Acid-Base and Electrolyte Teaching Case

Approach to Diagnosis and Treatment of Hypercalcemia in a

Patient With Malignancy
Patrick Reagan, MD,1 Antonello Pani, MD,2 and Mitchell H. Rosner, MD1

Hypercalcemia is a common complication of malignancy and portends a worse prognosis. It causes a variety
of symptoms in patients, which can range from confusion and polyuria to coma and death. There are 4 broad
mechanistic categories to classify hypercalcemia of malignancy: local osteolysis secondary to metastatic
cancer or multiple myeloma, excess parathyroid-related hormone, excess 1,25-dihydroxyvitamin D production,
and ectopic parathyroid hormone production. Volume expansion with normal saline solution and treatment with
intravenous bisphosphonates to decrease osteoclast-mediated bone destruction are effective initial therapies.
Calcitonin, gallium nitrate, and corticosteroids can serve as adjunctive therapies. Denosumab is an attractive
therapeutic option for refractory cases of hypercalcemia, although more data are required before this therapy
can be recommended.
Am J Kidney Dis. -(-):---. ª 2013 by the National Kidney Foundation, Inc.

INDEX WORDS: Hypercalcemia; cancer; parathyroid hormone–related protein; bisphosphonate.

calcium level of 16.1 mg/dL (uncorrected for albumin). His

Note from Feature Editor Jeffrey A. Kraut, MD: This article is
part of a series of invited case discussions highlighting the
diagnosis and treatment of acid-base and electrolyte
disorders.
INTRODUCTION
Hypercalcemia is an important and common
complication of malignancy, occurring in up to 30%
of patients.1-3 The development of hypercalcemia in
patients with cancer portends a worse prognosis, with
patients more likely to have advanced disease and
decreased survival.1-3 Hypercalcemia leads to
nonspecific symptoms, such as confusion, lethargy,
nausea, vomiting, and polyuria. Severe hypercalcemia
can result in coma. Importantly, hypercalcemia can
precipitate acute kidney injury, nephrogenic diabetes
insipidus, and cardiac arrhythmias. The focus of acute
treatment of symptomatic hypercalcemia is treating
hypovolemia to increase renal calcium excretion and
decreasing calcium efflux from bone to inhibit cal-
cium release. Long-term therapy requires control of
tumor growth and use of agents that decrease bone
turnover and release of calcium.
CASE REPORT
Clinical History and Initial Laboratory Data
A 67-year-old man with a history of squamous cell carcinoma of
the left buccal mucosa was admitted to the hospital with 2 days of
confusion, short-term memory loss, and lethargy, as well as
concern for an abscess of the neck at his surgical resection site.
The patient also described several days of nocturia, polyuria, and
thirst. The malignant lesion was removed previously, but he
recently had been found to have locally metastatic disease. In the
emergency department, he was treated with trimethoprim-
sulfamethoxazole and clindamycin. A computed tomographic
scan of the head and neck showed widely metastatic disease. His
laboratory test results were notable for hypercalcemia with a
admission laboratory data are included in Table 1. He was treated
for the hypercalcemia with intravenous fluids (6 L of 0.9% saline
solution) followed by intravenous pamidronate (60 mg).
Additional Investigations
Parathyroid hormone (PTH) and vitamin D levels were not
elevated. PTH-related peptide (PTHrP) level was significantly
abnormal at 4.8 pmol/L (Table 1).
Diagnosis
Humoral hypercalcemia of malignancy.
Clinical Follow-up
The patient’s hypercalcemia resolved after administration of
0.9% saline solution and pamidronate, and his mental status
improved. The patient’s abscess improved with drainage and
broad-spectrum antibiotics. His malignancy was treated with 5-
fluorouracil, cisplatin, and cetuximab. He was discharged to
home with a plan to continue chemotherapy as an outpatient with
monitoring of serum calcium and PTHrP levels.
DISCUSSION
The normal physiologic processes governing the
homeostasis of calcium provide an insight into the
pathophysiology of hypercalcemia of malignancy, as
well as guide the proper diagnostic workup when a
patient presents with hypercalcemia (Fig 1). Most
From the 1Department of Medicine, University of Virginia
Health System, Charlottesville, VA; and 2Division of Nephrology
and Dialysis, Azienda Ospedaliera “G. Brotzu,” Cagliari, Italy.
Received April 14, 2013. Accepted in revised form June 13,
2013.
Address correspondence to Mitchell H. Rosner, MD, Division of
Nephrology, University of Virginia Health System, Box 800133,
Charlottesville, VA 22908. E-mail: mhr9r@virginia.edu
 2013 by the National Kidney Foundation, Inc.
0272-6386/$36.00
http://dx.doi.org/10.1053/j.ajkd.2013.06.025

