Prevention
Managing Hypercalcemia
Mild Hypercalcemia
Moderate to Severe Hypercalcemia
Pharmacologic Inhibition of Osteoclastic Bone Resorption
        Bisphosphonates
        Calcitonin
        Plicamycin
        Gallium nitrate
Other Therapeutics for Hypercalcemia
        Glucocorticoids
        Phosphate
        Dialysis
        Prostaglandin synthesis Inhibitors
        Cisplatin
Patient and Family Education
Supportive Care
Psychosocial Management
        Management of hypercalcemia
Prognosis

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 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.[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.

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 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.[1]

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.[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 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.[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 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).[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 controlling nausea and vomiting, encouraging mobility, noting febrile episodes, and the minimal use of sedating medications.[6]

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.[7] 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]

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.[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] 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.[13-16] 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).[17] This finding 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 IV is administered over 2 to 24 hours.[18] 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.[19] It is recommended that a minimum of 7 days elapse before re-treatment with pamidronate to assess full response to the initial dose.[18] 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.[20] 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]

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.[24] In a subsequent study, 37 inpatients with terminal cancer received 45 clodronate infusions.[25] 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.[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 it generally persists longer than the effects produced by either calcitonin or plicamycin therapies.[19] 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.[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 (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.[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 μg/kg). Rapid IV 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 blood urea nitrogen, potassium wasting, and proteinuria), hypophosphatemia, a flulike syndrome, dermatologic reactions, and stomatitis.[31,34-39]

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 IV infusion schedule (200 mg/m² of body surface area per day) [6] and the potential for nephrotoxicity, particularly when it is used concurrently with other potentially nephrotoxic drugs (e.g., aminoglycosides and amphotericin B).[1]

Gallium nitrate has also been given by daily SC injection to prevent bone resorption and maintain bone mass in patients with multiple myeloma.[41]

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).[42,43] 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.[44] 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] Extraskeletal precipitation of calcium in vital organs may have adverse consequences and is especially significant after intravenous administration.[6,47,48] 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.[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 of more than 2 g of neutral phosphate per day.[6]

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.[49] Hemodialysis is equally effective.[50,51] 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.[52] It is recommended, however, that phosphate replacement should be limited to restoring serum inorganic phosphate concentrations to normal rather than supranormal.[44]

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.[53-56]

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.[57]

Future pharmacologic management is likely to combine osteoclastic inhibitors with cytotoxic or endocrine therapy.[9]

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.[58] 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 Cognitive Disorders and 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.

1. Correct dehydration due to calciuresis and vomiting with IV hydration using isotonic saline.
2. Prevent or manage fluid overload with a diuretic such as furosemide, 20 mg to 40 mg every 12 hours.
3. Treat hypercalcemia with one of the following agents:
   • pamidronate, 60 to 90 mg IV over 2 to 24 hours.
   • calcitonin, 4 IU/kg SC or IM every 12 hours.
   • plicamycin, 25 to 30 μg/kg IV over 30 minutes.
   • gallium nitrate, 200 mg/m² 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, and constipation).
6. Manage mental-status changes:
   • Haloperidol, 0.5 to 5 mg IV or by mouth 2 to 4 times a day for agitation or confusion.
   • Benzodiazepines such as lorazepam, 0.5 to 2 mg every 4 to 6 hours as needed for sedation.

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,[59-62] 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).[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]

References

1. Warrell RP Jr: Metabolic emergencies. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997, pp 2486-93. 
   
   
2. Bilezikian JP: Management of acute hypercalcemia. N Engl J Med 326 (18): 1196-203, 1992.  [PUBMED Abstract]
   
   
3. Theriault RL: Hypercalcemia of malignancy: pathophysiology and implications for treatment. Oncology (Huntingt) 7 (1): 47-50; discussion 52-5, 1993.  [PUBMED Abstract]
   
   
4. Mundy GR: Pathophysiology of cancer-associated hypercalcemia. Semin Oncol 17 (2 Suppl 5): 10-5, 1990.  [PUBMED Abstract]
   
   
5. Ralston SH, Gallacher SJ, Patel U, et al.: Cancer-associated hypercalcemia: morbidity and mortality. Clinical experience in 126 treated patients. Ann Intern Med 112 (7): 499-504, 1990.  [PUBMED Abstract]
   
   
6. Ritch PS: Treatment of cancer-related hypercalcemia. Semin Oncol 17 (2 Suppl 5): 26-33, 1990.  [PUBMED Abstract]
   
   
7. Suki WN, Yium JJ, Von Minden M, et al.: Acute treatment of hypercalcemia with furosemide. N Engl J Med 283 (16): 836-40, 1970.  [PUBMED Abstract]
   
   
8. Ignoffo RJ, Tseng A: Focus on pamidronate: a biphosphonate compound for the treatment of hypercalcemia of malignancy. Hosp Formul 26 (10): 774-86, 1991. 
   
