c h a p t e r

64
Hypercalcemia of Malignancy
Karena L. Swan and John J. Wysolmerski

CHAPTER OUTLINE
HISTORICAL INTRODUCTION,  1125 TREATMENT, 1131
NORMAL PHYSIOLOGY OF CALCIUM Hydration, 1131
METABOLISM, 1126 Inhibition of Bone Resorption,  1132
Parathyroid Hormone and the Calcium-Sensing Calcitonin, 1132
Receptor, 1126 Gallium Nitrate,  1133
Vitamin D,  1127 Mithramycin, 1133
Parathyroid Hormone–Related Protein,  1127 Bisphosphonates, 1133
MALIGNANCY-ASSOCIATED HYPERCALCEMIA,  1127 Denosumab, 1134
Humoral Hypercalcemia of Malignancy,  1128 Glucocorticoids, 1134
Ectopic Production of Parathyroid Hormone,  1128 Dialysis, 1134
Overproduction of 1,25-Dihydroxyvitamin D,  1129
Local Osteolytic Hypercalcemia,  1130

KEY POINTS
• H  ypercalcemia is a common complication of malignancy.
• Humoral hypercalcemia of malignancy is frequently caused by elevations in circulating
parathyroid hormone–related protein secreted by tumors not in the skeleton.
• Local osteolytic hypercalcemia is caused by local cytokine production by tumor cells
located within the bone microenvironment.
• Bone resorption is the key pathophysiologic mechanism by which excess calcium is
released into the circulation.
• Hypercalcemia of malignancy can be effectively treated by lowering bone resorption
and by treating the underlying malignancy if possible.
  

HISTORICAL INTRODUCTION
Hypercalcemia is a frequent complication of cancer and
can occur in 20% to 30% of patients during the course
of their malignant disease.1 It has been estimated that
patients with this disorder have a 30-day mortality of
50%.2 The first reported case of malignancy-associated
hypercalcemia (MAHC) was in the 1920s, coinciding
with the development of an assay to measure serum cal-
cium.3 In 1936, the first series of cases was published on
patients with MAHC.4 The reported patients suffered
from myeloma and breast cancer with skeletal involve-
ment, and their hypercalcemia was attributed to skeletal
destruction caused by local tumor invasion.
In 1941, Fuller Albright suggested an alternative mech-
anism: that a circulating humoral factor might cause some
cases of MAHC.5 Studies published in the 1950s and
1960s supported this hypothesis by describing patients
with hypercalcemia who lacked bony metastases.6,7 These
patients had squamous, renal, and genitourinary cancers as
opposed to breast cancer or myeloma. Lafferty concluded
that these tumors must secrete parathyroid hormone and
named this process pseudohyperparathyroidism.8
At that point, it was thought that tumors could cause
hypercalcemia through direct skeletal involvement or by
acting on the skeleton in a humoral fashion. We now
refer to these conditions as two subtypes of MAHC. The
first is local osteolytic hypercalcemia (LOH), and the sec-
ond is humoral hypercalcemia of malignancy (HHM).
The humoral type generally predominates in clinical
practice.9,10
As discussed later, in the 1980s investigators made
great strides in understanding the pathophysiology of both
1125