Am J Kidney Dis. 2013;-(-):--- 1

 Reagan, Pani, and Rosner

Table 1. Laboratory Parameters dominant hormone involved in calcium metabolism,

has a variety of effects that result in increasing serum
Parameter On Admission At Discharge
calcium levels. PTH acts in the kidney by increasing
Calcium (mg/dL) 16.1 7.2
the conversion of 25-hydroxyvitamin D to biologi-
Albumin (g/dL) 2.9 2.1
cally active 1,25-dihydroxyvitamin D. PTH also
Corrected calcium (mg/dL) 16.98 8.72
stimulates reabsorption of calcium in the thick
Sodium (mEq/L) 138 135
ascending limb of the loop of Henle, as well as the
Potassium (mEq/L) 4.2 3.4
distal convoluted tubule, and inhibits phosphate
Chloride (mEq/L) 95 98
reabsorption in the proximal tubule.4 PTH affects
Bicarbonate (mEq/L) 23 24
both osteoblasts and osteoclasts and increases both
Urea nitrogen (mg/dL) 24 17
resorption and formation of bone. PTH also activates
Creatinine (mg/dL) 0.7 0.5
receptor-activated nuclear factor-kB ligand (RANKL)
eGFR (mL/min/1.73 m2)a .60 .60 production, which acts to promote the maturation of
PTH (pg/mL) 9.9 — osteoclasts and ultimately leads to resorption of
PTHrP (pmol/L)b 4.8 — bone and release of calcium. Osteoprotegerin, which
25(OH)D (ng/mL) 9 — serves as a competitive inhibitor of RANKL, is
1,25(OH)2D (pg/mL) 40 — decreased by the actions of PTH, which is another
Note: Conversion factors for units: calcium in mg/dL to
mechanism by which PTH promotes the maturation
mmol/L, 30.2495; urea nitrogen in mg/dL to mmol/L, 30.357; of osteoclasts.4
creatinine in mg/dL to mmol/L, 388.4; 25(OH)D in ng/mL to The kidney converts vitamin D to 1,25-dihydroxy-
nmol/L, 32.496; 1,25(OH)2D in pg/mL to pmol/L, 32.6. vitamin D, which acts to increase intestinal absorption
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, of calcium. Active vitamin D also acts through its
1,25-dihydroxyvitamin D; eGFR, estimated glomerular filtration
rate; MDRD, Modification of Diet in Renal Disease; PTH, para-
nuclear receptor in immature osteoblast/stromal cells to
thyroid hormone; PTHrP, PTH-related peptide. trigger osteoclastogenesis. This facilitates bone cal-
a
eGFR calculated using the MDRD Study equation.43 cium release, especially from cancellous bone. Calci-
b
PTHrP reference, ,2.0 pmol/L. tonin’s role in calcium homeostasis is not well defined,
but calcitonin decreases reabsorption of calcium in the
total-body calcium resides in bone. A small percentage kidney and directly acts on osteoclasts to disrupt bone
of calcium in bone is readily available for exchange resorption.4
and contributes to the homeostasis of serum calcium PTHrP and PTH are related molecules and both
level under the control of vitamin D and PTH. The activate the same type I PTH/PTHrP receptor
remaining calcium in the body is distributed between (PTHR1).5 It initially was thought that PTH and
the extracellular and intracellular compartments. Half PTHrP bind and stimulate the PTHR1 identically, but
the serum calcium is protein bound, and only the studies of humans show that PTH infusions are more
ionized component in serum is biologically active.4 effective at increasing circulating calcium and 1,25-
Calcium homeostasis is maintained by the actions dihydroxyvitamin D levels than PTHrP infusions
of PTH, vitamin D, PTHrP, and calcitonin. PTH, the due to differences in the affinity and conformational

Figure 1. Diagnostic algorithm for

the workup of hypercalcemia. The
diagnostic workup for patients pre-
senting with hypercalcemia rests on
the measurement of parathyroid hor-
mone (PTH) to divide patients into
those with elevated versus sup-
pressed PTH values. Urine calcium-
creatinine ratio should be derived
from a 24-hour urine collection.44 Of
note, at calcium-creatinine ratio cutoff
value of 0.0115, sensitivity for correct
classification of familial hypocalciuric
hypercalcemia (FHH) was 0.80 and
specificity was 0.88, thus misclassify-
ing 20% of patients with FHH and
12% of primary hyperparathyroid pa-
tients.45 Thus, further testing and
family history should be used to
conclusively diagnose FHH. Abbrevi-
ations: CaSR, calcium-sensing re-
ceptor; iPTH, intact PTH; PTHrP,
PTH-related peptide.

