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Information from PDQ -- for Health Professionals
Hypercalcemia
208/04462
** OVERVIEW **
Hypercalcemia is the most common life-threatening metabolic disorder associated
with neoplastic diseases, occurring in an estimated 10% to 20% of all persons
with cancer. Solid tumors (such as lung or breast cancer) as well as certain
hematologic malignancies (particularly multiple myeloma) are most frequently
associated with hypercalcemia.[1] Although early diagnosis followed by
hydration and treatment with agents that decrease serum calcium concentrations
(hypocalcemic drugs) can produce symptomatic improvements within a few days,
diagnosis may be complicated because symptoms may be insidious at onset and can
be confused with those of many malignant and nonmalignant diseases. It should
be emphasized, however, that diagnosis and timely interventions are not only
lifesaving in the short term, but also may enhance the patient's compliance
with primary and supportive treatments and may improve quality of life.[2]
When a patient has a refractory, widely disseminated malignancy for which
specific therapy is no longer being pursued, the patient may want to consider
withholding therapy for hypercalcemia. For patients or family who have
expressed their wishes regarding end-of-life issues, this may represent a
preferred timing and/or mode of death (as compared to a more prolonged death
from advancing metastatic disease). This option is best considered long before
the onset of severe hypercalcemia or other metabolic abnormalities that impair
cognition, so that the patient may be involved in the decision-making.
-- Normal calcium homeostasis --
Hormonal influences
Calcium homeostasis is maintained by two hormones, parathormone (parathyroid
hormone or PTH) and calcitriol (1,25-dihydroxy vitamin D). Minute-to-minute
regulation of serum ionized calcium is regulated by PTH. PTH secretion is
stimulated when ambient serum ionized calcium is decreased. PTH acts on
peripheral target cell receptors, increasing the efficiency of renal tubular
calcium reabsorption. In addition, PTH enhances calcium resorption from
mineralized bone and stimulates conversion of vitamin D to its active form,
calcitriol, which subsequently increases intestinal absorption of calcium and
phosphorus. Pharmacologic doses of calcitonin act as an antagonist to PTH,
lowering serum calcium and phosphorus, and inhibiting bone reabsorption.
Renal function
Normal, healthy kidneys are capable of filtering large amounts of calcium that
is subsequently reclaimed by tubular reabsorption. The kidneys are capable of
increasing calcium excretion nearly fivefold to maintain homeostatic serum
calcium concentrations. However, hypercalcemia may occur when the
concentration of calcium present in the extracellular fluid overwhelms the
kidneys' compensatory mechanisms.
Although calcium reabsorption is linked to sodium and fluid reabsorption in the
proximal renal tubules, fine regulation occurs in the distal renal tubules
primarily under the influence of PTH. Tumors that are capable of producing a
substance similar to normal PTH such as PTH-related peptide (see "Mechanisms of
cancer-associated hypercalcemia", below) drive the renal tubules to increase
calcium reabsorption. Under these circumstances, hypercalcemia and high
calcium concentrations in urine (hypercalciuria) impair sodium and water
reabsorption, causing polyuria (a "calcium diuresis") with subsequent loss of
circulating fluid volume (dehydration). As a consequence of dehydration, renal
blood flow and the glomerular filtration rate decrease and proximal tubular
calcium and sodium reabsorption increase leading to further increases in serum
calcium concentrations. Anorexia, nausea, and vomiting associated with
circulating volume contraction exacerbate dehydration.[3] Immobilization
caused by weakness and lethargy may exacerbate calcium resorption from bone.
The kidneys may be irreversibly compromised if the concentration of calcium in
the glomerular filtrate exceeds its solubility, resulting in calcium
precipitation in the renal tubules (nephrocalcinosis).
Bone resorption
In healthy adults before midlife, bone formation and resorption are in dynamic
balance primarily through the activity of osteoblasts (bone-forming cells) and
osteoclasts (bone-reabsorbing cells). Even though 99% of total body calcium is
contained in bone, bone seems to have a minor function in the daily maintenance
of plasma calcium levels. The normal daily exchange between bone and
extracellular fluid is quite small.[4]
-- Mechanisms of cancer-associated hypercalcemia --
The fundamental cause of cancer-induced hypercalcemia is increased bone
resorption with calcium mobilization into the extracellular fluid and
secondarily, inadequate renal calcium clearance. Two types of cancer-induced
hypercalcemia have been described: osteolytic and humoral hypercalcemia.
Osteolytic hypercalcemia is due to direct bone destruction by primary or
metastatic tumor. Humoral hypercalcemia is mediated by circulating factors
secreted by malignant cells without evidence of bony disease.[5,6] It is now
believed that hypercalcemia is due to the release of factors by malignant cells
that ultimately cause calcium reabsorption from bone.[1]
One such factor is a PTH-like protein known as parathyroid hormone-related
protein or peptide (PTHrP). PTHrP is a primitive protein that appears to have
important roles in calcium transport and developmental biology. It shares
partial amino acid sequence and conformational homology with normal PTH, binds
with the same receptors on skeletal and renal target tissues, and affects
calcium and phosphate homeostasis as does PTH.[6-8] Increased blood levels of
PTHrP have been found in patients with solid tumors, but not in patients with
hematologic malignancies who develop hypercalcemia.[1]
Circulating growth factors may also mediate hypercalcemia. Potential mediators
include transforming growth factor (TGF) alpha and beta, interleukin-1, tumor
necrosis factors (TNF) alpha and beta, and interleukin-6.[9]
-- Potentiating factors --
Immobility is associated with an increase in resorption of calcium from bone.
Dehydration, anorexia, nausea, and vomiting that exacerbate dehydration reduce
renal calcium excretion.
