Ann. Din. Biochem.: Regulation of Calcium Metabolism

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

is outside the skeleton, the remainder within it. This
Most of the body's calcium resides within bone exchangeable pool of calcium is very important in
(Table 1). The other major inorganic constituent homoeostasis, and movements of calcium ions be-
of bone is phosphorus, as inorganic phosphate (Pi). tween body fluids. cells, and the surfaces of bone
Unlike calcium, the concentration of which is low occur continuously. Between 1 and 4 %of the human
in most soft tissues, about 15 % of the body's adult skeleton is thought to be renewed each year.
phosphorus lies outside the skeleton, in body fluids Trabecular bone has a faster turnover than cortical
and in tissues, mostly as organic phosphate com- bone.
pounds, e.g., nucleic acids and nucleotides, phospho- In order to understand the way in which the body
lipids and phosphorylated metabolites. gains and loses calcium from the external environ-
Studies with radioisotopes (45Ca and 47Ca) have ment and the way in which internal control is
shown that in normal human adults the exchangeable achieved the system can be simplified to a considera-
pool of calcium represents less than 1 % of total tion of the roles of the three major organs involved,
body calcium (in the region of 70 mg/kg during the i.e., gut, lddney, and bone, and the pool to and from
first few days after injection). About half of this which calcium moves.
518
RegUlation 0/ calcium metabolism 519
MAJOR FLUXES OF CALCIUM During growth there is a net daily gain to provide
AND NET CALCIUM BALANCE the calcium necessary for skeletal growth. In preg-
nant or lactating women the foetus or child pins
. The major movements (fluxes) of calcium through calcium from the mother. In these situations the
tbeIlc organs in an adult human are shown in extra requirements are met by increased net intestinal
Pia. 1. absorption and diminished renal excretion of Ca so
Calcium enters the body by intestinal absorption. that a neutral balance is maintained in the mother.
The true absorption of calcium is greater than the Calcium homoeostasis is concerned with the
uet absorption because some calcium is returned relative rates of flux through these organs and the
to the gut lumen in biliary, pancreatic, and intestinal complex way in which these are changed by regulat-
ICCI'Ctions. Calcium is lost from the body by urinary ing factors, particularly parathyroid hormone (PTH),
excretion and also in sweat. The latter is usually calcitonin (Cf), and vitamin D (vit D). The concen-
ianored in balance studies because the loss is small trations of calcium and phosphate in extracellular
and cannot be measured easily. However, losses in fluid (ECF) are set by the relative sizes of the various
sweat can be as high as 300 mg/day under extreme fluxes and by the influence of controlling agents
conditions. It will be noted that the fluxes of calcium on them.
through the kidney, as filtered and reabsorbed The properties of the hormones acting on calcium
. calcium are many times higher than the fluxes metabolism will be discussed first, followed by a
through the intestine and bone. description of some features of the individual organ
In the adult under normal conditions the body is responses to them. The hormones can be subdivided
, neither gaining nor losing calcium, so that inflow into "controlling" hormones and "influencing" hor-
; and outflow are matched precisely (intake = output). mones. The controllers are the primary calcium
In disease states there may be transient or sustained regulating hormones, PTH, cr and vitamin D
net gains or losses, to produce calcium balances metabolites, the secretion of each of which is altered
that are positive (intake exceeds output) or negative in response to changes in plasma ionised calcium
(output exceeds intake). concentration (and phosphate in the case of vit D).
Mljor .It..
of PTH.cllcitonin & vitlmln D
of .ctlon
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
l000mg
in plasma calcium and phosphate.
1 Vii D
G>
.. ----_.-- .... -.
THE CoNTROLLING HORMONES
! ',200mg
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
BOOmg 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
200mg biologically active fragment and a larger inactive
C-terminal fragment. The function of this cleavage
Fig. 1.-The majOl' movements of calcium (mgfday) through is unknown. The C-terminal piece is the major
the principal organs (intestine, kidney, and bone) involved PTH component measured in many radioimmuno-
In calcium bomoeostasls in a normal adult man. The major
sites of acrion of parathyroid bormone (PTH), calcitonin
assays.
(en, and vitamin D are shown. Note that balance is In common with several other peptide hormones
maintained, oot only by the skeleton (mIner'lllisatioo = PTH is synthesised as a prohormone, which contains
resorption) but also by the whole organism (net intestinal an additional 6 amino acids on its N-terminal end
absorption = urinary loss). (Fig. 2). A further precursor form, pre-pro PTH,
520 R. G. G. Russell
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
Fig. 2.--Structure of bovine proparathyrold hormone. The and Deftos, 1974). The complete structure is knowr
arrow between positions 6 and 7 shows the site of cleavage for the bovine, ovine, porcine, salmon, and human
of the probormone to produce PTH itself (after Potts and hormones (see Fig. 4). There are many differences
Deftos, 1974). in the amino acid composition of the calcitonins
from different species and this is associated with.
containing a total of 115 amino acids has now been different potencies. Surprisingly, the salmon hor-
identified in studies in vitro (Habener et al., 1975). mone resembles the human more than other mam-
These precursor forms are probably converted to the malian calcitonins. In the treatment of Paget's
84-amino acid peptide before secretion from the disease the salmon hormone is more effective on a :
gland. molar basis than the human hormone itself.
The major physiological stimulus to secretion of Calcitonin is secreted by specialised cells desig-
PTH is a fall in plasma ionised calcium concentra- nated C cells, which are part of the APUD cell
tion (Ca2+). A rise in plasma Ca2+ above normal series derived embryologically from the neural cres
suppresses PTH secretion (Fig. 3). Other ions play (pearse and Polak, 1972). The C cells are located ill
only a minor role, but in the presence of low levels different sites in different species. In man and pig
of Mg2+, the secretion of PTH is impaired and this, they are found mainly in the thyroid gland, although
together with an impaired target organ response to in man there are some in the thymus. In fishes and !
PTH, may explain the hypocalcaemia occasionally birds the C cells comprise a separate endocrine
seen in severe magnesium deficiency in humans. gland known as the ultimo branchial body. In experi-
In humans secondary hyperparathyroidism, such mental animals and birds CT is secreted in response
as that seen in chronic renal failure or vit D deficiency, to a rise in ionised calcium (Fig. 3), and also to
is due to stimulation of parathyroid secretion by the infusion of certain other hormones, notably glucagon
longstanding low plasma calcium rather than by or gastrin.
changes in plasma phosphate or other ions. The most important action of CT in mammals is to
PTH acts on the kidney to increase the tubular inhibit bone resorption and thereby lower plasma
reabsorption of calcium (Massry et al., 1973; calcium. Large doses of CT also increase the renal
Nordin et al., 1967) and to depress the tubular excretion of calcium, sodium, and phosphate and
reabsorption of phosphate. This leads to a rise 'in alter the soft tissue distribution of these ions. In
plasma Ca and fall in plasma Pi. PTH also diminishes man the renal effects can probably be considered
the secretion of H+ by the kidney, which leads to an 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 cr may have a physiological function in other
unclear. There is a continuing debate, based on species, e.g., in birds during egg laying and in fisb
conflicting radioimmunoassay data, about whether during migration from fresh to salt water. It is note-
cr circulates at all in normal man and whether its worthy that cr is found in elasmobranch fishes.
secretion can be increased in response to hypercal- which have a cartilaginous and non-calcified skeleton
caemia. Some assays of cr have indicated the exist- This suggests that, from an evolutionary point
ence of large forms of the hormone in the circula- view, the prime function of cr was not concerned
tion in normal and disease states. The significance of with bone.
this is obscure. On the basis of current evidence it
has yet to be shown that cr has an important Vitamin D
physiological role in man.
The assay of cr is important, however, in the Animals derive their vitamin D from the diet anc
diagnosis of medullary carcinoma of the thyroid from ultraviolet irradiation of dehydrocholestero.
and for the detection of family members with the in the skin (Fig. 5).
disease in its presymptomatic form. This condition Before it becomes biologically active vitamin D
occurs either alone, inherited as an autosomal (cholecalciferol, CC) has to be metabolised (Avioli
dominant, or in association with other endocrine and Haddad, 1973; DeLuca, 1972; Omdahl anc
abnormalities-e.g., parathyroid adenomas and DeLuca, 1973). The first step involves its conversion
phaeochromocytomas and mucosal neuromas (in in the liver to a 25-hydroxylated derivative. This
MEA Type 11). In man CT is also of interest because step may be regulated by feedback inhibition. The
it reduces the excessive resorption and turnover of second step involves further hydroxylations in the
bone characteristic of Paget's disease of bone. 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
l,25(OH)2Da on bone in culture is to increase THE INFLUENCING HORMONES

