Joint Bone Spine 70 (2003) 407–413

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Review

What keeps serum calcium levels stable?

Pascal Houillier *, Laurence Nicolet-Barousse, Gérard Maruani, Michel Paillard
Department of Physiology and Radioisotopes, European Georges Pompidou Teaching Hospital, Paris VI University, Inserm unit 356,
20, rue Leblanc, 75015 Paris, France

Received 30 September 2002; accepted 13 November 2002

Abstract

Many body functions require that serum calcium levels remain stable over time. This stability is provided by cooperation among three
organs: two effectors, the bone and the kidney, which control calcium movements into and out of the extracellular compartment, and the
parathyroid glands, which produce and release parathyroid hormone (PTH). PTH acts on the bone and renal tubule. Provided the amount
released is appropriate, this keeps extracellular calcium levels stable.
© 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.

Keywords: Calcium; Parathyroid hormone; Calcium-sensing receptor; Bone; Kidney

1. Introduction calcium; about 10% is complexed with low-molecular-

Serum calcium levels remain stable in healthy adults be-
cause the amount of calcium entering the extracellular com-
partment matches the amount excreted through the kidneys.
This match is achieved mainly by a calcium-sensing receptor
(CaSR) located on the surface of the parathyroid gland cells.
This receptor responds to serum calcium level changes by
modifying the amount of parathyroid hormone (PTH) re-
leased by the gland. The calcium level set point is the value
corresponding to the PTH level for which the calcium inflow
equals the calcium outflow.
2. Body calcium content and calcium assays
The body of a healthy adult contains about 25 000 mmol
(about 1 kg) of calcium, of which 999‰ is part of the mineral
component of bone and 1‰ (about 20 mmol) is in the
extracellular fluid. Calcium levels in the extracellular fluid
vary across vascular and interstitial compartments. The nor-
mal range for serum calcium is 2.10–2.50 mmol/l; this is the
95% confidence interval for mean serum calcium levels in
healthy adults, the mean being 2.30 mmol/l. Serum calcium
is composed of three fractions: 50–55% is free (ionized)
* Corresponding author.
E-mail address: pascal.houillier@egp.ap-hop-paris.fr (P. Houillier).
© 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.
doi:10.1016/S1297-319X(03)00052-6
weight anions; and 35–40% is bound to proteins, mainly
albumin and, to a lesser extent, globulins. In the interstitial
compartment, albumin levels are low, so that there are only
two calcium fractions, ionized calcium and calcium in anion
complexes, which together constitute the diffusible or ultra-
filtrable calcium fraction.
The calcium homeostatic system targets, not the body
calcium content or total calcium level, but rather the concen-
tration of ionized calcium. In healthy adults in the fasting
state, serum ionized calcium levels are comprised between
1.15 and 1.32 mmol/l (the 95% confidence interval of the
mean value in healthy adults). In a given healthy individual,
this value is remarkably stable over time, never deviating by
more than 2% from its set point [1]. This stability is the basis
for the stability of the total serum calcium level under normal
conditions. Thus, as a rule, an abnormal total calcium level
usually predicts an abnormal ionized calcium level. Excep-
tions occur, however, when the levels of protein-bound cal-
cium and anion-complexed calcium are abnormal (Table 1).
Variations in serum albumin are a classic example.
Hypoalbuminemia is responsible for a decrease in the
fraction of total calcium bound to albumin and, therefore,
causes the total calcium level to decline, whereas the ionized
calcium level remains unchanged. Conversely, high serum
levels of albumin, or globulins in patients with myeloma,
translate into an increase in total calcium with no change in
ionized calcium [2,3]. To a smaller extent, changes in serum
408 P. Houillier et al. / Joint Bone Spine 70 (2003) 407–413
Table 1
Causes for dissociation between serum total calcium and ionized calcium levels
Causes Calcium bound to proteins Calcium complexed with anions
Low serum albumin ↓ N
High serum albumin or globulin ↑ N
Infusion of anions (citrated blood, N ↑
bicarbonate, sodium lactate)
Acute acidosis ↓ N
Chronic acidosis ↓ N
Acute alkalosis ↑ N
Chronic alkalosis ↑ N
proton levels and, therefore, in extracellular pH can modify
the amount of calcium bound to albumin because the H+ and
Ca2+ ions compete for the albumin binding sites. Acute
acidosis displaces part of the albumin-bound calcium to the
serum: the decrease in the level of albumin-bound calcium
matches the increase in free calcium, so that the total calcium
level remains unchanged. In chronic acidosis, the calciotro-
pic hormones (see below) return the ionized calcium level to
its set point, thus decreasing the total calcium level. Varia-
tions in the opposite direction occur in patients with alkalo-
sis. Finally, intravenous administration of a large amount of
anions that form complexes with calcium (citrate, lactate,
bicarbonate) induces a large increase in the calcium fraction
