Onco-Nephrology: The

Pathophysiology and Treatment of

Malignancy-Associated
Hypercalcemia

Mitchell H. Rosner and Alan C. Dalkin

CJASN October 2012, 7 (10) 1722-1729; DOI: https://doi.org/10.2215/CJN.02470312

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Summary

Hypercalcemia complicates the course of 10%–30% of all patients with malignancies

and can be a sign of very poor prognosis and advanced malignancy. Prompt recognition
of the nonspecific signs and symptoms of hypercalcemia and institution of therapy can
be lifesaving, affording the opportunity to address the underlying etiology. The
mechanisms of malignancy-associated hypercalcemia generally fall into three
categories: humoral hypercalcemia due to secreted factors (such as parathyroid-related
hormone), local osteolysis due to tumor invasion of bone, and absorptive hypercalcemia
due to excess vitamin D produced by malignancies. The mainstays of therapy for
hypercalcemia are aggressive intravenous volume expansion with saline,
bisphosphonate therapy, and perhaps loop diuretics. Adjunctive therapy may include
calcitonin and corticosteroids. In refractory cases, gallium nitrate and perhaps
denosumab are alternatives. In patients presenting with severe AKI, hemodialysis with a
low-calcium bath can be effective. In most cases, therapy normalizes calcium levels and
allows for palliation or curative therapy of the malignancy.

Introduction

Hypercalcemia (defined as a serum calcium level above the upper limit of the normal
reference range of 10.5 mg/dl or 2.5 mmol/L, 40%–45% of which is ionized calcium) can
complicate the course of 10%–30% of all patients with cancer (1–4). The incidence of
hypercalcemia is low at the initial presentation of cancer (1%–5%) but increases
dramatically in patients with advanced disease and a poor prognosis (5). In fact, the
median duration of survival for patients with malignancy-associated hypercalcemia is
only 2–6 months from the onset of hypercalcemia (3,5).
 The symptoms of hypercalcemia are nonspecific, often develop gradually, and may
resemble the symptoms of the underlying malignancy and its treatment. These
nonspecific symptoms may lead to a delay in diagnosis, with increased morbidity and
mortality. Clinical presentation is influenced by the rate of onset as well as the severity of
hypercalcemia. Typical symptoms include nausea, vomiting, constipation, abdominal
pain, anorexia, weight loss, bone pain, polyuria, fatigue, and weakness. In patients with
more severe degrees of hypercalcemia (serum calcium > 14 mg/dl), neurologic
symptoms such as confusion and even coma may become more apparent. These
patients require hospitalization and urgent therapeutic intervention (6).

Given the presence of concomitant cachexia and malnutrition in this population, it is also
critical to correct the serum calcium for a low albumin level or measure an ionized serum
calcium level in order to assess the true degree of hypercalcemia (7). Although ionized
calcium is more sensitive than albumin-corrected total calcium in the diagnosis of
hypercalcemia of malignancy, the clinical usefulness of this measurement is unclear. In
at least one study, slightly increased ionized calcium levels did not predict the
development of frank hypercalcemia in patients with solid malignant tumors (8,9). Thus,
evaluation of total calcium concentration in light of changes in bound versus ionized
calcium is essential in order to obtain a complete patient assessment.

Mechanisms of Malignancy-Associated Hypercalcemia

Perturbations of calcium regulation in patients with hypercalcemia of malignancy fall into

three general categories (Figure 1). First, most common are humoral factors secreted in
a paracrine or endocrine fashion (humoral hypercalcemia of malignancy). Second, in
patients with substantial tumor burden metastatic to bone, the local effects of tumor can
directly facilitate bone dissolution and calcium mobilization (local osteolysis). Third, less
commonly, absorptive hypercalcemia results from excess vitamin D activation by the
neoplasm. The cellular basis for the former two mechanisms includes changes in the
activity and balance at the level of the bone-remodeling unit.
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Figure 1.
Mechanism of malignancy-associated hypercalcemia. PTHrP, parathyroid hormone–
related hormone.
Bone turnover involves the highly coordinated activity of two distinct types of cells (10).
The osteoblast, or bone-forming cell, is derived from a mesenchymal stem cell and is
closely related to adipocytes, chondrocyte, myocytes, and fibroblasts. In contrast, the
osteoclast, or bone-removing cell, is derived from stems cells populating the monocyte
and macrophage lineage. Although the specifics remain incompletely understood,
communication between osteoblasts and osteoclasts primarily involves the receptor
activator of nuclear factor κ B (RANK) ligand (RANKL) signaling pathway (10–12). RANK
is a receptor expressed on osteoclast precursor cells. The naturally occurring ligand,
RANKL, is produced by osteoblasts and drives proliferation and differentiation of the
osteoclasts into mature, multinucleated units. In addition, the osteoblast cell produces
osteoprotegerin (OPG), a decoy receptor that binds to and inactivates RANKL.