resorption.
The metabolism of vitamin D in the kidney Calcium and phosphate metabolism are also
appears to be closely regulated in experimental affected by growth hormone, thyroid hormones
animals. The production of 1,25(OH>2CC is stimu- glucocorticoids, and sex hormones. '
lated under conditions of vitamin D deficiency, and Growth hormone (GH) is best known for its effect
by low dietary calcium or phosphate. Increased on growth of cartilage, an effect which is probably
production of l,25(OH)zCC is accompanied by a brought about indirectly by the growth hormone-
reciprocal diminution of 24,25(OH)C and vice dependent production of somatomedin (Van Wyk
versa. The function of 24,25(OH)zCC is unknown. et al., 1974). There are probably several somato-
There is evidence that the effect of calcium depriva- medins, not all of which are dependent on GH.
tion in increasing 1,25(OH)2CC is mediated by Their biochemical characterisation is incomplete.
increased secretion of PTH, whereas the effect of . GH ,also causes an elevation in plasma Pi by
phosphate restriction is independent of PTH increasmg the apparent reabsorption of phosphate
(Hughes et al., 1975). by the kidney. Excess or deficiency of GH is associ-
However, since studies on the regulation of produc- ated with skeletal growth abnormalities. In acro-
tion of 1,25(OH)zCC in experimental animals megaly there is an increased periosteal apposition
have necessarily been done under extreme conditions of bone, but there is no convincing evidence that
often using animals or birds already deficient in acromegaly causes osteoporosis.
vitamin D, caution is needed before extrapolating Deficiency of thyroid hormones early in life
these findings to man. Evidence that the same produce the well known skeletal deformities of
relationships may exist in man comes from recent cretinism. In the adult, excess of triiodothyronine
measurements of 1,25(OH)2CC in plasma which or thyroxine can be associated with hypercalciuria,
indicate that the levels are higher than normal in hyperphosphataemia, a raised alkaline phosphatase,
hyperparathyroidism and lower than normal in and occasionally hypercalcaemia. In hyperthyroid-
hypoparathyroidism (Hughes et al., 1975). They are ism there is increased bone turnover often with net
also low in renal failure (Mawer et al., 1973) per- loss of bone. These effects are probably due to a
haps because renal mass is diminished or as a result direct action of thyroid hormones on bone, and an
of the hyperphosphaternia that exists in this condi- increase in resorption of bone can be demonstrated
tion. The possible importance of phosphate as a in organ culture. In humans resorption is probably
regulating ion for 1,25(OHhCC synthesis in man increased by thyroid hormones to a somewhat
is also indicated by the enhanced intestinal absorp- greater extent than formation, leading to a slight
tion of calcium and the hypercalciuria that follows increase in plasma calcium. This may suppress the
dietary deprivation of phosphate. It is possible that secretion of PTH and explain the diminished renal
hypophosphatemia stimulates the production of tubular reabsorption of calcium and enhanced reab-
l,25(OH)2CC in this situation, and may do the same sorption of phosphate.
in primary hyperparathyroidism and in those cases
of "idiopathic" hypercalciuria where intestinal Adrenal steroids
hyperabsorption of calcium is the cause. The in- Adrenal insufficiency is rather frequently accorn-
creased intestinal absorption of calcium to meet the panied by hypercalcaemia, probably due in part to
physiological requirements of growth, pregnancy,
haemoconcentration but also to altered renal hand-
and lactation are also probably mediated by in-
ling of calcium.
creased production of 1,25(OHhCC, which may In spontaneous or iatrogenic glucocorticoid excess,
explain the apparently increased requirement for the
osteopenia may develop. In experimental animals
precursor vit D under these conditions. glucocorticoids produce a variety of effects on bone
There is an interesting interrelationship between
depending on the compound given, the dose and the
the actions ofvit D and PTH, such that in the absence animal species. The relative contributions of dim-
of vit D some of the target organ responses to PTH
inished intestinal absorption, increased renal excre-
are impaired, notably the effect on bone resorption.
tion of calcium and of diminished bone formation
In addition it is clear that the diminished intestinal
and excessive resorption of bone, all of which may
absorption of calcium seen in vit D deficiency is not
occur, is not well defined.
overcome by the increased secretion of PTH that
follows deprivation of vit D. This may mean that Sex steroids
effects normally ascribed to PTH itself are in reality
mediated by an increase in 1,25(OH>2CC induced Characteristic growth abnormalities are associated
by PTH. with deficiencies of either male or female sex hor-
mones. In adults the effects of oestrogens are of The mechanism may be that when the inflow of
_, particular interest because of the loss of bone that calcium from the gut falls, there is a tendency to
occurs in women after the menopause. Administra- hypocalcaemia which stimulates PTH secretion; this
tion of exogenous oestrogen may slow down this in turn enhances the synthesis of 1,25(OH)zCC
