Ann. din. Biochem.

13 (1976) 518-539

Regulation of Calcium Metabolism

R. G. G. RUSSELL

From the Department of Medicine, Harvard Medical School, and the Medical Services (Endocrine and
Arthritis Units), Massachusetts General Hospital, Boston, Massachusetts 02114, and the Nuffield
Department of Orthopaedic Surgery, University of Oxford, Nuffield Orthopaedic Centre,
Headington, Oxford, England (address for correspondence)

This paper reviews the regulation of calcium metabolism in man. The body's calcium economy
is determined by the relationship between the intestinal absorption of calcium, the renal handling
of calcium, and by the movements of calcium in and out of the skeleton. These processes are
influenced by many factors, the most important of which are parathyroid hormone and the
hormones derived from the renal metabolism of vitamin D, notably l,25-dihydroxyvitamin D a-
The role of endogenous calcitonin in man is still controversial, but there are severalother hormones
which have some influence on calcium metabolism, including thyroid hormone, growth hormone,
and the adrenal and gonadal steroids. Clinical disorders of calcium metabolism and their treat-
ment are discussedin terms of the disturbances in normal physiologythey represent.

There has been a rapid growth in knowledge about Table 1. Distribution ofcalcium and phosphate in normal
calcium metabolism in the past decade, particularly human adults
in understanding the biochemistry of the calcium-
regulating hormones. This recent work has meant
that many old concepts have had to be re-examined,
a process which is still far from complete, especially Calcium" Phosphorus
in relation to human disease. The purpose of this (as P)
paper is to review current concepts in outline and to
refer the reader to other sources for more detailed Total body content 1QOO-1500 s 700-1()()() g
(for 70 kg human)
information (see Bibliography). Skeleton 98% 85%
Regulation of calcium metabolism can be con- Skeletal muscle 0.3% 6%
sidered from at least three distinct but interrelated Skin 0.08% 1%
aspects: (i) control of the concentration of calcium Liver 0.02% 1%
in extracellular fluid and tissues; (ii) control of the Central nervous system 0.01% 1%
body's overall calcium balance, i.e., the relationship Other tissues 0.6% 5%
between gains and losses; (iii) control of the shape, Extracellular fluid 1% 1%
structure and composition of bone and the way these
respond to changes in external factors such as load
bearing. From Widdowson and Dickerson (1964).

DISTRIBUTION OF CALCIUM AND PHOSPHATE

Most of the body's calcium resides within bone
(Table 1). The other major inorganic constituent
of bone is phosphorus, as inorganic phosphate (Pi).
Unlike calcium, the concentration of which is low
in most soft tissues, about 15 % of the body's
phosphorus lies outside the skeleton, in body fluids
and in tissues, mostly as organic phosphate com-
pounds, e.g., nucleic acids and nucleotides, phospho-
lipids and phosphorylated metabolites.
Studies with radioisotopes (45Ca and 47Ca) have
shown that in normal human adults the exchangeable
pool of calcium represents less than 1 % of total
body calcium (in the region of 70 mg/kg during the
first few days after injection). About half of this
518
is outside the skeleton, the remainder within it. This
exchangeable pool of calcium is very important in
homoeostasis, and movements of calcium ions be-
tween body fluids. cells, and the surfaces of bone
occur continuously. Between 1 and 4 %of the human
adult skeleton is thought to be renewed each year.
Trabecular bone has a faster turnover than cortical
bone.
In order to understand the way in which the body
gains and loses calcium from the external environ-
ment and the way in which internal control is
achieved the system can be simplified to a considera-
tion of the roles of the three major organs involved,
i.e., gut, lddney, and bone, and the pool to and from
which calcium moves.

MAJOR FLUXES OF CALCIUM
AND NET CALCIUM BALANCE
. The major movements (fluxes) of calcium through
tbeIlc organs in an adult human are shown in
Pia. 1.
Calcium enters the body by intestinal absorption.
The true absorption of calcium is greater than the
uet absorption because some calcium is returned
to the gut lumen in biliary, pancreatic, and intestinal
ICCI'Ctions. Calcium is lost from the body by urinary
excretion and also in sweat. The latter is usually
ianored in balance studies because the loss is small
and cannot be measured easily. However, losses in
sweat can be as high as 300 mg/day under extreme
conditions. It will be noted that the fluxes of calcium
through the kidney, as filtered and reabsorbed
. calcium are many times higher than the fluxes
through the intestine and bone.
In the adult under normal conditions the body is
, neither gaining nor losing calcium, so that inflow
; and outflow are matched precisely (intake = output).
In disease states there may be transient or sustained
net gains or losses, to produce calcium balances
that are positive (intake exceeds output) or negative
(output exceeds intake).
Mljor .It..
of PTH.cllcitonin & vitlmln D
of .ctlon
l000mg
1 Vii D
G>
.. ----_.-- .... -.
! ',200mg
//
BOOmg
200mg
Fig. 1.-The majOl' movements of calcium (mgfday) through
the principal organs (intestine, kidney, and bone) involved
In calcium bomoeostasls in a normal adult man. The major
sites of acrion of parathyroid bormone (PTH), calcitonin
(en, and vitamin D are shown. Note that balance is
maintained, oot only by the skeleton (mIner'lllisatioo =
resorption) but also by the whole organism (net intestinal
absorption = urinary loss).
RegUlation 0/ calcium metabolism 519
During growth there is a net daily gain to provide
the calcium necessary for skeletal growth. In preg-
nant or lactating women the foetus or child pins
calcium from the mother. In these situations the
extra requirements are met by increased net intestinal
absorption and diminished renal excretion of Ca so
that a neutral balance is maintained in the mother.
Calcium homoeostasis is concerned with the
relative rates of flux through these organs and the
complex way in which these are changed by regulat-
ing factors, particularly parathyroid hormone (PTH),
calcitonin (Cf), and vitamin D (vit D). The concen-
trations of calcium and phosphate in extracellular
fluid (ECF) are set by the relative sizes of the various
fluxes and by the influence of controlling agents
on them.
The properties of the hormones acting on calcium
metabolism will be discussed first, followed by a
description of some features of the individual organ
responses to them. The hormones can be subdivided
into "controlling" hormones and "influencing" hor-
mones. The controllers are the primary calcium
regulating hormones, PTH, cr and vitamin D
metabolites, the secretion of each of which is altered
in response to changes in plasma ionised calcium
concentration (and phosphate in the case of vit D).
The "influencing" hormones are those other hor-
mones, e.g., thyroid hormones, growth hormone,
and adrenal and gonadal steroids, which have
effects on calcium metabolism but whose secretion
is determined primarily by factors other than changes
in plasma calcium and phosphate.
THE CoNTROLLING HORMONES
Parathyroid hormone (PTH)
Mammalian PTH consists of a single peptide
200mg t 1t chain containing 84 amino acids in the case of the
bovin'e, porcine, and human hormone (Fig. 2).
(j;) 'Cil The complete amino acid sequence is known fo~ the
PTH Vii 0
o bovine and porcine hormones but only partially
CT for the human. Synthesis of different segments of
the chain has shown that only the first 32-34 amino
acids (reading from the N-terminal end) are necessary
for biological activity. There is evidence that cleavage
occurs naturally to produce a short N-terminal
biologically active fragment and a larger inactive
C-terminal fragment. The function of this cleavage
is unknown. The C-terminal piece is the major
PTH component measured in many radioimmuno-
assays.
In common with several other peptide hormones
PTH is synthesised as a prohormone, which contains
an additional 6 amino acids on its N-terminal end
(Fig. 2). A further precursor form, pre-pro PTH,
520 R. G. G. Russell
Fig. 2.--Structure of bovine proparathyrold hormone. The
arrow between positions 6 and 7 shows the site of cleavage
of the probormone to produce PTH itself (after Potts and
Deftos, 1974).
containing a total of 115 amino acids has now been
identified in studies in vitro (Habener et al., 1975).
These precursor forms are probably converted to the
84-amino acid peptide before secretion from the
gland.
The major physiological stimulus to secretion of
PTH is a fall in plasma ionised calcium concentra-
tion (Ca2+). A rise in plasma Ca2+ above normal
suppresses PTH secretion (Fig. 3). Other ions play
only a minor role, but in the presence of low levels
of Mg2+, the secretion of PTH is impaired and this,
together with an impaired target organ response to
PTH, may explain the hypocalcaemia occasionally
seen in severe magnesium deficiency in humans.
In humans secondary hyperparathyroidism, such
as that seen in chronic renal failure or vit D deficiency,
is due to stimulation of parathyroid secretion by the
longstanding low plasma calcium rather than by
changes in plasma phosphate or other ions.
PTH acts on the kidney to increase the tubular
reabsorption of calcium (Massry et al., 1973;
Nordin et al., 1967) and to depress the tubular
reabsorption of phosphate. This leads to a rise 'in
plasma Ca and fall in plasma Pi. PTH also diminishes
the secretion of H+ by the kidney, which leads to an
increased excretion of HC03 ions and to a hyper-
chloraemic acidosis, which is often present to some-
extent in patients with primary hyperparathyroidism
(Wills, 1971).
The major classic effect of PTH on bone is'
increase resorption, an effect which can be readif
demonstrated on explants of bone in tissue cultur-
(Raisz, 1970; Raisz and Bingham, 1972). Both
primary and secondary hyperparathyroidism can be
associated with obvious radiological and histologi-
cal evidence of increased bone resorption. There ;.
increasing evidence, however, that low doses
PTH, thought to be within the physiological range
may increase bone formation and in adult man can
be associated with increased intestinal absorption
of calcium and positive calcium balance.
The ability of PTH to increase the intestinal
absorption of calcium may be an indirect effect.
brought about by PTH increasing the renal synthesii
of 1,25-dihydroxy cholecalciferol (1,25 (OH)2CC).
Calcitonin (CT)
CT is also a peptide hormone but contains 32'
amino acids with a disulphide bridge between
cysteine residues in positions 1 and 7. The entire
sequence is essential for biological activity (Potts
and Deftos, 1974). The complete structure is knowr
for the bovine, ovine, porcine, salmon, and human
hormones (see Fig. 4). There are many differences
in the amino acid composition of the calcitonins
from different species and this is associated with.
different potencies. Surprisingly, the salmon hor-
mone resembles the human more than other mam-
malian calcitonins. In the treatment of Paget's
disease the salmon hormone is more effective on a :
molar basis than the human hormone itself.
Calcitonin is secreted by specialised cells desig-
nated C cells, which are part of the APUD cell
series derived embryologically from the neural cres
(pearse and Polak, 1972). The C cells are located ill
different sites in different species. In man and pig
they are found mainly in the thyroid gland, although
in man there are some in the thymus. In fishes and !
birds the C cells comprise a separate endocrine
gland known as the ultimo branchial body. In experi-
mental animals and birds CT is secreted in response
to a rise in ionised calcium (Fig. 3), and also to
infusion of certain other hormones, notably glucagon
or gastrin.
The most important action of CT in mammals is to
inhibit bone resorption and thereby lower plasma
calcium. Large doses of CT also increase the renal
excretion of calcium, sodium, and phosphate and
alter the soft tissue distribution of these ions. In
man the renal effects can probably be considered
pharmacological.
 Regulation 0/ calcium metabolism 521
Sirum Ca
mll'l!)OlIIl
10.0 r - - - - - - - - - - - - - - , P T H
Irl.mCT
1100

