Calcif Tissue Int (2004) 74:1–11

DOI: 10.1007/s00223-001-1135-6 Calcified

Tissue
International

2003 Springer-Verlag New York Inc.

Review
Medical Management of Hypercalcemia
S. H. Ralston,1 R. Coleman,4 W. D. Fraser,8 S. J. Gallagher,5 D. J. Hosking,6 J. S. Iqbal,7 E. McCloskey,3
D. Sampson2
1
Department of Medicine & Bone Metabolism, University of Aberdeen, AB25 2ZD, UK
2
Department of Hematology, Hammersmith Hospital, London, W12 ONN, UK
3
Department of Medicine, University of Sheffield, Sheffield, S10 2RX, UK
4
Department of Medical Oncology, University of Sheffield, Sheffield, S10 2SJ, UK
5
Consultant Physician, Southern General Hospital Glasgow, Glasgow, G51 4TF, UK
6
Department of Mineral Metabolism, Nottingham City Hospital, Nottingham, NG5 1PB, UK
7
Department of Biochemical Medicine, Leicester Royal Infirmary, Leicester, LE1 5WW, UK
8
Department of Clinical Chemistry, University of Liverpool, Liverpool, L69 3GA, UK

Received: 29 November 2001 / Accepted: 11 February 2003 / Online publication: 6 October 2003