loss. Oral contraceptives may reduce bone turnover which causes the intestinal absorption of calcium
in premenopausal women. to return to its original value.
This adaptation is a slow one. Unlike the responses
INDIVIDUAL ORGAN REsPONSES by the kidney and bone to PTH and CT, which occur
within minutes or hours, the intestinal responses take
Intestine 1-3 days. Intestinal absorption of calcium also varies
The intestinal absorption of calcium appears to with age arid sex and in disease states. It is likely that,
involve both active transport and diffusion processes, with better knowledge about the metabolism of
Absorption occurs throughout the small intestine 1,25(OH)zCC in man, many of these variations will
and is quantitatively greater in the ileum than the be explicable in terms of changes in the metabolism
duodenum, even though active transport is more of vitamin D.
evident in the duodenum. The fraction of the dietary The biochemical mechanisms involved in calcium
intake absorbed varies with the dietary content so absorption through the intestinal mucosa are not
that net absorption remains relatively constant understood in detail, though several features of the
except at extremely low or high intakes. The adapta- system have been identified (see Fig. 6). There is a
tion to dietary intake of calcium is now thought to calcium binding protein (CaBP) as well as a Caz+_
be mediated mainly by changes in 1cc25(OH)zCC. 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).
as intestinal alkaline phosphatase), which are both tion of phosphate. This may help to explain why
dependent on the presence of vitamin D or its treatment of such patients with vitamin D or its
derivatives (Coburn et al., 1973). It is the synthesis derivatives results in a fall in plasma phosphate as the
of these components as well as the metabolism plasma calcium rises. In contrast, as plasma calcium
of vitamin D itself which probably accounts for the is increased above normal, an opposite effect on the
relatively long lag period between giving vitamin D renal handling of phosphate may come into being so
and achieving an intestinal response. One puzzling that there is enhanced rather than diminished
feature is that both the CaBP and Ca2+-ATP-ase reabsorption of phosphate.
are located on the luminal surface of the intestinal Both calcium and phosphate excretion are influ-
epithelial cell. It is difficult to see why they need to enced by other factors, notably Na + excretion,
be present at this site since the luminal calcium extracellular fluid volume expansion and by the
concentration is much higher than the presumed administration of diuretics (Massry et al., 1973).
intracellular concentration of calcium and there There is evidence for both proximal and distal sites
seems therefore to be no need for an assisted transport of tubular reabsorption and both can be influenced
mechanism against an electrochemical gradient. by PTH for phosphate, whereas the action of PTH
An active extrusion mechanism however is required on Ca is probably mainly distal. Infusion of NaCI
at the basal border, unless, as some workers postu- increased the excretion of both calcium and phos-
late, the calcium traverses the intestinal epithelium phate, an effect which probably contributes to its
in the intercellular space. It seems likely that the value in the treatment of hypercalcaemia.
Ca binding protein delivers calcium from the lumen The biochemical mechanisms involved in renal
to a site essential for further translocation. transport of calcium and phosphate are not eluci-
There is now good evidence that calcium and dated, but the action of PTH on the kidney is
phosphate can be absorbed separately from each known to produce an increase in cortical adenylate
other and that 1,25(OH)2CC has independent effects cyclase activity which increases tubular cell and
to enhance the absorption of each. For calcium, urinary concentrations of 3'5' cyclic adenosine
1,25(OHhCC acts on both the diffusion and satur- monophosphate (cyclic AMP). It is not known
able components of the transport system. Absorp- whether this increase in cyclic AMP is the cause of
tion of calcium and phosphate is also enhanced by a the subsequent changes in phosphate and calcium
water-soluble factor (possibly an analogue of vitamin transport. However, in the clinical disorder pseudo-
D) from a South American plant, Solanum glauco- hypoparathyroidism there is probably a defective
phyllum, which can cause fatal hypercalcaemia in receptor mechanism for PTH in both kidney and
cattle that eat it. bone, so that administration of PTH does not pro-
duce a normal response of an increased excretion
Kidney of phosphate and cyclic AMP. This is analogous
to the failure of patients with nephrogenic diabetes
The kidney is a key organ in determining the insipidus to respond to antidiuretic hormone. In
plasma concentrations of both calcium and phos- pseudohypoparathyroidism the low plasma calcium
phate. Of the various hormones mentioned PTH is and high plasma phosphate resemble the findings
probably the most important under physiological in simple hypoparathyroidism but there are addi-
circumstances, enhancing reabsorption of calcium tional abnormalities in that the condition is familial
and reducing reabsorption of phosphate. There is and the patients are of short stature and have short