2 Am J Kidney Dis. 2013;-(-):---

Hypercalcemia in Malignancy
Table 2. Major Differences in the Effects of PTH and PTHrP on Their Target Organs
PTH
PTHR1 Higher affinity binding compared to PTHrP
Bone Increases bone resorption via activation of osteoclasts
Greater increase in osteoblast activity
Kidney Increases reabsorption of calcium
Increases 1,25(OH)2D production
Increases phosphorus excretion
GI tract Increases absorption of calcium by the ileum
Abbreviations: 1,25(OH)2D, 1,25-dihydroxyvitamin D; GI, gastrointestinal; PTH, parathyroid hormone; PTHrP, PTH-related
peptide.
binding.6,7 PTH and PTHrP are compared and con-
trasted in Table 2.
PTHrP is produced by many cell types and organs,
but its functional significance is still being eluci-
dated.8 PTHrP likely has important effects on the
mammary gland, chondrocyte and dental develop-
ment, and placental calcium transfer to the developing
fetus.8 During lactation, PTHrP serves to ensure a
consistent supply of calcium for milk production.
PTHrP also has anabolic effects on bone.8
Common conditions associated with hypercalce-
mia can be separated broadly into those with
elevated versus suppressed PTH levels (Fig 1).
Although most patients with both malignancy and
hypercalcemia will have a linkage between the 2,
this is not always the case. In one case series, 7 of
47 patients with a malignancy and hypercalcemia
had coexisting primary hyperparathyroidism, which
portends a much better prognosis.9 Thus, a thorough
rational diagnostic algorithm should be followed in
all patients and begins with an assessment of intact
PTH concentration.10
There are a variety of mechanisms by which
hypercalcemia arises in patients with malignancy
(Fig 2). Those mechanisms include excessive
Figure 2. Mechanism of malignancy-
associated hypercalcemia. Abbreviations:
1,25(OH)2D, 1,25-dihydroxyvitamin D;
NHL, non-Hodgkin lymphoma; PTH, para-
thyroid hormone; PTHrP, PTH-related
peptide.
Am J Kidney Dis. 2013;-(-):---
PTHrP
Lower affinity binding compared to PTH
Increases bone resorption via activation of osteoclasts
Lesser increase in osteoblast activity
Increases reabsorption of calcium
Minimal to no increase in 1,25(OH)2D production
Increases phosphorus excretion
No increase in absorption of calcium by the ileum
production of PTHrP, osteolytic metastases, 1,25
dihydroxyvitamin D overproduction, and ectopic
PTH secretion.
PTHrP may be overproduced by various tumor
cells (Box 1).8 PTHrP increases calcium levels
similarly to PTH with the 2 notable differences:
PTHrP does not increase the synthesis of 1,25-
dihydroxyvitamin D to the same extent as PTH and
does not induce increased gastrointestinal calcium
absorption.7,11,12 The increased renal tubular reab-
sorption of calcium induced by PTHrP may partially
explain the persistent lower level hypercalcemia
despite inhibition of osteoclast function with
bisphosphonates or RANKL inhibitors when these
agents are used in treatment.2
The role of PTHrP in hypercalcemia associated
with breast cancer serves as an example of the com-
plex pathophysiology involved in this syndrome. As
mentioned, mammary cells normally produce PTHrP,
but in the setting of bone metastases due to breast
cancer, PTHrP can lead to excessive osteolysis and
calcium release coupled with increased renal reab-
sorption of calcium leading to hypercalcemia.13
Interestingly, in response to the bone microenviron-
ment, breast cancer cells metastasized to the skeleton
3

