Mechanisms and treatment of hypercalcemia of malignancy

Gregory A. Clinesa,b
a

Division of Endocrinology, Diabetes, and Metabolism,

Department of Medicine, University of Alabama at
Birmingham and bVeterans Affairs Medical Center,
Birmingham, Alabama, USA
Correspondence to Gregory A. Clines, MD, PhD,
Assistant Professor of Medicine and Cell Biology,
Division of Endocrinology, Diabetes, and Metabolism,
Department of Medicine, University of Alabama at
Birmingham, 1808 7th Avenue South, BDB 730
Birmingham, AL 35294-0012, USA
Tel: +1 205 934 4187; fax: +1 205 975 9372;
e-mail: clines@uab.edu
Current Opinion in Endocrinology, Diabetes &
Obesity 2011, 18:339346

Purpose of review
Hypercalcemia of malignancy is a common paraneoplastic syndrome and a frequent
complication of advanced breast and lung cancer, and multiple myeloma. The
development of this malignancy complication often purports a poor prognosis.
Thorough evaluation to establish the cause of hypercalcemia is essential because some
patients may actually have undiagnosed primary hyperparathyroidism.
Recent findings
Production of humoral factors by the primary tumor, collectively known as humoral
hypercalcemia of malignancy (HHM), is the mechanism responsible for 80% of cases.
The vast majority of HHM is caused by tumor-produced parathyroid hormone-related
protein followed by infrequent tumor production of 1,25-dihydroxyvitamin D and
parathyroid hormone. The remaining 20% of cases are caused by bone metastasis with
consequent bone osteolysis and release of skeletal calcium. Key therapies are saline
hydration to promote calciuresis and bisphosphonates to reduce pathologic
osteoclastic bone resorption. Calcitonin and glucocorticoids, especially in 1,25dihydroxyvitamin D-mediated HHM, also have calcium-lowering effects.
Summary
Recent discoveries on mechanisms of malignancy-associated hypercalcemia highlight
the critical role of the osteoclast. Bisphosphonates and other novel therapies being
evaluated in clinical trial target this bone-resorbing cell type and provide effective
and durable serum calcium reduction.
Keywords
bisphosphonate, bone metastasis, hypercalcemia, malignancy, parathyroid hormonerelated protein
Curr Opin Endocrinol Diabetes Obes 18:339346
2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
1752-296X

Introduction
Malignancy-associated hypercalcemia is a common paraneoplastic syndrome occurring in up to 20% of cancer
patients. The development of hypercalcemia in a cancer
patient often translates to a poor prognosis [1]. Despite
strategies to lower serum calcium and treat the hypercalcemic symptoms, median survival after discovery of
hypercalcemia is approximately 30 days [2]. The poor
prognosis is not necessarily due to the hypercalcemia
itself but reflects correlation of this condition with an
advanced cancer stage. Although hypercalcemia can
occur with many types of malignancy, it is most often
associated with breast cancer, lung cancer and multiple
myeloma [3,4].

Signs and symptoms

Symptoms of hypercalcemia vary in individual patients
and are related to both the absolute concentration and the
rate of rise of serum calcium [1,5]. Hypercalcemia associ1752-296X 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

ated with malignancy is likely to be more severe and rapid

in onset, and therefore such patients are more likely to
present with symptoms associated with acute onset.
Gastrointestinal complaints that include nausea, vomiting, anorexia, abdominal pain and constipation are common. Pancreatitis is a less common but serious complication [6]. Neurologic manifestations range from fatigue
to coma especially with very high calcium excursion.
Psychiatric conditions such as depression, anxiety and
cognitive dysfunction can occur. Shortening of the electrocardiogram QT interval and cardiac arrhythmia are
associated with acute and markedly elevated serum
calcium [7,8]. Muscular weakness is a common complaint
with hypercalcemia. Nephrogenic diabetes insipidus is an
incompletely understood complication of hypercalcemia
and is likely to be related to downregulation of aquaporin2 water channels in the collecting ducts resulting in a
renal concentrating defect [9,10]. As a result, dehydration
and intravascular volume contraction is further exacerbated by anorexia, nausea and vomiting leading to
worsening hypercalcemia.
DOI:10.1097/MED.0b013e32834b4401

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340 Parathyroids, bone and mineral metabolism