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1126 PART 6  PARATHYROID GLAND, CALCIOTROPIC HORMONES, AND BONE METABOLISM
LOC and HHM. First, it was appreciated that tumor cells
could make cytokines that stimulated the local produc-
tion and activity of bone-resorbing osteoclasts within the
bone microenvironment surrounding tumor cells. Second,
investigations into HHM led to the discovery of a new
hormone, parathyroid hormone-related peptide (PTHrP),
which is evolutionarily related to parathyroid hormone
and uses the same receptor. As a result, when tumors
secrete PTHrP into the circulation, it acts like PTH to
increase osteoclast differentiation and activity throughout
the skeleton. It has also become clear that two additional
types of MAHC exist: 1,25(OH)2–vitamin D-induced
hypercalcemia in patients with lymphomas and true ecto-
pic production of parathyroid hormone. These will be
discussed further in this chapter.
NORMAL PHYSIOLOGY OF CALCIUM METABOLISM
Calcium can be found in the body in two predominant
forms. First, calcium salts are key components of bone
hydroxyapatite, which provides structural integrity to
the skeleton so that this organ can bear weight, support
locomotion, and protect internal organs. Second, soluble
calcium ions in the extracellular fluid (ECF) and cytosol
contribute to a multitude of biochemical reactions, signal-
ing cascades, and electrical systems. In the adult human,
there are about 1000 g of calcium, of which 99% is found
in bone.11 Thus, only 1% of calcium is found in the ECF
and soft tissues. Skeletal and ECF calcium are exchange-
able allowing bone to provide calcium to the ECF, when
calcium concentrations are low and also to store excess
calcium when needed. Ionized or free calcium represents
approximately 50% of the circulating pool, and the
remaining fraction is bound to serum proteins. Calcium
is largely bound to albumin in the circulation, but can
also be complexed with citrate or sulfate.11 The ionized
fraction is the physiologically important one, but it is dif-
ficult to measure, as it requires anaerobic conditions for
collection and handling. Therefore, clinically total serum
calcium is most commonly used as an indirect measure-
ment of the ionized fraction, although some medical cen-
ters now routinely measure the ionized fraction.
The parathyroid glands, kidneys, skeleton, and gut are
the organs involved in calcium homeostasis through the
action of parathyroid hormone (PTH), vitamin D, and
PTH-related protein (PTHrP). These interactions will be
described in further detail.
Parathyroid Hormone and
the Calcium-Sensing Receptor
PTH is produced from the four parathyroid glands
located near the upper and lower poles of the thyroid
gland. These glands are derived from the fourth and third
branchial pouches, respectively, and can be found any-
where along the path of embryologic migration.
PTH is an 84–amino acid protein synthesized as a
single-chain, pre-pro parathyroid peptide. This peptide is
cleaved twice to generate the biologically active form of
the hormone, PTH 1-84.12 PTH has a very short half-
life (minutes) and is degraded by the liver and kidney.
The C-terminal fragment of PTH is released into the
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circulation upon degradation and is excreted by the kid-
ney. Parathyroid secretory granules also digest the amino-
terminal portion of PTH and release the C-­ terminal
portion into the circulation during hypercalcemic condi-
tions.13 PTH secretion is regulated by extracellular ion-
ized calcium concentrations, and small changes in ionized
calcium concentrations can result in large changes in PTH
secretion.14-16
Parathyroid cells regulate PTH secretion by detect-
ing changes in extracellular calcium concentrations
through a G-protein–coupled-receptor known as the
calcium-­sensing receptor (CaSR).17-21 Calcium binds to
the calcium-sensing receptor and activates a downstream
signaling cascade that suppresses PTH synthesis and sub-
sequent secretion.18,19,22 Persistently elevated calcium
levels can result in degradation of PTH within parathy-
roid cells.23 The CaSR is also expressed in the kidney,
where it regulates calcium handling by the renal tubules.
Hypercalcemia activates the CaSR, resulting in suppres-
sion of renal calcium reabsorption24 and excretion of
excess calcium in the urine.
The actions of PTH are mediated through a G-­protein–
coupled-receptor known as the type 1 PTH/PTHrP
receptor (PTH1R), because it responds to both PTH
and PTHrP. Activation of the receptor by PTH activates
several signaling cascades, but the best documented has
been the adenylyl cyclase pathway. In the kidney, PTH
acts on proximal tubular cells to inhibit reabsorption
of phosphate through removal and degradation of the
sodium-phosphate co-transporters 2a and 2c (NPT2a
and NPT2c) from the luminal membranes.25 It also stim-
ulates the activity of renal 1α hydroxylase in proximal
tubular cells and inhibits 24-hydroxylase, which results
in an increase in the biologically active 1,25 (OH)2 vita-
min D.26 PTH increases the reabsorption of calcium in
the kidney through reclaiming calcium from the glo-
merular filtrate. There is also a PTH-independent para-
cellular process linked to the reabsorption of sodium. By
increasing the positive charges on the luminal side of the
tubule, PTH promotes calcium reabsorption in the corti-
cal thick ascending loop of Henle. In the distal tubule,
calcium channels are inserted into apical membranes to
stimulate the basolateral sodium-calcium exchanges.27 In
the skeleton, PTH activates bone turnover and releases
stored calcium. It does this by stimulating transport of
calcium across bone lining cells from a pool of calcium at
the surface of bone. It also stimulates both bone resorp-
tion and bone formation. PTH increases the number and
activity of bone-forming osteoblasts and bone-resorbing
osteoclasts, increases the size of the osteoblast precur-
sor pool,28 increases the bone-forming activity of mature
osteoblasts, and promotes the release of colony-stimulat-
ing factor 1 and receptor activator of nuclear factor κB
(NF-κB) ligand (RANKL), which stimulate the formation
of new osteoclasts and activate mature osteoclasts.29 PTH
inhibits osteoblast production of osteoprotegerin, which
is a soluble decoy receptor for RANKL that inhibits
osteoclast development. The ultimate effects of PTH on
bone turnover depend on the pattern of PTH exposure.
Continued long-term elevations in PTH stimulate net
bone resorption while intermittent PTH stimulation can

