HORMONES 2009, 8(2):83-95
Review
Medical treatment of hypercalcaemia
Polyzois Makras1, Socrates E. Papapoulos2
Department of Endocrinology & Diabetes, 251 Hellenic Air Force & VA General Hospital, Athens, Greece, 2Department
of Endocrinology & Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
1
ABSTRACT
Hypercalcaemia results from the failure of renal calcium excretion to compensate increased
influx of calcium into the circulation from the intestine, the kidneys and the skeleton. Hypercalcaemia is a common metabolic abnormality of varying severity that can be adequately diagnosed and treated. Primary hyperparathyroidism and malignant neoplasms are responsible
for >90% of all cases. The management of hypercalcaemia depends on the underlying cause
and involves approaches aiming at reducing serum calcium concentrations and correcting
associated metabolic disturbances. A number of pharmacological interventions are currently
available for the treatment of hypercalcaemia related to malignancy as well as other forms of
hypercalcaemia. Knowledge of the pathophysiology of hypercalcaemia and of the properties
of these interventions is essential for the successful management of affected individuals. We
herein review available therapeutic interventions for hypercalcaemia of varying aetiology.
Key words: Bisphosphonates, Calcimimetics, Hypercalcaemia, Hyperparathyroidism, Malignancy,
Parathyroid hormone, Parathyroid hormone related protein
IntroductIon
Calcium is a critical ion for many physiological
processes. Circulating calcium concentrations fluctuate within a narrow range due to the tight regulation of
the fluxes at the three main sites of calcium transport
(intestine, bone, kidney) mainly by the calciotropic
hormones.1-3 Serum total calcium concentrations,
adjusted to serum albumin values, range between 8.5
Address for correspondence:
Polyzois Makras, Dept. of Endocrinology & Diabetes
251 Hellenic Air Force & VA General Hospital,
3 Kanellopoulou St., 115 25 Goudi, Athens,
Tel.: +30 210 7463606, Fax: +30 210 7715690
E-mail: makras@internet.gr
Received 22-01-09, Revised 28-02-09, Accepted 15-03-09
and 10.5 mg/dl (2.1-2.5 mmol/l). The adjustment to
serum albumin is accomplished by adding or subtracting 0.08 mg/dl (0.02 mmol/l) to the measured total
serum calcium for every 1.0 gr/l of albumin below or
above 40 gr/l albumin, respectively. Measurement of
ionized serum calcium concentration is rarely needed
in clinical practice. Hypercalcaemia develops when
the amount of calcium entering the circulation from
the sites of its transport exceeds the capacity of the
kidney to excrete it.
Symptoms of hypercalcaemia are non-specific or
can be related to the underlying disease (Table 1).
Furthermore, the severity of the symptoms depends
on the level of serum calcium and on the rate of its
increase. The most frequent causes of hypercalcaemia are primary hyperparathyroidism and malignant
84
P. Makras, s.E. PaPaPoulos
Table 1. Symptoms and signs of hypercalcaemia
Table 2. Causes of hypercalcaemia
Neurological
muscle weakness
fatigue
headache
mental instability
lethargy
confusion
psychotic behaviour
stupor
coma
Gastrointestinal
abdominal pain
constipation
anorexia
nausea – vomiting
peptic ulcer
pancreatitis (rare)
Renal
polyuria (nocturia)
polydipsia
nephrocalcinosis
nephrolithiasis
renal failure
Cardiovascular
arrhythmias
bradycardia
short QT interval; bundle branch block; atrioventricular
block
hypertension (rare)
arrest (rare)
venous thrombosis
Skeletal
bone pain
arthralgias
Malignancy-associated hypercalcaemia
Local osteolytic hypercalcaemia
Humoral hypercalcaemia of malignancy
Ectopic production of 1,25(OH)2 vitamin D
Other humoral factors
Parathyroid Hormone (PTH) mediated hypercalcaemia
Autonomous hyperparathyroidism
Primary (isolated or within the context of syndromes)
Tertiary hyperparathyroidism
Parathyroid carcinoma
Familial benign hypocalciuric hypercalcaemia
Granulomatous disorders
Sarcoidosis
Tuberculosis
Leprosy
Candidiasis
Histoplasmosis
Wegener’s granulomatosis
Crohn’s disease
Drugs
Thiazides
Lithium
Vitamin D
Vitamin A
Aluminium intoxication in renal failure
Miscellaneous
Thyrotoxicosis
Adrenal insufficiency
Pheochromocytoma
VIP-producing tumour
Milk-alkali syndrome
Parenteral nutrition
Renal failure (acute, chronic)
Immobilization
William’s syndrome
diseases in out-patients and in-patients, respectively.4
Other, less frequent causes of hypercalcaemia are
shown in Table 2.