bound to these low-molecular-weight anions and a commen-
surate decrease in the level of ionized calcium. This occurs
during transfusion of citrated blood or infusion of sodium
lactate or bicarbonate.
Thus, provided serum proteins and extracellular pH are
normal, in patients who are not receiving blood transfusions
or infusions of sodium lactate or bicarbonate, total serum
calcium levels predict ionized calcium levels, provided a
reliable assay method is used. Atomic absorption spectrom-
etry is the method of choice and provides results identical to
those obtained by isotope-dilution mass spectrometry [4,5].
The excellent precision of atomic absorption spectrometry is
shown by the low between-run coefficient of variation, of
about 1%. Automated methods using calcium-complexing
substances produce acceptable results provided that valida-
tion by a reference method is performed at regular intervals.
In healthy adults, values measured by atomic absorption
spectrometry are in the 2.10–2.50 mmol/l range; they are
higher in adolescents (by about 0.05 mmol/l) and higher still
in children (by 0.1 mmol/l) [6]. Serum calcium should be
assayed in the morning after an overnight fast to reproduce
the conditions that were used to determine normal values.
After a meal, serum calcium can increase by 0.15 mmol/l in
healthy individuals, and considerably larger increases can be
seen in patients with excessive intestinal calcium absorption.
In patients with abnormalities in blood proteins or extra-
cellular pH and in those recently treated with blood transfu-
sions or with sodium bicarbonate or lactate infusions, the
best method for detecting serum calcium alterations is direct
measurement of the ionized calcium level using a specific
electrode [7]. Blood should be collected with the arm relaxed
and no tourniquet, to avoid variations in blood pH. When this
Ionized calcium Total calcium Total Ca/ionized Ca
N ↓ ↓
N ↑ ↑
↓ N ↑
↑ N ↓
N ↓ ↓
↓ N ↑
N ↑ ↑
direct assay technique is not available, the calcium level can
be estimated from the measured calcium level and the albu-
min level, based on the fact that 1 g of albumin normally
binds 0.02–0.025 mmol of calcium. Thus, in a patient whose
serum albumin level is 20 g/l, the corrected calcium level is
the measured level plus 0.4–0.5 mmol/l. This method pro-
vides a rough estimate, as do the nomograms in the literature.
3. Serum calcium regulation under normal conditions
The regulation of serum calcium involves mechanisms
that keep the serum calcium level at its set point and mecha-
nisms that correct variations from this set point [8–14].
3.1. Maintaining serum calcium at its set point
Three organs can create calcium movement into or out of
the extracellular fluid: the intestine, the bone, and the kidney.
Intestinal calcium absorption after meals does not contribute
to maintain serum calcium at its set point but, on the contrary,
induces a short-lived elevation in serum calcium. Neverthe-
less, an adequate dietary calcium intake and normal intestinal
calcium absorption are essential to the maintenance of a
normal calcium balance and of normal calcium bone stores.
As explained below, in the fasting state, the extracellular
calcium level depends on the release of calcium from bone to
compensate for the calcium lost in urine. When the dietary
calcium intake is inadequate (<600 mg/j in young adults) and
or intestinal calcium absorption is abnormal, the serum cal-
cium level is kept stable only at the cost of gradual depletion
of the calcium bone stores. For instance, a daily calcium
intake of 400 mg (10 mmol) or less results in loss of 1–4
mmol of calcium from the body each day [1]. Thus, although
intestinal calcium absorption does not regulate serum cal-
cium levels, it provides the calcium needed to maintain the
bone calcium mass within the normal range: the calcium lost
in the fasting state is replaced by absorption of an identical
amount of calcium from the gut lumen. Consequently, in
healthy individuals who have completed their growth, and
with the exception of pregnant or breast-feeding women,
when the dietary calcium intake and intestinal calcium ab-
sorption are normal, the amount of calcium excreted is equal
to the amount absorbed by the intestine.
The bone and kidney are the two organs that determine the
serum calcium level in the fasting state. To maintain the
 P. Houillier et al. / Joint Bone Spine 70 (2003) 407–413
Fig. 1. Relations between serum calcium level in the fasting state and serum
PTH level (top) or calcium inflow from bone to extracellular compartment
(CECC) and calcium outflow from extracellular compartment to urine (bot-
tom). In the fasting state, serum calcium is stable because the calcium lost in
the urine is replaced by release of the same amount of calcium from the
bone. A decrease in serum calcium causes an increase in PTH release, which
stimulates calcium release from bone and decreases urinary calcium excre-
tion, thus returning the calcium level to its set point. Thus, maintenance of
the set point requires presence of the CaSR in the parathyroid cells and
adequate levels of PTH and calcitriol.
serum calcium level in the fasting state, the bone releases an
amount of calcium identical to the amount excreted in the