little evidence in man that vitamin D or its metabol- fourth metacarpal bones. It is noteworthy that in
ites, at physiological concentrations, have a major pseudohypoparathyroidism there is an appropriate
effect on the renal handling of calcium or phosphate response of the parathyroids to hypocalcaemia, so
that cannot be accounted for by changes in the that these patients have elevated plasma concentra-
secretion of PTH. Thus the enhanced reabsorption tions of PTH, which however do not cause the usual
of phosphate seen after restoring vitamin D to target organ responses. There is now an additional
patients deficient in vitamin D is probably due to variety of pseudohypoparathyroidism described in
suppression of the parathyroid hypersecretioncharac- which PTH causes an increase in cyclic AMP but
teristic of this state. However vitamin D in doses far no change in renal phosphate clearance.
in excess of physiological requirements can increase
excretion of both calcium and phosphate. Bone
The calcium ion itself affects phosphate handling.
Infusion of calcium into hypoparathyroid patients The structural organisation of bone is complex,
to restore their plasma calcium towards normal can as can be seen from Fig. 7.
also partially reverse the increased tubular reabsorp- In mature bone three main cell types exist:
Table 2
Cllment Ii,...
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)
Newbor.e
Metastatic
Ca or P concentrations high
Fig. 7.-To show some of the histological features of e.g., blood vessels in renal failure, also cornea,
compact hone of the type found in 11mb bones (from Harris gastric mucosa, lung alveolar septa (perhaps
aDd Heaney, 1969). because CO. is liberated and pH raised)
brain in hypoparathyroidism, kidney in hyper-
osteoblasts, responsible for bone formation, osteo- calcaemia
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 ling and growth of existing bone (Table 2). The
system and are probably responsible for many ot the concentrations of calcium and phosphate in ECF
rapid ion fluxes that occur in bone. The origin, life are insufficient to initiate the deposition of calcium
span, and fate of the various cells in bone is only phosphate but can sustain crystal growth once it has
partially understood. The tissue fluid surrounding started. The first steps in calcification are now
bone cells probably has an unique composition, being thought to take place in or around small membrane-
high in K + and containing particular plasma proteins bound vesicles found in the matrix. These vesicles
in preference to others. appear to arise from the plasma membranes of
The mineral component of bone is predominantly hypertrophic chondrocytes during the maturation
hydroxyapatite. Since ionic exchange occurs between of epiphysial cartilage. Their source in bone is not
bone mineral and surrounding fluids, it also con- identified. These vesicles are rich in alkaline phos-
tains other ions such as HCOa-, M g2 +, Na +, K +, etc. phatase, an enzyme which has been known for many
Collagen is a major constituent of the organic matrix years to be associated with calcification. Alkaline
of bone and is largely responsible for its tensile phosphatase may function in calcification as a
strength. Bone collagen is of the type I variety. component of a membrane pump for calcium and
In addition, the matrix contains several proteo- phosphate, or it may be involved in the removal
glycan components. The rate of deposition of bone of potential inhibitors of calcification such as
is controlled by hormonal status (e.g., PTH, GH), inorganic pyrophosphate (PPi).
by levels of calcium and phosphate, and by mechani- In hypophosphatasia, which is a recessively
cal and electrical forces acting on bone. inherited skeletal disorder characterised by a defic-
Calcification is an important step in the transition iency of alkaline phosphatase, there are increased
between matrix production and the formation of concentrations of PPi in plasma. Since PPi is an
mineralised bone. In the skeleton calcification takes inhibitor of the crystal growth of calcium phosphate
place in two main sites in epiphysial cartilage during it may be responsible for the defective calcification
the growth of long bones and in bone matrix during of cartilage and bone seen in this condition (Russell
intra-membraneous ossification and in the remodel- and Fleisch, 1975). Some other causes of defective
skeletal mineralisation are included in Table 3. calcification of bone and cartilage in chronic renal
Rickets is the term used to define failure of minerali- failure. Acidosis, such as occurs after ureterosig-
sation of cartilage in long bones and is seen in grow- moidostomy or in renal tubular acidosis, can lead
ing children. Osteomalacia has several meanings to excess osteoid. The mechanism may be that initia-
and to some people implies a state of vitamin D tion of mineralisation is more difficult in an acid
deficiency. The term may be used to describe the environment because of increased solubility of
clinical features of D deficiency, or it may be calcium phosphate but it may also be due to the
restricted to the histological abnormality in bone hypophosphataemia which is usually also present.
irrespective of the cause. Excess osteoid is perhaps Conceivably acidosis may also disturb the metabol-
a better term for the latter abnormality and is ism of vitamin D.