In this article we briefly discuss the pathophysiology of hypercalcaemia and review current approaches
to its management.
MalIgnancy-assocIated
hypercalcaeMIa (Mah)
Hypercalcaemia occurs in about 20-30% of patients
with malignancies during the course of the disease, is
associated with poor prognosis and can be a medical
emergency.4-6 In malignant diseases hypercalcaemia
is mainly due to increased bone resorption by factors
released by the tumour cells locally or systemically
(Figure 1). Various pathophysiological classifications
of malignancy-associated hypercalcaemia have been
proposed. One such classification recognizes four
separate types:4,7
1. Local Osteolytic Hypercalcaemia (LOH). This
Treatment of Hypercalcaemia
is encountered in patients with extensive skeletal
involvement, such as multiple myeloma and breast
cancer, and is the most frequent cause of LOH
among solid tumours.7 The primary mechanism of
hypercalcaemia in LOH is increased bone resorption. Once in the bone microenvironment, tumour
cells release factors which stimulate the formation
and/or the activity of osteoclasts. Bone matrix
components, which are liberated during resorption, act chemotactically for tumour cells or alter
their characteristics and increase their metastatic
potential thus amplifying the metastatic process.
For example, Parathyroid Hormone related Peptide
(PTHrP), which is expressed by the majority of
bone metastases from breast cancer, stimulates
the production of the receptor activator of nuclear
factor-κΒ ligand (RANKL) by osteoblastic/stromal
cells in the bone/bone-marrow microenvironment, thereby enhancing osteoclastogenesis and
bone resorption. This, in turn, leads to release of
Transforming Growth Factor β (TGF-β) from bone
which acts on PTHrP receptors, present on the
cancer cells to produce more PTHrP. In addition,
factors that suppress osteoblast function (Dkk1)
may also be secreted and contribute to increased
bone resorption, as shown in multiple myeloma.8
Increased bone resorption, biochemically assessed,
has also been shown to predict the development
of skeletal complications in cancer patients.
2. Humoral Hypercalcaemia of Malignancy (HHM).
Figure 1. Schematic representation of the pathophysiology of
hypercalcaemia in different conditions, depicting the contribution of intestine, kidney and bone to its development. FBH:
Familial Benign Hypercalcaemia.
85
This type results mainly from the systemic secretion
of PTHrP by squamous carcinomas (esophagus,
lung, cervix, vulva, head and neck, etc) as well as
renal, bladder, ovarian or even breast carcinomas and pancreatic neuroendocrine tumours.7,9,10
PTHrP induces hypercalcaemia by increasing
osteoclastic bone resorption and the renal tubular
reabsorption of calcium. Biochemical findings
resemble those of primary hyperparathyroidism
(PHP) but serum PTH is markedly suppressed.11
Other as yet unidentified humoral factors may
also induce hypercalcaemia in some patients with
malignant diseases.
3. Vitamin D-mediated hypercalcaemia. This type is
due to ectopic production of 1,25-dihydroxyvitamin
D [1,25(OH)2D] by some lymphomas and ovarian
dysgerminomas.4,7,12-14 It is a rare cause of MAH
and is considered the malignant counterpart of
sarcoidosis.4,7,12,13
4. Ectopic secretion of authentic PTH by the tumour.
It is an extremely rare cause of hypercalcaemia in
patients with cancer.7,15,16 About ten cases of ectopic
hyperparathyroidism have been reported,7,16 but
the condition should be considered in the differential diagnosis of hypercalcaemia in patients
with cancer and elevated serum PTH.
treatMent of Mah
Development of hypercalcaemia in patients with
malignant diseases is a poor prognostic sign and can
be fatal if left untreated. The management of MAH
aims at reducing serum calcium concentrations and
correcting the associated metabolic disturbances but
it is not curative. It consists of general and specific
measures.
