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Hypercalcemia is the most common life-threatening metabolic disorder associated with neoplastic diseases, occurring in an estimated 10% to 20% of all adults with cancer. It also occurs in children with cancer, but with much less frequency (approximately 0.5%–1%).[1,2,3] Solid tumors (such as lung or breast cancer tumors) as well as certain hematologic malignancies (particularly multiple myeloma) are most frequently associated with hypercalcemia. 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. However, diagnosis and timely interventions not only are lifesaving in the short term but also may enhance the patient's compliance with primary and supportive treatments and may improve quality of life. 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 families who have expressed their wishes regarding end-of-life issues, this may represent a preferred timing and/or mode of death (as compared with 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.
In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.
Normal Calcium Homeostasis
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.
Normal, healthy kidneys are capable of filtering large amounts of calcium, which is subsequently reclaimed by tubular reabsorption. The kidneys are capable of increasing calcium excretion nearly fivefold to maintain homeostatic serum calcium concentrations. Hypercalcemia may occur, however, 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 (refer to the Mechanisms of Cancer-associated Hypercalcemia section of this summary) 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 loss of circulating fluid volume exacerbate dehydration. 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).
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.
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 hypercalcemia and humoral hypercalcemia. Osteolytic hypercalcemia results from direct bone destruction by primary or metastatic tumor. Humoral hypercalcemia is mediated by circulating factors secreted by malignant cells without evidence of bony disease.[8,9] It is believed that hypercalcemia results from the release of factors by malignant cells that ultimately cause calcium reabsorption from bone.
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.[9,10,11] Increased blood levels of PTHrP have been found in patients with solid tumors but not in patients with hematologic malignancies who develop hypercalcemia.
Circulating growth factors may also mediate hypercalcemia. Potential mediators include transforming growth factor-alpha and -beta, interleukin-1 and -6, and tumor necrosis factor (TNF)-alpha and -beta.
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.
Hematologic malignancies may stimulate osteoclastic bone resorption through the production of cytokines such as TNF-alpha and -beta and interleukin-1 and -6, formerly referred to as osteoclast-activating factor(s).[7,9,14]
Hypercalcemia occurs more frequently in some malignancies (e.g., breast cancer, multiple myeloma, and squamous cell carcinoma of the lung) 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.
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 caused in part by 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), and some patients may not experience any symptoms. Patients with corrected total serum calcium concentrations higher than 14 mg/dL (>7.0 mEq/L or 3.49 mmol/L) are generally symptomatic. 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 higher than 13 mg/dL (>6.5 mEq/L or 3.24 mmol/L) with few symptoms. Neuromuscular manifestations are generally more marked in older patients than in young patients.
One author observed that malaise and fatigue were the most common complaints at patient presentation, followed by (in order of decreasing prevalence rate) varying degrees of obtundation, anorexia, pain, polyuria-polydipsia, constipation, nausea, and vomiting.
Clinical manifestations can be categorized according to body systems and functions.
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. Abnormal electroencephalograms are seen in patients with marked hypercalcemia.
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, shortened or absent S-T segments, and possibly abrupt sloping and early peaking of the proximal limb of T waves. 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 atrioventricular 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 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.
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.
Hypercalcemia of malignancy can result from osteolytic metastases or humerally mediated bone resorption with secondary fractures, skeletal deformities, and pain.
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 hypocalcemia or hypercalcemia are caused by abnormalities in the ionized fraction of the plasma calcium concentration; however, ionized calcium levels are rarely checked 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. Because 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) × 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.
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. Ionized calcium fraction concentration can be corrected for changes in pH as follows: ionized calcium fraction 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.
It is important to measure the serum calcium and albumin concentrations. Other selected tests (as shown below) may be useful in some instances:
Primary assessment should include the following:[3,4]
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 when no further active treatment is available or desired for reversal of the primary disease process.
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 intake of 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.
Even though the gut has a role in normal calcium homeostasis, absorption is usually diminished in individuals with hypercalcemia, making dietary calcium restriction unnecessary.
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. 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 performed 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 who have been adequately rehydrated.
