transforming growth factor- β, insulin-
like growth factor, androgens, and low physio-
logical amounts of glucocorticoids [45]. In con-
trast, osteoclasts degrade bone, and are activated
by PTH, vitamin D, interleukin-1, tumor necro-
sis factor, and prostaglandin E1 . Conversely, os-
teoclast activity is inhibited by estrogens [46].
There are two general mechanisms by which
bone is laid down. In the first, bone formation
occurs in the absence of a pre-existing structure.
Primordial cells differentiate directly into os-
teoblasts, which secrete soluble collagen into the
extracellular space. The soluble collagen then
self-assembles to form fibrils, which are stabi-
lized by extensive intermolecular cross-linking.
Initially, the bone matrix is randomly oriented
(or woven), and hydroxyapatite deposition oc-
curs in irregular patches by the formation of
matrix vesicles as a result of exocytosis from
the plasma membrane of osteoblasts. Mineral-
ization occurs on these vesicles. and as the crys-
tals grow, the vesicle is subsequently destroyed.
Bones which are formed by this method include
flat bones, such as the skull, jaw, and ribs. The
second method of bone formation occurs on a
previously existing cartilaginous structure as an
initial supporting structure which undergoes ini-
tial calcification. Remodeling of this calcified
matrix by osteoclasts and osteoblasts eventually

replace the calcified cartilage in the formation
first of woven bone, and then compact bone.
Mineralization in compact bone occurs within
the tightly spaced organic matrix within vesicle
formation. This process occurs in the develop-
ment of the long bones of the legs and arms [47].
Remodeling of bone occurs throughout life.
During growth, the midshaft of long bones un-
dergoes growth on the outer surface, and resorp-
tion at the inner surface to maintain net bone
thickness. At puberty, the growth plates present
on both ends of long bone close and prevent fur-
ther bone lengthening. As bone ages, the organic
matrix becomes brittle and weak, and undergoes
microfractures. Bone remodeling continuously
replaces old matrix with new matrix in a steady-
state process of osteoclastic destruction of dam-
aged bone and generation of new bone by os-
teoblasts. This aspect of bone physiology is the
subject of numerous books [44, 48].
Mineralization of Bone. The mineral in
bone is hydroxyapatite, and makes approxi-
mately 60 – 65 wt % of bone. For the hexag-
onal form of hydroxyapatite, the content of
the unit cell is Ca10 (PO4 )6 (OH)2 . In vitro, hy-
droxyapatite can be generated by mixing CaCl2
with KPO4 . An unstable amorphous phase
(ACP1) is initially formed, followed by the ap-
pearance of a second amorphous phase (ACP2),
which is less soluble than ACP1. ACP2 then
transforms to Ca4 H(PO4 )3 , which polymerizes
into deficient hydroxyapatite [49, 50]. Other ions
can influence hydroxyapatite formation. Fluo-
ride generates two crystal forms: hydroxyapatite
covered with fluorapatite, and fluorapatite co-
vered with hydroxyapatite [51]. In contrast,
magnesium, carbonate, and cadmium inhibit
hydroxyapatite formation by substitution into
the apatite crystals, preventing further crystal-
lization. The inhibition of crystal growth by
magnesium can be attenuated by fluoride ion
[52, 53]. In vivo, hydroxyapatite crystal for-
mation and attachment to collagen is regulated
by calcium-binding proteins. Osteopontin and
bone sialoprotein initiate and regulate crystal
growth and mediate the turnover of bone in
areas of growth [54, 55]. In compact bone, hy-
droxyapatite is maintained by osteocalcin [14,
56, 57] and osteonectin [58 – 60].