result in net bone formation. See Chapter 56 for further
discussion on PTH.
Vitamin D
In the skin, keratinocytes absorb ultraviolet light and
convert 7-dehydrocholesterol to vitamin D3.30 This is
the biologically inert form of vitamin D, and it must be
hydroxylated in the liver by vitamin D 25-hydroxylase
to 25-hydroxyvitamin D3.31 The second hydroxylation
occurs in the kidney, when 25-hydroxyvitamin D3 is
converted to 1,25 (OH)2 vitamin D3, by 25 (OH)D-1α
hydroxylase (1α hydroxylase).31 This enzymatic pro-
cess in the kidney is stimulated by PTH and phosphate
and inhibited by hypercalcemia and FGF23. The 1α
hydroxylase enzyme is also expressed in immune cells,
especially activated macrophages. Therefore, 1,25(OH)2
vitamin D3 can be produced by macrophages, classically
in granulomas.
Vitamin D is a steroid hormone that interacts with
specific nuclear receptors to regulate gene expression.
The vitamin D receptor (VDR) is a member of the steroid
hormone receptor family of ligand-binding transcription
factors.31-33 When 1,25(OH)2 vitamin D is present, the
vitamin D receptor heterodimerizes with the retinoid acid
x receptor and binds to specific DNA sequences within the
target gene.34,35 1,25(OH)2 vitamin D stimulates calcium
absorption from the diet by stimulating expression of
TRPV6, an apical membrane calcium channel that allows
calcium influx into intestinal epithelial cells by enhanc-
ing production of mediators, such as calbindin D. This
facilitates calcium movement through the cytoplasm by
stimulating the calcium pump, Ca ATPase 1b (PMCA1b),
which moves calcium across the basolateral membrane of
gut enterocytes, and by enhancing paracellular calcium
absorption through a change in charge selectivity of the
tight junctions, possibly through changes in Claudin 2
and 12 levels.34 At pathologic levels, 1,25 (OH)2 Vitamin
D can increase bone resorption by binding to the VDR
on osteoblasts and stimulating osteoblastic production
of RANKL, leading to osteoclast activation and bone
resorption.36,37 See Chapter 59 for detailed treatment of
vitamin D chemistry and biology.
Parathyroid Hormone–Related Protein
Parathyroid hormone-related protein (PTHrP) is a
“cousin” of PTH; both peptides are derived from related
genes that together with TIP-39 define a small gene fam-
ily. PTHrP was initially identified as a cause of MAHC.
Much research has now shown that PTHrP is a widely
expressed cytokine that is involved in a variety of physi-
ologic functions. PTHrP is discussed in greater length
in Chapter 57. What follows here is a short discussion
enabling the reader to appreciate its pathophysiologic
role in humoral hypercalcemia of malignancy (see later).
In humans, PTHrP is encoded by a single-copy gene
containing 8 exons and at least 3 promoters located on
the short arm of chromosome 12.38-40 Alternative splic-
ing at the 3′ end of the gene gives rise to three different
classes of mRNAs coding for specific translation prod-
ucts of 139, 141, or 173 amino acids. PTHrP mRNA has
been found in almost every organ at some time during
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64  HYPERCALCEMIA OF MALIGNANCY 1127
its development or functioning. Many different hormones
and growth factors regulate the transcription and/or
stability of PTHrP mRNA. As with PTH, the CaSR has
been found to regulate PTHrP gene expression in many
cells.41,42
The amino terminus of PTHrP is remarkably similar to
that of PTH. The two peptides share 8 of the first 13 amino
acids and a high degree of predicted secondary structure
over the next 21 amino acids. These common sequences
allow both proteins to bind and activate the same PTH/
PTHrP receptor (PTH1R). The vast majority of studies
in vitro suggest that this receptor binds PTHrP and PTH
with equal affinity and that both activate the receptor in
an identical manner. However, the human PTH1R may
respond slightly differently to PTH and PTHrP. There
appear to be physical differences in the binding of the two
peptides to different conformational states of the recep-
tor, so that the duration of cAMP production is shorter
for PTHrP 1 to 36 than for PTH 1 to 34.43 Nevertheless,
when PTHrP enters the systemic circulation, it can mimic
the effects of PTH and cause hypercalcemia in HHM.44
PTHrP has been found in at least some cells of almost
all organs, and a variety of functions have been ascribed
to PTHrP. The best documented are its roles in the
growth plate during the development of endochondral
bone, the development of the mammary gland, its ability
to relax smooth muscle in the vasculature and uterus, and
its stimulation of pancreatic islet cell proliferation. These
functions are discussed at greater length in Chapter 57.
Pertinent to its role in causing hypercalcemia in cancer, it
is worth highlighting PTHrP’s function during lactation.
Milk production requires a great deal of calcium, much of
which comes from the maternal skeleton. As a result, lac-
tating women lose 5% to 8% of their bone mass over the
first 6 months of full-time nursing, and lactating rodents
can lose 25% to 30% of their skeletal mass in as little
as 12 to 14 days. Bone loss during this time is mediated,
in part, by the secretion of PTHrP from breast epithelial
cells into the systemic circulation. This is the only time
that PTHrP circulates in normal individuals in apprecia-
ble amounts and, like PTH, during lactation it increases
bone resorption to liberate skeletal calcium stores. This
PTH-like function during reproductive cycles is probably
the principal evolutionary pressure that helped to main-
tain PTHrP’s ability to share the same receptor with PTH,
even though, in every other aspect, the two peptides func-
tion much differently. Since HHM exists because PTHrP
and PTH share the same receptor, ultimately, this evolu-
tionary pressure also explains why hypercalcemia occurs
in many malignancies.45
MALIGNANCY-ASSOCIATED HYPERCALCEMIA
Historically, MAHC has been subdivided into two main
categories. The first occurs in patients with few or no bone
metastases but a diffuse upregulation of bone resorption.
These tumors produce a humoral factor(s) (usually PTHrP)
that circulates and causes increased osteoclast numbers
and activity. This type of MAHC has been referred to as
humoral hypercalcemia of malignancy (HHM). The second
main category includes tumors with extensive osteolytic
1128 PART 6  PARATHYROID GLAND, CALCIOTROPIC HORMONES, AND BONE METABOLISM
bone metastases. In these tumors, the metastatic cells
within the skeleton produce local paracrine factors that
increase osteoclastic bone resorption around the tumor
deposits, but not systemically. These tumors require an
extensive skeletal tumor burden to cause hypercalcemia.
Humoral Hypercalcemia of Malignancy
HHM is the more common of the two types of MAHC,
representing 75% to 80% of cases in consecutive series of
patients with MAHC.9,10 Classically, it occurs most com-
monly in squamous, renal, and genitourinary malignan-
cies, some breast cancers, and human T-cell leukemia virus
(HTLV) 1–associated adult T-cell leukemia/lymphomas.46
However, almost all tumor types have been reported to
occasionally cause HHM. It is difficult to determine the
exact incidence of HHM in patients with different types of
cancer as the frequency generally increases as cancer pro-
gresses. For instance, approximately 15% of patients with
renal cell carcinoma were shown to have hypercalcemia
prior to treatment.47 In contrast, up to 50% of patients
with squamous cell tumors of the head and neck followed
for several years eventually developed HHM.48 In fact,
hypercalcemia is typically a complication of advanced can-
cer, and the prognosis is poor in patients with HHM, with
reports suggesting a median survival of 2 to 3 months.49,50
HHM is most commonly caused by a tumor, distant
from the skeleton, releasing PTHrP into the systemic circu-
lation. PTHrP is often a normal product of the cells of ori-
gin of the tumor, but in the setting of malignancy, PTHrP
production is upregulated by tumor cells, and the tumors
evade the normal barriers that usually keep PTHrP within
the local tissue environment. As a result, PTHrP enters the
systemic circulation and gains access to the PTHR1 pool in
the skeleton and kidney that are normally reserved for PTH.
This is associated with a characteristic pattern of biochemi-
cal abnormalities first defined by Stewart and colleagues in
1980.9 Patients typically demonstrate elevated serum cal-
cium levels associated with suppressed PTH levels and low
1,25 (OH)2 vitamin D levels. As a result, calcium clear-
ance in the kidneys is increased and gut calcium absorp-
tion is decreased, contributing to a profound negative
calcium balance. Serum phosphorus levels are low-normal
or low with a decreased TmP/GFR. Nephrogenous cAMP
(NcAMP) excretion rates are elevated, reflecting activation
of the renal proximal tubular PTH receptor despite the
reduction in circulating PTH levels. The elevated NcAMP
levels in HHM formed the basis for biochemical assays
that resulted in the purification of PTHrP from tumors and
the cloning of the PTHrP gene in the 1980s.
Hypercalcemia in HHM results from the release of cal-
cium from the skeleton at a rate that exceeds the kidney’s
ability to excrete the excess load (Fig. 64-1). Patients ini-
tially develop hypercalciuria but eventually develop dehy-
dration due to an osmotic diuresis combined with the effects
of calcium to induce a form of nephrogenic diabetes insipi-
dus due to activation of the CaSR on the distal tubule and
collecting duct. Once patients become dehydrated, serum
calcium levels typically rise rapidly and patients develop
symptoms of lethargy, anorexia, and confusion from the
elevated ionized calcium levels that only worsen the dehy-
dration and accelerate the rise in serum calcium levels.
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Although PTH and PTHrP act on the same receptor,
several biochemical aspects of HHM differ from changes
seen in primary hyperparathyroidism. First, as noted ear-
lier, renal calcium clearance is higher in HHM than it is
in hyperparathyroidism. Second, although PTHrP levels
are elevated, 1,25(OH)2 vitamin D levels are suppressed
in HHM, whereas the elevations in PTH in primary hyper-
parathyroidism result in increased 1,25(OH)2 vitamin D
levels. Finally, bone histomorphometric studies in patients
with HHM demonstrate very elevated rates of bone resorp-
tion but suppressed bone formation rates.51 In contrast,
typically in primary hyperparathyroidism, rates of both
bone formation and bone resorption are elevated. Similar
differences in bone formation rates in HHM as compared to
hyperparathyroidism are noted when biochemical markers
of bone turnover such as total deoxypyridinoline (Dpyd),
pyridinoline cross-linked carboxyterminal telopeptide of
type 1 collagen (ICTP), serum osteocalcin (OC), and serum
bone type alkaline phosphatase (B-ALP) were measured.52
It is still not entirely clear why elevations in PTHrP produce
different effects on the kidney and bone cells if both pep-
tides act on the same receptor. Nonetheless, studies by Hor-
witz and colleagues revealed that infusions of PTHrP are
less effective at stimulating 1,25(OH)2 vitamin D produc-
tion than are infusions of PTH.53 Interestingly, in the same
studies PTH and PTHrP stimulated renal tubular reabsorp-
tion of calcium equivalently.53-55 As for the uncoupling of
bone formation from bone resorption, tumor production
of IL-6 has been implicated in human squamous carcinoma
cells that also secrete PTHrP, and this cytokine may accel-
erate osteoclastic bone resorption and suppress osteoblastic
function.56 Finally, although PTHrP and PTH appear to act
equivalently in many experimental systems, recent studies
have documented differences in the way the two peptides
bind to the PTH1R, thus providing a potential mechanism
through which the two proteins might have tissue-specific
differences in signaling that would explain their divergent
effects on 1,25 vitamin D production and the stimulation
of bone formation by osteoblasts.43,44,57,58
Ectopic Production of Parathyroid Hormone
Although HHM was originally thought to be secondary to
ectopic PTH production, it is quite rare that MAHC is actu-
ally caused by ectopic production of PTH. Approximately
18 cases exist in the literature of ectopic hyperparathy-
roidism caused by a nonparathyroid tumor. These tumors
include neuroendocrine tumors, hepatocellular carcinoma,
medullary thyroid cancer, ovarian carcinoma, small-cell
lung carcinoma, squamous carcinoma, rhabdoid tumor of
the kidney, endometrial adenosquamous carcinoma, and
thymoma.59-73 Immunoradiometric two-site assays for
intact PTH and PTHrP allow for the determination as to
whether PTH or PTHrP is causing hypercalcemia in malig-
nancy. There is no cross-reactivity between PTH and PTHrP
in these assays.59 Nussbaum and coworkers described a
patient with ovarian carcinoma, in which genetic evaluation
of the tumor cells revealed DNA amplification and rear-
rangement in the upstream regulatory region of the PTH
gene. This resulted in increased PTH expression.59 Van-
Houten and associates described a patient with a high-grade
neuroendocrine carcinoma of the pancreas found to have
 64  HYPERCALCEMIA OF MALIGNANCY 1129

