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

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Table 2. Major Differences in the Effects of PTH and PTHrP on Their Target Organs

PTH PTHrP

PTHR1 Higher affinity binding compared to PTHrP Lower affinity binding compared to PTH
Bone Increases bone resorption via activation of osteoclasts Increases bone resorption via activation of osteoclasts
Greater increase in osteoblast activity Lesser increase in osteoblast activity
Kidney Increases reabsorption of calcium Increases reabsorption of calcium
Increases 1,25(OH)2D production Minimal to no increase in 1,25(OH)2D production
Increases phosphorus excretion Increases phosphorus excretion
GI tract Increases absorption of calcium by the ileum No increase in 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- production of PTHrP, osteolytic metastases, 1,25
trasted in Table 2. dihydroxyvitamin D overproduction, and ectopic
PTHrP is produced by many cell types and organs, PTH secretion.
but its functional significance is still being eluci- PTHrP may be overproduced by various tumor
dated.8 PTHrP likely has important effects on the cells (Box 1).8 PTHrP increases calcium levels
mammary gland, chondrocyte and dental develop- similarly to PTH with the 2 notable differences:
ment, and placental calcium transfer to the developing PTHrP does not increase the synthesis of 1,25-
fetus.8 During lactation, PTHrP serves to ensure a dihydroxyvitamin D to the same extent as PTH and
consistent supply of calcium for milk production. does not induce increased gastrointestinal calcium
PTHrP also has anabolic effects on bone.8 absorption.7,11,12 The increased renal tubular reab-
Common conditions associated with hypercalce- sorption of calcium induced by PTHrP may partially
mia can be separated broadly into those with explain the persistent lower level hypercalcemia
elevated versus suppressed PTH levels (Fig 1). despite inhibition of osteoclast function with
Although most patients with both malignancy and bisphosphonates or RANKL inhibitors when these
hypercalcemia will have a linkage between the 2, agents are used in treatment.2
this is not always the case. In one case series, 7 of The role of PTHrP in hypercalcemia associated
47 patients with a malignancy and hypercalcemia with breast cancer serves as an example of the com-
had coexisting primary hyperparathyroidism, which plex pathophysiology involved in this syndrome. As
portends a much better prognosis.9 Thus, a thorough mentioned, mammary cells normally produce PTHrP,
rational diagnostic algorithm should be followed in but in the setting of bone metastases due to breast
all patients and begins with an assessment of intact cancer, PTHrP can lead to excessive osteolysis and
PTH concentration.10 calcium release coupled with increased renal reab-
There are a variety of mechanisms by which sorption of calcium leading to hypercalcemia.13
hypercalcemia arises in patients with malignancy Interestingly, in response to the bone microenviron-
(Fig 2). Those mechanisms include excessive ment, breast cancer cells metastasized to the skeleton

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.