Hypercalcemia is a common problem in routine clinical
practice. It has many causes (Table 1), but the vast
majority of cases are due to one of three disorders;
malignant disease, primary hyperparathyroidism and
vitamin D intoxication [1]. Of these conditions, cancer-
associated hypercalcemia is the one that most often re-
quires medical antihypercalcemic therapy, since surgery
remains the treatment of choice for primary hyperpar-
athyroidism [2] and most patients with vitamin D in-
toxication respond satisfactorily when treatment with
Vitamin D is stopped [3].
Pathophysiology of Hypercalcemia
Hypercalcemia occurs when influx of calcium to the
extracellular space from bone resorption and intestinal
calcium absorption exceeds the rate at which it can be
excreted by the kidney [4]. The relative importance of
bone, gut and kidney to the pathogenesis of hypercal-
cemia in various disorders is summarized in Table 2 and
the mediators of hypercalcemia in more common dis-
orders are discussed below.
Cancer-Associated Hypercalcemia
Hypercalcemia associated with solid tumors is usually
caused by a combination of increased osteoclastic bone
resorption and increased renal tubular calcium reab-
sorption [5–8]. In most cases, the hypercalcemia is me-
diated by parathyroid hormone related protein (PTHrP)
Correspondence to: S. H. Ralston; E-mail: s.ralston@abdn.
ac.uk
which is released in excessive amounts by tumor tissue
[9–11]. The raised levels of PTHrP act both locally and
systemically to increase osteoclastic bone resorption and
act on the kidney to increase renal tubular calcium re-
absorption [12, 13]. This mechanism of hypercalcemia
occurs both in the presence and absence of bone meta-
stases [7, 8, 10]. Ectopic production of PTH by tumors
has been described [14, 15], but is exceptionally rare,
except in parathyroid carcinomas [16]. Production of
PTHrP has also been described in myeloma but this
appears to be less common than in solid tumors [17, 18].
Osteoclast activation in myeloma is instead, thought to
be mainly due to local osteolysis mediated by the release
of bone-resorbing cytokines such as interleukin-1, tumor
necrosis factors MIP-1 alpha and IL-6 by the malignant
plasma cells [19, 20]. Increased intestinal calcium ab-
sorption does not play a major role in the pathogenesis
of hypercalcemia in malignancy [21], but can do so in
patients with hematological tumors such as lymphoma
and Hodgkin’s disease where there is increased conver-
sion of 25(OH)D3 to 1,25(OH)2D3 by tumor cells [22–
24]. The resulting increase in circulating levels of
1,25(OH)2D3 causes hypercalcemia by stimulating bone
resorption and increasing intestinal calcium absorption.
Primary and Tertiary Hyperparathyroidism
Hypercalcemia in primary hyperparathyroidism is
mainly due to increased renal tubular calcium reab-
sorption and increased intestinal calcium absorption
[25–27]. The increased renal tubular calcium reabsorp-
tion is mediated by a direct effect of PTH on the distal
renal tubule, and the increased intestinal calcium ab-
sorption is due to elevated 1,25(OH)2D3 production
stimulated by PTH. Increased bone resorption may also
2 S. H. Ralston et al.: Management of Hypercalcemia
Table 1. Conditions associated with hypercalcaemia
Common Cancer
Primary hyperparathyroidism
Vitamin D intoxication
Tertiary hyperparathyroidism
Less common Sarcoidosis
Immobilization
Calcium-Alkali syndrome
Thyrotoxicosis
Familial hypocalciuric hypercalcemia
Drug treatment*
Rare Granulomatous disease other than sarcoidosis
Addison’s disease
Chronic liver disease
Recovery phase of acute renal failure
Manganese poisoning
Jansen’s metaphyseal chondrodyplasia
Hypophosphatasia
Oxalosis
Gaucher’s disease
Benign breast disease
Lactation
The reader is referred to recent reviews for more information
on the rare causes of hypercalcemia mentioned in the table [30,
103]
* Drugs associated with hypercalcemia include thiazides, lith-
ium therapy, treatment with retinoids, theophylline, 8-Chloro-
cAMP, growth hormone, and Foscarnet
play a role in patients with severe hyperparathyroidism
[28]. Tertiary hyperparathyroidism is the term given to
describe autonomous production of PTH, sufficient to
cause hypercalcemia. It may arise either as the result of
hyperplasia of all four parathyroid glands, and/or as the
result of an adenoma arising in hyperplasic tissue [29].
The most common cause is chronic renal failure and
here, hypercalcemia is caused by increased bone re-
sorption and failure of renal calcium excretion, due to
reduced glomerular filtration rate.
Granulomatous Disease and Vitamin D Intoxication
Hypercalcemia in sarcoidosis and other granulomatous
conditions is due to increased intestinal calcium ab-
sorption and increased bone resorption. This occurs
because of unregulated production of 1,25(OH)D3
by macrophages within granulomatous tissue [30]. Re-
cently, evidence has been presented to show that PTHrP
is also expressed in sarcoid tissue [31] although the role
of this factor in the pathogenesis of hypercalcemia is
unclear. Hypercalcemia in granulomatous disease may
be precipitated by increased dietary intake of vitamin D
or excessive exposure to sunlight and ultraviolet irradi-
ation, since this increases the amount of precursor
25(OH)D available for 1,25(OH)2D synthesis [24].
Similar pathophysiological mechanisms of hypercal-
cemia operate in vitamin D intoxication due to increased
intake of active vitamin D metabolites [32]. Hypercal-
cemia can also occur in patients treated with large
amounts of 25(OH)D. Though this metabolite is a weak
agonist at the vitamin D receptor, significant activation
can occur if the levels are high enough [32].
Immobilization and Thyrotoxicosis
Hypercalcemia in thyrotoxicosis is caused by increased
bone resorption due to direct stimulatory effects of
thyroid hormones on osteoclast activity [33]. The
hypercalcemia of immobilization is also caused by in-
creased bone resorption [27, 34], but the mediators re-
sponsible are poorly defined. The hypercalcemia of
immobilization is usually restricted to children, adoles-
cents and patients who have preexisting abnormalities of
bone turnover due to Paget’s disease or hyperparathy-
roidism, suggesting that uncoupling between bone for-
mation and bone resorption plays an important role in
pathogenesis.
Calcium-Alkali Syndrome
Calcium alkali syndrome is primarily due to increased
absorption of calcium from the intestine due to excessive
intake of calcium-containing antacids or phosphate
binders [35]. The combination of calcium and alkali
ingestion seems to be crucial to the pathogenesis of this
syndrome since hypercalcemia does not occur when
excessive amounts of calcium are taken in the absence of
alkali, or when alkali is taken in the absence of calcium.
It has been speculated that the coexistence of alkalosis
and hypercalciuria may predispose to hypercalcemia by
causing renal parenchymal calcification and tubular
damage since affected patients almost always have sig-
nificant renal impairment.
Familial Hypocalciuric Hypercalcemia
Reduced urinary calcium excretion due to increased re-
nal tubular reabsorption of calcium is the main factor in
the pathogenesis of familial hypocalciuric hypercalcemia
[36, 37]. The mechanism is independent of PTH and
presumably due to the effect of mutations in the calci-
um-sensing receptor on the renal tubular reabsorption
of calcium [38].
Hypercalcemic Nephropathy
Hypercalcemia has deleterious effects on renal function
and this can contribute to a syndrome of ‘‘disequilib-
rium hypercalcemia’’ characterized by a deteriorating
spiral of rising serum calcium values, dehydration, and
progressive renal impairment [39–41]. This syndrome
can occur in association with virtually any underlying
cause of hypercalcemia except familial hypocalciuric
hypercalcaemia (FHH). One of the primary events is an
increased filtered load of calcium due to increased influx
S. H. Ralston et al.: Management of Hypercalcemia 3