The cellular regulation of RANK, RANKL, and OPG expression is incompletely

understood, but the osteoblast is the focal point for the integration of endocrine and
paracrine signals that alter bone remodeling. For example, osteoblast cells express
estrogen receptors that when occupied with ligand can reduce RANKL and increase
OPG (13). Directly related to the hypercalcemia of malignancy, osteoblasts also express
the cell surface receptor for parathyroid hormone (PTH) and parathyroid hormone–
related hormone (PTHrP), PTH1R (14). Both PTH and PTHrP stimulate PTH1R, which,
in turn, increases osteoblast activity and RANKL signaling to the osteoclast. OPG
expression may decline as well. In sum, PTH/PTHrP signaling results in an increased
bone turnover with a greater increase in bone resorption than formation, resulting in a
net efflux of calcium and hypercalcemia from the bone microenvironment.

Tumors that commonly produce PTHrP include squamous cell carcinomas of the lung,
cervix, and esophagus; certain lymphomas; renal cell carcinoma; and adenocarcinoma
of the breast, prostate, and ovary (15–17). In addition, several case reports have
documented PTHrP secretion in other malignancies. Ectopic secretion of PTH secretion
is less common than that of PTHrP. The number of cases in which tumor-related
production of PTH has been verified are few but include pulmonary, thyroid, ovarian, and
pancreatic malignancies (18–20).

Local osteolysis as the basis for hypercalcemia occurs most frequently in widely
metastatic disease, and the degree of hypercalcemia correlates with the extent of tumor
burden. Local osteolysis is most commonly seen in patients with metastatic breast and
lung cancers (21,22). Probably due to a common pathophysiology, multiple myeloma,
usually extensive in nature, can present with significant areas of osteolysis and
hypercalcemia (23). Underlying the release of calcium from the bone microenvironment
is increased osteoclast activity, probably due to PTHrP and other factors that can
increase resorption. As a result of the paracrine nature of this condition, circulating levels
of PTHrP may be “normal” or only slightly above normal, in contrast to levels in patients
with humoral hypercalcemia due to PTHrP.
 Vitamin D has numerous physiologic actions, including the enhancement of calcium and
phosphate absorption from the intestinal tract. Stored vitamin D (25-[OH]D) is 1-
hydroxylated in the kidney to the active compound 1,25-(OH)2D, which in turn
acts via the vitamin D receptor. PTH actively drives the 1-hydroxylase step at the kidney,
and states of hyperparathyroidism, including ectopic PTH from malignancies, are
associated with elevated 1,25-(OH)2D levels. Of note, despite its action through the
common PTH1R, PTHrP is a poor stimulus for 1α-hydroxylation compared with PTH,
and levels of active vitamin D are often low or normal in patients with humoral
hypercalcemia of malignancy (24). Important for the understanding of hypercalcemia, the
1-hydroxylase enzyme is expressed in tissues outside of the kidney, including
macrophages and some neoplastic tissues. Patients with Hodgkin lymphoma and non-
Hodgkin lymphoma, as well as multiple myeloma, have been described as having
vitamin D–mediated hypercalcemia (25). In these individuals, 1,25-(OH)2D levels, along
with calcium levels, are high while PTH is suppressed from the negative feedback to the
parathyroid cells. Similarly, measurements of bone turnover markers are low in vitamin
D–mediated hypercalcemia because the reduction in PTH results in a diminution of
osteoblast and osteoclast activity.