Pathogenesis
Four distinct mechanisms are responsible for hypercalcemia of malignancy. Three of these involve secretion of an
endocrine factor and are collectively described as humoral
hypercalcemia of malignancy (HHM). The last is the
result of bone metastasis and massive osteolysis (Fig. 1).
Parathyroid hormone-related protein and humoral
hypercalcemia of malignancy

Before the discovery of parathyroid hormone-related

protein (PTHrP), the presence of a parathyroid hormone
(PTH)-like factor was proposed that possessed similar
hypercalcemic and phosphaturic actions of PTH. In 1987,
PTHrP was purified from human cancer cells [11,12] by
independent groups and cloned shortly thereafter [13].
PTHrP was subsequently found to have important biological roles in mammary gland development [14], lactation [15], endochondral bone formation [16] and islet
beta-cell function [17].
The PTHrP gene encodes a 141 amino acid protein that
shares a 60% sequence homology with PTH over the first
13 amino acids at the N terminus [13]. Beyond the initial
amino-terminal sequence, the two proteins are unique
and show no further sequence homology. Other PTHrP
endoproteolytic fragment species have been identified,
with the PTHrP (136) fragment having similar activity
as the full-length protein. PTHrP (3894) may have
antitumorigenic properties [18,19
] and PTHrP (107
139), also known as osteostatin, may inhibit osteoclastic
bone resorption [20,21].
Despite differences between PTH and PTHrP protein
structure, both bind to a common PTH/PTHrP receptor
(PTH1R) [22,23]. Three mechanisms of PTH1R activation by PTH that increase serum calcium and alter
phosphate homeostasis are well described: PTH activates
osteoclastic bone resorption and release of skeletal
calcium and phosphate through increased osteoblast
receptor activator of nuclear factor kB ligand (RANKL)
expression leading to activation of the receptor activator
of nuclear factor kB (RANK) located on osteoclast precursors [24]. PTH increases calcium reabsorption in the
loop of Henle ascending limb and distal convoluted
tubule [25] and inhibits phosphate reabsorption in the
proximal convoluted tubule [26]. PTH increases renal
1a-hydroxylase with production of 1,25-dihydroxyvitamin D [1,25-(OH)2D], the active form of vitamin D, in
the proximal convoluted tubule resulting in targeted
intestinal absorption of calcium and phosphate [27].
PTHrP has equivalent actions as PTH in regulating bone
resorption and renal calcium/phosphorus. However,
unlike PTH, PTHrP does not increase 1a-hydroxylase
activity and 1,25-(OH)2D production. This is illustrated

Key points

Hypercalcemia of malignancy is associated with a
poor prognosis.

PTHrP is a common mediator of humoral hypercalcemia of malignancy.

Local production of PTHrP and other factors mediate local bone osteolysis and hypercalcemia during
bone metastasis.

Saline hydration and bisphosphonates are the key
therapies for hypercalcemia of malignancy.
in patients with primary hyperparathyroidism who generally have an elevated circulating 1,25-(OH)2D, which is
reflective of heightened PTH activity. Such an increase is
not seen in patients with PTHrP-dependent HHM, even
though stores of the vitamin D precursor may be normal
[28]. Differences between PTH and PTHrP ligand
receptor binding kinetics and activation of PTH1R
downstream signaling pathways are the likely mechanisms responsible for this difference [23,29]. The discordant effects between PTH and PTHrP on 1,25-(OH)2D
production were confirmed in human controlled trials
studying PTH (134) versus PTHrP (136) infusion
[30].
Normally, PTHrP circulates at a concentration of less
than 2.0 pmol/l. Approximately 80% of the hypercalcemic
patients with solid tumors have plasma PTHrP concentration above this value [31,32]. Hypercalcemia ensues
only when PTHrP reaches a threshold concentration that
replaces and surpasses the analogous actions of PTH.
Hypercalcemia attributed to elevated concentrations
of humoral PTHrP has been estimated to occur in 33
84% of breast cancers [3338], 4676% of lung cancers
[35,36,38], 2163% of non-Hodgkins lymphomas
(NHLs) [3840] and 92% of adult T-cell leukemia/
lymphomas due to the human T-lymphotropic virus
type 1 (HTLV-1) infection [39]. Infrequently, PTHrPmediated hypercalcemia occurs in head and neck tumors
[41,42], renal cell carcinoma [43,44], bladder cancer [45],
pancreatic carcinoma [46], hepatocellular carcinoma [47],
carcinoid tumors [48] and melanoma [49].