Hormonal therapy (estrogens, antiestrogens, androgens, and progestins) may
precipitate hypercalcemia. Thiazide diuretics increase renal calcium
reabsorption and may precipitate or exacerbate hypercalcemia.[10]
Hematologic malignancies may stimulate osteoclastic bone resorption through the
production of cytokines such as TNF (alpha and beta) and interleukins 1 and 6,
formerly referred to as osteoclast-activating factor(s).[4,6,11]
References:
1. Warrell RP Jr: Metabolic emergencies. In: DeVita VT Jr, Hellman S,
Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology.
Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp
2486-2493.
2. Theriault RL: Hypercalcemia of malignancy: pathophysiology and
implications for treatment. Oncology (Huntington NY) 7(1): 47-50, 1993.
3. Mundy GR, Ibbotson KJ, D'Souza SM, et al.: The hypercalcemia of cancer:
clinical implications and pathogenic mechanisms. New England Journal of
Medicine 310(26): 1718-1727, 1984.
4. Mundy GR: Pathophysiology of cancer-associated hypercalcemia. Seminars
in Oncology 17(2, Suppl 5): 10-15, 1990.
5. Mundy GR, Martin TJ: Hypercalcemia of malignancy: pathogenesis and
management. Metabolism 31(12): 1247-1277, 1982.
6. Broadus AE, Mangin M, Ikeda KL, et al.: Humoral hypercalcemia of cancer:
identification of a novel parathyroid hormone-like peptide. New England
Journal of Medicine 319(9): 556-563, 1988.
7. Horiuchi N, Caufield MP, Fisher JE, et al.: Similarity of synthetic
peptide from human tumor to parathyroid hormone in vivo and in vitro.
Science 248(4833): 1566-1568, 1987.
8. Suva LJ, Winslow GA, Wettenhall RE, et al.: A parathyroid hormone-related
protein implicated in malignant hypercalcemia: cloning and expression.
Science 237(4817): 893-896, 1987.
9. Dodwell DJ: Malignant bone resorption: cellular and biochemical
mechanisms. Annals of Oncology 3(4): 257-267, 1992.
10. Coleman RE: Bisphosphonate treatment of bone metastases and hypercalcemia
of malignancy. Oncology (Huntington NY) 5(8): 55-60, 1991.
11. Warrell RP: Etiology and current management of cancer-related
hypercalcemia. Oncology (Huntington NY) 6(10): 37-43, 1992.
** INCIDENCE BY CANCER TYPE **
Hypercalcemia occurs more frequently in some malignancies (e.g., squamous cell
cancers of the lung, head, neck, and esophagus) than in others. Within each
disease type, the incidence of hypercalcemia varies greatly in reported series.
The frequency of hypercalcemia in some of the commonly involved neoplastic
disorders is shown in Table 1 below.
===============================================================================
-------------------------------------------------------------------------------
Table 1. Incidence of Hypercalcemia by Tumor Type *
------------------------------------------------------------------------------
Tumor Type Percentage of Patients
Who Develop Hypercalcemia
------------------------------------------------------------------------------
lung 27.3%
breast 25.7%
multiple myeloma 7.3%
head and neck 6.9%
unknown primary 4.7%
lymphoma/leukemia 4.3%
renal 4.3%
gastrointestinal 4.1%
-------------------------------------------------------------------------------
* Adapted from Lang-Kummer.[1]
-------------------------------------------------------------------------------
===============================================================================
References:
1. Lang-Kummer J: Hypercalcemia. In: Groenwald SL, Goodman M, Frogge MH,
et al., eds.: Cancer Nursing: Principles and Practice. 4th ed. Sudbury,
Mass: Jones and Bartlett Publishers, 1997, pp 684-701.
** MANIFESTATIONS **
There is little correlation between the presenting symptoms of hypercalcemia
and serum calcium concentrations. Rapid diagnosis of hypercalcemia may be
complicated because symptoms associated with hypercalcemia are
characteristically nonspecific and are easily attributed to chronic or terminal
illness.[1,2] Symptom severity may be due in part to confounding factors such
as previous cancer treatment, drug-disease state interactions, or comorbid
pathologies.
Few patients experience all the symptoms that have been associated with
hypercalcemia (see Table 2 below), and some patients may not experience any.
Patients with corrected total serum calcium concentrations greater than 14
mg/dL (>7.0 mEq/L or 3.49 mmol/L) are generally symptomatic.[1] It must be
emphasized that clinical manifestations are closely related to the rapidity of
hypercalcemia onset. Some patients develop signs and symptoms when calcium is
only slightly elevated, while others with long-standing hypercalcemia may
tolerate serum calcium levels greater than 13 mg/dL (>6.5 mEq/L or 3.24 mmol/L)
with few symptoms. Neuromuscular manifestations are generally more marked in
elderly than in young individuals.
One author observed that malaise and fatigue were the most common complaints at
patient presentation, followed (in order of decreasing prevalence rate) by
varying degrees of obtundation, anorexia, pain, polyuria-polydipsia,
constipation, nausea, or vomiting.[3]
===============================================================================
-------------------------------------------------------------------------------
Table 2. Symptom prevalence among patients treated for hypercalcemia
of malignancy stratified by corrected serum total calcium
concentrations at presentation *
------------------------------------------------------------------------------
Serum Calcium Concentration
-------------------------------
Symptoms <3.5 mmol/L >/= 3.5 mmol/L
------------------------------------------------------------------------------
CNS symptoms 41% 80%
constipation 21% 25%
malaise-fatigue 65% 50%
anorexia 47% 59%
nausea and/or vomiting 22% 30%
polyuria and/or polydipsia 34% 35%
pain 51% 35%
-------------------------------------------------------------------------------
* Adapted from Ralston, Gallacher, Patel, et al.[3]
-------------------------------------------------------------------------------
===============================================================================
Clinical manifestations can be categorized according to body systems and
functions.
-- Neurologic symptoms --
Calcium ions have a major role in neurotransmission. Increased calcium levels
decrease neuromuscular excitability, which leads to hypotonicity in smooth and
striated muscle. Symptom severity correlates directly with the magnitude of
serum ionized calcium concentrations and inversely with their rate of change.
Neuromuscular symptoms include weakness and diminished deep tendon reflexes.