ectopic PTH production. Genetic evaluation of these tumor
cells revealed transactivation of the PTH gene promoter
associated with hypomethylation of the PTH gene locus,
indicative of re-activation of PTH gene transcription in the
tumor cells.70
Overproduction of 1,25-Dihydroxyvitamin D
Another rare cause of HHM is the overproduction of
1,25(OH)2 vitamin D by lymphomas, both Hodgkin’s
and non-Hodgkin’s types.74-78 In this setting, local acti-
vation of 1α-hydroxylase activity within or around the
tumor results in the overproduction of the active form of
vitamin D. In at least one carefully studied patient, the
source of the 1α-hydroxylase was the tumor-associated
macrophages and not the lymphoma cells themselves.
This would suggest that the tumor cells make some para-
crine factor that upregulates 1α-hydroxylase expression in
macrophages, although it is not clear whether lymphoma
cells can also sometimes express 1α-hydroxylase. Unlike
the kidney, there is no systemic feedback inhibition of the
tumor-associated 1α-hydroxylase activity, but 1,25(OH)2
vitamin D production is responsive to 25 vitamin D levels.
Hypercalcemia in these patients is largely secondary to
the hyperabsorption of calcium in the intestine, although
high 1,25 vitamin D levels can also directly cause bone
resorption (see Fig. 64-1). Patients typically have normal

NORMAL HOMEOSTASIS
Oral Ca intake
1000 mg

500 mg
ECF Ca2+
150 mg
1000 mg
GI tract 0 mg Skeleton
Stimulated Serum Ca
by 1,25 9.5 mg/dL
500 mg
vit D

Filtered load of Ca in kidney

10,000 mg

Distal tubular calcium reabsorption is

stimulated by PTH
850 mg

150 mg
A Kidney
HUMORAL HYPERCALCEMIA OF MALIGNANCY

Oral Ca intake
Skeleton

Decreased ↑ PTHrP levels

absorption results in
Serum Ca
GI tract uncoupling of
10.5->14 mg/dL
↓ levels bone formation
1,25 vit D and resorption.