"
11.0 I,
: P1H 1400
'1.0

14.0
1'1
.
! \
I '~
\
1100

lOGO 1100
Fig. 3.-To show the re-
IatJooship between changes
: \ in plasma calcium and the

11.0
secretion of parathyroid
.aD 1000 hormone and calcitonin In
10.0 the pig. In (a) a fall In
.aD 1100
plasma calcium was Induced
by lnfuslngEGTA and a rise
1.0
by infusing calcium. In (b)
400 1000 the values for peripheral
1.0 Immuooreactive porcine.
100 100 PTH (IPPTH) and cal-
citonin (lPCf) are plotted
4.0
against serum calcium
(from Arnaud et al., 1969)
1.0
Undetectable

0
0 134 D I 7
1
Tlml,hour.

Interrelationships between peripheral IPCr 6. - - - 6. and IPPTH 0 - - - 0

during sequential induced changes in the sea x-x.
Fig. 3 (8)
4000

700

JOOO 100
....
~
t
:i
I..: 1000
Q..

l...
~
1000 100

" , I" ~~.tlctabl'

,
Und.t ctobll
"
134 D I 7 I 10 II II 13 14 III III rr III
Serum calclum,mll'looml

Plot of IPCr and IPPTH 0---0 values as a function of those

obtained for sea in the same serum samples. r for IPCr - +0964 and for IPPTH
- -0-942. p for both 0-001.
Fig. 3 (b)
S22 R. G. G. Russell

PORCINE
..... . ..
. '
H!M-ICYS,SER',ASII'llEU'ISER'ITHI'ICYS.VAL1UU SEIALATYITlHII&&SIllEU'ASM&SIlP1IHISAI& ;~'SER' &lNIEHlYPHE'I PIO.&lIHHI PlIO, MH,
:0\,
:i~~;.
U Y'
./
':.~~-:'.

BO~NE I 1 I

~:~:~iiir'r",mmLft'.L~u.~m"r~'H'~'MrUTHt
H2M-CY1S.SER,ASN1l1EU.SE1R. T1HI'CY1S'VAl' UIU.SER.ALA 'TYR 'TIIPlYIA$PlEUASIlASN 'TTR' HII'AIl8 '~.:;"SER'&lNIET' elY' PHE lll:I'. PlIO&lU 'TIII'PIlOI~ MH.
~ .

SALMON
~ M ~.~
I ~ M ~
H2M-CIYS'SER'ASIM'UIU'SERI'TIHR'CY5I'VAl'UIU'~'lYS'lEU'SER'~'&LU'lEU'HIS'l~'lEU'lil.M'~'~:';'AR&~'ASM'THR16lY'SER'~'THR'PIlot ...
~ ~ ~ ~~~ ~ ~
HUMAN