Table 2. Relative importance of bone, intestine and kidney to the pathogenesis of hypercalcemia in different diseases

Condition Bone resorption Intestinal absorption Renal tubular reabsorption

Primary hyperparathyroidism › › ›
Cancer-associated hypercalcemia › - ›
Vitamin D intoxication › › -
Granulomatous disease › › -
Familial hypocalciuric hypercalcemia - - ›
Immobilization › - -
Thyrotoxicosis › - -
Calcium-alkali syndrome - › -

of calcium into the extracellular space. This acts on the
proximal renal tubule to increased urinary sodium and
water loss and causes the clinical symptom of polyuria.
If the increased urinary losses of water and electrolytes
are not matched by a commensurate increase in oral
fluid intake, the patient becomes dehydrated and volume
depleted. This stimulates the renin-angiotensin system,
causing increased sodium-linked calcium reabsorption
in the proximal renal tubule, thereby reducing calcium
excretion and causing an elevation in serum calcium
values. The resulting hypercalcemia has a number of
deleterious effects on renal function; glomerular filtra-
tion rate and renal blood flow fall due to volume de-
pletion and direct effects on the renal vasculature [40].
The concentrating mechanism in the distal renal tubule
is also impaired, leading to increased water loss and
worsening of dehydration. There then ensues a wors-
ening spiral of dehydration, renal dysfunction and pro-
gressive hypercalcemia, which can be fatal if untreated.
Presentation and Symptoms of Hypercalcemia
Most patients with mild hypercalcemia (<3.0 mM) are
asymptomatic and in these circumstances, the condition
is usually discovered as an incidental finding on routine
biochemical screening. When serum calcium values rise
above 3.0 mM, symptoms of hypercalcemia start to
develop and are almost invariable when calcium values
rise above 3.5 mM. These symptoms are listed in Table
3. Polyuria and polydipsia occur because hypercalcemia
impairs renal concentrating ability [40]. Constipation
and weakness are due to the suppressive effects of
hypercalcemia on neuromuscular transmission, whereas
nausea, vomiting, anorexia, coma, confusion and alter-
ation in pain threshold are thought to be due to the
effects of hypercalcemia in the central nervous system.
The severity of symptoms can differ in different dis-
orders. Patients with cancer-associated hypercalcemia
seem to develop symptoms of hypercalcemia at lower
levels of serum calcium than patients with benign dis-
ease. This may be due to potentiation of symptoms by
the underlying tumor or the fact that the symptoms of
advanced cancer and its treatment overlap with those of
hypercalcemia. Patients with familial hypocalciuric
Table 3. Symptoms of hypercalcemia