Box 1. Tumor Types Producing PTHrP
Common
 Breast cancers
 Lung cancers
 Non-Hodgkin lymphoma
 Adult T-cell leukemia/lymphoma associated with human
T-lymphotropic virus type 1 (HTLV-1)
Less Common
 Head and neck tumors
 Renal cell carcinoma
 Bladder cancer
 Pancreatic cancer
 Hepatocellular carcinoma
 Carcinoid tumors
 Melanoma
Abbreviation: PTHrP, parathyroid hormone–related peptide.
Source: Wysolmerski.8
produce more PTHrP than cells in the primary tumor.13
This likely is due to transforming growth factor b,
which is released at sites of bone resorption and has
been shown to upregulate PTHrP production.14 In turn,
PTHrP increases the production of RANKL and de-
creases the production of osteoprotegerin, increasing
osteoclast numbers and activity.13 This is amplified
further because, unlike in normal breast cells, calcium-
sensing receptor (CaSR) signaling in breast cancer cells
stimulates PTHrP production.15 Thus, the combination
of local transforming growth factor b production due to
osteolysis and increased local calcium levels that acti-
vate the CaSR greatly increases PTHrP production by
the tumor cells in a vicious cycle with resultant
hypercalcemia.
The hypercalcemia associated with some metastatic
carcinomas and multiple myeloma appears to be
mediated through the local effects of malignant cells
on bone to release calcium in excess of the renal ca-
pacity to excrete it. Multiple myeloma cells produce
a variety of cytokines (macrophage inflammatory
protein-1a, RANKL, interleukin 3, and interleukin 6)
that act in a paracrine fashion to stimulate osteo-
clasts.16,17 Other malignancies, such as breast cancer,
metastatic lung cancers, and T-cell lymphomas,
locally produce PTHrP that acts in the bone micro-
environment to cause osteolysis.16,17 In these cases, as
described, the hypercalcemia is multifactorial in
origin. These patients usually do not have elevated
circulating PTHrP levels.
Certain lymphomas (Hodgkin and non-Hodgkin)
and rare tumors possess 1a-hydroxylase activity
that can produce 1,25-dihydroxyvitamin D and lead
to hypercalcemia through increased renal reab-
sorption of calcium and increased gastrointestinal
absorption.1,2
Hypercalcemia of malignancy also can be due
to the ectopic production of PTH by tumor cells,
4 Am J Kidney Dis. 2013;-(-):---
Reagan, Pani, and Rosner
such as in rare cases of small cell lung carcinoma,
ovarian cancer, pancreatic cancer, and several
others.18 This must be distinguished from coexist-
ing hyperparathyroidism. Diagnosis rests on finding
elevated calcium and PTH levels without a tech-
netium 99m sestamibi scan identifying a para-
thyroid adenoma.
Patients with hypercalcemia often are profoundly
volume depleted. This may be secondary to
hypercalcemia-induced nausea and vomiting, along
with decreased oral intake. Additionally, hypercal-
cemia can cause nephrogenic diabetes insipidus,
which results in further volume loss. In addition,
through activation of CaSR in the thick ascending
limb of the loop of Henle, hypercalcemia leads to
natriuresis and exacerbation of volume depletion.19
An important first step in the treatment of hypercal-
cemia is to restore the extracellular volume of the
patient with intravenous fluids. A typical regimen is a
1- to 2-L bolus of 0.9% saline solution followed by
200-250 mL/h, with frequent monitoring of serum
calcium levels and the patient’s volume status.2
Given the presence of nephrogenic diabetes insip-
idus, hypernatremia may result with 0.9% saline so-
lution infusions, and hypotonic fluids may be
required.
There is scant evidence to support using furose-
mide or other loop diuretics in the treatment of hy-
percalcemia. A recent literature review revealed only
case reports and case series advocating the role of
furosemide despite their widespread clinical use.20
Perhaps the limited data for loop diuretics to in-
crease urinary calcium excretion in the setting of
hypercalcemia reflect the fact that stimulation of
CaSR independently leads to natriuresis through its
inhibition of the sodium/potassium/chloride (Na1/
K1/2Cl-) cotransporter 2 (NKCC2) in the thick
ascending limb of the loop of Henle. In general,
published attempts to use furosemide to promote
increased urinary calcium excretion required
extremely high doses of the diuretic along with
intensive monitoring of urine output and serum elec-
trolyte levels.21 Given the large volume of normal
saline solution required to treat the hypovolemia, loop
diuretics should be reserved only for those who
demonstrate signs of volume overload.
Bisphosphonates are highly effective agents in the
management of malignancy-associated hypercalce-
mia. Bisphosphonates exert several effects on osteo-
clasts, including inhibiting their recruitment, activity,
and adhesion to bone matrix. They also appear to
decrease osteoclast survival.22 For example, etidro-
nate directly causes apoptosis in osteoclasts and dis-
rupts actin ring formation that is important to the
cell’s function in bone resorption.23 One mechanism
by which bisphosphonates may cause apoptosis in
Hypercalcemia in Malignancy