i
.."
~ ~
if/.
~~~ ~
jII7. ...... . " . "
~
jII7.,O
N2 M-en 6LY nMUUSEITHR-CYSIIETUUlil.Y THRTYR-TNRlil.M ASpPHEASHYS PHE HIS, THR PHEPlOGlNTHRALAILEGLY VAL GLULAPRO
~ W ~ ~~W W ~ ~-
.J

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

Fig. 4.--Structure of calcltooJns from several species. Solid bani show amino acids common to the cakitonins of all 8"
species. The shaded bars show positions of partial homology (potts and Deftos, 1974).

The exact physiological role of cr in man is
unclear. There is a continuing debate, based on
conflicting radioimmunoassay data, about whether
cr circulates at all in normal man and whether its
secretion can be increased in response to hypercal-
caemia. Some assays of cr have indicated the exist-
ence of large forms of the hormone in the circula-
tion in normal and disease states. The significance of
this is obscure. On the basis of current evidence it
has yet to be shown that cr has an important
physiological role in man.
The assay of cr is important, however, in the
diagnosis of medullary carcinoma of the thyroid
and for the detection of family members with the
disease in its presymptomatic form. This condition
occurs either alone, inherited as an autosomal
dominant, or in association with other endocrine
abnormalities-e.g., parathyroid adenomas and
phaeochromocytomas and mucosal neuromas (in
MEA Type 11). In man CT is also of interest because
it reduces the excessive resorption and turnover of
bone characteristic of Paget's disease of bone.
cr may have a physiological function in other
species, e.g., in birds during egg laying and in fisb
during migration from fresh to salt water. It is note-
worthy that cr is found in elasmobranch fishes.
which have a cartilaginous and non-calcified skeleton
This suggests that, from an evolutionary point
view, the prime function of cr was not concerned
with bone.
Vitamin D
Animals derive their vitamin D from the diet anc
from ultraviolet irradiation of dehydrocholestero.
in the skin (Fig. 5).
Before it becomes biologically active vitamin D
(cholecalciferol, CC) has to be metabolised (Avioli
and Haddad, 1973; DeLuca, 1972; Omdahl anc
DeLuca, 1973). The first step involves its conversion
in the liver to a 25-hydroxylated derivative. This
step may be regulated by feedback inhibition. The
second step involves further hydroxylations in the
kidney, to produce 1,2S(OHfiCC or 24,25(OHfiCC.
 Regulation of calcium metabolism 523
The latter can be metabolised further to 1,24,25-

T --. .-
(OH)aCC. The l-hydroxylated metabolites appear
to be the biologically active forms of the vitamin,
with 1,25(OH)2CC probably being the most import-
ant and worthy of the name, hormone, rather than
1- ' . . ._ ...
vitamin (Norman and Henry, 1974).
ebY n
\ -.. ' _ 0 1
The major actions of 1,25(OH)2CC are on the

i_~ICl~~r:
intestine to increase calcium absorption and on bone
to increase resorption. Although lack of vit D in
man is associated with defective mineralisation of

~:"'...J
l"IOIIlio lIsI
2I-OH-_..il....
cartilage and bone, the question whether vit D
or its metabolites act directly on bone to increase
mineralisation is still unsettled. It is possible that the
t4f' effects of vit D on bone mineralisation are secondary
2!i,M-IDHI.--"'...
to changes in extracellular fluid concentrations of
calcium and phosphate, but this explanation may be
too simple to account for all the experimental and
clinical observations. Unfortunately, there are no
good experimental systems for studying skeletal
mineralisation in vitro and the major effect of

1,14,21-IDHI.-
_ o i l....

-
1./__.... Fig. 5.-The major intercoDverslons in vitamin D metabol-
Ism: <a)structural formulae (Coburn et al.,l974); (b) some
of the proposed sites of regulation of D metabolism to show
stimulatory ( +) and inhibitory ( - ) effects.
TARGET TISSUES BIOLOGICAL RESPONSES

Fig. 5 (a>

LIVER KIDNEY

Gut

~_4_~Bone

Vitamin 0 3 - - .
Muscle

Bone
Fig. 5 (h) Gut
524 R. G. G. Russell
l,25(OH)2Da on bone in culture is to increase
resorption.
The metabolism of vitamin D in the kidney
appears to be closely regulated in experimental
animals. The production of 1,25(OH>2CC is stimu-
lated under conditions of vitamin D deficiency, and
by low dietary calcium or phosphate. Increased
production of l,25(OH)zCC is accompanied by a
reciprocal diminution of 24,25(OH)C and vice
versa. The function of 24,25(OH)zCC is unknown.
There is evidence that the effect of calcium depriva-
tion in increasing 1,25(OH)2CC is mediated by
increased secretion of PTH, whereas the effect of
phosphate restriction is independent of PTH
(Hughes et al., 1975).
However, since studies on the regulation of produc-
tion of 1,25(OH)zCC in experimental animals
have necessarily been done under extreme conditions
often using animals or birds already deficient in
vitamin D, caution is needed before extrapolating
these findings to man. Evidence that the same
relationships may exist in man comes from recent
measurements of 1,25(OH)2CC in plasma which
indicate that the levels are higher than normal in
hyperparathyroidism and lower than normal in
hypoparathyroidism (Hughes et al., 1975). They are
also low in renal failure (Mawer et al., 1973) per-
haps because renal mass is diminished or as a result
of the hyperphosphaternia that exists in this condi-
tion. The possible importance of phosphate as a
regulating ion for 1,25(OHhCC synthesis in man
is also indicated by the enhanced intestinal absorp-
tion of calcium and the hypercalciuria that follows
dietary deprivation of phosphate. It is possible that
hypophosphatemia stimulates the production of
l,25(OH)2CC in this situation, and may do the same
in primary hyperparathyroidism and in those cases
of "idiopathic" hypercalciuria where intestinal
hyperabsorption of calcium is the cause. The in-
creased intestinal absorption of calcium to meet the
physiological requirements of growth, pregnancy,
and lactation are also probably mediated by in-
creased production of 1,25(OHhCC, which may
explain the apparently increased requirement for the
precursor vit D under these conditions.
There is an interesting interrelationship between
the actions ofvit D and PTH, such that in the absence
of vit D some of the target organ responses to PTH
are impaired, notably the effect on bone resorption.
In addition it is clear that the diminished intestinal
absorption of calcium seen in vit D deficiency is not
overcome by the increased secretion of PTH that
follows deprivation of vit D. This may mean that
effects normally ascribed to PTH itself are in reality
mediated by an increase in 1,25(OH>2CC induced
by PTH.
THE INFLUENCING HORMONES
Calcium and phosphate metabolism are also
affected by growth hormone, thyroid hormones
glucocorticoids, and sex hormones. '
Growth hormone (GH) is best known for its effect
on growth of cartilage, an effect which is probably
brought about indirectly by the growth hormone-
dependent production of somatomedin (Van Wyk
et al., 1974). There are probably several somato-
medins, not all of which are dependent on GH.
Their biochemical characterisation is incomplete.
. GH ,also causes an elevation in plasma Pi by
increasmg the apparent reabsorption of phosphate
by the kidney. Excess or deficiency of GH is associ-
ated with skeletal growth abnormalities. In acro-
megaly there is an increased periosteal apposition
of bone, but there is no convincing evidence that
acromegaly causes osteoporosis.
Deficiency of thyroid hormones early in life
produce the well known skeletal deformities of
cretinism. In the adult, excess of triiodothyronine
or thyroxine can be associated with hypercalciuria,
hyperphosphataemia, a raised alkaline phosphatase,
and occasionally hypercalcaemia. In hyperthyroid-
ism there is increased bone turnover often with net
loss of bone. These effects are probably due to a
direct action of thyroid hormones on bone, and an
increase in resorption of bone can be demonstrated
in organ culture. In humans resorption is probably
increased by thyroid hormones to a somewhat
greater extent than formation, leading to a slight
increase in plasma calcium. This may suppress the
secretion of PTH and explain the diminished renal
tubular reabsorption of calcium and enhanced reab-
sorption of phosphate.
Adrenal steroids
Adrenal insufficiency is rather frequently accorn-
panied by hypercalcaemia, probably due in part to
haemoconcentration but also to altered renal hand-
ling of calcium.
In spontaneous or iatrogenic glucocorticoid excess,
osteopenia may develop. In experimental animals
glucocorticoids produce a variety of effects on bone
depending on the compound given, the dose and the
animal species. The relative contributions of dim-
inished intestinal absorption, increased renal excre-
tion of calcium and of diminished bone formation
and excessive resorption of bone, all of which may
occur, is not well defined.
Sex steroids
Characteristic growth abnormalities are associated
with deficiencies of either male or female sex hor-
 Regulation of calcium metabolism 525

mones. In adults the effects of oestrogens are of
_, particular interest because of the loss of bone that
occurs in women after the menopause. Administra-
tion of exogenous oestrogen may slow down this
loss. Oral contraceptives may reduce bone turnover
in premenopausal women.
INDIVIDUAL ORGAN REsPONSES
Intestine
The intestinal absorption of calcium appears to
involve both active transport and diffusion processes,
Absorption occurs throughout the small intestine
and is quantitatively greater in the ileum than the
duodenum, even though active transport is more
evident in the duodenum. The fraction of the dietary
intake absorbed varies with the dietary content so
that net absorption remains relatively constant
except at extremely low or high intakes. The adapta-
tion to dietary intake of calcium is now thought to
be mediated mainly by changes in 1cc25(OH)zCC.
The mechanism may be that when the inflow of
calcium from the gut falls, there is a tendency to