General measures
The first step in the management of MAH is
volume repletion with physiological saline (NaCl
0.9%). Hypercalcaemia has a potent diuretic effect
leading to volume depletion and dehydration. To
protect against sodium loss, the kidney increases
its tubular reabsorption. However, this is associated
with increased tubular reabsorption of calcium which
further worsens the hypercalcaemia. Administration
of physiological saline, which interrupts this sequence
86
of events, is the cornerstone in the treatment of hypercalcaemia of any cause.1,4 Saline can be continuously
infused (3-6 liters over 24-48 hours) and can lower
serum calcium concentration by approximately 1.03.0 mg/dl (0.25mmol/L-0.75mmol/l) by decreasing
the concomitant reabsorption of sodium and calcium
in both the proximal and distal renal tubule and enhancing urinary calcium excretion by increasing its
glomelurar filtration rate. However, volume repletion
is usually not enough to normalize serum calcium
concentration and should be followed by more specific
interventions. Care should be taken in the administration of physiological saline in elderly patients with
compromised cardiac and/or renal function because
there is the possibility of volume overload.
Diuretics
Loop diuretics, particularly furosemide, are traditionally recommended in the management of MAH
because they increase urinary calcium excretion.
However, although in most textbooks loop diuretics
are still considered the first step of treatment of MAH,
scientific evidence to support their use is lacking.17
In addition, if loop diuretics are given to patients
who are not volume replete, they may even worsen
the hypercalcaemia because of their concomitant
natriuretic effect. The use of loop diuretics should
therefore be restricted to patients at risk of volume
overload.
Bisphosphonates
Bisphosphonates are currently the treatment of
choice for MAH due to their inhibitory action on
bone resorption.18,19 MAH was one of the first clinical
applications of bisphosphonates and currently two
bisphosphonates (zoledronate, pamidronate) are approved for this indication in the USA, while in Europe
clodronate and ibandronate are also approved.1,20-23
Bisphosphonates are given by single intravenous
infusion over a period of between 15 minutes and 4
hours depending on the bisphosphonate and in the
majority of patients normal serum calcium concentrations are obtained within seven days following the
bisphosphonate administration. The recommended
doses are: clodronate 300mg, pamidronate 90 mg,
ibandronate 6 mg and zoledronate 4 mg, as a single
infusion. There are only a few head-to-head studies
of bisphosphonates in the treatment of MAH. In an
analysis of two randomized, controlled clinical trials,
P. Makras, s.E. PaPaPoulos
zoledronate was reported to be more effective than
pamidronate in reducing serum calcium concentrations in patients with MAH.24 In addition, its effect
on serum calcium concentrations appeared to last
longer. The clinical significance of the relatively
small differences between the two bisphosphonates
has, however, been questioned.1,4 It should be noted
that the effect of bisphosphonates on serum calcium
concentrations is apparent after 24-48 hours.25 In lifethreatening hypercalcaemia, when a rapid decrease of
serum calcium concentrations is needed, high doses
of parenteral calcitonin can be given concomitantly
with the bisphosphonate every 6 to 8 hours during
the first 24 hours. With the exception of such cases,
calcitonin has currently no place in the management
of MAH. The beneficial effect of bisphosphonates
on serum calcium concentrations can be sustained
from several days to several weeks.1 In the case of an
incomplete response, the infusion can be repeated
after at least one week.
Adverse effects of aminobisphosphonates include
flu-like symptoms due to the induction of an acute
phase reaction during the first administration of these
agents. This reaction is transient and symptoms can
be ameliorated with acetaminophen or paracetamol.
Mild, short-term hypophosphataemia and asymptomatic hypocalcaemia may also occur. Bisphosphonates
should be used with care in patients with renal insufficiency and recommendations on the dose and rate
of infusion of every bisphosphonate should be strictly
followed. Rapid infusion of the older bisphosphonates
may cause renal damage, while doses of newer bisphosphonates higher than those recommended may
adversely affect renal function.4 Osteonecrosis of the
jaw (ONJ) which has been reported in patients with
malignant diseases and bone metastases treated with
intravenous bisphosphonates, is related to the total
dose and the duration of treatment with bisphosphonates. It is, therefore, highly unlikely to occur after
treatment of patients with MAH.