Higher filtered load of

Ca in kidney

↓ PTH levels
↑ PTHrP levels leads to enhanced
Increased renal retention of Ca
excretion
Greater, but insufficient Ca excretion
B Kidney
Figure 64-1  Comparison of normal calcium fluxes with MAHC. A, The central box represents extracellular fluid (ECF), which contains approxi-
mately 1000 mg of calcium. This compartment interfaces with the gastrointestinal tract, the kidney, and the skeleton. The fluxes into and out of the
ECF are measured in milligrams per day. There is a zero calcium balance under homeostatic conditions. B, In humoral hypercalcemia of malignancy,
elevated circulating PTHrP levels result in an uncoupling of bone resorption from bone formation and a net output of calcium from bone. There is
decreased intestinal absorption of calcium secondary to reduced 1,25 vitamin D levels. The kidney filters an increased load of calcium, and PTHrP
acts on the kidney to enhance renal retention of calcium. However, this is insufficient to reduce serum calcium concentrations to normal levels.
Continued

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1130 PART 6  PARATHYROID GLAND, CALCIOTROPIC HORMONES, AND BONE METABOLISM

LOCAL OSTEOLYTIC HYPERCALCEMIA

Oral Ca intake
Skeleton

Decreased
absorption ↑ local release of
Serum Ca factors by
GI tract
10.5->14 mg/dL skeletal
↓ levels metastasis leads
1,25 vit D to uncoupling of
bone formation
and resorption.
Higher filtered load of
Ca in kidney

↓ PTH levels
↑ excretion of urinary calcium
Increased
excretion
Greater, but insufficient Ca excretion
C Kidney
1,25 VITAMIN D MEDIATED HYPERCALCEMIA

Oral Ca intake
Skeleton

Increased
absorption ↑↑ 1,25 vit D may
Serum Ca
GI tract lead to increased
10.5->14 mg/dL
↑↑ 1,25 bone resorption
vit D

Higher filtered load of

Ca in kidney

↓ PTH levels
↑ excretion of urinary calcium
Decreased
excretion
Greater, but insufficient Ca excretion
D Kidney
Figure 64-1, cont’d  C, In local osteolytic hypercalcemia, local release of factors from skeletal metastases leads to the local uncoupling of bone
resorption from formation. If there are enough metastases, there is a net output of calcium from bone. There is decreased intestinal absorption of
calcium secondary to reduced 1,25 vitamin D levels. The kidney filters an increased load of calcium, but this is insufficient to reduce serum calcium
concentrations to normal levels. D, In 1,25 vitamin D-mediated hypercalcemia, there is a marked increase in intestinal calcium absorption, and there
also may be an increase in bone resorption. The kidney filters an increased load of calcium, but this is insufficient to reduce serum calcium concentra-
tions to normal levels. (A, Adapted from Stewart AF. Normal physiology of bone and mineral homeostasis. In Andreoli TE, et al. (eds.). Andreoli and
Carpenter’s Cecil essentials of medicine. Philadelphia: Elsevier Saunders; 2010.)

serum phosphate levels and increased renal calcium excre-
tion. PTH levels are appropriately suppressed in the face
of hypercalcemia, and PTHrP concentrations are unmea-
sureable.77 However, hypercalcemia can also be caused
by lymphomas that secrete PTHrP. Therefore, measuring
PTHrP levels is clinically important in this setting.
Local Osteolytic Hypercalcemia
Local osteolytic hypercalcemia (LOH) is the second most
common form of MAHC composing approximately 20%
to 30% of patients in consecutive series of patients with
MAHC.9,10,79 In patients with LOH, the hypercalcemia
is caused by tumor growth within bone, which leads to
the stimulation of osteolysis around the bone metastases
with release of calcium into the systemic circulation. In
order to develop hypercalcemia, patients usually must
have extensive skeletal metastases. Classically, the most
common tumors presenting with this syndrome include
myeloma, breast cancer, and lymphoma.
The biochemical findings in the disorder are hypercal-
cemia with reduced PTH and 1,25(OH)2 vitamin D lev-
els, similar to HHM. However, in this condition, patients
have normal serum phosphorus concentrations and a
normal renal phosphate threshold. In contrast to HHM,
PTHrP levels are undetectable, so nephrogeneous cAMP
(NcAMP) levels are reduced secondary to the suppressed