Parathyroid hormone and humoral hypercalcemia of

malignancy

PTHrP is responsible for the vast majority of cases HHM.

However, rare cases have been reported of ectopic PTH
secretion by tumors, which is often clinically indistinguishable from primary hyperparathyroidism. Suspicion
of malignancy-associated ectopic PTH should arise in a
patient with a known malignancy that has an elevated
calcium and PTH, and when a standard technetium
(99mTc) sestamibi scan does not identify a parathyroid
adenoma in the neck. Ectopic PTH production has been

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Mechanisms and treatment of hypercalcemia of malignancy Clines 341

Figure 1 Production of a humoral factor by the primary tumor comprises 80% of cases of hypercalcemia of malignancy, collectively
known as humoral hypercalcemia of malignancy

PTHrP is by far the most common factor implicated in HHM, especially in cases of breast and lung cancer. PTH is a rare cause of HHM. PTHrP and PTH
activate a common PTH1R receptor located on osteoblasts precursors resulting in RANKL expression, osteoclast activation and bone resorption.
Tumor-produced 1,25-(OH)2D by hematologic malignancies is an uncommon mechanism of HHM. The principal action of tumor-produced 1,25(OH)2D is to promote excessive calcium gut absorption. Approximately 20% of hypercalcemia of malignancy cases is the result of bone metastasis and
local production of tumor factors in the bone microenvironment. Breast and lung cancer bone metastasis primarily produce PTHrP. Osteolytic lesions of
multiple myeloma are the result of a complement of other bone-resorbing factors. 1,25-(OH)2D, 1,25-dihydroxyvitamin D; ATLL, adult T-cell leukemia/
lymphoma; HHM, humoral hypercalcemia of malignancy; HL, Hodgkins lymphoma; NHL, non-Hodgkins lymphoma; PTHrP, parathyroid hormonerelated protein; RANKL, receptor activator of nuclear factor kB ligand.

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342 Parathyroids, bone and mineral metabolism

documented in a small cell carcinoma of the lung [50], a

squamous cell carcinoma of the lung [51], an ovarian
cancer [52], a widely metastatic primitive neuroectodermal tumor [53], a papillary adenocarcinoma of the thyroid
[54], a thymoma [55], a rhabdomyosarcoma [56] and a
pancreatic cancer [57].
1,25-Dihydroxyvitamin D and humoral hypercalcemia of
malignancy

Another mechanism of HHM is overproduction of 1,25(OH)2D, a cause of hypercalcemia of malignancy in less

than 1% of cases [32]. Analogous to granulomatous
diseases such as sarcoidosis, certain cancers possess 1ahydroxylase activity that produce 1,25-(OH)2D from the
available 25-(OH)2D precursor [58,59]. Activated tissue
macrophages adjacent to tumor tissue may be another
source of 1,25-(OH)2D [60].
Most patients with 1,25-(OH)2D-mediated HHM have
Hodgkins lymphoma and NHL [61]. In one report,
4.1% of the patients with newly diagnosed NHL were
hypercalcemic and the likelihood of hypercalcemia
increased with the higher grade of disease [61,62]. The
incidence of hypercalcemia with Hodgkins lymphoma is
similar to NHL with 5.4% of patients diagnosed with this
complication [62]. Hypercalcemia from production of 1,25(OH)2D in acute lymphoblastic leukemia and dysgerminomas are a rare complication of these malignancies
[63,64].

advanced disease develop bone metastasis and hypercalcemia with localized osteolysis [67]. Multiple myeloma is
far less common than breast or lung cancer, but osteolytic
bone lesions are a nearly universal feature in advanced
cases. Although not typically characterized as a metastatic
malignancy, multiple myeloma shares many of the molecular mechanisms of pathologic bone resorption with
breast cancer bone metastasis [65]. Other malignancies
rarely causing hypercalcemia and osteolytic bone disease
include melanoma [68], acute lymphoblastic leukemia
[6971] and NHL [72,73].
PTHrP secretion into the metastatic bone microenvironment is the principal mechanism of pathogenic osteoclast
activation and osteolysis from breast and lung cancer
bone metastasis [7477]. PTHrP also plays a significant
role in the process of metastasis to bone, as evidenced by
clinical studies indicating that PTHrP expression by
primary breast cancer is more commonly associated with
the development of bone metastasis and hypercalcemia
[78]. In the case of breast and lung cancer, HHM and
skeletal osteolysis share PTHrP as the principal factor
leading to hypercalcemia; in one situation, it is a local
mediator, whereas in another, it is a humoral mediator.
Multiple myeloma secretes a complement of osteoclast
activating factors that include macrophage inflammatory
protein-1a [79], receptor activator of nuclear factor kB
ligand (RANKL) [80], interleukin-3 and interleukin-6
[81,82].