   
9. Warrell RP Jr: Etiology and current management of cancer-related hypercalcemia. Oncology (Huntingt) 6 (10): 37-43; discussion 43, 47-50, 1992.  [PUBMED Abstract]
   
   
10. Coleman RE: Bisphosphonate treatment of bone metastases and hypercalcemia of malignancy. Oncology (Huntingt) 5 (8): 55-60; discussion 60-2, 65, 1991.  [PUBMED Abstract]
    
    
11. McCloskey EV, Yates AJ, Beneton MN, et al.: Comparative effects of intravenous diphosphonates on calcium and skeletal metabolism in man. Bone 8 (Suppl 1): S35-41, 1987.  [PUBMED Abstract]
    
    
12. Mautalen C, Gonzalez D, Blumenfeld EL, et al.: Spontaneous fractures of uninvolved bones in patients with Paget's disease during unduly prolonged treatment with disodium etidronate (EHDP). Clin Orthop (207): 150-5, 1986.  [PUBMED Abstract]
    
    
13. Fleisch H: Bisphosphonates. Pharmacology and use in the treatment of tumour-induced hypercalcaemic and metastatic bone disease. Drugs 42 (6): 919-44, 1991.  [PUBMED Abstract]
    
    
14. Fenton AJ, Gutteridge DH, Kent GN, et al.: Intravenous aminobisphosphonate in Paget's disease: clinical, biochemical, histomorphometric and radiological responses. Clin Endocrinol (Oxf) 34 (3): 197-204, 1991.  [PUBMED Abstract]
    
    
15. Adamson BB, Gallacher SJ, Byars J, et al.: Mineralisation defects with pamidronate therapy for Paget's disease. Lancet 342 (8885): 1459-60, 1993.  [PUBMED Abstract]
    
    
16. Boyce BF, Adamson BB, Gallacher SJ, et al.: Mineralisation defects after pamidronate for Paget's disease. Lancet 343 (8907): 1231-2, 1994.  [PUBMED Abstract]
    
    
17. Gucalp R, Ritch P, Wiernik PH, et al.: Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol 10 (1): 134-42, 1992.  [PUBMED Abstract]
    
    
18. Novartis Pharmaceuticals Corporation.: Aredia: package insert. May 1998. 
    
    
19. Elomaa I, Blomqvist C, Porkka L, et al.: Diphosphonates for osteolytic metastases. Lancet 1 (8438): 1155-6, 1985.  [PUBMED Abstract]
    
    
20. Kerdudo C, Aerts I, Fattet S, et al.: Hypercalcemia and childhood cancer: a 7-year experience. J Pediatr Hematol Oncol 27 (1): 23-7, 2005.  [PUBMED Abstract]
    
    
21. Nussbaum SR, Younger J, Vandepol CJ, et al.: Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med 95 (3): 297-304, 1993.  [PUBMED Abstract]
    
    
22. Burckhardt P, Thiébaud D, Perey L, et al.: Treatment of tumor-induced osteolysis by APD. Recent Results Cancer Res 116: 54-66, 1989.  [PUBMED Abstract]
    
    
23. Bounameaux HM, Schifferli J, Montani JP, et al.: Renal failure associated with intravenous diphosphonates. Lancet 1 (8322): 471, 1983.  [PUBMED Abstract]
    
    
24. Walker P, Watanabe S, Lawlor P, et al.: Subcutaneous clodronate. Lancet 348 (9023): 345-6, 1996.  [PUBMED Abstract]
    
    
25. Walker P, Watanabe S, Lawlor P, et al.: Subcutaneous clodronate: a study evaluating efficacy in hypercalcemia of malignancy and local toxicity. Ann Oncol 8 (9): 915-6, 1997.  [PUBMED Abstract]
    
    
26. Ostenstad B, Andersen OK: Disodium pamidronate versus mithramycin in the management of tumour-associated hypercalcemia. Acta Oncol 31 (8): 861-4, 1992.  [PUBMED Abstract]
    