Laboratory Investigation

Given that the malignancy is usually advanced by the time hypercalcemia develops, a
thorough history and physical examination can often lead to the correct diagnosis with
limited laboratory evaluation. Measurement of intact PTH through an immunoradiometric
or immunochemoluminescent assay will confirm a PTH-independent process. In this
case, the PTH levels will be suppressed (often <20 pg/ml) and should prompt further
testing to distinguish among the multiple possible causes in patients with malignancy.
This would include measurement of PTHrP, 1,25-(OH)2D levels, serum and urine protein
electrophoresis, assessment of serum free light chains, and possibly imaging studies
(such as a skeletal survey). Less common causes of hypercalcemia in malignancy
include drugs (e.g., retinoic acid [26]) and, rarely, parathyroid carcinomas producing
excessive PTH.

Therapy for Malignancy-Associated Hypercalcemia

Patients presenting with acute and symptomatic hypercalcemia require prompt therapy
that rapidly reduces the serum calcium level, restores the GFR, and leads to longer-term
normalization of the serum calcium level. An algorithmic approach is shown in Figure 2.
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Figure 2.
Treatment algorithm for malignancy-associated hypercalcemia. IV, intravenous.

Intravenous Fluid and Diuretics

Hypercalcemia leads to a decrease in the GFR through a combination of the natriuretic

effects of high serum levels of calcium and renal vasoconstriction (27). In fact, polyuria is
the most common renal manifestation of hypercalcemia, and it is thought that the
impaired urinary concentrating ability is due to activation of the calcium-sensing receptor
in the thick ascending limb of the loop of Henle (28). Activation of the calcium-sensing
receptor leads to decreased resorption of sodium and chloride in the loop of Henle,
resulting in decreased countercurrent multiplication and decreased ability to concentrate
the urine. In addition, activation of the calcium-sensing receptor in the collecting duct
blunts the response of this segment to the actions of arginine vasopressin (29). Thus,
patients presenting with hypercalcemia are usually profoundly volume depleted.
Furthermore, patients usually will present with poor oral intake and may have had
nausea and vomiting that further worsen the volume depletion. The decrease in GFR
leads to impaired calcium clearance and, thus, restoration of extracellular fluid volume,
and GFR is a key goal of therapy.

Thus, initial therapy should begin with intravenous (IV) volume expansion with 0.9%
saline at 200–500 ml per hour. Volume expansion will lead to an increase in GFR and an
increase in urine calcium excretion. The goal should be establishing an adequate urine
output (>75 ml per hour). In milder cases of hypercalcemia, this therapy can be sufficient
to restore normal calcium levels (30). However, the effect of repleting the extracellular
volume is transient, and other therapies are required. Careful monitoring of the patient’s
vital signs and laboratory values must occur during the acute phase of volume repletion,
along with vigilance for evidence of volume overload. Hypernatremia may be seen
during this phase of therapy because of hypercalcemia-induced nephrogenic diabetes
insipidus and may require changing from isotonic to hypotonic fluid therapy (31).
 A common practice is to add a loop diuretic to saline therapy in an effort to increase
urine calcium excretion (forced saline diuresis). LeGrand and colleagues reviewed the
evidence-base for this approach (32). By inhibiting the sodium-potassium-chloride
(NKCC2) transporter in the thick ascending limb of the loop of Henle, a loop diuretic
decreases the lumen positive charge that normally drives calcium reabsorption; thus, a
loop diuretic increases urine calcium excretion and theoretically should be useful in
therapy for hypercalcemia (33,34). However, LeGrand et al. could find only nine articles
that documented the use of furosemide in the treatment of hypercalcemia, the last of
which was published in 1983. These studies comprised a total of 37 patients. The
average dosage of furosemide was 1120 mg given over 24 hours, and serum calcium
normalized in 14 of 39 episodes of hypercalcemia; however, normalization was rapid
(<12 hours) in only two cases. Lower dosages of furosemide (40–60 mg/d) did not
achieve normalization of the serum calcium. Most important, monitoring in these patients
was intensive and included aggressive replacement of hourly urine output losses, and
secondary electrolyte disorders, such as hypernatremia, hypophosphatemia,
hypomagnesemia, and metabolic acidosis, were seen. Thus, the routine use of loop
diuretics in the therapy for hypercalcemia cannot be recommended, and their use should
be restricted to patients who develop fluid overload while receiving aggressive volume
resuscitation.