urine during the same period of time (Fig. 1). The calcium set
point is the value for which the net calcium inflow, from the
bone pool to the extracellular compartment, matches the net
calcium outflow, from the extracellular compartment to the
urine. This match is achieved mainly by PTH. PTH is a
peptide produced by the parathyroid gland chief cells as a
preprohormone composed of 115 amino acids. Two succes-
sive cleavages of this preprohormone (signal peptide) release
the propeptide and finally the 84-amino acid mature hor-
mone, which is then released from the cell. Three character-
istics of PTH have a major impact on calcium regulation.
First, most of the mature peptide is stored in intracytosolic
vesicles where it constitutes a rapidly available reserve [10].
Secretion occurs by exocytosis after fusion of these vesicles
to the cell membrane. Second, about 50% of synthesized
PTH is broken down within the cell. This proportion de-
creases when serum calcium is low, leaving a greater amount
409
of PTH available for secretion [10]. Finally, the half-life of
secreted PTH is only a few minutes, so that the extracellular
level of PTH shows rapid and large variations when the
secretion rate changes. This allows a nearly instantaneous
response to deviations of the serum calcium level from its set
point. PTH acts rapidly on its target organs, namely, the bone
and the kidney. It binds to a G-protein-coupled receptor
belonging to the superfamily of seven-transmembrane recep-
tors. This increases the release of calcium from bone tissue
and the tubular reabsorption of calcium from the ultrafiltrate
in the ascending limb of the loop of Henle and in the distal
tubule.
3.2. Correcting deviations from the calcium steady state
level
In the fasting state, serum calcium tends to decrease below
its set point because calcium is lost in the urine. The parathy-
roid glands respond immediately by releasing larger amounts
of PTH, which stimulate calcium release from bone tissue
and calcium reabsorption by the kidney, returning the serum
calcium level to its set point (Fig. 1). A specific bone cell
type, the osteocyte, probably mediates release of calcium
from bone tissue. Calcium release is rapid, of marked ampli-
tude, and of limited capacity, since only the superficial bone
layers are involved; these characteristics are well suited to the
rapid correction of serum calcium levels [15]. Calcium re-
lease is different from bone remodeling, which involves tight
coupling between synthesis of organic bone matrix by osteo-
blasts and destruction of mature bone by osteoclasts: at the
scale of the entire skeleton and at a given point in time, the
amount of newly formed bone is equal to the amount of
destroyed bone. It follows that bone remodeling does not
produce a net inflow of calcium from the bone pool to the
extracellular compartment and, therefore, does not help to
maintain the serum calcium level at its set point. Finally bone
remodeling is a slow process of limited amplitude but con-
siderable capacity, since it potentially involves the entire
skeleton [15]. Conversely, a rise in serum calcium (e.g. after
ingestion of dairy products) decreases the secretion of PTH,
leading to reductions in the amounts of calcium released
from bone and reabsorbed in the kidney, and therefore, to
normalization of the serum calcium level.
In sum, maintenance of the serum calcium level at its set
point, and the value of this set point, are achieved by a close
match between calcium release from bone and calcium reab-
sorption in the kidney, which are regulated from 1 min to the
next by variations in PTH secretion. It should be pointed out
that determination of the value of the set point and correction
of deviations from the set point are conceptually two inde-
pendent phenomena, although they involve the same hor-
mone. For instance, in conditions characterized by primary
hyperparathyroidism, the calcium set point is higher than in
normal individuals because calcium release and reabsorption
are increased; however, the ability to correct variations from
the set point is preserved, so that the calcium level remains
410 P. Houillier et al. / Joint Bone Spine 70 (2003) 407–413
stable at its high value. The same is true in conditions char-
acterized by inadequate low PTH secretion.
The second important calciotropic hormone is 1,25-
dihydroxy-vitamin D, which is a vitamin D metabolite made
active by two hydroxylations, the first in the liver at position
25 and the second in the kidney at position 1. This last step is
the rate-limiting reaction in the production of 1,25-
dihydroxy-vitamin D. This hormone, also called calcitriol, is
a steroid whose main mechanism of action involves binding
to a nuclear vitamin D receptor followed by migration of the
hormone-receptor complex to specific DNA sites called vita-
min D-responsive elements, where it controls the transcrip-
tion activity of a large number of genes. Because this process
takes time, 1,25-dihydroxy-vitamin D is not useful for short-
term serum calcium regulation. Conversely, it plays a major
role in regulating the fractional calcium absorption by the
intestine, in either direction, according to the amount of