Gastrointestinal

Nausea

Vomiting

Anorexia

Constipation

Kidney

Thirst

Polyuria

Central nervous System

Malaise

Confusion

Coma

Lowered pain threshold
hypercalcemia do not present with symptoms related to
hypercalcemia, presumably because the elevation in se-
rum calcium values is ‘‘appropriate’’ to the fact that
affected individuals have a mutation in calcium-sensing
receptor which blunts the response to the raised serum
calcium concentrations.
Identifying the Cause of Hypercalcemia
Hypercalcemia has a wide differential diagnosis, and
several investigations may be required to determine the
underlying cause (Table 4 and Fig. 1). A biochemical
screen with measurement of urea and electrolytes, serum
albumin, globulins and parathyroid hormone should be
done in all cases. It is important to adjust the total
calcium value for serum albumin, since total calcium can
be in the normal range in hypercalcemia patients who
have hypoalbuminaemia [42]. Measurements of ionized
calcium are seldom required except patients with gross
abnormalities of plasma proteins where spurious
‘‘hypercalcemia’’ has been reported due to calcium
binding by gamma globulins [43]. The most important
biochemical investigation is PTH since this can distin-
guish primary hyperparathyroidism from other causes
of hypercalcemia. The levels of PTH need to be inter-
preted with caution in patients who have received cal-
cium lowering therapy however, since values can
become raised before serum calcium values return to
normal in bisphosphonate-treated patients with non-
parathyroid hypercalcemia [44].
4 S. H. Ralston et al.: Management of Hypercalcemia

Table 4. Laboratory investigation of hypercalcemia

Test Comment/Interpretation

Indicated in all cases

Serum PTH Raised values suggest hyperparathyroidism (primary or tertiary); low values
suggest other causes
Urea and electrolytes Required to assess renal function. Raised serum bicarbonate suggests
calcium-alkali syndrome
Serum albumin To adjust total calcium values for albumin. Albumin of £ 35 g/L suspicious
of underlying tumor
Indicated in some cases
FBC/ESR Anemia and raised ESR suggest occult malignancy
Immunoglobulins/serum and urine Paraproteinaemia suggests myeloma. Polyclonal increase in immunoglobulins
electrophoresis suggest sarcoidosis or occult tumor
Serum PTHrP May help in diagnosis of occult cancer-associated hypercalcemia
Thyroid function tests To exclude thyrotoxicosis
Ratio of calcium clearance to To differentiate FHH from PHPT. A ratio of calcium clearance to creatinine
creatinine clearance in fasting clearance of <&0.01 suggests FHH
urinary sample
Chest x-ray May reveal signs of sarcoidosis or lung cancer
Serum angiotensin-converting enzyme Elevated values suggest sarcoidosis
Serum vitamin D metabolites Greatly elevated levels of 25(OH)D typical of vitamin D intoxication. 1,25(OH)2D3
high in sarcoidosis and other granulomatous disease
Synacthen test To exclude AddisonÕs disease
Radionuclide bone scan/Imaging Indicated in patients suspected to have occult cancer-associated hypercalcemia
of other organs

