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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.
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
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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