Muscle strength is impaired, and respiratory muscular capacity may be
decreased. Central nervous system impairment may manifest as delirium with
prominent symptoms of personality change, cognitive dysfunction,
disorientation, incoherent speech, and psychotic symptoms such as
hallucinations and delusions. Obtundation is progressive as serum calcium
concentrations increase and may progress to stupor or coma.[1,2] Local
neurologic signs are not common, but hypercalcemia has been documented to
increase cerebrospinal fluid protein, which may be associated with headache.
Headache can be exacerbated by vomiting and dehydration.[2] Abnormal
electroencephalograms are seen in patients with marked hypercalcemia.[1]
-- Cardiovascular symptoms --
Hypercalcemia is associated with increased myocardial contractility and
irritability. Electrocardiographic changes are characterized by slowed
conduction, including prolonged P-R interval, widened QRS complex, shortened
Q-T interval, S-T segments may be shortened or absent, and the proximal limb of
T waves may slope abruptly and peak early. Hypercalcemia enhances patients'
sensitivity to the pharmacologic effects of digitalis glycosides (e.g.,
digoxin). When serum calcium concentrations exceed 16 mg/dL (>8.0 mEq/L or
3.99 mmol/L), T waves widen, secondarily increasing the Q-T interval. As
calcium concentrations increase, bradyarrhythmias and bundle branch block may
develop. Incomplete or complete AV block may develop at serum concentrations
around 18 mg/dL (9.0 mEq/L or 4.49 mmol/L) and may progress to complete heart
block, asystole, and cardiac arrest.[1,2]
-- Gastrointestinal symptoms --
Gastrointestinal symptoms are probably related to the depressive action of
hypercalcemia on the autonomic nervous system and resulting smooth muscle
hypotonicity. Increased gastric acid secretion often accompanies hypercalcemia
and may intensify gastrointestinal manifestations. Anorexia, nausea, and
vomiting are intensified by increased gastric residual volume. Constipation is
aggravated by dehydration that accompanies hypercalcemia. Abdominal pain may
progress to obstipation and can be confused with acute abdominal obstruction.
-- Renal symptoms --
Hypercalcemia causes a reversible tubular defect in the kidney resulting in the
loss of urinary concentrating ability and polyuria. Decreased fluid intake and
polyuria lead to symptoms associated with dehydration, including thirst, dry
mucosa, diminished or absent sweating, poor skin turgor, and concentrated
urine. Decreased proximal reabsorption of sodium, magnesium, and potassium
occur as a result of salt and water depletion that is caused by cellular
dehydration and hypotension. Renal insufficiency may occur as a result of
diminished glomerular filtration, a complication observed most often in
patients with myeloma.
Although nephrolithiasis and nephrocalcinosis are usually not associated with
hypercalcemia of malignancy, calcium phosphate crystals can precipitate within
renal tubules to form renal calculi as a consequence of long-standing
hypercalciuria. When they occur, coexisting primary hyperparathyroidism should
be considered.
-- Bone symptoms --
Hypercalcemia of malignancy can result from osteolytic metastases or
humerally-mediated bone resorption with secondary fractures, skeletal
deformities, and pain.
References:
1. Bajorunas DR: Clinical manifestations of cancer-related hypercalcemia.
Seminars in Oncology 17(2, Suppl 5): 16-25, 1990.
2. Mahon SM: Signs and symptoms associated with malignancy-induced
hypercalcemia. Cancer Nursing 12(3): 153-160, 1989.
3. Ralston SH, Gallacher SJ, Patel U., et al.: Cancer-associated
hypercalcemia: morbidity and mortality. Clinical experience in 126
treated patients. Annals of Internal Medicine 112(7): 499-504, 1990.
** ASSESSMENT **
-- Laboratory assessment --
Normal serum calcium levels are maintained within narrow and constant limits,
approximately 9.0 to 10.3 mg/dL (= 4.5-5.2 mEq/L or 2.25-2.57 mmol/L) for men
and 8.9 to 10.2 mg/dL (= 4.4-5.1 mEq/L or 2.22-2.54 mmol/L) for women.
Symptoms of hypo- or hypercalcemia are due to abnormalities in the ionized
fraction of the plasma calcium concentration. However, ionized calcium levels
are rarely done routinely in clinical laboratories. The total plasma calcium
is used to infer the ionized calcium fraction and is usually accurate except in
the setting of hypoalbuminemia. Since hypoalbuminemia is not uncommon among
patients with cancer, it is necessary to "correct" the total plasma calcium
concentration for the percent of calcium that would have been measured if the
albumin level were within normal range. The calculation is as follows:
TOTAL SERUM CALCIUM CORRECTED FOR ALBUMIN LEVEL
((normal albumin - patient's albumin) x 0.8) + patient's measured total calcium
This calculated value is fairly accurate, except in the presence of elevated
serum paraproteins, such as in multiple myeloma. In this case, laboratory
measurement of the actual ionized calcium concentration may be necessary.[1]
Calcium also binds to globulins in blood. In contrast with hypoalbuminemia,
hypogammaglobulinemia has a relatively small effect on calcium protein binding.
Serum total calcium concentration can be corrected for changes in globulins as
follows: total serum calcium concentration varies directly by 0.16 mg/dL, 0.08
mEq/L, or 0.04 mmol/L with each 1 g/dL change in globulin concentration. In
clinical practice, changes in serum globulin concentrations rarely effect
clinically significant changes in the ionized calcium fraction.
Acid-base status also affects the interpretation of serum calcium values.