    
27. Ralston SH, Gardner MD, Dryburgh FJ, et al.: Comparison of aminohydroxypropylidene diphosphonate, mithramycin, and corticosteroids/calcitonin in treatment of cancer-associated hypercalcaemia. Lancet 2 (8461): 907-10, 1985.  [PUBMED Abstract]
    
    
28. Thiébaud D, Jacquet AF, Burckhardt P: Fast and effective treatment of malignant hypercalcemia. Combination of suppositories of calcitonin and a single infusion of 3-amino 1-hydroxypropylidene-1-bisphosphonate. Arch Intern Med 150 (10): 2125-8, 1990.  [PUBMED Abstract]
    
    
29. Ralston SH, Gallacher SJ, Dryburgh FJ, et al.: Treatment of severe hypercalcaemia with mithramycin and aminohydroxypropylidene bisphosphonate. Lancet 2 (8605): 277, 1988.  [PUBMED Abstract]
    
    
30. Parsons V, Baum M, Self M: Effect of mithramycin on calcium and hydroxyproline metabolism in patients with malignant disease. Br Med J 1 (538): 474-7, 1967.  [PUBMED Abstract]
    
    
31. Kennedy BJ: Metabolic and toxic effects of mithramycin during tumor therapy. Am J Med 49 (4): 494-503, 1970.  [PUBMED Abstract]
    
    
32. Perlia CP, Gubisch NJ, Wolter J, et al.: Mithramycin treatment of hypercalcemia. Cancer 25 (2): 389-94, 1970.  [PUBMED Abstract]
    
    
33. Ashby MA, Lazarchick J: Acquired dysfibrinogenemia secondary to mithramycin toxicity. Am J Med Sci 292 (1): 53-5, 1986.  [PUBMED Abstract]
    
    
34. Benedetti RG, Heilman KJ 3rd, Gabow PA: Nephrotoxicity following single dose mithramycin therapy. Am J Nephrol 3 (5): 277-8, 1983 Sep-Oct.  [PUBMED Abstract]
    
    
35. Fillastre JP, Maitrot J, Canonne MA, et al.: Renal function and alterations in plasma electrolyte levels in normocalcaemic and hypercalaemic patients with malignant diseases, given an intravenous infusion of mithramycin. Chemotherapy 20 (5): 280-95, 1974.  [PUBMED Abstract]
    
    
36. Purpora D, Ahern MJ, Silverman N: Toxic epidermal necrolysis after mithramycin. N Engl J Med 299 (25): 1412, 1978.  [PUBMED Abstract]
    
    
37. Bashir Y, Tomson CR: Cardiac arrest associated with hypokalaemia in a patient receiving mithramycin. Postgrad Med J 64 (749): 228-9, 1988.  [PUBMED Abstract]
    
    
38. Ahr DJ, Scialla SJ, Kimbali DB Jr: Acquired platelet dysfunction following mithramycin therapy. Cancer 41 (2): 448-54, 1978.  [PUBMED Abstract]
    
    
39. Margileth DA, Smith FE, Lane M: Sudden arterial occlusion associated with mithramycin therapy. Cancer 31 (3): 708-12, 1973.  [PUBMED Abstract]
    
    
40. Warrell RP Jr, Murphy WK, Schulman P, et al.: A randomized double-blind study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia. J Clin Oncol 9 (8): 1467-75, 1991.  [PUBMED Abstract]
    
    
41. Warrell RP Jr, Lovett D, Dilmanian FA, et al.: Low-dose gallium nitrate for prevention of osteolysis in myeloma: results of a pilot randomized study. J Clin Oncol 11 (12): 2443-50, 1993.  [PUBMED Abstract]
    
    
42. Mundy GR, Rick ME, Turcotte R, et al.: Pathogenesis of hypercalcemia in lymphosarcoma cell leukemia. Role of an osteoclast activating factor-like substance and a mechanism of action for glucocorticoid therapy. Am J Med 65 (4): 600-6, 1978.  [PUBMED Abstract]
    
    
43. Ralston SH, Fogelman I, Gardiner MD, et al.: Relative contribution of humoral and metastatic factors to the pathogenesis of hypercalcaemia in malignancy. Br Med J (Clin Res Ed) 288 (6428): 1405-8, 1984.  [PUBMED Abstract]
    
    
44. Potts JT: Diseases of the parathyroid gland and other hyper- and hypocalcemic disorders. In: Isselbacher KJ, Braunwald E, Wilson JD, et al., eds.: Principles of Internal Medicine. New York: McGraw-Hill, 1994, pp. 2151-71. 
    