osteoclasts is through inhibition of the enzyme
squalene synthase, which interferes with cholesterol
biosynthesis.24
The efficacy of different bisphosphonates has been
evaluated in various clinical trials. Pamidronate and
zoledronate are approved by the US Food and Drug
Administration (FDA) for the treatment of hypercal-
cemia of malignancy. Both have been shown to be
effective in clinical trials.25-27 Head-to-head com-
parison of pamidronate and zoledronate was per-
formed in 2 randomized controlled trials comparing 4
or 8 mg of zoledronate to 90 mg of pamidronate.
Both doses of zoledronate were superior to pamidr-
onate in initial efficacy and duration of response.25
The 4-mg dose of zoledronate was as effective as
the 8-mg dose in this study. Another bisphosphonate,
ibandronate, is FDA approved for treatment of oste-
oporosis, but not yet for malignancy-related
hypercalcemia.
Bisphosphonates generally are well tolerated, but
there are some important potential adverse effects.
Both pamidronate and zoledronate cause an
infusion-related fever, which generally is self-
limited.25-27 Hypocalcemia, hypomagnesemia, and
hypophosphatemia also have been described. Rare but
serious treatment-related toxicities include nephro-
toxicity and osteonecrosis of the jaw. Pamidronate
and zoledronate have been associated with nephrotic-
range proteinuria in case series,28-31 with a histologic
pattern of collapsing and noncollapsing focal
segmental glomerulosclerosis.28-31 Acute tubular ne-
crosis as a mechanism of kidney injury also has been
associated with zoledronate.32 Monitoring of kidney
function and urine protein excretion thus is recom-
mended in patients receiving prolonged treatment
with these agents.
Calcitonin has been used as therapy for hypercal-
cemia of malignancy and has been shown to tran-
siently lower serum calcium levels.33,34 Calcitonin
may serve as an adjunctive treatment in the initial
phase of hypercalcemia treatment, especially when
coupled with a bisphosphonate.34 However, the
overall efficacy is relatively low and its effect is
limited due to tachyphylaxis, which typically occurs
after 48 hours.
Gallium nitrate has been used successfully to treat
hypercalcemia of malignancy. Its mechanism of ac-
tion is not completely understood, but it may inhibit
the resorption of bone by osteoclasts.35,36 The effec-
tive dose for hypercalcemia associated with malig-
nancy is 200 mg/m2 daily for 5 days.37,38 Gallium
was compared to pamidronate in a phase 2 study in
which it appeared to be at least as effective as
pamidronate, though only descriptive statistics were
used.39 Gallium appeared to be superior to calcitonin
in both duration of response and percentage of
Am J Kidney Dis. 2013;-(-):---
Box 2. Key Teaching Points
 The most common cause of severe hypercalcemia in
hospitalized patients is malignancy
 Malignancy-associated hypercalcemia portends a worse
prognosis because the underlying cancer usually is
advanced
 Diagnosis relies on a structured approach using mea-
surement of parathyroid hormone (PTH), PTH-related
peptide, 1,25-dihydroxyvitamin D, and urine calcium-
creatinine ratios
 Emergent treatment includes aggressive volume expan-
sion along with intravenous bisphosphonates
 Newer therapies that target bone resorption pathways,
such as denosumab, hold promise
patients responding.38 The most serious adverse
events associated with the use of gallium are acute
kidney injury and anemia.
Denosumab is a human monoclonal antibody
directed against RANKL. Given the importance of
RANKL in the pathogenesis of both osteolytic hy-
percalcemia and humoral hypercalcemia of malig-
nancy, denosumab has been seen as an attractive
therapeutic option in hypercalcemia.2 It has been
studied in metastatic carcinomas and multiple
myeloma. Denosumab was compared to zoledronate
in 2 double-blind, randomized, controlled trials,
which showed either noninferiority or superiority of
denosumab to zoledronate with regard to skeletal-
related events.40,41 Denosumab has been used effec-
tively off label for the treatment of hypercalcemia of
malignancy.42 With the exception of hypocalcemia,
other adverse events, such as infectious complications
and osteonecrosis of the jaw, were similar between
patients receiving zoledronate and denosumab.40,41
Further trials with denosumab are needed before
broad recommendations for its use can be offered.
Malignancy is the most common cause of hyper-
calcemia seen in hospitalized patients.1-3 Although it
often is a late complication and portends a worse
prognosis, proper treatment can lead to improvements
in quality of life when instituted promptly. Under-
standing the mechanisms involved in the development
of hypercalcemia allows for a physiologically ori-
ented treatment approach that in the future may
include novel therapies targeting key pathways such
as RANKL with denosumab. Box 2 summarizes the
important teaching points associated with this case.
ACKNOWLEDGEMENTS
Support: None.
Financial Disclosures: The authors declare that they have no
relevant financial interests.
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