While acidosis decreases the protein-bound fraction (consequently increasing
the ionized calcium fraction), alkalosis increases protein binding. Serum
total calcium concentration can be corrected for changes in pH as follows:
total serum calcium concentration varies inversely by 0.12 mg/dL, 0.06 mEq/L,
or 0.03 mmol/L with each 0.1 unit change in pH. Unlike changes in serum
albumin concentration, alterations in blood pH rarely effect clinically
significant changes in the ionized calcium fraction.[2]
Laboratory studies:
It is important to measure the serum calcium and albumin concentrations. There
are other selected tests (as shown below) which may be useful in some
instances:
- Blood urea nitrogen and creatinine concentrations (renal function)
- Immunoreactive parathormone (iPTH)
- iPTH concentration is increased or rarely normal in hyperparathyroid
disease; iPTH is typically decreased or undetectable in hypercalcemia
of malignancy
- Parathormone-related peptide (PTHrP; if available)
- Serum 1,25-dihydroxy vitamin D concentration in patients with hematologic
malignancies
- Other serum electrolyte concentrations (phosphate, magnesium)
-- Patient assessment --
Primary assessment should include the following:[3,4]
History:
- How rapidly have symptoms developed? Symptoms of malignancy are usually
present when hypercalcemia is due to cancer. Rapid symptom onset is more
typical of hypercalcemia of malignancy than hypercalcemia associated with
hyperparathyroidism and other diseases.
- Is there radiographic evidence of primary or metastatic bony disease?
- Has the patient recently received treatment with tamoxifen or estrogenic
or androgenic steroids?
- Is the patient taking digoxin?
- Is there an exogenous calcium source such as intravenous fluids or
parenteral nutrition?
- Is the patient receiving thiazide diuretics, vitamins A or D, or
lithium?
- Is there concurrent disease predisposing to dehydration or
immobility?
- Are there potentially effective treatments for the patient's underlying
malignancy?
Clinical status (refer to the Manifestations of Hypercalcemia section above):
- Neuromuscular (evaluate muscular strength, muscle tone, decreased deep
tendon reflexes)
- Neurologic (fatigue, apathy, depression, confusion, restlessness)
- Cardiovascular (hypertension, EKG changes, arrhythmias, digitalis
toxicity)
- Renal (urine output polyuria, nocturia, glucosuria, polydipsia)
- Gastrointestinal (anorexia, nausea, abdominal pain, constipation,
decreased bowel sounds, abdominal distention)
- Miscellaneous (musculoskeletal pain, pruritus)
-- Decision to treat hypercalcemia --
The decision to correct clinical hypercalcemia must be considered within the
context of therapeutic goals as determined by the patient, the caregivers, and
the medical staff. The natural course of untreated hypercalcemia is well known
to clinicians: as with hepatic or metabolic encephalopathy, untreated
hypercalcemia will progress to loss of consciousness and coma. This clinical
course may be desirable at the end of life in patients with intractable
suffering and/or unmanageable symptoms where no further active treatment is
available or desired for reversal of the primary disease process.
References:
1. Beers MH, Berkow R, eds.: The Merck Manual of Diagnosis and Therapy.
17th ed., Whitehouse Station, NJ: Merck Research Laboratories, 1999.
2. Bajorunas DR: Clinical manifestations of cancer-related hypercalcemia.
Seminars in Oncology 17(2, Suppl 5): 16-25, 1990.
3. Calafato A, Jessup AL: Body fluid composition, alteration in:
hypercalcemia. In: McNally JC, Somerville ET, Miaskowski C, et al.,
eds.: Guidelines for Oncology Nursing Practice. Philadelphia: WB
Saunders Company, 2nd Edition, 1991, pp 397-401.
4. Coward DD: Hypercalcemia knowledge assessment in patients at risk of
developing cancer-induced hypercalcemia. Oncology Nursing Forum 15(4):
471-476, 1988.
** MANAGEMENT **
-- Prevention --
Individuals at risk of developing hypercalcemia may be the first to recognize
symptoms such as fatigue. Patients should be advised about the ways in which
hypercalcemia most frequently manifests itself and should also be given
guidelines for seeking professional intervention. Preventive measures include
ensuring adequate fluid 3 to 4 L (100-140 fl. oz.) per day if not
contraindicated) and salt intake, nausea and vomiting control, encouraging
patient mobility, attention to febrile episodes, and cautious use or
elimination of drugs that may complicate management. This includes drugs that
inhibit urinary calcium excretion or decrease renal blood flow, as well as
medications that contain calcium, vitamin D, vitamin A, or other retinoids.[1]
Even though the gut has a role in normal calcium homeostasis, absorption is
usually diminished in individuals with hypercalcemia, making dietary calcium
restriction unnecessary.
-- Managing hypercalcemia --
Symptomatic treatment of hypercalcemia focuses first on correcting dehydration
and enhancing renal calcium excretion, followed by specific hypocalcemic
treatment with agents that inhibit bone resorption (e.g., calcitonin,
bisphosphonates, gallium nitrate, and plicamycin).[2,3] Definitive treatment
is that which effectively treats the malignant disease underlying
hypercalcemia.[4] At one time, hypercalcemia was treated with aggressive
intravenous hydration using isotonic saline followed by the administration of a
diuretic. This volume expansion and natriuresis was done to increase renal
blood flow and enhance calcium excretion. This approach is not very effective
in correcting hypercalcemia and can lead to complications of fluid overload.
Intravenous fluid should be administered to correct water loss associated with
calciuresis and dehydration due to vomiting. Administration of diuretics
should be restricted to balancing urine output in patients that have been
adequately rehydrated.[1]
The magnitude of hypercalcemia and the severity of symptoms is typically the
basis for determining whether treatment is indicated. Immediate aggressive
hypocalcemic treatment is warranted in patients with a corrected total serum
calcium greater than 14 mg/dL (>7 mEq/L or 3.5 mmol/L). In patients with total
corrected serum calcium concentration between 12 and 14 mg/dL (6-7 mEq/L or
3.0-3.5 mmol/L), clinical manifestations should guide the type of therapy and
the urgency with which it is implemented.[2] Treatment response is indicated
by resolution of symptoms attributable to hypercalcemia and by diminishing
serum calcium concentrations and urinary calcium and hydroxyproline excretion.