Bisphosphonates

High-potency IV bisphosphonates are effective agents for the treatment of malignancy-

associated hypercalcemia. The three high-potency bisphosphonates are pamidronate,
zoledronate, and ibandronate (dosing guidelines are shown in Table 1). Because the IV
bisphosphonates are excreted unchanged by the kidneys through glomerular filtration,
their dosing must be adjusted for impaired renal function to avoid toxicity (35,36).
Mechanistically, bisphosphonates decrease bone resorption through extracellular and
intracellular mechanisms (37–41). In the extracellular space, bisphosphonates bind to
calcium phosphate and stabilize the bone matrix, while intracellularly these agents inhibit
osteoclast activity, in part through inhibition of the mevalonate pathway (37–39).
Furthermore, bisphosphonates impair cellular adenosine triphosphate–dependent
metabolic pathways, disrupt the osteoclast cytoskeleton, and induce apoptosis (40,41).

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Table 1.
Dosing guidelines for intravenous bisphosphonates in the treatment of acute hypercalcemia
Randomized clinical trials with pamidronate, zoledronate, and ibandronate have all
shown efficacy in the treatment of hypercalcemia of malignancy (42–44). However, the
three bisphosphonates differ in terms of their potency and risk for toxicity. Nussbaum et
al. demonstrated a dose response using pamidronate, with 40%, 61%, and 100% of
patients achieving normocalcemia with 30, 60, and 90 mg, respectively (45). Similar
efficacy of pamidronate is seen over a dosing span ranging from 2 to 24 hours (46).
Thus, a practical approach is to administer pamidronate, 60–90 mg, over 2–6 hours, with
the longer dosing time reserved for patients with lower GFRs and the higher doses for
patients with more severe hypercalcemia. The efficacy of pamidronate (and probably
other bisphosphonates) is influenced by the mechanism of hypercalcemia (more
effective in cases of hypercalcemia associated with bone metastases); the level of
hypercalcemia (higher doses required to treat more severe hypercalcemia); and, in
patients with humoral hypercalcemia, the level of PTHrP (higher levels of PTHrP are
associated with a lower response rate) (47,48). The fact that patients with higher levels
of PTHrP show less of a hypocalcemic response to bisphosphonates is probably due to
the continued actions of PTHrP on the kidney to decrease calcium excretion, an effect
that is not modulated by bisphosphonates.

Zoledronate is 100 times more potent than pamidronate, and two parallel randomized
trials evaluated the efficacy of 4 or 8 mg of zoledronate versus 90 mg of pamidronate in
restoring normocalcemia by day 10 after treatment (49). Both doses of zoledronate were
superior to pamidronate, with serum calcium normalizing by day 10 in 88%, 87%, and
70% of patients receiving 4 and 8 mg of zoledronate and 90 mg of pamidronate,
respectively (49). Moreover, the mean duration of complete response was 32, 43, and
18 days, respectively, in the three treatment groups (49).

Ibandronate is also effective in treating malignancy-associated hypercalcemia (44,50).

Doses of 2, 4, and 6 mg had success rates of 50%, 76%, and 77%, respectively (44).
Compared with pamidronate, the duration of response is longer with ibandronate (50).
However, ibandronate is not approved by the Food and Drug Administration (FDA) to
treat malignancy-associated hypercalcemia.

The most common side effect associated with these agents is infusion-related fever,
which is usually mild (51). However, bisphosphonate-associated nephrotoxicity affecting
both glomerular and tubular structures has been described in both case series and
randomized clinical trials (35). In terms of glomerular toxicity, bisphosphonates (most
commonly, pamidronate and, only rarely, zoledronate) have been associated with
collapsing focal segmental glomerulosclerosis (FSGS), noncollapsing FSGS, and
minimal-change disease in several case series (52–56). The most common lesion is
collapsing FSGS, which is seen with high-dose IV pamidronate often in patients with
underlying multiple myeloma and usually after repeated doses (35). In clinical trials,
glomerular toxicity of the bisphosphonates was not reported (35). In some cases, the
nephrotic syndrome resolves after cessation of the drug, but some patients may
progress to ESRD, especially if the glomerular lesion is collapsing FSGS.