hypocalcaemia which stimulates PTH secretion; this
in turn enhances the synthesis of 1,25(OH)zCC
which causes the intestinal absorption of calcium
to return to its original value.
This adaptation is a slow one. Unlike the responses
by the kidney and bone to PTH and CT, which occur
within minutes or hours, the intestinal responses take
1-3 days. Intestinal absorption of calcium also varies
with age arid sex and in disease states. It is likely that,
with better knowledge about the metabolism of
1,25(OH)zCC in man, many of these variations will
be explicable in terms of changes in the metabolism
of vitamin D.
The biochemical mechanisms involved in calcium
absorption through the intestinal mucosa are not
understood in detail, though several features of the
system have been identified (see Fig. 6). There is a
calcium binding protein (CaBP) as well as a Caz+_
stimulated ATP-ase (which may be the same enzyme

MUCOSAL CELL
BRUSH
LUMEN BORDER BLOOD

Co*ATP-ase
"wlII~ZF~(Olk Ptasel ~25(OHIa D.
Co.... ----l~---W.'----I~-I--.
ATP

<
Na-Co- ATP-ase
(ETHACRYNIC
ACID SENSlTIVEI


~
~
NO - K-AT P - ase
(OUABAIN
PROTEIN SYNTHESIS SENSITIVE)
- - - - -CoSP
-( -Co*ATP-ase \
?-Other ATP-D5n)

:I ]I :m:
FACILITATED INTRACELLULAR ACTIVE TRANSPORl
DIFFUSION MOVEMENT
EnellJY dependent
? Active transport Mitochondrial
+ ionic diffusion binding

Fig. 6.-HypotheticalintestJnal mucosal cellto show some of the factorsthoughtto heinvolved In calcium transportand In
the stlmulatOl'Yeffect of 1,25 (OH.)-vltamin DB' CaOP = calcium binding protein, CaB+ATP-ase = calcium stimu-
lated adenosine triphosphatase (from Coburn et al., 1973).
526 R. G. G. Russell
as intestinal alkaline phosphatase), which are both
dependent on the presence of vitamin D or its
derivatives (Coburn et al., 1973). It is the synthesis
of these components as well as the metabolism
of vitamin D itself which probably accounts for the
relatively long lag period between giving vitamin D
and achieving an intestinal response. One puzzling
feature is that both the CaBP and Ca2+-ATP-ase
are located on the luminal surface of the intestinal
epithelial cell. It is difficult to see why they need to
be present at this site since the luminal calcium
concentration is much higher than the presumed
intracellular concentration of calcium and there
seems therefore to be no need for an assisted transport
mechanism against an electrochemical gradient.
An active extrusion mechanism however is required
at the basal border, unless, as some workers postu-
late, the calcium traverses the intestinal epithelium
in the intercellular space. It seems likely that the
Ca binding protein delivers calcium from the lumen
to a site essential for further translocation.
There is now good evidence that calcium and
phosphate can be absorbed separately from each
other and that 1,25(OH)2CC has independent effects
to enhance the absorption of each. For calcium,
1,25(OHhCC acts on both the diffusion and satur-
able components of the transport system. Absorp-
tion of calcium and phosphate is also enhanced by a
water-soluble factor (possibly an analogue of vitamin
D) from a South American plant, Solanum glauco-
phyllum, which can cause fatal hypercalcaemia in
cattle that eat it.
Kidney
The kidney is a key organ in determining the
plasma concentrations of both calcium and phos-
phate. Of the various hormones mentioned PTH is
probably the most important under physiological
circumstances, enhancing reabsorption of calcium
and reducing reabsorption of phosphate. There is
little evidence in man that vitamin D or its metabol-
ites, at physiological concentrations, have a major
effect on the renal handling of calcium or phosphate
that cannot be accounted for by changes in the
secretion of PTH. Thus the enhanced reabsorption
of phosphate seen after restoring vitamin D to
patients deficient in vitamin D is probably due to
suppression of the parathyroid hypersecretioncharac-
teristic of this state. However vitamin D in doses far
in excess of physiological requirements can increase
excretion of both calcium and phosphate.
The calcium ion itself affects phosphate handling.
Infusion of calcium into hypoparathyroid patients
to restore their plasma calcium towards normal can
also partially reverse the increased tubular reabsorp-
tion of phosphate. This may help to explain why
treatment of such patients with vitamin D or its
derivatives results in a fall in plasma phosphate as the
plasma calcium rises. In contrast, as plasma calcium
is increased above normal, an opposite effect on the
renal handling of phosphate may come into being so
that there is enhanced rather than diminished
reabsorption of phosphate.
Both calcium and phosphate excretion are influ-
enced by other factors, notably Na + excretion,
extracellular fluid volume expansion and by the
administration of diuretics (Massry et al., 1973).
There is evidence for both proximal and distal sites
of tubular reabsorption and both can be influenced
by PTH for phosphate, whereas the action of PTH
on Ca is probably mainly distal. Infusion of NaCI
increased the excretion of both calcium and phos-
phate, an effect which probably contributes to its
value in the treatment of hypercalcaemia.
The biochemical mechanisms involved in renal
transport of calcium and phosphate are not eluci-
dated, but the action of PTH on the kidney is
known to produce an increase in cortical adenylate
cyclase activity which increases tubular cell and
urinary concentrations of 3'5' cyclic adenosine
monophosphate (cyclic AMP). It is not known
whether this increase in cyclic AMP is the cause of
the subsequent changes in phosphate and calcium
transport. However, in the clinical disorder pseudo-
hypoparathyroidism there is probably a defective
receptor mechanism for PTH in both kidney and
bone, so that administration of PTH does not pro-
duce a normal response of an increased excretion
of phosphate and cyclic AMP. This is analogous
to the failure of patients with nephrogenic diabetes
insipidus to respond to antidiuretic hormone. In
pseudohypoparathyroidism the low plasma calcium
and high plasma phosphate resemble the findings
in simple hypoparathyroidism but there are addi-
tional abnormalities in that the condition is familial
and the patients are of short stature and have short
fourth metacarpal bones. It is noteworthy that in
pseudohypoparathyroidism there is an appropriate
response of the parathyroids to hypocalcaemia, so
that these patients have elevated plasma concentra-
tions of PTH, which however do not cause the usual
target organ responses. There is now an additional
variety of pseudohypoparathyroidism described in
which PTH causes an increase in cyclic AMP but
no change in renal phosphate clearance.
Bone
The structural organisation of bone is complex,
as can be seen from Fig. 7.
In mature bone three main cell types exist:

Cllment Ii,...
Newbor.e
Fig. 7.-To show some of the histological features of
compact hone of the type found in 11mb bones (from Harris
aDd Heaney, 1969).
osteoblasts, responsible for bone formation, osteo-
clasts responsible for bone destruction, and osteo-
cytes which are derived from osteoblasts and become
trapped within the bone matrix as maturation pro-
ceeds. The osteocytes lie within a complex canalicular
system and are probably responsible for many ot the
rapid ion fluxes that occur in bone. The origin, life
span, and fate of the various cells in bone is only
partially understood. The tissue fluid surrounding
bone cells probably has an unique composition, being
high in K + and containing particular plasma proteins
in preference to others.
The mineral component of bone is predominantly
hydroxyapatite. Since ionic exchange occurs between
bone mineral and surrounding fluids, it also con-
tains other ions such as HCOa-, M g2 +, Na +, K +, etc.
Collagen is a major constituent of the organic matrix
of bone and is largely responsible for its tensile
strength. Bone collagen is of the type I variety.
In addition, the matrix contains several proteo-
glycan components. The rate of deposition of bone
is controlled by hormonal status (e.g., PTH, GH),
by levels of calcium and phosphate, and by mechani-
cal and electrical forces acting on bone.
Calcification is an important step in the transition
between matrix production and the formation of
mineralised bone. In the skeleton calcification takes
place in two main sites in epiphysial cartilage during
the growth of long bones and in bone matrix during
intra-membraneous ossification and in the remodel-
Regulation of calcium metabolism 527
Table 2
Calcification
Biological
Cartilage
Bone
Teeth
Pathological
Dental calculus
Urinary tract stones
Ectopic bone, e.g., my ositisossificans progressiva,
haematomas, paraplegia
Dystrophic
Ca and P concentrations normal. Mechanism
possibly tissue damage leading to nucleation
of crystals, e.g., blood vessels, Monkeberg's
medial calcinosis, costal cartilage, TB lesions,
haematomas, bursitis, skin (calcinosis, sclero-
derma, dermatomyositis)
Metastatic
Ca or P concentrations high
e.g., blood vessels in renal failure, also cornea,
gastric mucosa, lung alveolar septa (perhaps
because CO. is liberated and pH raised)
brain in hypoparathyroidism, kidney in hyper-
calcaemia
ling and growth of existing bone (Table 2). The
concentrations of calcium and phosphate in ECF
are insufficient to initiate the deposition of calcium
phosphate but can sustain crystal growth once it has
started. The first steps in calcification are now
thought to take place in or around small membrane-
bound vesicles found in the matrix. These vesicles
appear to arise from the plasma membranes of
hypertrophic chondrocytes during the maturation
of epiphysial cartilage. Their source in bone is not
identified. These vesicles are rich in alkaline phos-
phatase, an enzyme which has been known for many
years to be associated with calcification. Alkaline
phosphatase may function in calcification as a
component of a membrane pump for calcium and