Aggressive treatment is not generally indicated in patients with mild
hypercalcemia (corrected total serum calcium <12 mg/dL (<6 mEq/L or 3.0
mmol/L)). Clear treatment decisions are problematic for patients with mild
hypercalcemia and coexistent central nervous system symptoms, especially for
younger patients in whom hypercalcemia is generally better tolerated. It is
very important to evaluate other causes for altered central nervous system
function before attributing them solely to hypercalcemia.[2]
Treatment can provide marked improvement of distressing symptoms. Polyuria,
polydipsia, central nervous system symptoms, nausea, vomiting, and constipation
are more likely to be managed successfully than are anorexia, malaise, and
fatigue. Pain control may be improved for some patients who achieve
normocalcemia.[5] Effective calcium-lowering therapy usually improves
symptoms, enhances the quality of life, and may allow patients to be managed in
a subacute, ambulatory, or home care setting.
After normocalcemia is achieved, serum calcium should be monitored serially
with the frequency determined by anticipated response duration for any
particular hypocalcemic regimen.
-- Mild hypercalcemia --
Corrected total serum calcium <12 mg/dL (<6 mEq/L or 3.0 mmol/L).
Hydration followed by observation is an option. This option should be
considered for asymptomatic patients who are about to be treated for tumors
that are likely to respond to antineoplastic treatment (e.g., lymphoma, breast
cancer, ovarian cancer, head and neck carcinoma, and multiple myeloma).[6]
In symptomatic patients, or when tumor response to therapy is expected to occur
slowly, therapy for hypercalcemia should be implemented to manage symptoms and
stabilize patients' metabolic states. Additional ancillary interventions
should be directed toward nausea and vomiting control, encouraging mobility,
attention to febrile episodes, and minimal use of sedating medications.[6]
-- Moderate to severe hypercalcemia --
Corrected total serum calcium equal to 12-14 mg/dL (6-7 mEq/L or 3.0-3.5
mmol/L).
Rehydration is the essential first step in treating moderate or severe
hypercalcemia. Although fewer than 30% of patients achieve normocalcemia with
hydration alone, replenishing extracellular fluid, restoring intravascular
volume, and saline diuresis are fundamental to initial therapy. Adequate
rehydration may require 3,000 to 6,000 mL of 0.9% sodium chloride for injection
(normal saline) within the first 24 hours to restore fluid volume. Restoring
normal extracellular fluid volume will increase daily urinary calcium excretion
by 100 to 300 mg. Clinical improvement in mental status and nausea and
vomiting is usually apparent within 24 hours for most patients; however,
rehydration is a temporizing intervention. If definitive cytoreductive
therapies (surgery, radiation, or chemotherapy) are not forthcoming,
hypocalcemic agents must be used to achieve long-term control.
Thiazide diuretics increase renal tubular calcium absorption and may exacerbate
hypercalcemia. Thus, thiazide diuretics are contraindicated in hypercalcemia
patients. Loop diuretics (e.g., furosemide, bumetanide, and ethacrynic acid)
induce hypercalciuria by inhibiting calcium reabsorption in the ascending limb
of the loop of Henle, but should not be administered until volume expansion is
achieved. Otherwise, loop diuretics can exacerbate fluid loss, further
reducing calcium clearance. Because sodium and calcium clearance are closely
linked during osmotic diuresis, loop diuretics will depress the proximal
tubular resorptive mechanisms for calcium, increasing calcium excretion to 400
to 800 mg/day.
Moderate doses of furosemide (20-40 mg every 12 hours) increase saline-induced
urinary calcium excretion and are useful in preventing or managing fluid
overload in adequately rehydrated patients. Aggressive treatment with
furosemide (80-100 mg every 2-4 hours) is problematic because it requires
concurrent administration of large volumes of saline to prevent intravascular
dehydration.[7] This in turn requires intensive hemodynamic monitoring to
avoid volume overload and cardiac decompensation as well as frequent serial
urinary volume and electrolytes measurements to prevent life-threatening
hypophosphatemia, hypokalemia, and hypomagnesemia.[6,8]
-- Pharmacologic inhibition of osteoclastic bone resorption --
Described below are therapies that can inhibit osteoclastic bone resorption.
The most widely used modality for this purpose is a bisphosphonate (such as
pamidronate). The use of other agents, such as calcitonin, mithramycin, or
gallium nitrate, is less common.
Bisphosphonates
Bisphosphonates are one of the most effective pharmacologic alternatives for
controlling hypercalcemia. They bind to hydroxyapatite in calcified bone,
rendering it resistant to hydrolytic dissolution by phosphatases, thereby
inhibiting both normal and abnormal bone resorption.[9] Bisphosphonate
treatment reduces the number of osteoclasts in sites undergoing active bone
resorption and may prevent osteoclast expansion by inhibiting differentiation
from their monocyte-macrophage precursors.[10] Bisphosphonates have variable
effects on other aspects of bone remodeling such as new bone formation and
mineralization. For example, etidronate at clinically relevant dosages
(300-1,600 mg/day) inhibits new bone formation and mineralization.[11] With
prolonged etidronate use, osteomalacia and pathologic fractures may
occur.[12,13] In contrast, clodronate, pamidronate, and alendronate are 10,
100, and 1000 times more potent inhibitors of bone resorption than etidronate,
and are clinically useful at dosages that are less likely to adversely affect
new bone formation and mineralization.[14-17] Clinicians should note that many
bisphosphonates may be useful in treating hypercalcemia of malignancy In the
United States, etidronate and pamidronate are the only bisphosphonates approved
for treating hypercalcemia.
In a randomized, double blind study comparing pamidronate with etidronate for
the treatment of cancer-related hypercalcemia, pamidronate (60 mg given
intravenously as a single dose over 24 hours) has been demonstrated to be more
effective with respect to serum calcium reduction and duration of hypocalcemic
response than etidronate (7.5 mg/kg body weight per day administered over 2
hours as a daily intravenous infusion for 3 consecutive days).[18] This has
led to the diminished use of etidronate.[1]
In treating moderate hypercalcemia (corrected serum calcium <13.5 mg/dL, <6.75
mEq/L, or <3.37 mmol/L), pamidronate 60 to 90 mg is administered intravenously
over 2 to 24 hours.[19] Onset of pamidronate's effect is apparent within 3 to
4 days, with maximal effect within 7 to 10 days after commencing treatment.