Bone metastasis and skeletal osteolysis

Extensive bone metastasis and local osteolysis accounts

for approximately 20% of cases of malignancy-associated
hypercalcemia [32]. During massive osteolysis, the amount
of calcium released from bone is greater than the renal
calcium excretion capacity resulting in a net increase in
serum calcium. Hypercalcemia-related nausea, anorexia,
nephrogenic diabetes insipidus and volume depletion further impair renal function and exacerbate hypercalcemia.
The most common malignancy associated with this mechanism of hypercalcemia is breast cancer metastasis to bone,
a complication that occurs in 70% of patients with
advanced disease. The formation of bone metastasis
begins with a series of sequential steps starting with cancer
cell escape from the primary tumor site, embolization in
the circulation followed by cancer cell adherence to bone
vascular endothelium and extravasation into the bone
microenvironment [65]. With the arrival of cancer cells
to bone, a unique synergetic interaction between cancer
and bone was first recognized by Stephen Paget [66] in
1889 and formed the basis for the seed and soil
hypothesis.
Humoral PTHrP is responsible for most cases of hypercalcemia in lung cancer, but 3040% of the patients with

Differential diagnosis
Hypercalcemia, especially in the hospital setting and
when the serum calcium is above 13 mg/dl, is likely
due to malignancy. In the outpatient setting, primary
hyperparathyroidism is a more likely cause of hypercalcemia. Therefore, hypercalcemia in a patient with a
known malignancy may not necessarily indicate an
advanced disease stage or even be linked to the malignancy itself [83]. In one study, seven out of 47 patients
with hypercalcemia and a malignancy had coexisting
primary hyperparathyroidism [84]. Differentiating
between the two has prognostic value because the likelihood of survival past 100 days is likely with primary
hyperparathyroidism, whereas an elevated PTHrP was
associated with a high mortality within 100 days [84].
Other conditions associated with hypercalcemia including excessive calcium intake, vitamin D toxicity and
thiazide diuretics may also coexist in malignancy. It is
therefore critical to fully evaluate the cause of hypercalcemia in all the patients with malignancy, even in those
with advanced disease.
Assessing circulating intact PTH concentration is the
initial step in determining the cause of hypercalcemia
in all patients. During hypercalcemia of malignancy and

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Mechanisms and treatment of hypercalcemia of malignancy Clines 343

in the absence of parathyroid disease, hypercalcemia will

overactivate the calcium-sensing receptor of the parathyroid glands resulting in suppressed PTH production. In
patients without a known malignancy, PTHrP testing is
generally not necessary in the initial diagnostic workup of
hypercalcemia. In patients with a malignancy and hypercalcemia, both PTH and PTHrP should be measured.

Treatment
The principal goals are two-fold: restore and promote
renal calciuresis and inhibit pathologic osteoclastic bone
resorption.
Hydration

Volume resuscitation is a critical early treatment to

restore renal perfusion and calciuresis [85]. The rate of
hydration depends on the severity of hypercalcemia, the
age of the patient and comorbidities such as congestive
heart failure, which may limit the rate of saline infusion.
A 1-liter normal saline bolus followed by 200300 ml/h is
a reasonable approach. Once euvolemia is established,
either oral or maintenance intravenous fluids is continued
to maintain a reasonable urine output. The addition of
furosemide to promote calciuresis is generally not recommended given the paucity of clinical evidence supporting
its use in this setting [86].
Calcitonin

Calcitonin is a useful adjunctive initial therapy that inhibits osteoclastic bone resorption and renal calcium reabsorption. A disadvantage of calcitonin is the development
of tachyphylaxis within 48 h of initiation. The effectiveness of this medication can be extended with the combination of glucocorticoids [87]. Calcitonin is administered
either intramuscularly or subcutaneously at a dose of 4 U/
kg every 12 h up to 8 U/kg every 6 h if the initial dose is not
satisfactory. Intranasal administration of calcitonin has
shown not to be effective [88]. Few studies have examined
the efficacy of calcitonin alone in the acute management of
hypercalcemia of malignancy [87,89].
Bisphosphonates