calcium ingested. Furthermore, an adequate 1,25-dihydroxy-
vitamin D level is needed for optimal expression of PTH
effects on the bone and kidney [11].
The key to calcium homeostasis is, therefore, the mecha-
nism by which a change in serum calcium can rapidly induce
a change in PTH secretion to return the serum calcium to its
set point. This mechanism rests on the CaSR, a membrane
receptor that binds extracellular calcium. CaSR belongs to
family-C of the seven-transmembrane G-protein-coupled
proteins. This family also includes eight metabotropic
glutamate receptors (mGluR1-8), two type B gamma-
aminobutyric acid receptors, and a subfamily of pheromone
receptors. These receptors do not share sequence homology
with the receptors of the other seven-transmembrane recep-
tor families, and their extracellular domain is considerably
larger. For instance, the human parathyroid calcium receptor
(HuPCaR) has three main domains: a large extracellular
hydrophilic aminoterminal domain (612 amino acids), a 250-
amino acid hydrophobic domain that predicts the seven-
transmembrane segments characteristic of the protein-G-
coupled receptor superfamily, and a 216-amino acid
intracytosolic carboxyterminal domain. The 20 cysteine resi-
dues (17 in the aminoterminal domain and three in the extra-
cellular loops) may govern the three-dimensional configura-
tion of the molecule. According to the current concept, the
aminoterminal extracellular domain forms two globular
lobes held together by a molecular hinge; in analogy with the
periplasmic binding proteins of prokaryotes, attachment of
the ligand to the extracellular receptor domain probably
causes a cleft to form in the molecule, converting an open
inactive conformation to a closed active conformation
[16,17]. The extracellular domain of HuPCaR has two highly
acidic regions, similar to those present in other proteins
(calsequestrine and calreticulin) that bind calcium with low
affinity. Several sites have recently been found to play a key
role in receptor activation. Mutations converting the serines
at 147 and/or 170 to alanines induce loss of receptor function
[18]. Conversely, several mutations in the 116–136 region
result in a gain in function by increasing the affinity of the
receptor for its ligand [19]. The mechanisms that lead from
the conformational change in the molecule to activation of
the intracellular signal transduction pathways have not been
identified. In vivo, CaSR dimers form as a result of interac-
tions between cysteine residues in the extracellular domain
of each monomer. The cysteine residues at positions 101 and
236 of HuPKaR seem particularly important, as their muta-
tion to serines substantially decreases dimer formation and
membrane CaSR expression [20]. Furthermore, CaSR ex-
pressed as the monomer has less affinity for the agonist and
responds more slowly to variations in agonist levels [20].
CaR transcripts have been found not only in the parathy-
roid glands but also in the thyroid C cells; all the nephron
segments except the thin limbs, with a marked predominance
in the medullar and cortical segments of the thick ascending
limb of the loop of Henle; the brain, mainly the cerebellum,
hippocampus, olfactory tubercles, ependymal areas of the
ventricles, and cerebral arteries; the myenteric plexuses in
the intestinal tract wall; the epithelial cells in the lens; the
osteoblast line MC3T3-E1; and the monocytes/macrophages
[21]. In the thick ascending cortical limb of the loop of
Henle, CaSR plays a major role in controlling calcium reab-
sorption. CaSR activation by a rise in serum calcium causes a
decrease in calcium reabsorption in this segment; the oppo-
site occurs when serum calcium falls.
4. Mechanisms underlying abnormalities in serum
calcium levels [8–14,22–24]
As indicated above, the calcium set point value depends
on the equilibrium between calcium inflow, from the bone
pool to the extracellular compartment, and calcium outflow,
from the extracellular compartment to the kidney. Conse-
quently, only two situations can lead to a prolonged abnor-
mality in the serum calcium level:
• one is a change in the behavior of both the bone and the
kidney;
• the other is an increase in bone calcium release that
exceeds the maximal calcium outflow achievable by the
kidney.
An isolated change in the behavior of the kidney cannot
modify the serum calcium level. For instance, furosemide
therapy in standard dosages decreases the ability of the kid-
ney to reabsorb calcium, thereby inducing hypercalciuria,
which would be expected to result in hypocalcemia. How-
ever, when the serum calcium level begins to decline, PTH
secretion is stepped up, causing the bone to release larger
amounts of calcium; this compensates for the increased uri-
nary loss, thus maintaining serum calcium levels within the
normal range (Fig. 2A). Similarly, thiazide diuretics increase
tubular reabsorption of calcium but do not cause hypercalce-
mia because the PTH secretion decrease in response to the
decline in serum calcium translates into a reduction in cal-
cium release from bone. Under stable conditions, patients
taking thiazide diuretics have low urinary calcium and nor-
 P. Houillier et al. / Joint Bone Spine 70 (2003) 407–413 411