Duration of effect may persist for 7 to 30 days.[20] It is recommended that a
minimum of 7 days elapse prior to retreatment with pamidronate in order to
assess full response to the initial dose.[19] Adverse effects include
transient low-grade temperature elevations (1-2 degrees C) that typically occur
within 24 to 36 hours after administration and persist for up to 2 days in up
to 20% of patients. Other bisphosphonates (except clodronate) may also produce
transient temperature elevations; the incidence of temperature elevation,
nausea, anorexia, dyspepsia, and vomiting may be increased by rapid
administration.[21,22] New onset hypophosphatemia and hypomagnesemia may
occur; pre-existing abnormalities in the same electrolytes may be exacerbated
by treatment. Serum calcium may fall below the normal range, and hypocalcemia
(typically asymptomatic) may result. Renal failure has only been reported
after rapid etidronate and clodronate injection, but rapid administration
should be avoided with all bisphosphonates.[23] Intravenous pamidronate
administration has been associated with acute-phase responses, including
transiently decreased peripheral lymphocyte counts. Local reactions
(thrombophlebitis, erythema, and pain) at the infusion site have been
reported.[21]
Walker et al. has explored the use of subcutaneous administration of
clodronate. Initial experience suggested that clodronate was well tolerated
subcutaneously; however, aminobisphosphonates such as pamidronate resulted in
local irritation.[24] In a subsequent study, 37 inpatients with terminal
cancer received 45 clodronate infusions.[25] Clodronate, 1500 mg in one liter
of normal saline, was administered via a #23 gauge, 3/4 inch butterfly needle
in the subcutaneous space. All the infusions were completed, and none required
discontinuation due to discomfort. The authors concluded that their results
suggested that subcutaneous clodronate is an effective treatment for
hypercalcemia of malignancy and was associated with minimal toxicity. This
technique has advantages in the care of terminally ill patients at home and may
avoid the need for hospital admission and/or intravenous administration. In
addition, subcutaneous administration in the hospital setting has advantages
for patients for whom an intravenous site may be problematic.
Calcitonin and plicamycin have a more rapid hypocalcemic effect than
bisphosphonates, however pamidronate has several advantages over
nonbisphosphonate therapies. In comparison with plicamycin, response rates are
greater among patients treated with pamidronate.[26] Pamidronate more
frequently reduces serum calcium concentrations to normocalcemic ranges than
either calcitonin or plicamycin.[26,27] In addition, pamidronate's
hypocalcemic effect is dose-related and sustained after repeated
administration, and generally persists for durations longer than are produced
by either calcitonin or plicamycin therapies.[20] Pamidronate lacks the renal,
hepatic, and platelet toxic effects associated with plicamycin.
Calcitonin
Calcitonin is a peptide hormone secreted by specialized cells in the thyroid
and parathyroid. Its synthesis and secretion normally increase in response to
high serum ionized calcium concentrations. Calcitonin opposes physiologic
effects of parathyroid hormone on bone and renal tubular calcium resorption;
however, it is not known whether calcitonin has a significant role in calcium
homeostasis. Nevertheless, calcitonin rapidly inhibits calcium and phosphorous
resorption from bone and decreases renal calcium reabsorption. Calcitonin
derived from salmon is much more potent and has a longer duration of activity
than the human hormone. Initial dose schedule is 4 IU/kg body weight per dose,
administered subcutaneously or intramuscularly every 12 hours. Dose and
schedule may be escalated after 1 or 2 days to 8 IU/kg every 12 hours, and
finally to 8 IU/kg every 6 hours if the response to lower doses is
unsatisfactory. Unfortunately, tachyphylaxis commonly occurs. With repeated
use, calcitonin's beneficial hypocalcemic effect wanes, even at the upper
recommended limits of dose and schedule, so that its calcium-lowering effect
lasts for only a few days. In patients who are responsive to calcitonin, its
combination with bisphosphonates may hasten the onset and duration of a
hypocalcemic response due to calcitonin's rapid (2-4 hours) onset of
action.[28,29]
Calcitonin is usually well-tolerated; adverse effects include mild nausea,
transient cramping abdominal pain, and cutaneous flushing. Calcitonin is most
useful within the first 24 to 36 hours of treatment of severe hypercalcemia and
should be used in conjunction with more potent but slower-acting agents.
Plicamycin
Plicamycin (also referred to as mithramycin) is an inhibitor of osteoclast RNA
synthesis. It has been shown to inhibit bone resorption in vitro and is
clinically effective in the presence or absence of bone metastases. Onset of
response occurs within 12 hours of a single intravenous dose of 25 to 30 ug/kg
of body weight given as a short infusion for 30 minutes or longer. Maximum
response, however, does not occur until approximately 48 hours after
administration and may persist for 3 to 7 days or more after administration.