Calcium and Calcium Alloys 11
6.8. Disturbances in Plasma Calcium
Homeostasis
Hypercalcemia. Excessive calcium intake
may cause increased calcium levels. However,
this is rare, since intestinal paracellular Ca trans-
port is rather inefficient, and at least 2 – 3 grams
of additional Ca must be consumed to cause
toxicity. Hypercalcemia is usually due to exces-
sive intake of vitamin D, increased PTH secre-
tion (primary hyperparathyroidism), or a conse-
quence of bone destruction secondary to tumor
metastasis to bone. Hypercalcemia is manifested
by deposition of Ca salts into the heart, blood
vessels, kidneys, and skeletal muscles, anorexia,
nausea, vomiting, memory loss, confusion, mus-
cle weakness, increased urine excression, and
dehydration, and metabolic bone disease (see
below).
Hypocalcemia. may be due to inadequate di-
etary intake of Ca, vitamin D, or insufficient
sunlight. The most common endocrine cause
is inadequate or nonexistent secretion of PTH
(primary hypoparathyroidism). Hypocalcemia
is also caused by defects of the PTH receptor
in the target cells and is characterized by a resis-
tance to peripheral tissue to PTH rather than by
a low amount of active hormone (pseudohypor-
parathyroidism). The features of hypocalcemia
include neuromuscular excitability, which may
result in tetany and cardiac conduction defects.
6.9. Diseases of Bone
The strength of bone depends in part on the
molecular structure and organization of its con-
stituent mineral crystals in their organic matrix
[61]. Most common diseases of bone cause in-
creased propensity for fracture, and are due to a
failure in the ability to generate adequate matrix
or hydroxyapatite.
Osteoporosis is characterized by a reduc-
tion in mineral content per unit volume of bone
and is caused by reduced 17- β-estradiol secre-
tion (Type I) or a variety of mechanisms includ-
ing deficiencies in calcium, vitamins C, D or
K, hypogonadism, hyperthyroidism, glucocorti-
coid excess, rheumatoid arthritis, and immobi-
lization (Type II) [62]. Treatment of osteoporo-
sis includes Ca supplements, vitamin D and bis-
12 Calcium and Calcium Alloys
phosphates.[63]. Sodium fluoride is no longer
recommended for patients with osteoporosis.
As well as its beneficial effects on the skele-
ton, calcium supplements may favorably af-
fect serum lipids in postmenopausal women
and older men. In addition, there is evidence
that calcium consumption is inversely associated
with cardiovascular disease in postmenopausal
women. In the past, estrogen replacement was
considered a primary therapy for the preven-
tion of postmenopausal osteoporosis. Estrogen
had the additional advantages of controlling
menopausal symptoms and presumptive preven-
tion or delay of cardiovascular disease. How-
ever, data now indicates that estrogen-progestin
therapy does not reduce the risk of coronary
heart disease, and increases the risk of breast
cancer, stroke, and venous thromboembolic
events.
Osteomalacia is characterized by loss of bone
mineral Ca and connective tissue matrix as a
result of calcium or vitamin D deficiency. The
bony matrix is replaced by poorly ossified fi-
brous tissue.
Osteogenesis imperfecta is a genetic disease
due to defects in the synthesis of Type I colla-
gen, resulting in impaired fibril formation and
ossification.
Pagets’ disease of bone is caused by os-
teoclastic hyperactivity, resulting in widespread
bone resorption.
Osteopetrosis is characterized by excessive
bone ossification due to the relative absence of
osteoclasts. Narrowing and obliteration of bone
marrow reduces bone distensibility.
Metastatic Calcification. Calcification also
occurs in soft tissues, and may have serious con-
sequences. A major cause of soft tissue calcifica-
tion is a long-standing hypercalcemia. Aberrant
calcification can also occur as a consequence of
cell death and necrosis. Atherosclerosis is also
accompanied by dystrophic calcification, and
may be due to the ability of plaque-associated
lipids (cholesterol and phospholipids) [64, 65]
or bone-related proteins [66, 67] to nucleate hy-
droxyapatite. Calcification of the vascular wall
causes loss of elasticity and disruption of lam-
inar blood flow, which can lead to plaque rupture
and thrombosis.
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