In HHM, the effect of bisphosphonates is usually
short-lived and may also be incomplete due to the
contribution of coexisting skeletal and renal components to the hypercalcaemia. The renal component
includes the increased distal tubular calcium reabsorption driven by PTHrP, which does not respond
to bisphosphonates.7
Treatment of Hypercalcaemia
Steroids
Glucocorticoids have been used in the past to
treat hypercalcaemia, especially in patients with hematologic malignancies. Today their use is restricted
to the treatment of hypercalcaemia due to ectopic
production of 1,25(OH)2D.26 Glucocorticoids are
rarely efficacious in hypercalcaemia of solid tumours.1
Prednisone (30 mg daily) or hydrocortisone (120 mg
daily per os, or parenterally) are commonly used in
the treatment of hypercalcaemia resulting from endogenous production of 1,25(OH)2D. The circulating
1,25(OH)2D concentrations decrease usually within
three days followed by a decrease in serum calcium
concentrations.26 Nevertheless, steroid therapy may
not always be appropriate for these diseases and alternative treatments have been suggested, including
chloroquine or hydroxychloroquine and ketoconazole.26-28 There is limited experience in the use of
these agents as calcium-lowering therapies and they
should be given only in cases of severe hypercalcaemia
that does not respond to steroids or when steroids are
contraindicated.
Experimental treatments
Experimental therapies for MAH include agents
that interfere with the RANKL signalling pathway
such as monoclonal antibodies to RANKL or osteoprotegerin (a decoy receptor of RANKL).29,30 The
rationale for their use is based on their inhibitory
effect on bone resorption. This effect is exerted
through prevention of recruitment and of differentiation of osteoclasts and a decrease of their life-span.
Monoclonal antibodies against PTHrP have also been
used.31,32 It is still unknown whether these agents will
prove safe and effective in humans with MAH and if
they will reverse hypercalcaemia more efficiently and
at less expense than the potent bisphosphonates.
Hemodialysis
Kidney replacement therapy against a dialysate
containing little or no calcium is effective in patients
with severe MAH and renal failure, thus precluding
aggressive volume repletion and, probably, bisphosphonates.4 However, there are no specific guidelines
for such an approach.
Anti-tumour therapy
As already mentioned, the effect of anti-hypercal-
87
caemic therapy of patients with MAH is temporary.6
Moreover, in most of the cases hypercalcaemia is a
sign of progression of the tumour and specific antitumour therapy should be promptly initiated. Control
of calcium levels can provide the time needed for
the anti-tumour treatment to work. Finally, optimal
treatment of MAH should always be tailored to the
needs of the individual patient and initiation of aggressive anti-hypercalcaemic therapy in “terminal”
cancer cases should be carefully considered.4
BenIgn hypercalcaeMIas
Primary Hyperparathyroidism (HPT)
Classically, HPT is distinguished into primary,
secondary and tertiary. In clinical practice, the finding
of raised serum calcium concentrations with increased
or non-suppressed serum PTH values is indicative of
autonomous HPT (primary, tertiary), whereas secondary HPT is defined by increased PTH in the presence
of normal (or low) serum calcium concentrations.
Primary HPT is the most frequent cause of benign
hypercalcaemia, also being one of the most common
of the endocrinopathies with an incidence ranging
from 1 in 500 to 1 in 1000 subjects. It can occur at all
ages, but it is most frequent during the sixth decade
of life with a female to male ratio of 3:1. It is rather
uncommon in younger ages and, if present, the possibility of its being part of multiple endocrine neoplasia
(MEN) I or II should be considered. In about 80%
of the cases, HPT is due to a benign single adenoma;
four-gland hyperplasia occur in approximately 15-20%
of the cases, either sporadically or within the context
of MEN; parathyroid carcinomas are rare, accounting
for <0.5% of all HPT cases. PTH increases serum
calcium concentrations by acting directly on bone and
kidney (increased bone resorption and renal tubular
reabsorption of calcium, respectively) and indirectly
on the intestine [stimulation of the production of
1,25(OH)2D] (Figure 1).