characterised by the presence of unmineralised Resorption of bone is an essential part of the
matrix on trabecular surfaces in bone. remodelling and growth process (Harris and Heaney,
Calcification can occur outside the skeleton at 1969; Raisz, 1970; Raisz and Bingham, 1972),
many sites within the body in pathological states and is mediated by mononuclear and multinuclear
and it is remarkable how specific some of these sites osteoclasts, some of which may be macrophages
are for particular diseases, e.g., the basal ganglia originating outside bone. Osteoeytes are probably
in hypoparathyroidism, and ectopic bone formation responsible for some hormone dependent rapid
around the hips in paraplegia (Table 2). Inhibitors fluxes of ions in and out of bone.
of calcification may partly contribute to impaired Under physiological conditions resorption is
probably under the control of PTH, vitamin D,
thyroid hormones and steroids, but will occur at a
Table 3. Some causes of excess osteoid (uJfmineralised basal rate in the absence of these hormones. Several
bone matrix)
other agents can stimulate bone resorption under
experimental conditions and may be important
in disease. Vitamin A is one of these. Prostaglandins,
Vitamin D deficiency or defective metabolism particularly of the E series, are also resorbing agents
Nutritional deficiency of vitamin D and may be important in some of the hypercal-
Lack of sunlight caemias of malignancy and in the bone dissolution
Malabsorption of vitamin D
Chronic renal failure that accompanies rheumatoid arthritis (Robinson
Vitamin D-dependent rickets et al., 1975). Myeloma cells and activated lympho-
cytes can produce materials which cause resorption
Low plasma phosphate in vitro (Raisz et al., 1975, Fig. 8) and which have
Phosphate deficiency been designated OAF (osteoclast activating factors).
Renal tubular disorders (vitamin-D-resistant The biochemical events occurring during bone
rickets) resorption are poorly understood. Some resorbing
agents, such as PTH and prostaglandins, can stimulate
Chronic acidosis the production of cyclic AMP in bone but others.
Ureterosigmoidostomy
Renal tubular acidosis (proximal or distal) e.g., 1,25(OH)2CC, do not. Inflow of calcium ions
into bone cells may be an early event in their
High bone turnover stimulation. Ionophores which promote the entry
Fracture healing of calcium ions into cells can be shown to stimulate
Paget's disease resorption. Bone resorption in tissue culture is
Hyperparathyroidism accompanied by release of enzymes such as collagen-
Hyperthyroidism ase (Harris and Krane, 1974) and lysosomal enzymes
capable of degrading matrix. Osteoclasts viewed by
Drugs electron microscopy possess a ruffled border which
Anticonvulsants
Diphosphonates is closely applied to the bone surface and is presum-
Fluoride ably the site at which removal of bone mineral and
matrix occurs. Administration of calcitonin, which
Inherited inhibits resorption, causes retraction of this border
Fibrogenesisimperfecta ossium and eventually leads to a decreased number of
Hypophosphatasia osteoclasts. Apart from calcitonin several other
inhibitors of resorption exist. These include oestro-
Other unexplained gens, mithramycin and diphosphonates. Inhibitors
Axial osteomalacia of bone resorption are useful therapeutic agents in
certain clinical disorders (Table 4).
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.
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 which increase the transport of calcium into cells.
100-1000 times lower than extracellular-i.e., in the In the case of parathyroid hormone, cyclic AMP
range of 10-5-10- 6 mol/I. Within cells mitochondria and ionophores can each independently induce
are capable of accumulating large amounts of resorption in bone explants (Dziak and Stern, 1975)
calcium against electrochemical gradients, to the and each can also stimulate mitosis in lymphocyte
point at which intramitochondrial deposits of cultures. These interactions have been reviewed
insoluble calcium phosphate can form (Borle, 1973). extensively elsewhere (Borle, 1973; Rasmussen and
The activation of many different types of cells by Goodman, 1975; Robison et al., 1971). In some
hormones or pharmacological agents is now systems the concentration of 3'5'-cyclic guanosine
thought to be accompanied by increases in intra- monophosphate (cyclic GMP) changes in the oppo-
cellular calcium concentration, derived from outside site direction to that of cyclic AMP, and produces
the cell or by release from mitochondria (Rasmussen opposing effects, a phenomenon which has led to
and Goodman, 1975). Hormonal activation is often the so-called "Yin and Yang" hypothesis (Goldberg
associated with stimulation of adenylate cyclases et aI., 1973). An example of some of these inter-
specific to the target tissue. The changes in cyclic relationships are shown in Fig. 10 for the release of
AMP and intracellular Ca then produce further lysosomal enzymes from neutrophils (Smith and
responses within the cell, e.g., by changing enzyme Ignarro, 1975) a system which contrasts with those
activity. In many systems addition of cyclic AMP described above in that cyclic GMP is stimulatory
can mimic hormone action, as can those ionophores and cyclic AMP and calcium ions are inhibitory.
NEUTROPHL the system so that a new steady state comes into