Tubular injury (nephrotoxic acute tubular necrosis) associated with bisphosphonates

(mainly, zoledronate) has also been described in both case reports and clinical trials
(57–59). In 2003, the FDA Adverse Event Reporting System experience with
bisphosphonates and AKI revealed 72 cases associated with IV zoledronate (60). In this
cohort, AKI developed approximately 2 months after initiation of therapy and after a
mean of 2.4 doses of zoledronate. Risk factors for AKI included advanced cancer,
previous bisphosphonate therapy, and use of nonsteroidal anti-inflammatory agents.
Most patients did not fully recover to baseline renal function, and 37.5% of patients
required dialysis (60).

On the basis of the renal toxicity of bisphosphonates, the American Society of Clinical
Oncology developed dosing and monitoring guidelines (Table 1) and recommended that
zoledronate be avoided in patients with a creatinine clearance <30 ml/min (61).
Furthermore, serum creatinine should be monitored before each dose of bisphosphonate
and the drug withheld in patients with worsening of renal function. Urine albumin
excretion should be monitored at 3- to 6-month intervals, and the drug should be held if
albuminuria develops (61).

Interestingly, ibandronate appears to have minimal to no renal toxicity, even in patients

with underlying CKD (62–64). However, more experience with this drug for the treatment
of malignancy-associated hypercalcemia is needed before firm conclusions on its renal
safety can be made.

An increasingly recognized complication of bisphosphonate therapy is osteonecrosis of

the jaw (ONJ) (65,66). The precise etiology is not known, and the most common
precipitating factors include dental extraction, long-term sequential use of IV
pamidronate or zoledronate, smoking, and poor dental health (67). The absolute risk for
ONJ is unknown, although it is estimated to occur in <1:10,000 treated individuals and
may be seen even less often in patients receiving shorter-term treatment. Diagnosis is
based on clinical criteria that include pain and evidence of local infection. Management
is largely supportive, with occasional need for surgical debridement. The condition can
be prevented through good dental hygiene and avoidance of invasive dental procedures
during bisphosphonate therapy (68).

Gallium Nitrate

Gallium nitrate is approved for the treatment of cancer-related hypercalcemia. The

cellular basis for this action is unknown but appears to involve a reduction in osteoclast
activity and bone remodeling (69–72). Clinically, gallium nitrate is administered by a
continuous infusion at a dosage of 200 mg/m2 per day over 5 consecutive days. Reports
comparing gallium to bisphosphonates (73,74) and calcitonin (75) have shown equal or
perhaps even superior efficacy in decreasing calcium levels. Adverse effects from
treatment include hypocalcemia and hypophosphatemia, the latter being observed in
nearly 80% of patients. In addition, renal impairment has been reported, and hence
gallium nitrate is not recommended for use when the serum creatinine concentration
exceeds 2.5 mg/dl. Adequate fluid resuscitation is essential before initiation of treatment
with gallium, and BUN and creatinine must be followed closely during treatment. Patients
receiving gallium have reported nausea, vomiting, lethargy, altered mental status, and
both diarrhea and constipation.

Calcitonin

Calcitonin is a peptide hormone secreted by the parafollicular C cells of the thyroid

gland. It inhibits osteoclast bone resorption and increases urinary calcium excretion.
Synthetic calcitonin (derived from salmon) is administered as 4–8 U/kg intramuscularly
or subcutaneously every 6–8 hours. Calcitonin has a rapid onset of effect, leading to
reductions in serum calcium within 2–6 hours after dosing. The calcium-lowering effects
of calcitonin are modest and transient, with a mean duration of effect of 2–4 days (76).
Furthermore, repeated administration of calcitonin results in downregulation of the
calcitonin receptors on osteoclasts and dimunition in effect (tachyphylaxis) (77). Overall,
its efficacy is poor, inducing normocalcemia in just one third of patients (78). Calcitonin’s
major role may be as an adjunctive agent with bisphosphonates in the treatment of
severe, symptomatic hypercalcemia when calcium levels must be reduced rapidly (79).
Side effects are minimal; nausea, vomiting, and injection site pain are the most common.
Overall, there is little evidence that calcitonin use has better efficacy over volume
repletion and bisphosphonate therapy alone.