The magnitude of hypercalcemia and the severity of symptoms typically form the basis for determining whether treatment is indicated. Immediate aggressive hypocalcemic treatment is warranted in patients with a corrected total serum calcium level higher than 14 mg/dL (>7 mEq/L or 3.5 mmol/L). In patients with a 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. 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 level lower than 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.
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.[Level of evidence: III] 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 duration of response to any particular hypocalcemic regimen.
Mild hypercalcemia is defined as corrected total serum calcium level lower than 12 mg/dL (<6 mEq/L or 3.0 mmol/L).
Hydration followed by observation is a treatment 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).
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 controlling nausea and vomiting, encouraging mobility, noting febrile episodes, and the minimal use of sedating medications.
Moderate to Severe Hypercalcemia
Moderate to severe hypercalcemia is defined as corrected total serum calcium equal to 12 to 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 they should not be administered until fluid volume is restored. 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 per 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.[Level of evidence: III] This, in turn, requires intensive hemodynamic monitoring (to avoid volume overload and cardiac decompensation) and frequent serial measurements of urinary volume and electrolytes (to prevent life-threatening hypophosphatemia, hypokalemia, and hypomagnesemia).[6,8][Level of evidence: IV]
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 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. 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.[Level of evidence: IV] 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.[Level of evidence: II] With prolonged etidronate use, osteomalacia and pathologic fractures may occur.[Level of evidence: III] In contrast, clodronate, pamidronate, and alendronate are 10, 100, and 1,000 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.[Level of evidence: IV];[14,15,16][Level of evidence: II] 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 intravenous [IV] 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 of body weight per day administered over 2 hours as a daily IV infusion for 3 consecutive days).[Level of evidence: I] This finding has led to the diminished use of etidronate.
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 IV is administered over 2 to 24 hours. Onset of pamidronate's effect is apparent within 3 to 4 days, with maximal effect within 7 to 10 days after commencing treatment. The effect may persist for 7 to 30 days.[Level of evidence: I] It is recommended that a minimum of 7 days elapse before re-treatment with pamidronate to assess full response to the initial dose. Adverse effects include transient low-grade temperature elevations (1°C–2°C) that typically occur within 24 to 36 hours after administration and persist for up to 2 days in up to 20% of patients. Pamidronate has also been used successfully in children, with similar side effects.[Level of evidence: III] 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.[Level of evidence: I];[Level of evidence: III] 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.[Level of evidence: III] 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.
The use of subcutaneous (SC) administration of clodronate has been explored. Initial experience suggested that clodronate was well tolerated subcutaneously; however, aminobisphosphonates such as pamidronate resulted in local irritation. In a subsequent study, 37 inpatients with terminal cancer received 45 clodronate infusions.[Level of evidence: II] Clodronate, 1,500 mg in 1 L of normal saline, was administered via a 23-gauge, ¾-inch butterfly needle into the SC space. All the infusions were completed, and none required discontinuation due to discomfort. The authors concluded that their results suggested that SC clodronate is an effective treatment for hypercalcemia of malignancy and is 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 IV administration. In addition, SC administration in the hospital setting has advantages for patients for whom an IV 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.[Level of evidence: I] Pamidronate more frequently reduces serum calcium concentrations to normocalcemic ranges than either calcitonin or plicamycin.[26,27][Level of evidence: I] In addition, pamidronate's hypocalcemic effect is dose related and sustained after repeated administration, and it generally persists longer than the effects produced by either calcitonin or plicamycin therapies.[Level of evidence: I] Pamidronate lacks the renal, hepatic, and platelet toxic effects associated with plicamycin.