Other investigations that may be helpful in reaching a
diagnosis included liver function tests, serum immuno-
globulins and protein electrophoresis, thyroid function,
full blood count and ESR. Measurement of fasting
urinary calcium excretion on a second-voided morning
urine sample is helpful when FHH is suspected. Typi-
cally, patients with FHH have a ratio of calcium to
creatinine clearance of less than 0.01, whereas in PHPT,
values are typically above this [36, 37]. The ratio of
calcium to creatinine clearance can be assessed on a
second voided, untimed fasting urine sample using the
following formula (where the concentration of all ana-
lytes are expressed in millimoles):
½Ca(urine) ½Cr(serum)
 antihypercalcemic therapy is required in patients who
½Ca(serum) ½Cr(urine)
Since about 10% of FHH patients have urinary cal-
cium values that overlap with those in hyperparathy-
roidism [36, 45], screening family members for
hypercalcemia should also be considered when this di-
agnosis is suspected, especially in young patients with
hypercalcemia and in those who have PTH values within
the normal range. Molecular diagnosis is also possible
but is not generally available on a routine basis.
The diagnosis of tumor-induced hypercalcemia is
usually obvious on clinical grounds, but serum PTHrP
levels may be useful in reaching the correct diagnosis in
patients where hypercalcemia is the presenting feature of
an undiagnosed tumor [18]. Hypercalcemia can occur as
a complication of almost any tumor, but the most
common causes are squamous carcinomas, breast car-
cinoma, uro-epithelial tumors, and hematological tum-
ors such as myeloma and lymphoma. Common sites for
occult tumors presenting with hypercalcemia are the
liver (hepatoma and cholangiocarcinoma) and kidney
(clear cell carcinoma). These patients should be urgently
evaluated to try and identify the underlying tumor; if the
diagnosis can be made at an early stage before the tumor
has spread, then cure may be possible [46].
General Approach to the Management of Hypercalcemia
Long-term control of hypercalcemia is best achieved by
identifying and treating the underlying cause. Medical
have severe or life-threatening hypercalcemia and in
those where the underlying cause cannot be treated. In
practice, this situation most commonly arises in patients
with cancer-associated hypercalcemia. While patients
with cancer-associated hypercalcemia have a limited
survival even when treated [47, 48], effective anti-
hypercalcemic therapy is associated with symptomatic
improvement [47, 48], and in some cases may be a life-
saving measure that can buy time for anticancer therapy
to take effect. Reflecting this fact, the main determinant
of duration of survival in hypercalcemic cancer patients
is whether or not effective anticancer therapy is available
[47, 48]. Circumstances may arise in patients with ter-
minal cancer where it may be better to leave the
hypercalcemia untreated. This needs to be decided on an
S. H. Ralston et al.: Management of Hypercalcemia
Table 5. Intravenous bisphosphonates used in the acute treatment of cancer-associated hypercalcemia
Normocalcemia
Drug Dose (%)
Etidronate 5 mg/kg/day on 3 days 15–45
Clodronate 1500 mg 40–80
Pamidronate 30–90 mg 30–100
Ibandronate 2–6 mg 50–77
Zoledronate 4–8 mg 86–88
individual basis and will depend upon whether or not
the hypercalcemia is thought to be contributing signifi-
cantly to the patients symptoms.
In acute severe hypercalcemia, the main aims of
medical antihypercalcemic therapy are to promote uri-
nary excretion of calcium and improve renal function by
giving intravenous saline and to inhibit bone resorption
by giving osteoclast inhibitors [41, 49]. Limiting dietary
calcium and vitamin D intake may also be indicated in
conditions where increased intestinal absorption of cal-
cium contributes to the development of hypercalcemia.
This measure is seldom effective in the treatment of
patients with acute severe hypercalcemia since calcium
intake tends to be low in any case as the result of nausea
and vomiting. An algorithm giving details of a suggested
management plan for patients with hypercalcemia is
shown in Figure 2.
Management of Cancer-Associated Hypercalcemia
Volume Repletion
All patients should receive extracellular volume reple-
tion with intravenous 0.9% saline. The fluid regimen
needs to be adjusted on an individual basis depending
on cardiac status and co-existing disease, but a typical
protocol consists of 3–4 L 0.9% saline during the first 24
hours and 2–3 L per 24 hours thereafter until a good
urine output (2 L/day) has been established [41, 50].
Volume repletion improves hypercalcemia in most pa-
tients but seldom restores normocalcemia [41, 50, 51].
Loop diuretics are sometimes combined with volume
repletion in the treatment of hypercalcemia but there is
no direct evidence to show that they enhance the calci-