Fig. 2. Effect of an isolated alteration in renal calcium handling on the calcium set point and its determinants. (A) Adaptation to a furosemide-induced decrease
in tubular calcium reabsorption. Initially, serum calcium in the healthy adult is normal and stable, being defined by equality between net calcium inflow (from
bone) and outflow (to urine): this situation is represented by point a. Furosemide induces a decrease in calcium reabsorption by the renal tubule, which in turn
increases urinary calcium excretion, leaving the serum calcium level unchanged (passage from point a to b). The calcium inflow is still unchanged, so that the
serum calcium level starts to decline, causing an increase in PTH secretion, and therefore, an increase in calcium inflow (passage from b to c). The new set point
(point c) is slightly lower than the initial but remains within the normal range, whereas the urinary calcium excretion and serum PTH level are higher. (B)
Adaptation to a thiazide diuretic-induced increase in tubular reabsorption of calcium. Initially, serum calcium in the healthy adult is normal and stable, being
defined by equality between net calcium inflow (from bone) and outflow (to urine): this situation is represented by point a. A thiazide diuretic agent induces an
increase in tubular calcium reabsorption, which decreases the urinary calcium excretion without altering the serum calcium level (passage from point a to b). The
calcium inflow is still unchanged, so that the serum calcium level starts to rise, causing a decrease in PTH secretion, and therefore, a decrease in calcium inflow
(passage from b to c). The new set point (point c) is slightly higher than the initial but remains within the normal range, whereas the urinary calcium excretion
and serum PTH level are lower.