Repeated doses may be given to maintain plicamycin's hypocalcemic effect but
should not be given more frequently than every 48 hours, in order to determine
the maximum calcium-lowering effect produced by previous doses.[30] Multiple
doses may control hypercalcemia for several weeks, but rebound hypercalcemia
usually occurs without definitive treatment against the underlying
malignancy.[31] Although single-dose treatment of hypercalcemia is generally
well-tolerated with few adverse effects,[32] dysfibrinogenemia [33] and
nephrotoxicity [34] have been reported after single doses (20-25 ug/kg). Rapid
intravenous administration is associated with nausea and vomiting.[31] High
and repeated doses predispose the patient to thrombocytopenia, a qualitative
platelet dysfunction that may be associated with a bleeding diathesis,
transient increases in hepatic transaminases, nephrotoxicity (decreased
creatinine clearance, increased serum creatinine and BUN, potassium wasting,
and proteinuria), hypophosphatemia, a flu-like syndrome, dermatologic
reactions, and stomatitis.[31,34-39]
Gallium nitrate
Gallium nitrate was developed as an antineoplastic agent that was
coincidentally found to produce a hypocalcemic effect. Gallium nitrate
interferes with an adenosine triphosphatase-dependent proton pump in the
membrane of osteoclasts. This impairs osteoclast acidification and the
dissolution of the underlying bone matrix.[1] Gallium nitrate has been shown
to be superior to etidronate in the percentage of patients who achieve
normocalcemia and in the duration of normocalcemia.[40] Drawbacks to its use
include a continuous 5-day intravenous infusion schedule (200 mg/square meter
body surface area/day) [6] and the potential for nephrotoxicity, particularly
when used concurrently with other potentially nephrotoxic drugs (e.g.,
aminoglycosides and amphotericin B).[1]
Gallium nitrate has also been given by daily subcutaneous injection to prevent
bone resorption and maintain bone mass in patients with multiple myeloma.[41]
-- Other therapeutics for hypercalcemia --
Glucocorticoids
Glucocorticoids have efficacy as hypocalcemic agents primarily in
steroid-responsive tumors (e.g., lymphomas and myeloma) and in patients whose
hypercalcemia is associated with increased vitamin D synthesis or intake
(sarcoidosis and hypervitaminosis D).[42-44] Glucocorticoids increase urinary
calcium excretion and inhibit vitamin D-mediated gastrointestinal calcium
absorption. However, response is typically slow; 1 to 2 weeks may elapse
before serum calcium concentrations decrease. Oral hydrocortisone (100-300 mg)
or its glucocorticoid equivalent may be given daily; however, complications of
long-term steroid use limit its usefulness even in responsive patients.
Phosphate
Phosphate offers a minimally effective chronic oral treatment for mild to
moderate hypercalcemia. It is most useful after successful initial reduction
of serum calcium with other agents and should probably be reserved for patients
who are both hypercalcemic and hypophosphatemic. The usual treatment is 250 to
375 mg per dose given 4 times daily (1-1.5 g elemental phosphorus/day) to
minimize the potential for developing hyperphosphatemia.[45] Supranormal
phosphate administration results in decreased renal calcium clearance and
presumably decreases serum calcium concentrations by precipitating calcium into
bone and soft tissues.[46,47] Extraskeletal precipitation of calcium in vital
organs may have adverse consequences and is especially significant after
intravenous administration.[6,48,49] Intravenous administration of phosphate
produces a rapid decline in serum calcium concentrations but is rarely used
because there are safer and more effective antiresorptive agents for
life-threatening hypercalcemia (calcitonin and plicamycin). Hypotension,
oliguria, left ventricular failure, and sudden death can occur as a result of
rapid intravenous administration. Contraindications for phosphate include
normophosphatemia, hyperphosphatemia, and renal insufficiency. Oral phosphate
should be given at the lowest dose possible to maintain serum phosphorous
concentrations less than 4 mg/dL 1 to 2 hours after administration.
The use of phosphates is limited by individual patient tolerance and toxicity;
25% to 50% of patients cannot tolerate oral phosphates.[8] Oral
phosphate-induced diarrhea may be initially advantageous in patients who have
experienced constipation secondary to hypercalcemia; it is the predominant and
dose-limiting adverse effect for oral therapy and frequently prevents dosage
escalation greater than 2 g neutral phosphate per day.[6]
Dialysis
Dialysis is an option for hypercalcemia that is complicated by renal failure.
Peritoneal dialysis with calcium-free dialysate fluid can remove 200 to 2,000
mg of calcium in 24 to 48 hours and decrease the serum calcium concentration by
3 to 12 mg/dL (1.5-6 mEq/L or 0.7-3 mmol/L). Ultrafiltrable calcium clearance
may exceed that of urea with calcium-free dialysate exchanges of 2 L each every
30 minutes.[50] Hemodialysis is equally effective.[51,52] Because large
quantities of phosphate are lost during dialysis and phosphate loss aggravates
hypercalcemia, serum inorganic phosphate should be measured after each dialysis
session, and phosphate should be added to the dialysate during the next fluid
exchange or to the patient's diet.[53] It is recommended, however, that
phosphate replacement should be limited to restoring serum inorganic phosphate
concentrations to normal rather than supranormal.[45]
Prostaglandin synthesis inhibitors
Prostaglandin synthesis inhibitors such as the nonsteroidal anti-inflammatory
drugs may have some efficacy in the management of cancer-induced hypercalcemia.
The E-series prostaglandins mediate bone resorption. Despite experimental
evidence, however, aspirin and other nonsteroidal drugs have demonstrated only
modest clinical response rates in controlling hypercalcemia. For patients who
are unresponsive to or unable to tolerate other agents, aspirin may be given to
produce a serum salicylate concentration equal to 20 to 30 mg/dL, or 25 mg
indomethacin may be given orally every 6 hours.[54-57]
Cisplatin
Serum calcium was normalized for a median of 34 days (range: 4-115) in nine of
13 patients with various solid tumors given cisplatin at 100 mg/square meter
body surface area intravenously over 24 hours. Patients were re-treated as
frequently as every 7 days if necessary to maintain serum calcium
concentrations less than 11.5 mg/dL (<5.75 mEq/L or 2.87 mmol/L). Four of 7
patients responded to repeated treatment. Responders achieved a statistically
significant difference in serum calcium levels from baseline on the 10th day
after treatment, which continued thereafter. Serial tumor measurements
revealed that the hypocalcemic response did not correlate with tumor shrinkage;
there was no detectable antitumor response in any measurable or evaluable
disease.[58]
Future pharmacologic management is likely to combine osteoclastic inhibitors
with cytotoxic or endocrine therapy.[9]
-- Patient and family education --
Hypercalcemia compromises the patient's quality of life and can be
life-threatening if not promptly recognized and treated. Individuals at risk
and their caregivers should be made aware that hypercalcemia is a possible
complication. Patients and their significant others should be advised about
the type of symptoms that may occur with hypercalcemia, preventive measures,
exacerbating factors, and when to seek medical assistance.[59] They should be
taught measures to diminish the symptoms of hypercalcemia such as maintaining
mobility and ensuring adequate hydration.