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PTH levels. Urinary calcium excretion is increased as a
result of an increased filtered load of calcium found in
hypercalcemic conditions and a decreased distal tubular
calcium reabsorption in the setting of lower PTH levels.
Intestinal absorption of calcium is also reduced because of
the decreased circulating 1,25(OH)2 vitamin D levels. As
with HHM, this results in a net negative calcium balance.
The pathophysiology of LOH is an extension of the patho-
physiology of osteolytic bone metastases. In order for tumor
cells to survive and grow in bone, they influence the behavior
of normal bone cells to remodel the bone microenvironment,
often activating bone resorption and causing osteolysis. This
leads to the release of factors from the bone matrix that,
in turn, stimulate further growth of the tumor cells, causing
more osteolysis. This vicious cycle of peri-tumor osteolysis
and tumor growth has been the focus of many studies. In
short, it appears that tumor cells produce soluble factors
that lead to increased osteoclast recruitment, differentiation,
and activity.80-83 Some tumors also elaborate factors that
inhibit osteoblast-mediated bone formation. As a result, the
tumors cause progressive bone destruction, allowing them
to expand within the skeleton. If the number and size of the
osteolytic metastases is great enough, then the release of cal-
cium from the skeleton will exceed the kidney’s ability to
excrete the filtered load, and patients will develop clinical
hypercalcemia, usually associated with renal insufficiency
(see Fig. 64-1). As opposed to HHM, bone resorption does
not happen throughout the skeleton in LOH, just around the
individual tumor deposits. The general pathophysiology of
bone metastases has been reviewed in great detail previously.
In this setting, we will only briefly review some of the main
cytokines that have been implicated in driving the vicious
cycle of osteolysis, but the reader is referred to other reviews
for a more complete discussion of this topic.84-86
One of the tumors that frequently causes extensive
bone destruction and hypercalcemia is myeloma. Forty
years ago, Mundy described an osteoclast-activating fac-
tor (OAF) that was produced by myeloma cells.87 Many
subsequent studies have identified a series of cytokines
produced by myeloma cells that have the ability to cause
osteolysis. These include interleukin 1α (IL-1α), IL-1β,
tumor necrosis factor α (TNF-α), TNF-β (lymphotoxin),
transforming growth factor (TGF-α), MIP-1α (macrophage
inflammatory protein-1α), IL-3, IL-6, and CD-47.88 Many
of these cytokines increase osteoclast differentiation and
activity by increasing the production of receptor activator
of NF-κB ligand (RANKL) by osteoblasts.89-91 RANKL is
the dominant factor produced by osteoblasts to regulate
the production and activity of osteoclasts, and this factor
acts through a receptor, RANK, found on osteoclast pro-
genitors and mature osteoclasts. In recent years, it has also
become clear that suppression of bone formation is also
important in the pathogenesis of myeloma bone disease.
This appears to be related to the secretion of Dickkopf1
(DKK-1), an inhibitor of the WNT signaling pathway,
by myeloma cells. Inhibition of Wnt signaling suppresses
osteoblast activity and bone formation, augmenting the
local osteolysis and release of calcium from the bone.92-94
Breast cancer is the second tumor type classically asso-
ciated with LOH. Bone metastases are common in breast
cancer, occurring in up to 70% of patients with advanced
disease. As in myeloma, bone metastases from breast cancers
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64  HYPERCALCEMIA OF MALIGNANCY 1131
are typically osteolytic, and if the skeletal burden is great
enough, enough calcium can be released from the skeleton
to overwhelm the body’s adaptive mechanisms, resulting in
hypercalcemia. It is difficult to ascertain the current inci-
dence of hypercalcemia in patients with breast cancer and
bone metastases. Older studies suggested that 10% to 15%
of all patients with breast cancer developed hypercalcemia,
the majority of whom had bone metastases. More recent
studies (usually drug trials) group together hypercalcemia,
pathologic fracture, radiation treatment for impending frac-
ture, and bone pain under the term skeletal-related events
(SRE) and do not often report the incidence of hypercalce-
mia separately. In these trials, the control group of patients
with bone metastases had an SRE rate of approximately
60%. The use of prophylactic bisphosphonates is associated
with an aggregate 15% reduction in SREs, so it is likely
that the widespread use of these medications in patients
with breast cancer and bone metastases has reduced the
incidence of hypercalcemia by at least a similar amount.95
Like myeloma cells, breast cancer cells have been shown
to produce a variety of factors that induce local bone resorp-
tion (Fig. 64-2). One of the best studied of these factors is
PTHrP. It is well documented that PTHrP is produced by a
number of primary breast carcinomas and that this some-
times leads to classical HHM.96 However, animal models
have suggested that localized PTHrP production by breast
tumor cells contributes to the osteolysis associated with
skeletal metastases.97,98 These studies have suggested that, in
response to the bone microenvironment, breast cancer cells
metastatic to the skeleton produce more PTHrP than cells
in the primary tumor.98,99 TGF-β, released at sites of bone
resorption, has been shown to upregulate PTHrP produc-
tion through a signaling pathway involving the transcription
factor Gli2.100 PTHrP, in turn, increases the production of
RANKL and decreases the production of OPG, increasing
osteoclast numbers and activity.99 This sets up a feedforward
loop between PTHrP production and bone resorption, con-
tributing to a vicious cycle of osteolysis. In addition, unlike
in normal breast cells, CaSR signaling in breast cancer cells
stimulates PTHrP production and can synergize with the
effects of TGF-β.101,102 Finally, the mechanical stiffness of
bone tissue may also increase PTHrP production.103 Thus,
several aspects of the bone microenvironment conspire to
increase PTHrP production in skeletal metastases. How-
ever, PTHrP is not the only factor important in this pro-
cess. Breast cancer cells have been shown to produce other
osteolytic factors, such as IL-6, IL-11, prostaglandin E2,
Jagged 1, macrophage colony-stimulating factor (MCSF),
and macrophage-stimulating protein (MSP).83 MCSF and
MSP may act directly to stimulate osteoclast production and
activity, while the other factors act with PTHrP to stimulate
RANKL production by osteoblasts.83,104,105 As depicted in
Figure 64-2, the growth of osteolytic metastases depends
on a vicious cycle of bone resorption and tumor cell prolif-
eration that is fed by the release of growth factors from the
bone matrix, the breast cancer cells, and normal bone cells.
TREATMENT
Hydration
Hypercalcemia is associated with polyuria. In addition,
hypercalcemic patients also suffer from reduced oral intake,
1132 PART 6  PARATHYROID GLAND, CALCIOTROPIC HORMONES, AND BONE METABOLISM

Osteoblasts
Angiogenesis
↓ OB differentiation invasive growth
↑ OC activity bone resorption
immunosuppression
Active
Latent TGF-β
TGF-β
Cancer cells

Osteoclasts
Osteoclast
precursors IL-6

PTHrP
IL-11
CTGF
↑ RANKL
↓ OPG Jagged

Bone
matrix

Osteoblasts
Figure 64-2  Osteolytic bone metastasis in breast cancer. In skeletal metastases, the tumor cells make factors, including PTHrP, that upregulate
osteoclastic bone resorption. This results in the release of TGF-β from the bone matrix, which acts on cancer cells to further stimulate the production
of osteolytic factors, such as PTHrP, connective tissue growth factor (CTGF), IL-6, and IL-11. These factors increase the RANKL/OPG expression
ratio in bone stromal cells such as osteoblasts, resulting in osteoclastogenesis. Moreover, active TGF-β stimulates Jagged 1 expression in cancer cells,
which in turn stimulates Notch signaling in osteoclasts and osteoblasts, resulting in increased osteoclastogenesis and production of the cytokine IL-6
by osteoblast (blue dotted line), which stimulates proliferation of tumor cells. TGF-β also inhibits osteoblast differentiation. Thus, once osteolysis
is established, a vicious cycle of bone resorption and tumor cell proliferation is fed by the release of growth factors from bone matrix, tumor cells,
and bone cells. (Reproduced with permission from Buijs JT, Stayrook KR, Guise TA. The role of TGF-beta in bone metastasis: novel therapeutic
perspectives. Bonekey Rep. 2012 1:96.)