phosphate, or it may be involved in the removal
of potential inhibitors of calcification such as
inorganic pyrophosphate (PPi).
In hypophosphatasia, which is a recessively
inherited skeletal disorder characterised by a defic-
iency of alkaline phosphatase, there are increased
concentrations of PPi in plasma. Since PPi is an
inhibitor of the crystal growth of calcium phosphate
it may be responsible for the defective calcification
of cartilage and bone seen in this condition (Russell
and Fleisch, 1975). Some other causes of defective
528 R. G. G. Russell
skeletal mineralisation are included in Table 3.
Rickets is the term used to define failure of minerali-
sation of cartilage in long bones and is seen in grow-
ing children. Osteomalacia has several meanings
and to some people implies a state of vitamin D
deficiency. The term may be used to describe the
clinical features of D deficiency, or it may be
restricted to the histological abnormality in bone
irrespective of the cause. Excess osteoid is perhaps
a better term for the latter abnormality and is
characterised by the presence of unmineralised
matrix on trabecular surfaces in bone.
Calcification can occur outside the skeleton at
many sites within the body in pathological states
and it is remarkable how specific some of these sites
are for particular diseases, e.g., the basal ganglia
in hypoparathyroidism, and ectopic bone formation
around the hips in paraplegia (Table 2). Inhibitors
of calcification may partly contribute to impaired
Table 3. Some causes of excess osteoid (uJfmineralised
bone matrix)
Vitamin D deficiency or defective metabolism
Nutritional deficiency of vitamin D
Lack of sunlight
Malabsorption of vitamin D
Chronic renal failure
Vitamin D-dependent rickets
Low plasma phosphate
Phosphate deficiency
Renal tubular disorders (vitamin-D-resistant
rickets)
Chronic acidosis
Ureterosigmoidostomy
Renal tubular acidosis (proximal or distal)
High bone turnover
Fracture healing
Paget's disease
Hyperparathyroidism
Hyperthyroidism
Drugs
Anticonvulsants
Diphosphonates
Fluoride
Inherited
Fibrogenesisimperfecta ossium
Hypophosphatasia
Other unexplained
Axial osteomalacia
calcification of bone and cartilage in chronic renal
failure. Acidosis, such as occurs after ureterosig-
moidostomy or in renal tubular acidosis, can lead
to excess osteoid. The mechanism may be that initia-
tion of mineralisation is more difficult in an acid
environment because of increased solubility of
calcium phosphate but it may also be due to the
hypophosphataemia which is usually also present.
Conceivably acidosis may also disturb the metabol-
ism of vitamin D.
Resorption of bone is an essential part of the
remodelling and growth process (Harris and Heaney,
1969; Raisz, 1970; Raisz and Bingham, 1972),
and is mediated by mononuclear and multinuclear
osteoclasts, some of which may be macrophages
originating outside bone. Osteoeytes are probably
responsible for some hormone dependent rapid
fluxes of ions in and out of bone.
Under physiological conditions resorption is
probably under the control of PTH, vitamin D,
thyroid hormones and steroids, but will occur at a
basal rate in the absence of these hormones. Several
other agents can stimulate bone resorption under
experimental conditions and may be important
in disease. Vitamin A is one of these. Prostaglandins,
particularly of the E series, are also resorbing agents
and may be important in some of the hypercal-
caemias of malignancy and in the bone dissolution
that accompanies rheumatoid arthritis (Robinson
et al., 1975). Myeloma cells and activated lympho-
cytes can produce materials which cause resorption
in vitro (Raisz et al., 1975, Fig. 8) and which have
been designated OAF (osteoclast activating factors).
The biochemical events occurring during bone
resorption are poorly understood. Some resorbing
agents, such as PTH and prostaglandins, can stimulate
the production of cyclic AMP in bone but others.
e.g., 1,25(OH)2CC, do not. Inflow of calcium ions
into bone cells may be an early event in their
stimulation. Ionophores which promote the entry
of calcium ions into cells can be shown to stimulate
resorption. Bone resorption in tissue culture is
accompanied by release of enzymes such as collagen-
ase (Harris and Krane, 1974) and lysosomal enzymes
capable of degrading matrix. Osteoclasts viewed by
electron microscopy possess a ruffled border which
is closely applied to the bone surface and is presum-
ably the site at which removal of bone mineral and
matrix occurs. Administration of calcitonin, which
inhibits resorption, causes retraction of this border
and eventually leads to a decreased number of
osteoclasts. Apart from calcitonin several other
inhibitors of resorption exist. These include oestro-
gens, mithramycin and diphosphonates. Inhibitors
of bone resorption are useful therapeutic agents in
certain clinical disorders (Table 4).
 Regulation of calcium metabolism 529

Radioisotopes and bone: Bone scanning

The affinity of bone mineral for various ions is of
60 .PTH importance in radiobiology and clinical diagnosis.
-OAF Radioisotopes such as 226Ra and 239Pu are bone
a CQ\JTROI.
~ 50
seekers and can be derived from exposure to indust-
rial sources or fallout from nuclear explosions.

~ 40
Radium workers develop bone tumours and 239Pu
can produce tumours in experimental animals.

~
Isotopes such as B9Sr and 18F have been used
clinically as scintigraphic agents for detecting regions
~ 30 of increased bone turnover such as in metastatic
~ tumour deposits. Recently pyrophosphate, poly-
~ 20 phosphates and diphosphorates, all of which have a
~ high affinity for crystals of hydroxyapatite, have
~~ been used as effective bone scanning agents (Hosain
~~ 10 et al., 1973) by linking them to the gamma-emitting
t5 isotope, J9mtechnetium, in the presence of stannous
Q\3~
q:
ions to produce J9mTc-Sn-PP.
0
2 3 4
TREATMENT Cell calcium and cyclic AMP
DAYS IN CULTURE
Fig. 8.-BOIle resorptlOll stimulated by osteoclast activating It is now recognised that there are significant
factor (OAF) derived from Iympbold cell lines compared interrelationships between intracellular calcium,
with the action of PTH. The release of tiCa from pre- cyclic AMP, and cell activation in response to various
labelled rat fetal bone was measured In organ culture in stimuli. Fig. 9 shows a simple scheme to illustrate
vitro (from Raisz et al., 1975). some of these interrelationships.
Cell calcium

_____.1.-_-+__.......
Act Ive Ca 2 +
Ca2 +_ _....L..--,....-I---....L----_
(10- 3M) e1O-3M)

Hormones

Mitochondria

Fig. 9.-Simpllfled general scheme to show major events thought to Influence Intracellular calcium cOIlcentration. Cytosol
calcium is thougbt to lie in the range of 10- 1 - 10- 1 mol/I.
530 R. G. G. Russell

Table 4. Therapeutic agents in calcium metabolism

Agent Use Mechanism of Action

Calcium
dietary supplement osteoporosis Bone resorption ~
intravenous hypocalcaemia
Phosphate
oral renal tubular disorders, Bone mineralisation t
vitamin D resistant rickets in
which plasma P ~
renal stones Urine Ca t PPi t
intravenous hypercalcaemia ?precipitation of calcium
phosphate
Vitamin n, or D. } Correction of vitamin D Intestinal absorption t
deficiency Bone resorption t
Dihydrotachysterol
1,25(OH)zCC, 250HCC Hypoparathyroidism
Vitamin D-resistant rickets
la-OHCC Chronic renal failure
Calcitonin (porcine, salmon Paget's disease Bone resorption and turnover ~
or human) Hypercalcaemia Bone resorption and turnover ~
Oestrogens Post-menopausal or Bone resorption ~
post-oophorectomy bone loss
Fluoride Osteoporosis Bone formation t
(plus vitamin D and calcium
supplements)
Diphosphonate (EHDP) Ectopic calcification Calcification ~
Paget's disease Bone turnover ~
Mithramycin Paget's disease Bone turnover ~
Hypercalcaemia due to bone
metastases or myeloma
Thiazides Renal stones Urine Ca ~
Anabolic steroids Obsolete

Cytosol calcium concentrations are thought to be
100-1000 times lower than extracellular-i.e., in the
range of 10-5-10- 6 mol/I. Within cells mitochondria
are capable of accumulating large amounts of
calcium against electrochemical gradients, to the
point at which intramitochondrial deposits of
insoluble calcium phosphate can form (Borle, 1973).
The activation of many different types of cells by
hormones or pharmacological agents is now
thought to be accompanied by increases in intra-
cellular calcium concentration, derived from outside
the cell or by release from mitochondria (Rasmussen
and Goodman, 1975). Hormonal activation is often
associated with stimulation of adenylate cyclases
specific to the target tissue. The changes in cyclic
AMP and intracellular Ca then produce further
responses within the cell, e.g., by changing enzyme
activity. In many systems addition of cyclic AMP
can mimic hormone action, as can those ionophores
which increase the transport of calcium into cells.
In the case of parathyroid hormone, cyclic AMP
and ionophores can each independently induce
resorption in bone explants (Dziak and Stern, 1975)
and each can also stimulate mitosis in lymphocyte
cultures. These interactions have been reviewed
extensively elsewhere (Borle, 1973; Rasmussen and
Goodman, 1975; Robison et al., 1971). In some
systems the concentration of 3'5'-cyclic guanosine
monophosphate (cyclic GMP) changes in the oppo-
site direction to that of cyclic AMP, and produces
opposing effects, a phenomenon which has led to
the so-called "Yin and Yang" hypothesis (Goldberg
et aI., 1973). An example of some of these inter-
relationships are shown in Fig. 10 for the release of
lysosomal enzymes from neutrophils (Smith and
Ignarro, 1975) a system which contrasts with those
described above in that cyclic GMP is stimulatory
and cyclic AMP and calcium ions are inhibitory.

NEUTROPHL
ATP
-++tolfa~ENYLATE
EPlNE"HIIINE
PIlOSTAGLAMlINS
__
\:YCLASE A- .' 11.
'i~LI!iC.!.A!!M!!P:'4---ttr CYCLIC AMP
_,..OTEIN
! KINUE
IRUNE .[ACTANT PItOSPHllIlYLATION
IlUST IE ,,,,nUT
~_...
AT . - :