Corticosteroids

Corticosteroids are effective agents in the treatment of hypercalcemia associated with

malignancies that overproduce calcitriol. This is due to their effect in inhibiting 1α-
hydroxylase conversion of 25-hydroxyvitamin D to calcitriol. Typically, these patients
have underlying Hodgkin or non-Hodgkin lymphoma (80). The efficacy of corticosteroids
is based on case reports and thus the dosing guidelines are uncertain; however, a
reasonable regimen is IV hydrocortisone, 200–300 mg/d, for 3–5 days (79). Typically,
calcium levels are slow to decrease with corticosteroid treatment alone. Patients who do
respond with normalization of their serum calcium can be transitioned to maintenance
oral prednisone, 10–30 mg/d (81).

Hemodialysis

For patients with acute hypercalcemia and significant AKI (especially in the setting of
oliguria), saline-induced diuresis may not be feasible and may lead to volume overload.
In these circumstances, hemodialysis using a very-low-calcium dialysate (≤1 mmol/L) is
an option (82). For refractory cases of hypercalcemia, several case reports describe the
use of citrate anticoagulation to chelate calcium along with continuous venovenous
hemodiafiltration (83,84).

Denosumab

Given the important role RANKL in the pathogenesis of bone metastases and
secondarily in leading to hypercalcemia, inhibition of this pathway is an attractive means
of potentially treating forms of malignancy-associated hypercalcemia due to bone
calcium release. Denosumab is a fully human monoclonal antibody that binds to RANKL
and inhibits osteoclast maturation, activation, and function (85). It is FDA approved for
preventing skeletal-related events in patients with solid malignancy, as well preventing
bone fractures in postmenopausal women with osteoporosis. In clinical trials,
denosumab has shown efficacy in preventing skeletal-related events (such as bone
 metastases) in patients with prostate, breast, and other solid-organ cancers, as well as
multiple myeloma (85). Denosumab is well tolerated, with arthralgias as the most
common side effect (86). Because RANKL is expressed on B and T cells, there was
some concern that denosumab would increase the risk for serious infections. The FDA
has reported only a slightly increased incidence of serious infections (4.1% for
denosumab and 3.3% for placebo), with no increase in opportunistic infections seen
(86). Of note, denosumab has been associated with a similar incidence of osteonecrosis
of the jaw as zoledronic acid (87). Denosumab is not cleared through renal mechanisms
and does not require dosing adjustments for renal impairment.

In clinical trials in patients with malignancies, the most common laboratory abnormality
was hypocalcemia due to inhibition of bone resorption (88–90). This is not surprising
given the mechanism of action of denosumab and leads to the obvious question of
whether this drug can be used to treat malignancy-associated hypercalcemia. Hu et
al. studied patients with bisphosphonate-refractory malignancy-associated
hypercalcemia (91). These patients had solid malignancies or myeloma and elevated
corrected serum calcium levels (>12.5 mg/dl) despite recent IV bisphosphonate therapy.
Patients received denosumab, 120 mg subcutaneously, every 4 weeks, with additional
loading doses of 120 mg on days 8 and 15 of the first month. The primary end point was
reaching a response defined as a corrected serum calcium level ≤11.5 mg/dl within the
first 10 days after denosumab dosing. An interim analysis of this study (n=15) revealed
that 80% of patients achieved a response by day 10, with a median response time of 8
days and a response duration of 28 days. Furthermore, an ad hoc pooled analysis of the
clinical trials with denosumab (88–90) revealed that compared with zoledronic acid,
denosumab significantly delayed the time to first on-study episodes of hypercalcemia
(92). More work will be required to understand the role of denosumab in the treatment of
malignancy-associated hypercalcemia, but it holds much promise as a safe, more
convenient (subcutaneous versus IV) therapy.

Summary

Patients with underlying malignancy frequently encounter hypercalcemia. Indeed,

hypercalcemia carries a poor prognosis. Multiple cellular mechanisms underlie the
increase in calcium concentration, and a proper evaluation to elucidate the cause is
essential to guide treatment. The mainstay of initial management is aggressive fluid
resuscitation, with the addition of loop diuretics if volume overload is present. In addition,
antiresorptive agents, primarily the bisphosphonates, can aid in the treatment of these
patients. Although the physician must bear in mind potential pitfalls with the use of these
medications, prompt and assertive treatment of hypercalcemia in patients with cancer
can be successful and life-saving.

Disclosures
 None.

Footnotes


Published online ahead of print. Publication date available at www.cjasn.org.


 Copyright © 2012 by the American Society of Nephrology

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