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Reagan, Pani, and Rosner

Box 1. Tumor Types Producing PTHrP such as in rare cases of small cell lung carcinoma,
ovarian cancer, pancreatic cancer, and several
Common
 Breast cancers others.18 This must be distinguished from coexist-
 Lung cancers ing hyperparathyroidism. Diagnosis rests on finding
 Non-Hodgkin lymphoma elevated calcium and PTH levels without a tech-
 Adult T-cell leukemia/lymphoma associated with human netium 99m sestamibi scan identifying a para-
T-lymphotropic virus type 1 (HTLV-1)
thyroid adenoma.
Less Common Patients with hypercalcemia often are profoundly
 Head and neck tumors volume depleted. This may be secondary to
 Renal cell carcinoma
hypercalcemia-induced nausea and vomiting, along
 Bladder cancer
 Pancreatic cancer with decreased oral intake. Additionally, hypercal-
 Hepatocellular carcinoma cemia can cause nephrogenic diabetes insipidus,
 Carcinoid tumors which results in further volume loss. In addition,
 Melanoma through activation of CaSR in the thick ascending
Abbreviation: PTHrP, parathyroid hormone–related peptide. limb of the loop of Henle, hypercalcemia leads to
Source: Wysolmerski.8 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
produce more PTHrP than cells in the primary tumor.13 patient with intravenous fluids. A typical regimen is a
This likely is due to transforming growth factor b, 1- to 2-L bolus of 0.9% saline solution followed by
which is released at sites of bone resorption and has 200-250 mL/h, with frequent monitoring of serum
been shown to upregulate PTHrP production.14 In turn, calcium levels and the patient’s volume status.2
PTHrP increases the production of RANKL and de- Given the presence of nephrogenic diabetes insip-
creases the production of osteoprotegerin, increasing idus, hypernatremia may result with 0.9% saline so-
osteoclast numbers and activity.13 This is amplified lution infusions, and hypotonic fluids may be
further because, unlike in normal breast cells, calcium- required.
sensing receptor (CaSR) signaling in breast cancer cells There is scant evidence to support using furose-
stimulates PTHrP production.15 Thus, the combination mide or other loop diuretics in the treatment of hy-
of local transforming growth factor b production due to percalcemia. A recent literature review revealed only
osteolysis and increased local calcium levels that acti- case reports and case series advocating the role of
vate the CaSR greatly increases PTHrP production by furosemide despite their widespread clinical use.20
the tumor cells in a vicious cycle with resultant Perhaps the limited data for loop diuretics to in-
hypercalcemia. crease urinary calcium excretion in the setting of
The hypercalcemia associated with some metastatic hypercalcemia reflect the fact that stimulation of
carcinomas and multiple myeloma appears to be CaSR independently leads to natriuresis through its
mediated through the local effects of malignant cells inhibition of the sodium/potassium/chloride (Na1/
on bone to release calcium in excess of the renal ca- K1/2Cl-) cotransporter 2 (NKCC2) in the thick
pacity to excrete it. Multiple myeloma cells produce ascending limb of the loop of Henle. In general,
a variety of cytokines (macrophage inflammatory published attempts to use furosemide to promote
protein-1a, RANKL, interleukin 3, and interleukin 6) increased urinary calcium excretion required
that act in a paracrine fashion to stimulate osteo- extremely high doses of the diuretic along with
clasts.16,17 Other malignancies, such as breast cancer, intensive monitoring of urine output and serum elec-
metastatic lung cancers, and T-cell lymphomas, trolyte levels.21 Given the large volume of normal
locally produce PTHrP that acts in the bone micro- saline solution required to treat the hypovolemia, loop
environment to cause osteolysis.16,17 In these cases, as diuretics should be reserved only for those who
described, the hypercalcemia is multifactorial in demonstrate signs of volume overload.
origin. These patients usually do not have elevated Bisphosphonates are highly effective agents in the
circulating PTHrP levels. management of malignancy-associated hypercalce-
Certain lymphomas (Hodgkin and non-Hodgkin) mia. Bisphosphonates exert several effects on osteo-
and rare tumors possess 1a-hydroxylase activity clasts, including inhibiting their recruitment, activity,
that can produce 1,25-dihydroxyvitamin D and lead and adhesion to bone matrix. They also appear to
to hypercalcemia through increased renal reab- decrease osteoclast survival.22 For example, etidro-
sorption of calcium and increased gastrointestinal nate directly causes apoptosis in osteoclasts and dis-
absorption.1,2 rupts actin ring formation that is important to the
Hypercalcemia of malignancy also can be due cell’s function in bone resorption.23 One mechanism
to the ectopic production of PTH by tumor cells, by which bisphosphonates may cause apoptosis in