due to anorexia, nausea, and vomiting. These factors lead
to dehydration and a reduction in GFR.106 An impair-
ment in renal function, in turn, limits the ability to excrete
the increased calcium load coming usually from bone and
accelerates the development of hypercalcemia. As a result,
the first goal of therapy is to correct volume depletion
(Fig. 64-3). It has typically been recommended to hydrate
patients with 0.9% NS (normal saline) at 200 to 500 mL/
hour intravenously. The initial rate and duration of fluid
administration should be determined by clinical signs of
dehydration, the duration and severity of hypercalcemia,
and underlying medical conditions, especially cardiovascu-
lar disease. After initial volume repletion and establishment
of adequate urine output, fluids can be continued at >100
mL/hour, but it is important to carefully monitor vital signs
and watch for signs of fluid overload, especially in cases
with existing comorbidities such as congestive heart failure
(CHF).106,107 While intravenous fluid administration can
transiently lower serum calcium concentrations on the order
of 1 to 1.5 mg/dL, additional therapies are required to lower
calcium further and to maintain the lower calcium levels.
It has been common practice to add loop diuretics, such
as furosemide at a dose of 20 to 40 mg intravenously, after
rehydration has been achieved to promote calcium excre-
tion through a forced saline diuresis. The concept is to take
advantage of the fact that sodium delivery to the distal tubule
promotes urinary calcium excretion and helps to accelerate
calcium clearance by the kidneys.1,106 However, LeGrand
and colleagues reviewed the literature on this topic and
argued that routine use of loop diuretics in the treatment
of MAHC was not helpful.108 Clearly, if loop diuretics are
given before adequate volume repletion, they run the risk of
prolonging dehydration and may actually impair the excre-
tion of a calcium load on this basis. Therefore, if diuretics
are to be used, their administration must be delayed until
volume status has been fully restored. In addition, they are
valuable in managing hypercalcemic patients who develop
fluid overload after aggressive fluid resuscitation.108
Inhibition of Bone Resorption
The majority of patients with MAHC are hypercalcemic
because of excessive bone resorption. Therefore, the main-
stay of therapy is the administration of powerful antiresorp-
tive agents, primarily bisphosphonates and denosumab.
However other agents, such as calcitonin, gallium nitrate,
and mithramycin have also been described to be helpful in
lowering calcium levels. In the sections that follow, we will
discuss the available agents for inhibiting bone resorption,
concentrating on the most clinically useful and available
agents, pamidronate, zolendronic acid, and Denosumab.
Calcitonin
Calcitonin is a peptide hormone secreted by the parafol-
licular cells of the thyroid gland that acts to inhibit osteo-
clast activity. It has been utilized as an antiresorptive
therapy for both hypercalcemia of malignancy and Paget’s