The classical clinical manifestations of primary
HPT are nephrolithiasis and bone disease. However,
“osteitis fibrosa cystica”, as it was originally described,
is now encountered in <5% of cases, while the incidence of kidney stones has declined from 1/3 to 1/5
of the cases. Osteoporosis remains one of the most
frequently described manifestations of primary HPT
88
and many cases are discovered during the initial investigation of low bone mineral density. Moreover,
severe neuromuscular symptoms, as described earlier,
are no longer prominent, although vague symptoms
such as easy fatigue, a sense of weakness, or even an
intellectual weariness and a sense of less sharp cognitive function are rather common. 33 Whether these
are due to raised serum calcium concentrations, to
elevated PTH or both is not known. Gastrointestinal
manifestations are no longer prevalent in HPT with
the exception of patients with MEN. Asymptomatic
hypercalcaemia is currently the most common presentation of HPT and the vast majority of patients are
diagnosed accidentally following a routine laboratory
investigation. In addition, cases of normocalcaemic
HPT are now being described with increasing frequency, representing either a new clinical phenotype or
simply patients with an early diagnosis.34 In such cases,
vitamin D deficiency/insufficiency [serum 25(OH)D
<50 nmol/l (20 ng/ml)] should always be ruled out
and, if present, re-evaluation of these individuals must
take place after repletion with vitamin D and/or the
correction of other causes of secondary HPT. 33 In
the differential diagnosis of HPT, hypercalcaemic
disorders in which PTH may be increased should be
considered. These are familial benign hypocalciuric
hypercalcaemia (FBHH) and use of lithium or thiazide diuretics. Personal and family medical history
can assist the diagnosis, while PTH and calcium can
be re-assessed after 2-3 months of drugs withdrawal.
Differential diagnosis of primary HPT and HHM
presents no difficulties as there is no cross-reactivity
of PTHrP in current PTH assays.
Treatment of primary HPT
Primary HPT is a disease that can be cured by the
surgical removal of the hyper-functioning parathyroid
tissue. Controversies regarding the surgical approach
concern the timing of the intervention rather than its
efficacy. To address these controversies, a series of
Consensus conferences, which started in 1990, analysed available data and developed guidelines for the
management of primary HPT. In symptomatic primary
HPT (overt bone and/or renal disease, episodes of
life-threatening hypercalcaemia), the appropriate
treatment is the surgical excision of the abnormal
parathyroid tissue. The current criteria for surgery of
P. Makras, s.E. PaPaPoulos
patients with asymptomatic primary HPT are: serum
calcium >1 mg/dl (0.25 mmol/l) above the upper limit
of the local reference range; hypercalciuria of >400
mg/day (10 mmol/d); reduced creatinine clearance of
>30% compared to sex- and age-matched controls;
age <50 years; BMD T-score <-2.5 determined by
DXA scan at any site (forearm, lumbar spine, hip).35
The most recent criteria, however, do not include
hypercalciuria as an indication for surgery, while
a creatinine clearance less than 60ml/min is now
considered an indication for surgery. 36
Surgical treatment of HPT requires expertise due
to the variability of the locations where pathological
parathyroid glands can be found and the difficulty
in identifying them. Preoperative localization studies have become very popular and many patients
are routinely tested prior to surgery. However, an
experienced parathyroid surgeon will identify and
remove the abnormal parathyroid tissue in >95% of
neck surgery naive patients.33 This figure of successful localization is almost never achieved by localization studies and there is little evidence that these
can shorten the operation time or prevent operation failures. Preoperative localization of abnormal
parathyroid tissue should therefore be restricted to
cases with previous neck surgery. Transient mild,
and often asymptomatic, hypocalcaemia may occur
within the first few days following successful surgery,
which usually does not require specific treatment.
Although rarely seen today, prolonged symptomatic
hypocalcaemia resulting from rapid deposition of
calcium and phosphate into bone (“hungry bone”
syndrome) will need oral or parenteral calcium supplementation with active metabolites of vitamin D
(alpha calcidiol, calcitriol).33
Medical treatment
General measures
A number of patients with primary HPT and
hypercalcaemia are not candidates for surgery and
should be treated conservatively. Routine medical
follow-up includes yearly assessment of bone mineral
density at all sites and measurement of serum creatinine and calcium twice yearly.35 In addition, drugs
that increase serum calcium concentrations (e.g.