ATP existence. The flux rates through individual organs
-++tolfa~ENYLATE and the level of plasma Ca mayor may not be the
EPlNE"HIIINE
PIlOSTAGLAMlINS
__
\:YCLASE A- .' 11.
same as previously depending in part on whether
the disturbance to the system is sustained or not.
'i~LI!iC.!.A!!M!!P:'4---ttr CYCLIC AMP
_,..OTEIN
! KINUE LYSOSOMAL Regulation ofplasma calcium: Acute responses
IRUNE .[ACTANT PItOSPHllIlYLATION ENZYIIE
IlUST IE ,,,,nUT
$lCRETION The total concentration of calcium in plasma is
~_...
AT . - :
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-
IONOPHORES
e!IAY INIIOLVE LYSOSOMES. muscular function and other membrane responses
(DIVALENT)
llICROTUIULES. PLASMA MEMBRANE. ? and is also involved in biological events such as
blood coagulation.
Fig. lO.-Postuiated interactions between calcium ions, Deviations of plasma Ca2+ away from its normal
cyclic AMP and cyclic GMP, and other agents during the value are rapidly corrected by alterations in the
release of lysosomal enzymes from human neutropbil secretion of the regulating hormones. In many
blood cells in vitro (abbreviation PDE = phosphodiesterase) mammals PTH and calcitonin (Fig. 4) both respond,
(from Smith and Ignarro, 1975). but in opposite directions, but in man it is doubtful
whether CT changes. PTH and CT can be con-
INTEGRATION OF INDIVIDUAL ORGAN RESPONSES
sidered the fast acting (minutes to hours) component
of the regulatory system whereas vitamin D is
It is useful to draw some distinction between the responsible for adaptation in the longer-term (hours
way in which the plasma calcium is set at a particular to days). In experimental animals removal ofsources
value, and the way the movements of calcium of PTH and CT (e.g., thyroparathyroidectomy in
in and out of extracellular fluid (ECF) are controlled. dogs or rats) results in a slower than normal return
The plasma calcium is set close to a particular value of plasma calcium to starting values in response to
in different individuals in normal and disease states. acute changes in plasma calcium.
Deviations from this value are corrected by hormone- In man the most important regulator of acute
induced changes in the relative fluxes of calcium changes of the concentration of Ca2+ is parathyroid
in and out of the ECF. Alterations in the flux rates hormone (PTH) which increases within seconds of a
are therefore monitored and adjusted by the changes fall in plasma Ca2+, and decreases as Ca2+ rises.
in plasma calcium (or phosphate) concentration The rapid control of plasma Ca2+ by PTH is mainly
they induce. This homoeostatic system could operate due to its ability to regulate renal tubular reabsorp-
with the plasma Ca set at any number of different tion. After parathyroidectomy the fall in plasma
values with the relative rates of entry and exit Ca2+ can largely be accounted for by a continuing
of calcium to and from the ECF being altered as loss of Ca2+ into urine until a new steady state is
drift occurs from this set point. achieved in which calcium excretion may not be
Thus in hyper- and hypoparathyroidism the fluxes greatly below its starting value but takes place at a
of Ca across the gut and in and out of bone may not much reduced filtered load of calcium. The intestinal
be greatly different than normal and external responses are too slow to account for rapid changes
calcium balance can be maintained (net intestinal in plasma calcium but the bone does playa part.
absorption = urine loss) even though the plasma Ca Thus there is an important buffering action of bone,
is set at markedly different levels (Fig. II). The so that rises or falls of plasma calcium are partially
plasma Ca thus provides the point around which compensated by increased net movements of calcium
adjustments are made. into or out of bone respectively. This is partly a passive
In considering homoeostasis it is also helpful to process but there is probably also a contribution
distinguish between acute and chronic changes. from changes in PTH-mediated osteolysis. In animals
When the system is disturbed, a steady state no in whom the fluxes of calcium in and out of bone are
longer exists, and the response which occurs adjusts relatively much greater in relation to fluxes through
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 ing its uptake or release of calcium. In a variety
in bone resorption (and formation) are quantitatively of both physiological and pathological steady states
more important than in man for producing acute (see Fig. 12) it is clear that there is a remarkably
changes in plasma Ca. This is well illustrated by close correlation between rates of mineral deposition
examining the acute responses of plasma Ca to and mineral resorption. Even though these individual
injection of calcitonin, the most significant acute rates may be altered many-fold, the net gains or
effect of which is to inhibit bone resorption. In losses of skeletal mass are minimised by the tight
normal man there is a negligible fall in plasma coupling between these rates. This is an important
calcium, whereas in rats, particularly in young feature of homoeostatic adaptation (Harris and
animals in which bone turnover is high, there may Heaney, 1969) that is often overlooked. Thus it is
be a marked decrease in plasma calcium. Simple difficult to achieve a sustained dissociation between
calculations verify that in normal man complete rates of mineralisation and resorption and this is
abolition by calcitonin of the small flux of calcium one reason why so many potential therapeutic agents