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SUGGESTED TREATMENT OF MALIGNANCY ASSOCIATED HYPERCALCEMIA
Intravenous saline
0.9% NS 200–500 ml/hr
[Determined by the volume status of the patient and the
duration and severity of hypercalcemia]
Furosemide
20–40 mg IV
[After rehydration has been achieved]
Pamidronate Denosumab
60–90 mg IV over a 2 hour period 120 mg SQ weekly for 4 weeks
in 50–200 ml of saline or and then every 4 weeks
5% dextrose in water
Or
*Consider glucocorticoids
Zoledronate For example, prednisone 60 mg
4 mg IV over a 15 minute period orally daily for 10 days
in 50 ml of saline or In cases of lymphoma or elevated
5% dextrose in water 1,25 vitamin D levels
disease.106,107 It also has been shown to decrease the renal
tubular resorption of calcium, thus promoting renal cal-
cium excretion.109,110 The benefits of calcitonin are its rapid
action, but its limitations have been the rapid development
of tachyphylaxis and its relatively modest calcium-lowering
actions. Salmon calcitonin has a longer half-life in the cir-
culation than human calcitonin, and it is given as a subcu-
taneous or intramuscular injection at a dose of 4 to 8 IU
per kilogram every 12 hours.1 Administration of calcitonin
results in a rapid reduction in serum calcium concentrations
with a maximal response within 12 to 24 hours. However,
the reductions are small (approximately 1 mg/dL), and the
effects are usually lost within 48 to 96 hours, probably due
to the downregulation of calcitonin receptors.111 Neverthe-
less, it can be a valuable temporizing agent that can rap-
idly lower calcium levels acutely while waiting for the more
prolonged onset of other antiresorptive agents. This can be
an important initial therapy for patients in danger of dying
from extreme elevations in serum calcium levels.
Gallium Nitrate
Gallium nitrate was initially evaluated as a cancer chemo-
therapeutic, and patients receiving this treatment devel-
oped a positive calcium balance with reduced urinary
calcium excretion.112 The hypocalcemic effects result
from the inhibition of bone resorption.113 It is given as a
continuous intravenous infusion of 100 to 200 mg/m2 of
body surface area over a 24-hour period for 5 consecutive
days.1,106 Gallium nitrate can cause nephrotoxicity, and it
is important that adequate urine output be maintained on
this therapy.114 In one study comparing gallium nitrate
treatment to treatment with calcitonin, 18 of 24 patients
receiving gallium nitrate achieved normocalcemia, and
the median duration of normocalcemia was 6 days.114
In another study comparing gallium nitrate therapy to
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64  HYPERCALCEMIA OF MALIGNANCY 1133
*Consider calcitonin
4–8 IU/kg SQ/IM every
12 hours × 48–72 hrs
In conditions of altered
consciousness or
Ca >15 mg/dL
Figure 64-3  Suggested treatment for
malignancy-associated hypercalcemia.
treatment with etidronate, 28 of 34 patients (82%) who
received gallium nitrate achieved normocalcemia, and the
median duration of normocalcemia was 8 days.113
Mithramycin
Mithramycin, otherwise known as plicamycin, is an antibi-
otic agent that was initially used to treat testicular neoplasms
and was found to lower serum calcium levels.115 It was
utilized for the treatment of hypercalcemia of malignancy
prior to the introduction of bisphosphonates. It interferes
with osteoclastic function and can reduce serum calcium
levels within 24 hours.116 It is given as a single dose of 25
mcg/kg of body weight over a 4- to 6-hour period in saline.1
Its side effects include thrombocytopenia, platelet defects
resulting in bleeding diathesis, azotemia, proteinuria, and
hepatic toxicity.117 It is rarely, if ever, used currently.
Bisphosphonates
Bisphosphonates are the most commonly used medica-
tions to treat MAHC in the United States. These drugs
are analogues of pyrophosphates, which resist enzymatic
hydrolysis and have a high affinity for hydroxyapatite.118
Bisphosphonates concentrate at areas of high bone turn-
over and inhibit osteoclast function. Most patients are
treated either with pamidronate (aminohydroxy-propyl-
idene bisphosphonate) or zoledronate (zolendronic acid),
both potent nitrogen-containing bisphosphonates that
interfere with protein prenylation through the inhibition
of the mevalonate pathway enzyme, farnesyl disphosphate
synthase, which is downstream of HMG-CoA reductase.
These medications inhibit osteoclast function by inducing
apoptosis.118 The standard dose of pamidronate is 60 to 90
mg given intravenously over a 2-hour period in a solution
of 50 to 200 mL of saline or 5% dextrose in water.1,119
Zoledronate is given as a 4-mg intravenous infusion over
1134 PART 6  PARATHYROID GLAND, CALCIOTROPIC HORMONES, AND BONE METABOLISM
15 minutes in a solution of 50 mL of saline or 5% dex-
trose in water.1 The serum calcium level normalizes in
most patients, but the response can take 3 to 7 days and
last from 1 to 3 weeks. In one study examining the dose-
response to treatment with pamidronate in patients with
MAHC, corrected serum calcium normalized in 61% of
patients receiving 60 mg and 100% of patients receiving
90 mg.119 The mean duration of normalization in these two
groups was 13.3 and 10.8 days in the 60-mg and 90-mg
treatment groups, respectively.119 One study, which was
a pooled analysis from two randomized, double-blind,
parallel-group trials, showed that zolendronate was more
effective at normalizing serum calcium levels in patients
with HCM, with a significantly longer time to relapse than
pamidronate.120,121
In this study, two treatment doses of zoledronic acid, 4
mg and 8 mg, were compared to 90 mg of pamidronate. The
complete response rates were 88.4%, 86.7%, and 69.7%,
respectively.121 The corrected serum calcium normalized
by day 4 in 50% of the zoledronic acid-treated patients and
33.3% of the pamidronate-treated patients.121 The median
duration of complete response was 32 and 43 days in those
treated with 4 mg or 8 mg of zoledronic acid, respectively,
and 18 days in those treated with pamidronate.121
The dosing interval is every 3 to 4 weeks, depending on
the recurrence of hypercalcemia. There may be a reduction
in efficacy with repeated dosing. The intravenous bisphos-
phonates are excreted unchanged by the kidneys and must
be adjusted for impaired renal function. The most com-
mon adverse effects are renal failure and 24 to 48 hours
of transient flulike symptoms, including fever, aches, and
chills precipitated by the initial infusion. The fever is often
mild and usually occurs only with the first infusion.
In addition to the acute treatment of MAHC, bisphos-
phonates are now routinely given to patients with
myeloma and breast cancer in order to prevent the occur-
rence of SREs, including hypercalcemia. A recent com-
prehensive meta-analaysis demonstrated that treatment
of women with breast cancer and bone metastases with
regular infusions of bisphosphonates reduced the over-
all rate of SRE’s by 15% in randomized trials and also
delayed the onset of the first SRE in patients.95 However,
this treatment did not prolong survival, and adjuvant
treatment of breast cancer without bone metastases was
not associated with enhanced survival.122
Denosumab
Denosumab is the most recent antiresorptive therapy to be
approved for the treatment of MAHC. It is a humanized
monoclonal antibody that binds to RANKL and prevents it
from binding to the receptor RANK on osteoclast precur-
sors and mature osteoclasts. This leads to the inhibition of
the differentiation, activation, and function of osteoclasts
which, in turn, leads to a reduction in bone resorption.123 It
has a profound suppressive effect on biochemical markers
of bone resorption and is the most powerful antiresorptive
agent currently available.124 Denosumab is cleared through
the reticuloendothelial system, independent from the kid-
neys.123 The lack of renal toxicity makes it an attractive
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treatment option in patients with impaired renal function,
who cannot tolerate bisphosphonates. Hypocalcemia is
one of the main adverse effects of denosumab. Patients in
the Freedom trial also had a slightly increased incidence of
skin infections as compared to patients treated with pla-
cebo.125 In the denosumab group, 0.3% reported serious
adverse events of cellulitis, as compared with <0.1% in the
placebo group (P = .002).125
Denosumab has been shown to prevent SREs or hyper-
calcemia of malignancy in phase III studies of advanced
malignancies.126-128 Compared with monthly infusions of
zolendronate, administration of denosumab was associ-
ated with an 18% reduction in the risk for SREs127 and a
70% success rate in normalization of serum calcium levels
in a small study.129 It also appears that Denosumab may
be useful in patients with MAHC who do not respond to
bisphosphonates. In a recent study by Hu and coworkers,
patients with hypercalcemia of malignancy refractory to
bisphosphonate treatment received subcutaneous deno-
sumab on days 1, 8, 15, and 29, and then every 4 weeks
at a dose of 120 mg given as a subcutaneous injection.130
In this study, by day 10, 12/15 patients had responded
with albumin-corrected serum calcium levels (CSC) <11.5
mg/dL, and the median duration of response was 26 days.
In 10 of 15 patients, the CSC was <10.8 mg/dL.130
Glucocorticoids
Glucocorticoids can be an effective treatment for hyper-
calcemia associated with an overproduction of 1,25(OH)2
vitamin D in patients with lymphoma.106 This is likely
due to the ability of glucocorticoids to suppress local
cytokine production resulting in the suppression of 1,25
vitamin D production through a reduction in vitamin D
1α-hydroxylase activity.107 Treatment can consist of 60 mg/
day of prednisone for 10 days.1 This treatment can interfere
with some chemotherapeutic agents, and treatment can be
associated with hypokalemia, hyperglycemia, hyperten-
sion, Cushing’s syndrome, and immunosuppression.1
Dialysis
Patients with hypercalcemia and acute kidney injury with
oliguria may require dialysis to lower their calcium lev-
els. In these patients, a saline diuresis is not possible and
could lead to significant fluid overload. Hemodialysis or
peritoneal dialysis utilizing a very low calcium or cal-
cium-free dialysate is implemented in such situations.106
It can result in a rapid decrease in serum total calcium
levels.131
Acknowledgement
This work was supported by NIH Grants DK55501 and
CA153702 to JW and NIH Grant CA153702-09S1 to KS.
  
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