um-lowering response of volume repletion so long as the
patient can cope with the extra fluid load. Diuretics
should therefore be reserved for patients who have
limited cardiac reserve. Urea and electrolytes should be
5
Average
duration
of action (days) Comment
10–12 No longer marketed for this indication in
UK or US
12–14 Was found to have a shorter duration of
action than pamidronate in an RCT [59]
15–30 Doses of 30 mg and 60 mg were significantly
more effective than etidronate in RCTs
[54, 57]. Dose of 90 mg had longer duration of
action than 1500 mg clodronate in an RCT [59]
25–30 Overall efficacy similar to pamidronate
30–80 Both 4 mg and 8 mg doses were more effective
and had a longer duration of action than 90
pamidronate in RCTs [76]
monitored during rehydration and hypokalemia cor-
rected if necessary.
Inhibition of Osteoclastic Bone Resorption
Intravenous bisphosphonates are the osteoclast inhibi-
tors of first choice in cancer-associated hypercalcemia
because of their efficacy, relatively prolonged duration
of action and lack of toxicity [52]. At the time of writing,
five bisphosphonates are licensed for cancer-associated
hypercalcemia in various countries. These are (in as-
cending order of potency) etidronate (ethane-hydroxy
bisphosphonate), clodronate (dichloromethylene bis-
phosphonate), pamidronate (aminohydroxypropylidene
bisphosphonate), ibandronate (1-hydroxy-3-(methyl-
pentyl amino) propylidene-bisphosphonate) and zo-
ledronate (1-hydroxy-2-imidazole-1-yl-phosphono-ethyl
bisphosphonate). The dose regimens and reported rates
of response to these bisphosphonates are discussed in-
dividually below and the data are summarized in Table
5. The choice of bisphosphonate to be used in hyper-
calcemia will be influenced by several factors such as
side-effect profile, price and local availability, but on the
basis of calcium-lowering effect and duration of action,
intravenous zoledronate would appear to be the most
effective agent for the acute treatment of hypercalcemia.
Intravenous etidronate (7.5 mg per kg body weight on
three consecutive days by slow intravenous infusion) can
be used for the treatment of cancer-associated hyper-
calcemia, but normocalcemia is achieved in only 15–40%
of patients [53–55]. Serum calcium values start to fall
within 2–3 days of starting etidronate, with a nadir at 6
days and a median duration of effect ranging between
10–12 days [56]. Randomized controlled trials have
shown that etidronate is superior to volume repletion
alone [51], but is less effective than intravenous
pamidronate [54, 57]. Oral etidronate (20 mg kg/day) is
ineffective as a primary treatment for hypercalcemia, but
6 S. H. Ralston et al.: Management of Hypercalcemia
Fig. 1. Diagnosis of hypercalcemia.
has been shown in a randomized controlled study to
prolong the effect of intravenous etidronate to a median
of 30 days compared with 12 days in patients given
intravenous etidronate alone [55].
Intravenous clodronate (1500 mg as a single infusion
over 24 hours or in divided doses of 300 mg daily for 5
days) is an effective treatment for hypercalcemia [58].
Serum calcium values start to fall within 2–3 days, with
a nadir at day 6 and a duration of action of approxi-
mately 12 days [54, 59, 60]. Reported rates of normo-
calcemia range from 40–80% in different studies,
depending on the dose of clodronate given and mix of
tumor types [54, 58–60]. There have been two random-
ized studies comparing intravenous clodronate with
other bisphosphonates in cancer-associated hypercal-
cemia. In one study, intravenous clodronate 600 mg was
found to be significantly less effective than 30 mg in-
travenous pamidronate in the treatment of hypercal-
cemia, in terms of the number of patients rendered
normocalcemic (83% vs 41%; P < 0.05) and the dura-
tion of action (12 days vs. 30 days; P < 0.01) [54]. In the
same study, clodronate was found to give better control
of hypercalcemia than etidronate, but the difference was
not significant. In another study, 1500 mg of intrave-
nous clodronate and 90 mg of intravenous pamidronate
restored normocalcemia in an equivalent proportion of
cases (80% vs. 100%), but pamidronate had a longer
duration of action (14 days vs. 28 days; P < 0.01) [59].
Oral clodronate is effective in the treatment of cancer-
associated hypercalcemia [61], but is not recommended
for treating acute severe hypercalcemia; it is more
commonly employed as an adjunct to intravenous
clodronate or other intravenous bisphosphonates ther-
apies to prevent relapse of hypercalcemia [62]. The rec-
ommended doses are 1600–3200 mg daily (BonefosTM)
or 1040–2080 mg daily (LoronTM) for maintenance of
hypercalcemia, and this should be adjusted on an indi-
vidual patient basis according to the response of serum
calcium.
Intravenous pamidronate is an effective treatment for
cancer-associated hypercalcemia. Many regimens have