thiazides, lithium) should be avoided and adequate
hydration must be recommended. The influence of
calcium intake on serum calcium concentrations in
Treatment of Hypercalcaemia
patients with HPT remains controversial. A daily
calcium intake of 800-1000mg is indicated because
low calcium diets may further enhance PTH secretion, while high calcium intakes may increase serum
calcium concentrations, especially among patients
with elevated 1,25(OH)2D. Low doses of vitamin D
(400-800 u/d) should be given to patients with vitamin
D deficiency/insufficiency. 37
Bisphosphonates
Bisphosphonates have been used in the medical
management of patients with primary HPT; etidronate was ineffective, while clodronate resulted in a
temporary reduction of serum calcium concentrations.38 Alendronate has been more extensively studied
and either a small effect on serum calcium39,40 or no
change at all have been reported.41,42 Within a similar
context, PTH was reported either to increase39,42,43 or
to remain unchanged.40 A multicenter, double-blind,
randomized, placebo-controlled study reported no
effect of alendronate on either serum calcium or PTH
levels.44 However, consistent with its mechanism of
action, alendronate had a major effect in reducing
biochemical markers of bone turnover and improving bone mineral density of the lumbar spine and
the total hip. The increase in bone mineral density
has been a consistent finding of all studies using
alendronate.39-41 Similarly, risedronate reduced fasting serum calcium concentrations and biochemical
markers of bone turnover in a small series of patients
with primary HPT; additional studies are required to
evaluate the long-term efficacy of this bisphosphonate
in HPT.37,45 The use of intravenous bisphosphonates
(pamidronate, zoledronate) in primary HPT is restricted to the treatment of acute hypercalcaemia,33 as
it occurs, for example, in parathyroid crisis, which is
associated with serum calcium concentrations greater
than 15 mg/dl (3.75 mmol/l) and rapid deterioration
of central nervous system, cardiac, gastrointestinal
and renal function. Such cases can be fatal and neck
surgery should be performed as soon as possible.46
It should be noted that there are no data on the efficacy of yearly infusions of zoledronate as used in
the treatment of osteoporosis.
From the results of available studies and the pathophysiology of the disease, it can be concluded that
bisphosphonates given at doses used in the treatment
89
of osteoporosis prevent bone loss and improve bone
mineral density in patients with primary HPT but
have no effect on PTH secretion or serum calcium
concentrations.
Estrogens, raloxifene
Similar to bisphosphonates, estrogens decrease
bone resorption and improve bone mineral density
in postmenopausal women with primary HPT but
have no effect on PTH levels. Changes in serum
calcium concentrations are minimal and a decrease
of approximately 0.5 mg/dl (0.12mmol/l) has been
reported.33,37 However, the risks associated with estrogen use prevent their application to the long-term
treatment of postmenopausal women with primary
HPT. Limited data with raloxifene have shown similar
results.47
Calcimimetics
The minute-to-minute regulation of PTH secretion
by calcium is mediated by the parathyroid cell plasma
membrane Ca-Sensing Receptor (CaSR) which detects ambient serum Ca++.48 Increased serum calcium
suppresses parathyroid CaSR signalling, resulting
in diminished PTH secretion, while it stimulates
distal nephron CaSR to reduce renal tubular calcium
reabsorption. The net effect of these hypercalcaemia-driven changes is the lowering of serum calcium
concentrations. In patients with primary HPT, the
sigmoidal curve, which describes the relationship
between serum calcium and PTH, is shifted to the
right, resulting in decreased responsiveness of the
parathyroid cells to the elevated calcium concentrations. Consequently, increased PTH secretion is
observed despite hypercalcaemia.49 Calcimimetics
are drugs which increase the sensitivity of the CaSR
in parathyroid cells to circulating calcium, leading
to increased intracellular calcium and subsequently
reduction of PTH secretion (Figure 2).50 Cinacalcet is
an oral calcimimetic that interacts with the transmembrane domain of the CaSR and increases its affinity
for calcium. Cinacalcet was shown to reduce PTH
secretion and the risk of adverse clinical outcomes
in patients with secondary hyperparathyroidism due
to renal failure51,52 and is currently approved for this
indication.