Pamidronate and zoledronic acid are the two bisphosphonates approved by the US Food and Drug Administration for treatment of hypercalcemia of malignancy.
These nitrogen-containing bisphosphonates have a high
affinity for hydroxyapatite and are rapidly deposited
within bone after administration. Bisphosphonate
released during bone resorption becomes internalized
within the osteoclast, blocking prenylation of small
GTP-binding proteins important for structural integrity
of the osteoclast resulting in apoptosis [90
].
Clinical trials have demonstrated efficacy of both 60 and
90 mg doses of pamidronate administered intravenously

over 4 h [91,92]. The higher 90 mg dose can be used in

patients with more severe hypercalcemia. With the 90 mg
infusion of pamidronate, the mean time to normocalcemia was approximately 4 days, whereas the mean
duration of normocalcemia was 28 days in one study
[93]. An effective method for achieving a rapid and
sustained reduction in serum calcium concentration is
to use pamidronate in combination with calcitonin. The
combination of the durable action of a bisphosphonate
with rapid-acting calcitonin lowers serum calcium levels
more rapidly and effectively than either alone [94].
Zoledronic acid, a more potent bisphosphonate, is administered at a dose of 4 mg intravenously over 15 min.
Compared with pamidronate, zoledronic acid was
superior in respect to response rates, time to calcium
normalization and response duration [95]. Therefore,
many clinicians consider zoledronic acid the bisphosphonate of choice. The bisphosphonate ibandronate, currently approved in the USA for osteoporosis treatment,
has similar efficacy as pamidronate but is not yet
approved by the FDA for this indication [96]. Etidronate
and clodronate have been studied in hypercalcemia of
malignancy, but the availability of more potent bisphosphonates has supplanted the use of these low-potency
first-generation bisphosphonates. Disadvantages of
bisphosphonates are renal toxicity that can be minimized
with a dose adjustment and risk of osteonecrosis of the
jaw especially in patients who receive multiple doses and
those with poor dentition [97
].
Glucocorticoids

Glucocorticoids are the preferred therapy for patients

with 1,25-(OH)2D-mediated hypercalcemia and operate
by reducing extrarenal vitamin D 1a-hydroxylase
activity. Glucocorticoids also inhibit osteoclastic bone
resorption by decreasing tumor production of locally
active cytokines and maybe used in conjunction with
other standard therapies in patients with other forms of
hypercalcemia of malignancy [87,98]. Prednisone at dose
of 4060 mg administered daily is typically effective. If
no appreciable response is observed within 10 days, then
glucocorticoid therapy should be discontinued.
Other therapies

Plicamycin and gallium nitrate are two antineoplastic

agents that have calcium-lowering abilities. However,
these medications are no longer recommended for treating hypercalcemia of malignancy due to poor side-effect
profiles and inconvenient dosing schedules. Hemodialysis using a calcium-free dialysate effectively lowers
calcium in case reports [99,100]. This mode of therapy
should be reserved only for the most severe cases of
hypercalcemia when rapid normalization of calcium is
required. Denosumab is a RANKL-targeted monoclonal
antibody currently approved for treating osteoporosis and

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344 Parathyroids, bone and mineral metabolism

preventing skeletal-related events in bone metastasis

[101,102
]. The efficacy of denosumab for treating hypercalcemia of malignancy is currently being evaluated in a
phase II clinical trial.

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Conclusion
Hypercalcemia is a common complication of malignancy
caused by a heterogeneous group of tumor-derived
factors that disrupt normal calcium homeostasis. PTHrP,
either acting as endocrine factor or locally in cancer
metastasis to bone, is a central mediator of this paraneoplastic complication in breast and lung cancer. A complement of other factors is the foundation for hypercalcemia associated with multiple myeloma. Rarely, tumorproduced PTH and 1,25-(OH)2D are implicated. The
standard of care for hypercalcemia of malignancy in most
cases is bisphosphonate treatment combined with saline
hydration. Alternative therapies with potential benefit
include inhibitors of RANKL and neutralizing antibodies
to PTHrP. Clinical trials, in progress, should determine
whether these modalities would be as effective or complementary to bisphosphonate treatment.

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The author receives funding from the National Institutes of Health

(CA118428 and AR056826) and the Department of Defense
(W81XWH-08-1-0030).

Conflicts of interest
There are no conflicts of interest.

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