been used, ranging from repeated daily infusions of 15
mg for up to 6 days, to single intravenous infusions of
between 5 and 90 mg [57, 63–69]. The recommended
dose is 30 mg for mild (<3.0 mM) and 60–90 mg for
severe hypercalcemia. Serum calcium values start to fall
S. H. Ralston et al.: Management of Hypercalcemia
Fig. 2. Management of hypercalcemia.
within 2 days of starting pamidronate with a nadir at
day 6 and duration of action of between 28–30 days.
Reported rates of normocalcemia range from 30–100%,
depending on the dose given and mix of tumor types.
Patients with local osteolytic hypercalcemia respond
better to pamidronate than those with PTHrP-mediated
hypercalcemia [70]. Randomized comparative studies
have shown that intravenous pamidronate is superior to
both mithramycin and corticosteroids plus calcitonin in
the treatment of cancer-associated hypercalcemia, both
with respect to the calcium-lowering effect and the du-
ration of action [68, 71]. Pamidronate in single doses of
30 and 60 mg has been found to be superior to intra-
venous etidronate in two randomized treatment trials of
patients with cancer-associated hypercalcemia [54, 57].
Randomized studies have also shown that 30 mg
pamidronate is superior to 600 mg clodronate in can-
cer-associated hypercalcemia [54] and that 90 mg
pamidronate is slightly superior to 1500 mg clodronate
in calcium-lowering effect and significantly superior in
terms of duration of action [59]. Pamidronate is usually
well tolerated but up to 30% of patients experience an
acute phase response with pyrexia and in some cases
this is accompanied by flu-like symptoms with muscle
pains and malaise.
7
Ibandronate is an effective treatment for hypercal-
cemia at doses as low as 0.2 mg but clinical studies have
shown that the optimal response occurs over the dose
range of 2–6 mg [72, 73]. In one study, approximately
50% of patients achieved normocalcemia with 2 mg
ibandronate given by intravenous infusion compared
with 75–77% with 4 and 6 mg infusions [73]. The onset
of effect, time to maximal response and duration of
action of ibandronate is similar to that of pamidronate.
Like pamidronate, tumor type has been shown to in-
fluence response to ibandronate such that patients with
local osteolytic hypercalcemia respond best, and those
with humorally mediated hypercalcemia and raised
PTHrP values respond less well [74]. Intravenous
ibandronate is well tolerated but like other aminobis-
phosphonates, has been found to cause transient pyrexia
in up to 30% of cases [73].
Intravenous zoledronate is a highly potent bisphos-
phonate, which is extremely effective in the treatment of
cancer-associated hypercalcemia. In a dose-ranging
study, 19/20 (93%) patients treated with intravenous
zoledronate 0.02–0.04 mg/kg by single intravenous in-
fusion over 30 min were rendered normocalcemic and
remained so for between 32–39 days [75]. A pooled
analysis [76] of two randomized controlled trials of
8 S. H. Ralston et al.: Management of Hypercalcemia
zoledronate (4 and 8 mg) compared with intravenous
pamidronate (90 mg) showed that both doses of zo-
ledronate were significantly superior to pamidronate in
restoring normocalcemia (86–88% for zoledronate
compared with 70% for pamidronate) and in maintain-
ing normocalcemia (median time to relapse was 30 days
for 4 mg and 80 days for 8 mg zoledronate compared
with 17 days for pamidronate). The onset of effect for
zoledronate appears to be more rapid than with other
bisphosphonates since a significant reduction in serum
calcium generally occurs at day 1 after administration
[76] with restoration of normocalcemia in up to 50% of
cases by day 4. The current doses recommended by the
manufacturers are 4 mg for initial treatment and 8 mg
for relapse, given by slow intravenous injection over 5
min. Zoledronate appears to be generally well tolerated
but like other aminobisphosphonates has been found to
cause transient pyrexia in 30–40% of cases.
Calcitonin cannot be regarded as a first line treatment
for cancer-associated hypercalcemia, but it has been
used successfully in combination with intravenous bis-
phosphonate in patients with severe hypercalcemia. In
this situation, calcitonin and bisphosphonate treatment
has been found to give a more rapid reduction in serum
calcium values than bisphosphonate treatment alone
[77, 78]. Calcitonin lowers serum calcium by inhibiting
both osteoclastic bone resorption and by promoting
urinary calcium excretion, which perhaps explains why
the onset of action is more rapid than bisphosphonates.
It may be given by subcutaneous or intramuscular in-
jection in doses of between 50 i.u. and 400 i.u. 6–8
hourly or by slow intravenous infusion in doses of 5–10
units/Kg over 6 hrs. High doses of calcitonin may be
associated with nausea and vomiting, and there is no
evidence to suggest that they are more effective than