    
45. Massry SG, Mueller E, Silverman AG, et al.: Inorganic phosphate treatment of hypercalcemia. Arch Intern Med 121 (4): 307-12, 1968.  [PUBMED Abstract]
    
    
46. Hebert LA, Lemann J Jr, Petersen JR, et al.: Studies of the mechanism by which phosphate infusion lowers serum calcium concentration. J Clin Invest 45 (12): 1886-94, 1966.  [PUBMED Abstract]
    
    
47. Shackney S, Hasson J: Precipitous fall in serum calcium, hypotension, and acute renal failure after intravenous phosphate therapy for hypercalcemia. Report of two cases. Ann Intern Med 66 (5): 906-16, 1967.  [PUBMED Abstract]
    
    
48. Goldsmith RS, Ingbar SH: Inorganic phosphate treatment of hypercalcemia of diverse etiologies. N Engl J Med 274 (1): 1-7, 1966.  [PUBMED Abstract]
    
    
49. Nolph KD, Stoltz M, Maher JF: Calcium free peritoneal dialysis. Treatment of vitamin D intoxication. Arch Intern Med 128 (5): 809-14, 1971.  [PUBMED Abstract]
    
    
50. Cardella CJ, Birkin BL, Rapoport A: Role of dialysis in the treatment of severe hypercalcemia: report of two cases successfully treated with hemodialysis and review of the literature. Clin Nephrol 12 (6): 285-90, 1979.  [PUBMED Abstract]
    
    
51. Schreiner GE, Teehan BP: Dialysis of poisons and drugs - annual review. Trans Am Soc Artif Intern Organs 18 (0): 563-99, 1972.  [PUBMED Abstract]
    
    
52. Stoltz ML, Nolph KD, Maher JF: Factors affecting calcium removal with calcium-free peritoneal dialysis. J Lab Clin Med 78 (3): 389-98, 1971.  [PUBMED Abstract]
    
    
53. Seyberth HW, Segre GV, Morgan JL, et al.: Prostaglandins as mediators of hypercalcemia associated with certain types of cancer. N Engl J Med 293 (25): 1278-83, 1975.  [PUBMED Abstract]
    
    
54. Seyberth HW, Segre GV, Hamet P, et al.: Characterization of the group of patients with the hypercalcemia of cancer who respond to treatment with prostaglandin synthesis inhibitors. Trans Assoc Am Physicians 89: 92-104, 1976.  [PUBMED Abstract]
    
    
55. Coombes RC, Neville AM, Bondy PK, et al.: Failure of indomethacin to reduce hypercalcemia in patients with breast cancer. Prostaglandins 12 (6): 1027-35, 1976.  [PUBMED Abstract]
    
    
56. Brenner DE, Harvey HA, Lipton A, et al.: A study of prostaglandin E2, parathormone, and response to indomethacin in patients with hypercalcemia of malignancy. Cancer 49 (3): 556-61, 1982.  [PUBMED Abstract]
    
    
57. Lad TE, Mishoulam HM, Shevrin DH, et al.: Treatment of cancer-associated hypercalcemia with cisplatin. Arch Intern Med 147 (2): 329-32, 1987.  [PUBMED Abstract]
    
    
58. List A: Malignant hypercalcemia. The choice of therapy. Arch Intern Med 151 (3): 437-8, 1991.  [PUBMED Abstract]
    
    
59. Warrell RP Jr, Israel R, Frisone M, et al.: Gallium nitrate for acute treatment of cancer-related hypercalcemia. A randomized, double-blind comparison to calcitonin. Ann Intern Med 108 (5): 669-74, 1988.  [PUBMED Abstract]
    
    
60. Blomqvist CP: Malignant hypercalcemia--a hospital survey. Acta Med Scand 220 (5): 455-63, 1986.  [PUBMED Abstract]
    
    
61. Mundy GR, Martin TJ: The hypercalcemia of malignancy: pathogenesis and management. Metabolism 31 (12): 1247-77, 1982.  [PUBMED Abstract]
    
    
62. Fisken RA, Heath DA, Bold AM: Hypercalcaemia--a hospital survey. Q J Med 49 (196): 405-18, 1980 Autumn.  [PUBMED Abstract]
    
    

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