IONOPHORES
e!IAY INIIOLVE LYSOSOMES.
(DIVALENT)
llICROTUIULES. PLASMA MEMBRANE. ?
Fig. lO.-Postuiated interactions between calcium ions,
cyclic AMP and cyclic GMP, and other agents during the
release of lysosomal enzymes from human neutropbil
blood cells in vitro (abbreviation PDE = phosphodiesterase)
(from Smith and Ignarro, 1975).
INTEGRATION OF INDIVIDUAL ORGAN RESPONSES
It is useful to draw some distinction between the
way in which the plasma calcium is set at a particular
value, and the way the movements of calcium
in and out of extracellular fluid (ECF) are controlled.
The plasma calcium is set close to a particular value
in different individuals in normal and disease states.
Deviations from this value are corrected by hormone-
induced changes in the relative fluxes of calcium
in and out of the ECF. Alterations in the flux rates
are therefore monitored and adjusted by the changes
in plasma calcium (or phosphate) concentration
they induce. This homoeostatic system could operate
with the plasma Ca set at any number of different
values with the relative rates of entry and exit
of calcium to and from the ECF being altered as
drift occurs from this set point.
Thus in hyper- and hypoparathyroidism the fluxes
of Ca across the gut and in and out of bone may not
be greatly different than normal and external
calcium balance can be maintained (net intestinal
absorption = urine loss) even though the plasma Ca
is set at markedly different levels (Fig. II). The
plasma Ca thus provides the point around which
adjustments are made.
In considering homoeostasis it is also helpful to
distinguish between acute and chronic changes.
When the system is disturbed, a steady state no
longer exists, and the response which occurs adjusts
Regulation of calcium metabolism 531
the system so that a new steady state comes into
existence. The flux rates through individual organs
and the level of plasma Ca mayor may not be the
same as previously depending in part on whether
the disturbance to the system is sustained or not.
LYSOSOMAL Regulation ofplasma calcium: Acute responses
ENZYIIE
$lCRETION The total concentration of calcium in plasma is
normally around 2-2.5 mrnol/l. Of this about
1.2 mmol/l is present as ionised calcium (Ca2+),
the remainder is complexed to proteins especially
albumin, and to small ions such as citrate and
GMP phosphate. It is the ionic Ca2+ which is regulated.
Under most circumstances Ca2+ bears a constant
relationship to total plasma calcium. The concentra-
tion of extracellular Ca2+ is important for neuro-
muscular function and other membrane responses
and is also involved in biological events such as
blood coagulation.
Deviations of plasma Ca2+ away from its normal
value are rapidly corrected by alterations in the
secretion of the regulating hormones. In many
mammals PTH and calcitonin (Fig. 4) both respond,
but in opposite directions, but in man it is doubtful
whether CT changes. PTH and CT can be con-
sidered the fast acting (minutes to hours) component
of the regulatory system whereas vitamin D is
responsible for adaptation in the longer-term (hours
to days). In experimental animals removal ofsources
of PTH and CT (e.g., thyroparathyroidectomy in
dogs or rats) results in a slower than normal return
of plasma calcium to starting values in response to
acute changes in plasma calcium.
In man the most important regulator of acute
changes of the concentration of Ca2+ is parathyroid
hormone (PTH) which increases within seconds of a
fall in plasma Ca2+, and decreases as Ca2+ rises.
The rapid control of plasma Ca2+ by PTH is mainly
due to its ability to regulate renal tubular reabsorp-
tion. After parathyroidectomy the fall in plasma
Ca2+ can largely be accounted for by a continuing
loss of Ca2+ into urine until a new steady state is
achieved in which calcium excretion may not be
greatly below its starting value but takes place at a
much reduced filtered load of calcium. The intestinal
responses are too slow to account for rapid changes
in plasma calcium but the bone does playa part.
Thus there is an important buffering action of bone,
so that rises or falls of plasma calcium are partially
compensated by increased net movements of calcium
into or out of bone respectively. This is partly a passive
process but there is probably also a contribution
from changes in PTH-mediated osteolysis. In animals
in whom the fluxes of calcium in and out of bone are
relatively much greater in relation to fluxes through
532 R. G. G. Russell
Ca mg/day

Hypoparathyroidism Normal Hyparparathyroldlsm

Fig. 11 (a)

200lllll 200ml 200ml

Ca mg/day

Hypoparathyroidism Normal

+
Ca infusion -

200mg 1.200mg 200mg

Fig. 11 (b)

Fig. 11.---SCheme to show relationship between plasma and urine calcium. The arrow entering the kidney represents the
filtered load under various conditions. calculated assuming approximately 60 % of plasma calcium to be ultra Wtrable ..-
glomerular Wtration to be 120 ml/min. The arrow from the kidney to the plasma compartment represents tubu....
reabsorption. The difference between the filtered load and reabsorbed calcium Is that excreted In the urine. (a) Makes t.IIe
point that urine calcium can be normal in hypo and hyperparathyroidism even though plasma calcium Is markedly abnormaL
ThIs Is because there Is diminished tubular reabsorption of calcium In hypoparathyroidism Bnd enhanced reabsorptioB ..
hyperparathyroidism. This is Illustrated (b) by the Infusion or calcium Into hypoparathyroid patients; when plasma caldta
Is restored to normal by infusion, urine calcium Is much higher than In normal persons because of diminished renal tu!JIIIIr
reabsorption.

kidney and intestine than they are in man, changes
in bone resorption (and formation) are quantitatively
more important than in man for producing acute
changes in plasma Ca. This is well illustrated by
examining the acute responses of plasma Ca to
injection of calcitonin, the most significant acute
effect of which is to inhibit bone resorption. In
normal man there is a negligible fall in plasma
calcium, whereas in rats, particularly in young
animals in which bone turnover is high, there may
be a marked decrease in plasma calcium. Simple
calculations verify that in normal man complete
abolition by calcitonin of the small flux of calcium
out of bone could not be expected alone to cause a
significant fall in plasma calcium. However, in
situations where bone resorption is quantitatively
greater in relation to the other fluxes, e.g., in patients
with Paget's disease or with tumour metastases
in bone, then an acute fall in plasma calcium can be
seen after given calcitonin.
Chronic changes
The response to prolonged perturbations brings
in contributions from changes in vitamin D meta-
bolism and from the intestine and bone. An example
is the adaptation that occurs to a change in dietary
intake of calcium. If intake is reduced this will tend
to cause a gradual fall in plasma calcium which will
increase the secretion of PTH. Apart from its effect
on the kidneys, a sustained increased in PTH will
lead to enhanced osteoclastic resorption of bone,
and an increase in 1,25(OH)2CC synthesis which will
enhance intestinal absorption of calcium and resorp-
tion of calcium from bone. If the reduction in
dietary calcium continues, these changes will act
to restore the plasma calcium towards its previous
value and bone formation rate will increase to match
the rate of increased bone resorption by the coupling
mechanism described below. The new steady state
will come to consist of a greater efficiencyof intestinal
absorption of calcium and an increased rate of entry
and removal of calcium from bone so that net
balance can be maintained. This response can be
seen very clearly in experimental animals and there
is good evidence that these adaptive changes occur
in man too. When dietary deprivation is so severe
that intake can no longer match output the reserves
of calcium in bone are utilised.
Other examples of steady states that exist during
chronic disturbances in calcium metabolism will be
considered under clinical disorders of calcium
homoeostasis.
Coupling offormation and resorption: Control ofbone
shape and mass
The skeleton can respond to hormones by increas-
Regulation of calcium metabolism 533
ing its uptake or release of calcium. In a variety
of both physiological and pathological steady states
(see Fig. 12) it is clear that there is a remarkably
close correlation between rates of mineral deposition
and mineral resorption. Even though these individual
rates may be altered many-fold, the net gains or
losses of skeletal mass are minimised by the tight
coupling between these rates. This is an important
feature of homoeostatic adaptation (Harris and
Heaney, 1969) that is often overlooked. Thus it is
difficult to achieve a sustained dissociation between
rates of mineralisation and resorption and this is
one reason why so many potential therapeutic agents
have been disappointing in the treatment of bone
disease, for example in increasing bone mass in
osteoporosis. Transient dissociations can occur,
however, for example in the acute loss of bone
mineral that occurs in response to immobilisation.
Evidence for coupling also comes from measurement
of alkaline phosphatase and urinary total hydroxy-
proline (THP) in Paget's disease of bone. There is a
close correlation between these two measurements
over a wide range of values. Alkaline phosphatase
is thought to be an indirect measure of bone forma-
tion rate, and urine THP in this situation to reflect
mainly the rate of resorption of bone collagen. The
mechanisms underlying this coupling are unknown.
It may involve cell to cell communication within
bone, in addition to external endocrine influences.
Another suggestion is that there is an obligatory
cellular differentiation of osteoclasts to osteoblasts,
which would couple rates of bone formation to pre-
vious rates of bone resorption (Rasmussen and
Bordier, 1974). Although this is an attractive