mal serum calcium levels (Fig. 2B). Neither does an isolated
and moderate modification in calcium release from bone
cause major alterations in the serum calcium level. For ex-
ample, in early postmenopausal osteoporosis, the marked
increase in bone resorption does not cause hypercalcemia
because the kidney easily adapts to this moderate increase in
calcium inflow.
Conversely, primary abnormalities in PTH secretion (in
either direction) inevitably produce serum calcium levels
outside the normal range. A primary increase in PTH levels is
associated with increased calcium release from bone and
decreased renal excretion of calcium related to stimulation
by PTH of tubular calcium reabsorption. The result is an
increase in extracellular calcium levels. A new set point is
reached when the amount of calcium excreted by the kidney
is equal to the amount released from the bone (Fig. 3). At the
new set point, the net calcium outflow from the bone pool to
the extracellular compartment is again small, and the bone
mass and calcium balance remain normal. Primary hyperpar-
athyroidism is a typical example of this mechanism leading
to stable hypercalcemia. Conversely, a primary deficiency in
PTH leads to decreased calcium release from bone and in-
creased urinary calcium excretion related to diminished tu-
bular reabsorption. The serum calcium level decreases
slowly until the amount of calcium lost in the urine is again
equal to the amount released from bone. Again, the calcium
balance is normal and the hypocalcemia is stable.
Similar abnormalities occur when CaSR function is al-
tered, usually as a result of heterozygous mutations respon-
sible for loss or gain of function. Loss-of-function mutations
result in chronic hypercalcemia because normal calcium lev-
els are perceived as abnormally low, so that PTH secretion
increases, elevating the calcium level to the value that is
perceived as normal by the CaSR. This is the mechanism
412 P. Houillier et al. / Joint Bone Spine 70 (2003) 407–413
Fig. 3. Effect of a primary increase in PTH secretion on the calcium set point
and its bone and renal determinants. The normal situation present initially is
shown by the shaded lines. A primary excess in PTH (black line, top)
increases calcium inflow from the bone pool and increases tubular calcium
reabsorption, thereby decreasing calcium outflow into the urine. This shifts
the net calcium flow curves toward the right. The calcium level rises until the
calcium inflow from bone and calcium outflow to urine are again equal
(black lines, bottom).
underlying familial benign hypercalcemia, a condition that
differs from primary hyperparathyroidism in two ways. First,
serum PTH levels, although inappropriate, are normal,
whereas they are elevated in 90% of patients with primary
hyperparathyroidism. Second, because the mutated CaSR is
expressed in the renal tubule, tubular reabsorption of calcium
is greater in familial benign hypercalcemia than in primary
hyperparathyroidism. Consequently, urinary calcium is low
to normal in familial benign hypercalcemia and normal to
high in primary hyperparathyroidism. Conversely, gain-of-
function mutations cause chronic hypocalcemia. In this con-
dition, called autosomal dominant hypocalcemia, heterozy-
gous expression of the mutated CaSR within the parathyroid
glands results in normal calcium levels being perceived as
abnormally high, so that PTH secretion diminishes. This
decreases the release of calcium from bone and the reabsorp-
tion of calcium in the kidney, thereby lowering the serum
calcium level. The main difference between autosomal domi-
nant hypocalcemia and primary hypoparathyroidism is re-
lated to expression of the mutated CaSR in the renal tubule:
in autosomal dominant hypocalcemia, the amount of calcium
reabsorbed by the tubule is smaller, and the amount excreted
in the urine larger, than in primary hypoparathyroidism.
Fig. 4. Effect of a primary increase in calcium release from bone on the
calcium set point. The normal situation present initially is shown by the
shaded lines. When net osteolysis occurs, serum calcium rises, serum PTH
falls, and urinary calcium increases. If the osteolysis is marked, the serum
calcium level rises above the normal range. This situation differs from the
normal situation in that the serum calcium level depends almost entirely on
the degree of net bone resorption. The calcium inflow increase can induce
hypercalcemia (point a) without altering the handling of calcium by the
kidney. However, the hypercalcemia often causes renal wasting of sodium
chloride. The resultant decrease in the size of the extracellular compartment
increases tubular calcium reabsorption, so that the calcium outflow curve
(from the extracellular compartment to the urine) shifts to the right. This
further increases the serum calcium level (point b).
All the above-described mechanisms alter the calcium
level through a primary change in PTH secretion. Several
extraparathyroid mechanisms can cause hypercalcemia or
hypocalcemia. Abnormal bone remodeling with loss of cou-
pling between osteoclastic and osteoblastic activities and a
net increase in bone resorption produces a large inflow of
calcium from the bone to the extracellular compartment
(Fig. 4). When the size of this inflow exceeds the maximum
outflow that can be achieved by the kidney, hypercalcemia
ensues. In normal individuals, an experimentally induced net
calcium inflow to the extracellular fluid greater than
20 mmol/d necessarily produces hypercalcemia (Fig. 5) [1].
Osteolysis can result in a calcium inflow of this magnitude in
many cancers, granulomatous diseases with excessive and
unregulated calcitriol production, or complete immobiliza-
tion in younger individuals. In these situations, hypercalce-
mia can occur even when renal function is normal. The
course of the hypercalcemia depends on that of the underly-
ing disease. Vomiting and renal sodium wasting are common
and further worsen the hypercalcemia. The calcium balance
is negative, as the bone gradually loses its calcium: the
hypercalcemia cannot reach a steady state. Hypocalcemia
can also result from mechanisms located outside the parathy-
roid glands, when the renal tubule and bone become resistant
 P. Houillier et al. / Joint Bone Spine 70 (2003) 407–413
Fig. 5. Relation between urinary calcium excretion and serum calcium
studied experimentally in healthy individuals (95% confidence interval)
(from Ref. [1] and personal data). At the steady state, the amount of calcium
lost in the urine (calcium outflow) is equal to the amount that enters the
extracellular compartment (calcium inflow). An experimentally induced
increase in calcium inflow causes an increase in the serum calcium level.
When the inflow rate reaches 20 mmol/d, hypercalcemia is present in all the
study subjects.
to the effects of PTH. This occurs in genetically determined
abnormalities in the signal transduction pathways coupled to
the PTH receptors (pseudohypoparathyroidism). More often,
the cause is severe vitamin D deficiency, magnesium defi-
ciency, and renal failure.
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