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Hypercalcemia in Malignancy

osteoclasts is through inhibition of the enzyme Box 2. Key Teaching Points


squalene synthase, which interferes with cholesterol  The most common cause of severe hypercalcemia in
biosynthesis.24 hospitalized patients is malignancy
The efficacy of different bisphosphonates has been  Malignancy-associated hypercalcemia portends a worse
evaluated in various clinical trials. Pamidronate and prognosis because the underlying cancer usually is
advanced
zoledronate are approved by the US Food and Drug
 Diagnosis relies on a structured approach using mea-
Administration (FDA) for the treatment of hypercal- surement of parathyroid hormone (PTH), PTH-related
cemia of malignancy. Both have been shown to be peptide, 1,25-dihydroxyvitamin D, and urine calcium-
effective in clinical trials.25-27 Head-to-head com- creatinine ratios
parison of pamidronate and zoledronate was per-  Emergent treatment includes aggressive volume expan-
sion along with intravenous bisphosphonates
formed in 2 randomized controlled trials comparing 4
 Newer therapies that target bone resorption pathways,
or 8 mg of zoledronate to 90 mg of pamidronate. such as denosumab, hold promise
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 patients responding.38 The most serious adverse
the 8-mg dose in this study. Another bisphosphonate, events associated with the use of gallium are acute
ibandronate, is FDA approved for treatment of oste- kidney injury and anemia.
oporosis, but not yet for malignancy-related Denosumab is a human monoclonal antibody
hypercalcemia. directed against RANKL. Given the importance of
Bisphosphonates generally are well tolerated, but RANKL in the pathogenesis of both osteolytic hy-
there are some important potential adverse effects. percalcemia and humoral hypercalcemia of malig-
Both pamidronate and zoledronate cause an nancy, denosumab has been seen as an attractive
infusion-related fever, which generally is self- therapeutic option in hypercalcemia.2 It has been
limited.25-27 Hypocalcemia, hypomagnesemia, and studied in metastatic carcinomas and multiple
hypophosphatemia also have been described. Rare but myeloma. Denosumab was compared to zoledronate
serious treatment-related toxicities include nephro- in 2 double-blind, randomized, controlled trials,
toxicity and osteonecrosis of the jaw. Pamidronate which showed either noninferiority or superiority of
and zoledronate have been associated with nephrotic- denosumab to zoledronate with regard to skeletal-
range proteinuria in case series,28-31 with a histologic related events.40,41 Denosumab has been used effec-
pattern of collapsing and noncollapsing focal tively off label for the treatment of hypercalcemia of
segmental glomerulosclerosis.28-31 Acute tubular ne- malignancy.42 With the exception of hypocalcemia,
crosis as a mechanism of kidney injury also has been other adverse events, such as infectious complications
associated with zoledronate.32 Monitoring of kidney and osteonecrosis of the jaw, were similar between
function and urine protein excretion thus is recom- patients receiving zoledronate and denosumab.40,41
mended in patients receiving prolonged treatment Further trials with denosumab are needed before
with these agents. broad recommendations for its use can be offered.
Calcitonin has been used as therapy for hypercal- Malignancy is the most common cause of hyper-
cemia of malignancy and has been shown to tran- calcemia seen in hospitalized patients.1-3 Although it
siently lower serum calcium levels.33,34 Calcitonin often is a late complication and portends a worse
may serve as an adjunctive treatment in the initial prognosis, proper treatment can lead to improvements
phase of hypercalcemia treatment, especially when in quality of life when instituted promptly. Under-
coupled with a bisphosphonate.34 However, the standing the mechanisms involved in the development
overall efficacy is relatively low and its effect is of hypercalcemia allows for a physiologically ori-
limited due to tachyphylaxis, which typically occurs ented treatment approach that in the future may
after 48 hours. include novel therapies targeting key pathways such
Gallium nitrate has been used successfully to treat as RANKL with denosumab. Box 2 summarizes the
hypercalcemia of malignancy. Its mechanism of ac- important teaching points associated with this case.
tion is not completely understood, but it may inhibit
the resorption of bone by osteoclasts.35,36 The effec- ACKNOWLEDGEMENTS
tive dose for hypercalcemia associated with malig-
Support: None.
nancy is 200 mg/m2 daily for 5 days.37,38 Gallium Financial Disclosures: The authors declare that they have no
was compared to pamidronate in a phase 2 study in relevant financial interests.
which it appeared to be at least as effective as
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