Cinacalcet has been studied in patients with pri-
90
P. Makras, s.E. PaPaPoulos
Figure 2. Left panel: Schematic representation of the Calcium Sensing Receptor (CaSR) of parathyroid cell. Right panel: The action
of calcimimetics on CaSR.
mary HPT and was shown to reduce serum calcium
concentrations. In a small randomized, placebocontrolled study, cinacalcet (30mg, 40mg, or 50mg)
was given twice daily for 15 days and was found to
normalize serum calcium concentration within one
day after its administration and to decrease serum
PTH 2-4 hours after dosing; these effects were sustained throughout the period of treatment.49 While
there was no consistent dose-response, cinacalcet
doses of 40 and 50 mg twice daily resulted in larger
reductions in serum calcium concentrations.49 Based
on these findings, a larger randomized, placebocontrolled study was subsequently conducted in 78
patients with primary HPT.50 Cinacalcet was titrated
from 30-50mg twice daily and treatment was given
for one year. Normocalcaemia was achieved in up
to 73% of patients and, once a steady state had been
individually established, it was sustained during the
whole period of the study without evidence of fluctuations. In 90% of patients, the dose of 30mg twice daily
was sufficient to normalize serum calcium. Serum
PTH was reduced by 37% two hours after dosing
and gradually returned towards pre-dose levels by
eight hours. Urinary calcium excretion decreased
slightly.53 Forty-five patients were enrolled in a two-
year extension study in which all received cinacalcet.
After three years, 87% of those who completed the
study had normal serum calcium concentrations. 54
Cinacalcet has also been tested in the treatment of
primary HPT due to parathyroid carcinoma. In a
multicenter, open-label, single-arm study, 29 patients
with parathyroid carcinoma were given cinacalcet and
doses were titrated within a 16-week period from 30
mg twice daily up to 90 mg four times daily.55 Serum
calcium concentration was reduced by at least 1.0
mg/dl in 62% of patients, although PTH was not
significantly reduced; patients with higher baseline
calcium levels required higher doses of cinacalcet,
while cumulative doses up to 360 mg daily (90 mg
QID) were generally well tolerated.
Common adverse effects of cinacalcet include
nausea, vomiting and headache. In general, it seems
that cinacalcet is a promising medical treatment of
primary HPT, although further studies focusing on
changes in bone mineral density and fracture risk
are needed.
Cinacalcet is currently approved for the medical
treatment of parathyroid carcinoma when hypercalcaemia persists and a surgical approach is no longer
Treatment of Hypercalcaemia
91
indicated or feasible. They are also approved for
the management of “intractable” HPT, defined as
unresolved HPT, following unsuccessful parathyreoidectomy or contraindicated parathyroidectomy.
agents. However, evidence from a few case reports
suggests that cinacalcet might be effective.60,61
There is limited experience in the medical treatment of the HPT of MEN (1 or 2) but bisphosphonates
and cinacalcet are expected to act as in sporadic
primary HPT. Interestingly, in a recent small series,
six months of treatment with depot, long-acting octreotide, controlled hypercalcaemia and hypercalciuria
in 2/3 of patients with MEN1-related HPT, while
PTH decreased in all patients.56 It was suggested that
this response was due to a direct action of octreotide
on parathyroid tumour cells mediated by binding to
somatostatine receptors. This, however, has not been
the experience of others and more studies are needed
before a conclusion may be formed as to the efficacy
of octreotide in such patients.
Granuloma-forming disorders
Extra-renal production of 1,25(OH)2D by macrophages can occur in granuloma-forming disorders62
(Table 2). Sarcoidosis is the most extensively studied
of these diseases and hypercalcaemia and hypercalciuria have been reported in up to 10% and 50%
of patients, respectively, at some time during the
course of the disease.26 The successful management
of sarcoidosis-driven hypercalcaemia requires the
recognition of high risk patients. In addition, followup after a hypercalcaemic episode must include close
monitoring of urinary calcium excretion in order to
detect recurrence timely. Glucocorticoids are the
basis of treatment of hypercalcaemia of sarcoidosis
and other granuloma-forming diseases. Doses are
the same as those used in the treatment of malignant
lympho-proliferative disorders. However, infectious
diseases should be very carefully treated due to a
significant risk of disease exacerbation. Excessive
sunlight exposure (UV light) must be avoided in order
to prevent endogenous vitamin D production.
faMIlIal BenIgn hypocalcIurIc
hypercalcaeMIa (fBhh)
FBHH or Familial Benign Hypercalcaemia (FBH)
is an autosomal dominantly inherited disorder with
a lifelong high penetrance for hypercalcaemia and
relative hypocalciuria, which accounts for almost
2% of asymptomatic hypercalcaemic cases. 57 It is
most frequently caused by heterozygous loss-of-function mutations in the gene encoding the CaSR. 58,59
It is usually asymptomatic; however, the degree of
hypercalcaemia varies from very modest to quite
severe [12.5-14.5 mg/dl (3.12mmol/L-3.62mmol/l)].