out of bone could not be expected alone to cause a have been disappointing in the treatment of bone
significant fall in plasma calcium. However, in disease, for example in increasing bone mass in
situations where bone resorption is quantitatively osteoporosis. Transient dissociations can occur,
greater in relation to the other fluxes, e.g., in patients however, for example in the acute loss of bone
with Paget's disease or with tumour metastases mineral that occurs in response to immobilisation.
in bone, then an acute fall in plasma calcium can be Evidence for coupling also comes from measurement
seen after given calcitonin. of alkaline phosphatase and urinary total hydroxy-
proline (THP) in Paget's disease of bone. There is a
Chronic changes close correlation between these two measurements
The response to prolonged perturbations brings over a wide range of values. Alkaline phosphatase
in contributions from changes in vitamin D meta- is thought to be an indirect measure of bone forma-
bolism and from the intestine and bone. An example tion rate, and urine THP in this situation to reflect
is the adaptation that occurs to a change in dietary mainly the rate of resorption of bone collagen. The
intake of calcium. If intake is reduced this will tend mechanisms underlying this coupling are unknown.
to cause a gradual fall in plasma calcium which will It may involve cell to cell communication within
increase the secretion of PTH. Apart from its effect bone, in addition to external endocrine influences.
on the kidneys, a sustained increased in PTH will Another suggestion is that there is an obligatory
lead to enhanced osteoclastic resorption of bone, cellular differentiation of osteoclasts to osteoblasts,
and an increase in 1,25(OH)2CC synthesis which will which would couple rates of bone formation to pre-
enhance intestinal absorption of calcium and resorp- vious rates of bone resorption (Rasmussen and
tion of calcium from bone. If the reduction in Bordier, 1974). Although this is an attractive
dietary calcium continues, these changes will act idea it has certain weaknesses and even if true can only
to restore the plasma calcium towards its previous account for part of the phenomenon.
value and bone formation rate will increase to match An additional feature of bone is its ability to
the rate of increased bone resorption by the coupling respond to mechanical deformation by changing its
mechanism described below. The new steady state structure and shape to counteract the stress. One
will come to consist of a greater efficiencyof intestinal mechanism proposed to account for this involves
absorption of calcium and an increased rate of entry the generation of small electrical currents within
and removal of calcium from bone so that net bone as stresses are applied. Such currents can
balance can be maintained. This response can be be demonstrated experimentally and are thought to
seen very clearly in experimental animals and there be due to the piezoelectrical properties of the mineral
is good evidence that these adaptive changes occur and matrix components.
in man too. When dietary deprivation is so severe
that intake can no longer match output the reserves DISORDERS OF CALCIUM HOMOEOSTASIS
of calcium in bone are utilised.
Other examples of steady states that exist during Detailed description of disorders of calcium
chronic disturbances in calcium metabolism will be metabolism is beyond the scope of this review but
considered under clinical disorders of calcium there have been several books and reviews published
homoeostasis. on this topic recently (Fourman and Royer, 1968;
Morgan, 1973; Nordin, 1973; Paterson, 1974;
Coupling offormation and resorption: Control ofbone Krane and Potts, 1974; Potts and Deftos, 1974;
shape and mass Schneider and Sherwood, 1974). The purpose of this
The skeleton can respond to hormones by increas- 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 The calcium balance is usually normal but may be
states found in various diseases. negative, particularly in patients with severe bone
disease. The fact that bone and renal stone disease
ExcessPTH do not usually occur in the same patients is intriguing
and unexplained, but may imply important differ-
In primary hyperparathyroidism, due to adenomas, ences in relative target organ responses to increased
hyperplasia or carcinoma, the concentration of PTH.
PTH is inappropriately high for the prevailing plasma In secondary hyperparathyroidism, such as occurs
calcium, implying a defect in the gland for switching in renal failure or vitamin D deficiency, PTH is
off PTH secretion at normal levels of Ca2+. In high as an appropriate response to hypocalcaemia.
hyperparathyroidism the hypercalcaemia is main- In both these conditions there is an impaired target
tained mainly by a resetting of the renal tubular organ response to PTH which prevents the plasma
reabsorption mechanism for calcium, so that calcium from returning to normal. After removal of
reabsorption is enhanced at any given filtered load. the hypocalcaemic stimulus, e.g., after renal trans-
There is often also increased bone resorption and plantation, it may take a long time for the hyper-
increased intestinal absorption of calcium, and both plastic glands to respond appropriately to plasma
these will tend to increase urinary calcium excretion. calcium, so that hypercalcaemia may persist for
months. In pseudohypoparathyroidism there is so that urinary calcium may become undetectable.