-- Supportive care --
Despite encouraging developments in pharmacologic management, the prognostic
implications related to hypercalcemia remain relatively grim. Only patients
for whom effective anticancer therapy is possible can be expected to experience
a longer survival.
The adverse effects of therapy need to be prevented or recognized and managed.
Fluid overload and electrolyte imbalance can occur during initial therapy.
Serum sodium, potassium, calcium, phosphate, and magnesium concentrations may
be markedly decreased. Electrolyte levels should be monitored at least daily,
and clinical signs and symptoms should be assessed at least every 4 hours when
implementing hydration or specific hypocalcemic drug treatments.
The management of symptoms of hypercalcemia is crucial. Preventing accidental
or self-inflicted injury as a consequence of the patient's altered mental
status is a priority during acute management. Until serum calcium decreases,
additional pharmacologic interventions may be necessary to control nausea,
vomiting, and constipation.
Any acute severe exacerbation or development of new bone pain should be
evaluated for the presence of a pathological fracture. Many health care
facilities institute fracture precautions for patients with metastatic disease
to the bone. These precautions include gentle handling when moving or
transferring patients and fall-prevention strategies. Maximum mobility and
weight-bearing exercises are desirable.
Supportive care in terminal stages will likely consist of comfort measures for
patients and their caregivers. Changes in mentation and behavior may be
especially distressing to family members.
-- Psychosocial Management --
Supportive management of delirium, agitation, or mental-status changes is
implemented in patients with hypercalcemia. Primary treatment of
hypercalcemia and/or its underlying etiology will eventually lead to the
resolution of mental-status changes in most of these patients. Some patients
will present with clinically significant and distressing mental-status changes,
agitation, or delirium that warrant management or control (Refer to the PDQ
summary on Delirium for more information.) Clinical experience supports the
use of neuroleptic medications such as haloperidol (0.5-5.0 mg given
intravenously or orally twice a day to four times a day) alone or in
combination with benzodiazepines (i.e., 0.5-2.0 mg lorazepam given
intravenously or orally two to four times a day) for the control of agitation
and confusion. This enhances patient and family comfort and allows for easier
institution of primary therapies. The use of benzodiazepines in these
situations should be reserved for those instances where sedation (and not
improvement in mental status) is the primary goal of the intervention.
The relationship between mental status and serum calcium levels is variable.
Some patients will not manifest improvement in mental status until days to a
week or more after serum calcium levels are in the normal range; others will
display improvement before laboratory values catch up.
Many times, lethargy is a presenting symptom of hypercalcemia. Lethargic
patients are often mistakenly believed by family (and sometimes by staff)
to be depressed before the actual etiology of the mental-status changes becomes
known. The differential diagnosis is generally straightforward in that many of
these patients will lack the cognitive or ideational symptoms of a mood
disorder (hopelessness, helplessness, anhedonia, guilt, worthlessness, or
thoughts of suicide) and instead will appear mainly lethargic and apathetic,
and formal mental-status testing is likely to reveal cognitive deficits. This
is an important decision to be made, as the introduction of antidepressant
drugs during an organic confusional episode can worsen confusion.
Management of Hypercalcemia
1. Correct dehydration due to calciuresis and vomiting with intravenous
hydration using isotonic saline.
2. Prevent or manage fluid overload with a diuretic such as furosemide 20 mg-40
mg every 12 hours.
3. Treat hypercalcemia with one of the following agents:
- pamidronate 60-90 mg IV over 2-24 hours
- calcitonin 4 IU/kg SC or IM every 12 hours
- plicamycin 25-30 ug/kg IV over 30 minutes
- gallium nitrate 200 mg per square meter per day IV over 24 hours for 5
consecutive days
4. Provide patient and family education
- Signs and symptoms of hypercalcemia to report to the health care provider:
- lethargy
- fatigue
- confusion
- loss of appetite
- nausea/vomiting
- constipation
- excessive thirst
- Preventive measures:
- maintain mobility
- ensure adequate hydration
5. Provide supportive care:
- protect from injury
- prevent fractures
- manage related symptoms (e.g. nausea, vomiting, constipation)
6. Manage mental status changes:
- haloperidol 0.5-5 mg IV or po 2-4 times a day for agitation or confusion
- benzodiazepines such as lorazepam 0.5-2 mg every 4-6 hours as needed for
sedation
-- Prognosis --
Hypercalcemia generally develops as a late complication of malignancy; its
appearance has grave prognostic significance. It remains unclear, however,
whether death is associated with hypercalcemic crisis (uncontrolled or
recurrent progressive hypercalcemia) or with advanced disease. Currently
available hypocalcemic agents have little effect in decreasing the mortality
rate among patients with hypercalcemia of malignancy. Although there is some
disagreement among investigators who have evaluated survival among patients
with cancer-related hypercalcemia,[60-63] it has been observed that 50% of
patients with hypercalcemia die within 1 month and 75% within 3 months after
starting hypocalcemic treatment. In the same study, patients with
hypercalcemia who responded to specific antineoplastic treatment were found to
have a slightly greater survival advantage over nonresponders. Other
prognostic variables shown to correlate with improved survival duration
included serum albumin concentration (direct correlation), serum calcium
concentrations after treatment (inverse correlation), and age (inverse
correlation).[5] In contrast with their modest effect on survival, marked but
differential response rates were observed after hypocalcemic treatments as a
factor of symptom type. The most substantial improvements occurred in
renal- and central nervous system-related symptoms (nausea, vomiting, and
constipation). Symptoms of anorexia, malaise, and fatigue improved, but less
completely.[5]
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Date Last Modified: 09/2002
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