Parathyroid function is inappropriately normal or even
modestly elevated, thus reflecting the resistance of
parathyroid cell to elevated serum calcium levels. The
course of the disease is benign and patients should
be reassured. FBHH should always be considered in
the differential diagnosis of primary HPT in order
to avoid unnecessary parathyroidectomy. Immediate
(within one week) recurrence of hypercalcaemia occurs after a subtotal parathyroidectomy, since even
a small remnant of parathyroid tissue is enough to
maintain elevated calcium levels. Therefore, surgical
excision is contraindicated except in rare cases of
severe hypercalcaemia [>14.0 mg/dL (3.5mmol/l)]
and relapsing pancreatitis. Additionally, FBHH is
resistant to previously described calcium lowering
treatMent of other hypercalcaeMIas
Thyrotoxicosis
Up to one half of thyrotoxic patients manifest
mild hypercalcaemia ranging from 10.5mg/dL to
11.5 mg/dL (2.62mmol/L-2.87mmol/L).63 Excessive
bone resorption and calcium release into the circulation is the pathophysiological mechanism of serum
calcium increase. Therefore, in the absence of other
calcium-increasing disorders, PTH and 1,25(OH)2D
serum levels should be low in hyperthyroidism-driven
hypercalcaemia. The hypercalcaemia of thyrotoxicosis
is fully reversible after restoration of normal thyroid
function.63
Pheochromocytoma
Co-existence of hypercalcaemia with pheochromocytoma is most frequently described in the context
of MEN 2A. The cause is unknown but correction of
hypercalcaemia has been reported after removal of
pheochromocytoma, suggesting that tumour-derived
factors or catecholamines may be responsible.63 In
addition, increased PTHrP secretion, and subsequent
92
hypercalcaemia, have been reported in a few patients
with pheochromocytomas as well as in patients with
other tumours of neuroendocrine origin.
Adrenal insufficiency
Adrenal insufficiency, and in particular addisonian
crisis, has been linked with hypercalcaemia.63 The most
probable cause of hypercalcaemia is hypovolaemia
and hemoconcentration. Hypercalcaemia is corrected
with fluid repletion and steroid replacement.
Milk-alkali syndrome
The milk-alkali syndrome results from the consumption of large amounts of milk and absorbable
alkali, as previously used in the treatment of peptic
ulcer, or large quantities of calcium carbonate providing a daily calcium intake usually in excess of
5 gr.63 It is classically defined as the triad of systemic
alkalosis, hypercalcaemia and renal insufficiency.
Hypercalcaemia usually reverses with rehydration
and discontinuation of treatment.
Vitamin D intoxication
Vitamin D intoxication may occur with the use of
doses in excess of 50,000 IU per day and is associated
with serum 25(OH)D concentrations higher than 150
ng/ml (374 nmol/l) and hypercalcaemia.64 Discontinuation of treatment is usually sufficient to correct the
hypercalcaemia but in severe cases rehydration and
a short course of glucocorticoids may be required.
Reversal of hypercalcaemia is relatively slow due to
the plasma half-life of 25(OH)D, which is approximately 25 days. In contrast, hypercalcaemia occurring
during treatment with active vitamin D metabolites
(alphacalcidol or calcitriol) reverses quickly after
treatment arrest due to the short plasma half-life of
these metabolites.65
conclusIons
The management of hypercalcaemia depends on
the underlying cause. Volume expansion and inhibition of bone resorption are the most important medical interventions, independently of the aetiology of
hypercalcaemia. Bisphosphonates are the mainstay
of medical therapy for malignancy-associated hypercalcaemia and may provide the time necessary
for anti-tumour therapy to work. In PTH-mediated
hypercalcaemias, surgery is the treatment of choice
P. Makras, s.E. PaPaPoulos
when appropriate criteria are met. Bisphosphonates,
as used in the treatment of osteoporosis, prevent bone
loss in primary hyperparathyroidism but have no effect
on serum calcium levels. Calcimimetics can normalize
serum calcium concentrations in a large proportion
of patients with primary HPT and are approved for
the medical management of parathyroid carcinoma
and “intractable” autonomous hyperparathyroidism.
Novel therapeutic approaches directed at specific
molecular targets are currently being evaluated.
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