Calcitonin is a peptide hormone secreted by specialized cells in the thyroid and parathyroid. Its synthesis and secretion normally increase in response to high concentrations of serum-ionized calcium. 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 is longer acting than the human hormone. The initial dose schedule is 4 IU/kg of body weight per SC dose or intramuscular (IM) dose 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 caused by calcitonin's rapid (within 2–4 hours) onset of action.[Level of evidence: II];[Level of evidence: IV]
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 (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 IV dose of 25 to 30 μg/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 to determine the maximum calcium-lowering effect produced by previous doses. Multiple doses may control hypercalcemia for several weeks, but rebound hypercalcemia usually occurs without definitive treatment against the underlying malignancy. Although single-dose treatment of hypercalcemia is generally well tolerated with few adverse effects,[Level of evidence: II] dysfibrinogenemia [Level of evidence: III] and nephrotoxicity  have been reported after single doses (20–25 μg/kg). Rapid IV administration is associated with nausea and vomiting. 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 blood urea nitrogen, potassium wasting, and proteinuria), hypophosphatemia, a flulike syndrome, dermatologic reactions, and stomatitis.[31,34];[Level of evidence: II];[36,37,38,39][Level of evidence: III]
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. Gallium nitrate has been shown to be superior to etidronate in the percentage of patients who achieve normocalcemia and in the duration of normocalcemia.[Level of evidence: I] Drawbacks to its use include a continuous 5-day IV infusion schedule (200 mg/m2 of body surface area per day)  and the potential for nephrotoxicity, particularly when it is used concurrently with other potentially nephrotoxic drugs (e.g., aminoglycosides and amphotericin B).
Gallium nitrate has also been given by daily SC injection to prevent bone resorption and maintain bone mass in patients with multiple myeloma.[Level of evidence: I]
Other Therapeutics for Hypercalcemia
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).[Level of evidence: III];[Level of evidence: II] Glucocorticoids increase urinary calcium excretion and inhibit vitamin D–mediated gastrointestinal calcium absorption. Response, however, 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 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 of elemental phosphorus per day) to minimize the potential for developing hyperphosphatemia. Supranormal phosphate administration results in decreased renal calcium clearance and presumably decreases serum calcium concentrations by precipitating calcium into bone and soft tissues.[45,46][Level of evidence: II] Extraskeletal precipitation of calcium in vital organs may have adverse consequences and is especially significant after intravenous administration.;[47,48][Level of evidence: III] IV 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 IV 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 lower 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. 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 of more than 2 g of neutral phosphate per day.
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. Hemodialysis is equally effective.[Level of evidence: III];[Level of evidence: IV] 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.[Level of evidence: III] It is recommended, however, that phosphate replacement should be limited to restoring serum inorganic phosphate concentrations to normal rather than supranormal.
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.[53,54,55][Level of evidence: II];[Level of evidence: III]
Serum calcium was normalized for a median of 34 days (range, 4–115) in 9 of 13 patients with various solid tumors given IV cisplatin at 100 mg/m2 of body surface area over 24 hours. Patients were re-treated as frequently as every 7 days if necessary to maintain serum calcium concentrations lower than 11.5 mg/dL (<5.75 mEq/L or 2.87 mmol/L). Four of seven patients responded to repeated treatment. Responders achieved a statistically significant difference in serum calcium levels from baseline on the tenth 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.
Future pharmacologic management is likely to combine osteoclastic inhibitors with cytotoxic or endocrine therapy.
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 types of symptoms that may occur with hypercalcemia, preventive measures, exacerbating factors, and when to seek medical assistance. They should be taught measures to diminish the symptoms of hypercalcemia such as maintaining mobility and ensuring adequate hydration.
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 hydration or specific hypocalcemic drug treatments are being implemented.
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 typically consists of comfort measures for patients and their caregivers. Changes in mentation and behavior may be especially distressing to family members.
Supportive management of delirium, agitation, or changes in mental status is implemented in patients with hypercalcemia. Primary treatment of hypercalcemia and/or its underlying etiology eventually leads to the resolution of changes in mental status in most of these patients. Some patients present with clinically significant and distressing changes in mental status, agitation, or delirium that warrants 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 IV or by mouth 2–4 times a day) alone or in combination with benzodiazepines (e.g., 0.5–2.0 mg of lorazepam IV or by mouth 2–4 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 instances in which 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; formal testing of mental status is likely to reveal cognitive deficits. This is an important distinction to be made, as the introduction of antidepressant drugs during an organic confusional episode can worsen confusion.
Management of hypercalcemia
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,[59,60,61,62] 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 longer survival included serum albumin concentration (direct correlation), serum calcium concentrations after treatment (inverse correlation), and age (inverse correlation). 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.
Check NCI's list of cancer clinical trials for U.S. supportive and palliative care trials about hypercalcemia of malignancy that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of hypercalcemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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National Cancer Institute: PDQ® Hypercalcemia. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/supportivecare/hypercalcemia/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2013-01-09
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