idea it has certain weaknesses and even if true can only
account for part of the phenomenon.
An additional feature of bone is its ability to
respond to mechanical deformation by changing its
structure and shape to counteract the stress. One
mechanism proposed to account for this involves
the generation of small electrical currents within
bone as stresses are applied. Such currents can
be demonstrated experimentally and are thought to
be due to the piezoelectrical properties of the mineral
and matrix components.
DISORDERS OF CALCIUM HOMOEOSTASIS
Detailed description of disorders of calcium
metabolism is beyond the scope of this review but
there have been several books and reviews published
on this topic recently (Fourman and Royer, 1968;
Morgan, 1973; Nordin, 1973; Paterson, 1974;
Krane and Potts, 1974; Potts and Deftos, 1974;
Schneider and Sherwood, 1974). The purpose of this
section is to illustrate some of the principles of
S34 R. G. G. Russell

. I
,
. , , w'

,,.
,, "
,,
,
,,
. '.
,?'
, w-

" , ,,

A 1. _ .,',t
...
C,"I/d) ... .
. . .. .- }.""

. .
. . -.,4
~,.
"',,:4.- .-
,.
..
..
..... .,,.
.,,-.
...,'.,..,,' .
..

, .:

.
,,
,, w
0.1
..
0.1 1. 10

R (,MId)

Fig. 12.-Relationshlp between accretion rate (A) and resorption rate (R) of bone detennlned by
radioisotope methods in patients with a variety of disturbances in calcium metaboUsm. Note that the
plot Is logarltbmic and there Is close correspondence between rates of accretion and resorption over
a wide Ij8Dge of values (from HarrIs and Heaney, 1969).

calcium homoeostasis as applied to chronic steady
states found in various diseases.
ExcessPTH
In primary hyperparathyroidism, due to adenomas,
hyperplasia or carcinoma, the concentration of
PTH is inappropriately high for the prevailing plasma
calcium, implying a defect in the gland for switching
off PTH secretion at normal levels of Ca2+. In
hyperparathyroidism the hypercalcaemia is main-
tained mainly by a resetting of the renal tubular
reabsorption mechanism for calcium, so that
reabsorption is enhanced at any given filtered load.
There is often also increased bone resorption and
increased intestinal absorption of calcium, and both
these will tend to increase urinary calcium excretion.
The calcium balance is usually normal but may be
negative, particularly in patients with severe bone
disease. The fact that bone and renal stone disease
do not usually occur in the same patients is intriguing
and unexplained, but may imply important differ-
ences in relative target organ responses to increased
PTH.
In secondary hyperparathyroidism, such as occurs
in renal failure or vitamin D deficiency, PTH is
high as an appropriate response to hypocalcaemia.
In both these conditions there is an impaired target
organ response to PTH which prevents the plasma
calcium from returning to normal. After removal of
the hypocalcaemic stimulus, e.g., after renal trans-
plantation, it may take a long time for the hyper-
plastic glands to respond appropriately to plasma
calcium, so that hypercalcaemia may persist for

months. In pseudohypoparathyroidism there is
also an appropriate excess of PTH due to hypo-
calcaemia, but again a failure in the target organ
responses of bone and kidney.
Deficiency ofPTH
In hypoparathyroidism the persistent hypocal-
caemia is largely due to a resetting of renal tubular
reabsorption so that there is a relative renal leak
of calcium compared with normal. Bone turnover
(formation and resorption) is diminished and in-
testinal absorption of calcium can be low. External
balance can be maintained (urine Ca = net intestinal
absorption) even in the face of hypocalcaemia.
When vitamin D 1 , 1,25(OH)2CC or its analogue
lor. hydroxycholecalciferol (lor. (OH)CC) is given to
such patients plasma calcium can rise due to a massive
increase in intestinal absorption of calcium, and
possibly to enhanced bone resorption. Vitamin D
metabolites cause no obvious change in the renal
tubular handling of calcium, but large doses of
vitamin D itself may do so. Thus in treated hypo-
parathyroidism net intestinal absorption and urinary
loss of calcium may be matched but at high levels
(c. 1000 mg/day) and calcium balance thereby main-
tained. There is increasing evidence that, in untreated
hypoparathyroidism, 1,25(OH)2CC may be pro-
duced in less than normal amounts, perhaps due to
the lack of PTH or to hyperphosphatemia.
Excess of vitamin D
The metabolism of vitamin D is regulated so that
the rate of formation of l,25(OH)2CC is homoeo-
statically controlled. However other metabolites
have some biological activity which may be import-
ant when large doses of vitamin D are given. There
may then be enhanced intestinal absorption and
urinary excretion and increased resorption of bone.
Hypercalcaemia can occur, usually in association
with reduced glomerular filtration, and with some
evidence for increased renal tubular reabsorption of
calcium (Nordin, 1973).
Deficiency of vitamin D
In vitamin D deficiency bone mineralisation and
resorption both diminish, as does intestinal absorp-
tion of calcium. In chronic vitamin D deficiency
faecal calcium may exceed dietary intake because
absorption is less than the loss in intestinal secretions.
In the face of continuing net loss of calcium from the
body, at the expense of the bone, plasma calcium
falls below the renal threshold to a point at which
tubular reabsorption of calcium approaches 100%,
Regulation of calcium metabolism 535
so that urinary calcium may become undetectable.
The renal tubular handling of calcium in vitamin D
deficiency has not been studied in detail and it is
possible that vitamin D in physiological doses is
able to increase tubular reabsorption, either directly
or by allowing the action of PTH to be expressed.
In vitamin D deficiency the enhanced secretion of
PTH is apparently unable to exert its usual effect,
not only on the kidney, but also on bone.
Disturbed metabolism of vitamin D
Features of deficiency of vitamin D may be present
where there are adequate supplies of vitamin D
but its metabolism is disturbed. In osteomalacia
associated with anticonvulsant drugs it is claimed
though not proven that there is increased metabolic
degradation of vitamin D to inactive metabolites
due to hepatic enzyme induction. In the rare condi-
tion of pseudo-vitamin D deficiency (vitamin
D-dependent rickets) it is thought that the enzyme
responsible for the renal production of 1,25(OH)2CC
is deficient (Fraser et al., 1973). A much commoner
cause of this is renal failure itself, in which renal
production of 1,25(OH)2CC is probably defective
(Mawer et al., 1973).
Sarcoidosis may be another disorder in which the
metabolism of vitamin D is disturbed. Some patients
with sarcoidosis have increased intestinal absorption
of calcium and increased bone resorption which may
sometimes produce hypercalcaemia. They are ab-
normally sensitive to exogenous vitamin D and
respond to glucocorticoid therapy. These are the
features that might be expected from a condition
in which 1,25(OHl2CC would be produced in
excess of normal.
Calcitonin deficiency and excess
No examples are known of CT deficiency contri-
buting to human disease. The clinical syndrome of
medullary carcinoma of the thyroid, a cell tumour
medullary carcinoma of the thyroid, a C-cell
tumour which secretes large amounts of CT, is
remarkable for the lack of detectable disturbances in
calcium metabolism.
Disorders of calcium intake
Dietary deficiency of calcium is uncommon. In
experimental animals it leads to osteoporosis and
not to osteomalacia, and does not lead to significant
hypocalcaemia. In man dietary deficiency of calcium
has been postulated to contribute to senile osteo-
porosis and to the osteoporosis associated with
alcoholism. Experimentally in man it can be shown
that a low intake of calcium is associated with a rise
536 R. G. G. Russell
in PTH and an increase in bone resorption, and in
spite of increased efficiency of intestinal absorption,
this may be insufficient to prevent a negative balance
from occurring at very low intakes.
Malabsorption of calcium occurs in a variety of
intestinal disorders, usually in association with
malabsorption of vitamin D, as in gluten-sensitive
enteropathy and pancreatic steatorrhea. The changes
seen in calcium metabolism are those of vitamin D
deficiency.
Intestinal hyperabsorption of calcium may be an
important cause of the "idiopathic" hypercalciuria
associated with renal stone disease. The increased
intestinal absorption is matched by increased urinary
loss so that patients are usually in neutral calcium
balance.
Disorders 0/ renal excretion
There is no convincing evidence for primary
disorders of renal excretion. Increased renal loss
of calcium can be caused by acidosis and may be a
contributory factor to the development of bone
disease in patients with renal tubular acidosis or
pyelonephritis.
Disorders 0/ bone turnover
There are a number of disorders associated with
abnormal bone turnover. Several are inherited
diseases, e.g., osteogenesis imperfecta, hyperphos-
phatasia, fibrogenesis imperfecta ossium, various
epiphysial, metaphysial and diaphysial dysplasias,
neurofibromatosis, etc. (McKusick, 1972; Wynne-
Davies, 1973). In most of these there is no apparent
systemic disturbance in calcium metabolism.
In Paget's disease ofbone there is enhanced resorp-
tion and formation of bone but the two processes
remain coupled so that there is again no marked
systemic disturbance in calcium metabolism unless
coupling is temporarily disturbed. This may occur
during immobilisation when the rate of resorption
of bone can exceed formation so that hypercalcaemia
and hypercalciuria may develop. This again illustrates
the fact that when the fluxes of calcium in and out
of bone are high enough, acute changes in one of
these rates relative to the other can alter the plasma
calcium without any change in the renal handling
of calcium.
In osteopetrosis, bone resorption is impaired but