lower doses.
Other treatments have been used in the management
of cancer-associated hypercalcemia, but these are of
mainly historical interest. Mithramycin is a cytotoxic
agent that reduces serum calcium by inhibiting bone
resorption and by reducing renal tubular calcium reab-
sorption [68, 79]. It has a number of undesirable side
effects [68] and has been superseded by the bisphos-
phonates. Corticosteroids are ineffective in the treat-
ment of cancer-associated hypercalcemia unless the
tumor is corticosteroid-responsive such as myeloma and
lymphoma [80]. Intravenous phosphate is an effective
treatment for hypercalcemia which acts by forming in-
soluble calcium-phosphate complexes which are depos-
ited in bone and soft tissues [81]. Phosphate treatment of
hypercalcemia may be associated with several adverse
effects including hypotension, ectopic calcification and
acute renal failure, and because of this, it has largely
been superseded by other agents [82]. Ethylene diamine
tetra-acetic acid (EDTA) is another rapidly acting cal-
cium-lowering agent, which works by chelating calcium.
It has previously been used in the emergency treatment
of severe hypercalcemia [83], but is not currently li-
censed for this indication and is seldom if ever used in
routine practice. Gallium nitrate is an effective treat-
ment when given intravenously by continuous infusion
over 5 days, but is contraindicated in patients with renal
impairment and those in whom other nephrotoxic
agents such as aminoglycosides are being given [84].
Because of these problems, it is not much used in routine
clinical practice. Hamodialysis or peritoneal dialysis
with a low calcium dialysate may be of value in treating
hypercalcemia when other therapies have failed, espe-
cially in patients with acute renal failure [85].
Management of Hypercalcemia in Other Diseases
There is limited published data on the effects of medical
antihypercalcemic therapy in benign disease. If hyper-
calcemia is mild and non-progressive, then it is usually
sufficient to observe the patient while the underling
cause of the disease is treated or the drugs that caused it
are withdrawn. In patients with severe or progressive
hypercalcemia, medical antihypercalcemic therapy
should be given. The broad principles of management
are as outlined for cancer-associated hypercalcemia;
intravenous saline should be given to promote urinary
calcium excretion and correct renal impairment, along
with intravenous bisphosphonates to inhibit bone re-
sorption. Dietary calcium and vitamin D intake should
be limited in conditions where intestinal calcium
absorption is increased.
Intravenous fluids and bisphosphonates have been
found to be effective in isolated cases and in small
clinical series of patients, with hypercalcemia caused by
vitamin D intoxication [86] and immobilization [87–91].
Corticosteroids have long been used in the management
of hypercalcemia associated with vitamin D intoxica-
tion, but recent uncontrolled studies suggest that intra-
venous bisphosphonates may be more effective [86]. The
hypercalcemia of sarcoidosis responds to intravenous
fluids and bisphosphonates [92], but the treatment of
choice for this cause of hypercalcemia is corticosteroid
therapy (prednisolone 10–40 mg daily) [93]. The an-
timycotic agent ketoconazole and the antimalarial agent
hydroxychlorquine have also been reported to be effec-
tive in the treatment of hypercalcemia associated with
granulomatous disease [94, 95]. These agents appear to
work by inhibiting the macrophage 1-alpha hydroxylase
enzyme.
Medical treatment of primary hyperparathyroidism is
usually only required as a holding measure in patients
with severe hypercalcemia prior to surgical parathyroi-
dectomy, which remains the treatment of choice for
primary hyperparathyroidism [96]. Clinical experience
indicates that bisphosphonates improve hypercalcemia
S. H. Ralston et al.: Management of Hypercalcemia
in patients with primary hyperparathyroidism in the
short term [28, 97–101] and these should be given in-
travenously along with saline as described for cancer-
associated hypercalcemia. Short-term studies have
shown that R-568—an agonist of the calcium sensing
receptor—reduces PTH levels and serum calcium in
primary hyperparathyroidism, but this agent is not yet
available for clinical use [102]. Detailed discussion of the
indications for surgical management of primary hyper-
parathyroidism is beyond the scope of this review, but
surgical management should be considered in patients
with severe or progressive hypercalcemia, and those with
other complications such as parathyroid bone disease,
osteoporosis, pancreatitis and renal stone disease. It is
currently unclear whether patients with mild asympto-
matic PHPT should be treated by parathyroidectomy
[102].
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