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

Phosphate is used as a therapeutic agent in several
disorders of calcium metabolism. Intravenous
Decreased intestinal absorption phosphate can be used to lower plasma calcium in
Low dietary intake acute hypercalcemic states. The way in which it
Malabsorption works is uncertain and may include one or more of
Antacids (e.g. Al(OH). which binds PI)
Increased renal loss, low renal threshold the following effects: precipitation of calcium as
PTH excess primary hyperparathyroidism insoluble calcium phosphate, with uptake by soft
pancreatitis tissue, the reticuloendothelial system or bone;
Renal tubular disease increased uptake of calcium by cells or diminished
Inherited Familial (sex-linked and other) release of calcium from bone, either due to a direct
Cystinosis effect to inhibit bone resorption or by stimulating
Renal tubular acidosis (distal) secretion of calcitonin. Oral phosphate is also some-
Acquired Wilson's disease times used to treat chronic hypercalcaemia.
Neurofibromas and mesenchymal Oral supplements of phosphate can reduce the
tumours
Mercury poisoning rate of production of calcium-containing renal
Post-transplant kidney stones (Smith et al., 1973).
Acidosis (ureterosigmoidostomy)
Increased GPR-pregnancy
Increased entry into cells REFERENCES
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Ann. din. Biochem.

Regulation of Calcium Metabolism

DISTRIBUTION OF CALCIUM AND PHOSPHATE

increased excretion of HC03 ions and to a hyper-

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

" , I" ~~.tlctabl'

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

l,25(OH)2Da on bone in culture is to increase THE INFLUENCING HORMONES

Radioisotopes and bone: Bone scanning

Table 4. Therapeutic agents in calcium metabolism

Agent Use Mechanism of Action

NEUTROPHL the system so that a new steady state comes into

Hypoparathyroidism Normal Hyparparathyroldlsm

200lllll 200ml 200ml

200mg 1.200mg 200mg

months. In pseudohypoparathyroidism there is so that urinary calcium may become undetectable.

Table 6. Some causes 0/ hypophosphatemia Phosphate as a therapeutic agent

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