calcium metabolism is otherwise not remarkably
abnormal, and there are normal levels of PTH and no
increase in cr. However, the increased bone mass
in such patients implies that they must sustain a
slightly more positive calcium balance during growth
than is normal.
The calcium disturbances that occur in myeloma
and malignancy are also due to changes in bone
turnover. In myeloma bone resorption is increased,
perhaps by agents such as OAF, and this can cause
hypercalciuria. Renal tubular handling of calcium
does not appear to change (Nordin, 1973) so that
when hypercalcaemia occurs it is mainly due to a
superimposed fall in renal glomerular filtration rate
produced by deposition of immunoglobulin chains
in the kidney and by dehydration. The hypercal-
caemias of other malignant states are probably
caused in a similar way, although those associated
with ectopic secretion of PTH, especially by broncho-
genic and renal carcinomas, may be due to a PTH-
like action on the kidney.
Another group of important disorders of bone
turnover are those that cause osteoporosis. Osteo-
porosis or osteopenia may be defined as a diminution
of bone mass without there being any detectable
change in the chemical composition of the bone in
terms of its mineral versus matrix content. Osteo-
penic bone therefore differs from osteomalacic bone,
which has a diminished mineral versus matrix
content. Current methods for assessing bone mass
in vivo are not entirely satisfactory. They include
measurements of metacarpal cortical thickness by
x rays, and photon densitometry techniques applied
to long bones, especially the ulna and radius.
Neutron activation is the only method for measuring
total body calcium in vivo.
Some causes of diminished bone mass are shown
in Table 5. From a theoretical viewpoint, bone mass
can diminish as a result of a number of different
disturbances in calcium metabolism. These include
diminished rates of net intestinal absorption or net
bone formation, or increased rates of bone resorption
or urinary loss of calcium. Changes in one or more
of these have been claimed to contribute to the
osteoporosis of different causes. The most important
forms of osteoporosis from a public health stand-
point is that which occurs after the menopause in
women and that associated with old age, both of
which are major causes of fractures. Colles fractures,
vertebral crush fractures, and fractures of the neck of
the femur are the most common. The causes of this
type of osteoporosis are still debated and are likely
to be multifactorial.
One difficulty in studying the problem is that the
disturbances in calcium metabolism need only be
very small over a prolonged period to produce a
diminution in bone mass, e.g., in the order of a net
increase of bone resorption over bone mineralisation
of 30 mg/day, Such subtle changes are beyond the
sensitivity of techniques currently used to study
calcium homoeostasis. Good discussion of this
problem can be found in the monographs by
Morgan (1973) and Nordin (1973).

Table S. Some causes of osteoporosis iosteopenia or thin
bones)
Primary
Old age
Post menopause or post-oophorectomy
Idiopathic juvenile osteoporosis
Secondary
Dietary deficiency of calcium or malabsorption
Steatorrhea
Partial gastrectomy
Chronic liver disease
Endocrine
Hyperparathyroidism
Hyperthyroidism
Cushings syndrome
Hypogonadism
Metabolic
Vitamin C deficiency
Pregnancy
Osteogenesis imperfecta
Drugs
Corticosteroids
Heparin
Immobilisation generalised, e.g., space flight
localised, e.g., after fracture,
paraplegia
Rheumatoid arthritis
Chronic renal failure or dialysis
Rapidly developing bone loss, e.g., in response to
immobilisation (including space flight), pregnancy
or in idiopathic juvenile osteoporosis, can be shown
to be due to a greater rate of bone resorption com-
pared with bone formation, with the excess calcium
being lost in the urine to produce a negative calcium
balance. This state does not persist so that calcium
metabolism usually returns to normal after several
weeks.
Therapeutic agents in calcium metabolism
Table 4 contains a list of some of the agents used
in the treatment of disorders of calcium and phos-
phate metabolism. It should be stressed that most
agents that increase or decrease rates of bone
mineralisation and resorption relative to each other
only do so temporarily. Rates of mineralisation
and resorption soon readjust so that the coupling
between the two rates is maintained.
PHOSPHATE METABOLISM
Several aspects of phosphate metabolism have
already been discussed in relation to changes in
calcium metabolism.
Regulation of calcium metabolism 537
Distribution and fluxes ofphosphate
Table 1 showed that phosphate is an important
intracellular as well as extracellular ion.
In adult man phosphate intake (expressed in terms
of phosphorus) is usually in the range 0.5-2.0 g per
day. Unlike calcium the major part of this (c. 80%)
is absorbed from the intestine, and in normal
adults this amount appears in the urine each day.
As with calcium the major fluxes of phosphate
take place at the kidney, with about 85-95 % of the
filtered load being reabsorbed. The efficiency of
reabsorption can increase to nearly 100 % if plasma
phosphate falls. Phosphate movements in and out
of bone are approximately one-half those of calcium
in molar terms.
Plasma phosphate and the kidney
Plasma phosphate varies more than plasma
calcium, particularly in response to circadian
rhythms and to meals. The level of fasting plasma
phosphate is set mainly by the kidney and the
measurement of the renal handling of phosphate
is often used in clinical diagnosis, e.g., in primary
hyperparathyroidism. Of the several methods that
exist for determining the reabsorptive capacity
the best is probably the measurement of TmP/GFR.
A nomogram has been produced for deriving
this measurement (Walton and Bijvoet, 1975).
Phosphate reabsorption is increased by growth
hormone and in hypoparathyroidism, hyperthyroid-
ism and in phosphate deprivation. It is diminished in
hyperparathyroidism and in several inherited or
acquired renal tubular disorders, where it may also
be associated with defects in the reabsorption of
glucose, amino acids or bicarbonate.
Phosphate and bone in health and disease
Phosphate plays an important role in skeletal
mineralisation. The ability to produce mineralisation
is more than a simple function of the (Ca) x (P)
product, although low products do tend to be associ-
ated with defective skeletal mineralisation and high
products with the ectopic deposition of calcium
phosphate. Phosphate may have specific effects on
cells to enhance the uptake of calcium in calcifying
tissues.
It is noteworthy that defective skeletal mineralisa-
tion can occur, in several, though not all, situations
where a low plasma Pi exists, e.g., in phosphate
deprivation syndromes, or in the inherited or ac-
quired renal tubular disorders (see Table 6) in
which renal phosphate reabsorption is diminished.
In many of these conditions administration of phos-
phate alone can improve skeletal calcification. There
538 R. G. G. Russell
Table 6. Some causes 0/ hypophosphatemia
Decreased intestinal absorption
Low dietary intake
Malabsorption
Antacids (e.g. Al(OH). which binds PI)
Increased renal loss, low renal threshold
PTH excess primary hyperparathyroidism
pancreatitis
Renal tubular disease
Inherited Familial (sex-linked and other)
Cystinosis
Renal tubular acidosis (distal)
Acquired Wilson's disease
Neurofibromas and mesenchymal
tumours
Mercury poisoning
Post-transplant kidney
Acidosis (ureterosigmoidostomy)
Increased GPR-pregnancy
Increased entry into cells
Hyperalimentation
Diabetic ketoacidosis
during treatment
Alkalosis
Unexplained
Alcoholism
are interesting differences in the disturbances that
accompany hypophosphatemia. In some conditions
(e.g., dietary phosphate deprivation, vitamin D de-
ficiency, hyperparathyroidism and some renal tubular
disorders), but not all (e.g., X-linked hypophosphat-
emicrickets), there may bemuscular weakness. Dietary
deprivation of phosphate is associated with increas-
ed intestinal absorption of calcium which is not
seen in other hypophosphaternic states, perhaps
because this is the only condition in which hypo-
phosphatemia is able to stimulate the renal produc-
tion of l,25(OH)aCC.
Adequate concentrations of phosphate are prob-
ably required for proper formation of bone matrix
as well as for its subsequent mineralisation. There
is also experimental evidence that phosphate can
reduce the rate of bone resorption.
In rats it is noteworthy that rickets does not
develop with deficiency of vitamin D alone unless
phosphate deprivation is also superimposed. This
may mean that the high plasma phosphate found in
rats is able to sustain skeletal mineralisation even in
the absence of vitamin D and also indicates that
defective skeletal mineralisation due to vitamin D
deficiency in human disease could be largely due to
the accompanying hypophosphatemia.
Phosphate as a therapeutic agent
Phosphate is used as a therapeutic agent in several
disorders of calcium metabolism. Intravenous
phosphate can be used to lower plasma calcium in
acute hypercalcemic states. The way in which it
works is uncertain and may include one or more of
the following effects: precipitation of calcium as
insoluble calcium phosphate, with uptake by soft
tissue, the reticuloendothelial system or bone;
increased uptake of calcium by cells or diminished
release of calcium from bone, either due to a direct
effect to inhibit bone resorption or by stimulating
secretion of calcitonin. Oral phosphate is also some-
times used to treat chronic hypercalcaemia.
Oral supplements of phosphate can reduce the
rate of production of calcium-containing renal
stones (Smith et al., 1973).
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This work has been supported by,the US Public Health
Service (Grant No. Am-0(501) and by the National
Fund for Research into Crippling Diseases.