para>Lithium, thiazide diuretics, and vitamin D preparations all can increase serum calcium. None indicated for the immediate management of hypercalcemia, but studies such as a bone scan may be helpful for workup of underlying conditions.
TREATMENT
GENERAL MEASURES
- Treatment of underlying malignancy.
- Monitor for hypophosphatemia, which is common in and can worsen hypercalcemia. Replace phosphorus PO or by nasogastric tube.
- Discontinue use of oral calcium supplements, and remove calcium from parenteral feeding solutions.
- Discontinue medications that can independently cause hypercalcemia (e.g., thiazides).
- Promote weight-bearing ambulation.
MEDICATION
- Hydration
- The initial therapy of choice because many symptoms are caused by dehydration
- Vomiting and renal losses can cause profound dehydration.
- In severe hypercalcemia, initiate volume expansion with IV normal saline at 200 to 500 mL/hr to maintain urinary output of 100 to 150 mL/hr. Monitor fluids ' input and output closely. If hypernatremia develops, change from isotonic to hypotonic fluid therapy (3)[C].
- Loop diuretics (e.g., furosemide): increase renal calcium excretion but only after adequate hydration. Recent literature review suggests that loop diuretics should not be used except in fluid overloaded patients because hydration with saline, particularly when combined with other agents such as bisphosphonates, is more effective and safer than hydration plus diuretics (4)[B].
- Bisphosphonates: considered first-line medications; by inhibiting osteoclasts they reduce calcium release from bone, thereby counteracting the main mechanism of hypercalcemia of malignancy, which is bone reabsorption. They also decrease bone pain in patients with bone metastases. Side effects include osteonecrosis of the jaw, hypersensitivity reaction, and renal toxicity. Renal function should be monitored at the time of each infusion.
- Zoledronic acid (Zometa)
- The most potent bisphosphonate: 4 mg IV normalizes calcium levels in 88% of patients with a duration of action of 32 days (5)[A]. Nephrotoxic potential, especially in myeloma patients receiving thalidomide.
- Pamidronate (Aredia): 90 mg IV has the best effect normalizing calcium in 70% of patients with a duration of action of 18 days (5,6)[A].
- Ibandronate: 4 to 6 mg IV normalizes calcium in 77% of patients with a duration of action of 14 days (not FDA-approved for malignancy-associated hypercalcemia).
- Calcitonin: also requires adequate rehydration; inhibits osteoclast bone resorption and calcium reabsorption in the distal tubule
- Rapid onset of action (within 6 to 24 hours)
- Safe and relatively nontoxic; side effects include nausea, vomiting, abdominal cramps, rash, flushing, diarrhea, and tachyphylaxis.
- Its efficacy is limited for the first 48 hours.
- Most beneficial in symptomatic patients with calcium >14 mg/L
- For life-threatening hypercalcemia, consider 4 IU/kg IM calcitonin injections q12h.
- Plicamycin (previously mithramycin)
- It works on osteoclasts by inhibiting RNA synthesis; reserved for patients who do not respond to bisphosphonates; can induce normocalcemia in 80% of those who receive it.
- Side effects limit its use (e.g., nausea, vomiting, cellulitis at infusion site, cytopenias, hepatic toxicity, nephrotoxicity, and platelet inhibition); can have rapid rebound hypercalcemia
- Onset of action is within 12 hours, with maximal effect seen in 24 to 48 hours.
- Gallium nitrate
- Works through multiple mechanisms, including inhibition of osteoclast-mediated bone resorption, alteration in bone structure, and stimulation of bone formation
- Rarely used, except in cases of more severe hypercalcemia that has been unresponsive to initial therapy because treatment requires 5-day continuous IV infusion
- Onset of action is 48 to 72 hours.
- Side effects: nausea, vomiting, nephrotoxicity, hypophosphatemia, anemia, hypotension
- Inorganic phosphates
- Potentially lethal side effects limit use to patients with life-threatening hypercalcemia; IV use is no longer supported.
- Side effects: Precipitation of calcium into tissues of the lung, heart, kidneys, and blood vessels can lead to organ damage, hypotension, and death.
- Glucocorticoids
- Effective in malignancies with overproduction of calcitriol (typically Hodgkin or non-Hodgkin lymphoma): inhibit 1α-hydroxylase conversion of 25OH-vit D to calcitriol
- Most used: 200 to 300 mg IV hydrocortisone daily for 3 to 5 days (1)[C]
- They also have direct tumoricidal effects on hematologic cancers such as multiple myeloma, lymphoma, and leukemias.
- Denosumab
- Fully human monoclonal antibody against RANKL, the key mediator of bone resorption
- Administered subcutaneously
- Effectively lowers serum calcium in patients with hypercalcemia of malignancy who did not or no longer respond to recent treatment with IV bisphosphonates (7)[B]
ADDITIONAL THERAPIES
Hemodialysis is indicated when saline diuresis and medications fail or in the presence of congestive heart failure, severe kidney injury, severe neurologic deficits, or life-threatening hypercalcemia.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Avoid bed rest or immobilization as much as possible.
Patient Monitoring
Frequent serum calcium and electrolyte determinations; expect relapse
Prognosis
- Median survival after diagnosis of tumoral hypercalcemia depends on type and extent of the malignancy but usually indicates a poor prognosis.
- >50% of patients die within 50 days of diagnosis of hypercalcemia.
REFERENCES
11 Wright JD, Tergas AI, Ananth CV, et al. Quality and outcomes of treatment of hypercalcemia of malignancy. Cancer Invest. 2015;33(8):331 " 339.22 Diel IJ, Body JJ, Stopeck AT, et al. The role of denosumab in the prevention of hypercalcaemia of malignancy in cancer patients with metastatic bone disease. Eur J of Cancer. 2015;51(11):1467 " 1475.33 McCurdy MT, Shanholtz CB. Oncologic emergencies. Crit Care Med. 2012;40(7):2212 " 2222.44 LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Ann Intern Med. 2008;149(4):259 " 263.55 Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19(2):558 " 567.66 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 doses. Am J Med. 1993;95(3):297 " 304.77 Hu MI, Glezerman I, Leboulleux S, et al. Denosumab for patients with persistent or relapsed hypercalcemia of malignancy despite recent bisphosphonate treatment. J Natl Cancer Inst. 2013;105(18):1417 " 1420.
ADDITIONAL READING
- Soyfoo MS, Brenner K, Paesmans M, et al. Non-malignant causes of hypercalcemia in cancer patients: a frequent and neglected occurrence. Support Care Cancer. 2013;21(5):1415 " 1419.
- Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352(4):373 " 379.
- Wysolmerski JJ. Parathyroid hormone-related protein: an update. J Clin Endocrinol Metab. 2012;97(9):2947 " 2956.
SEE ALSO
- Addison Disease; HIV/AIDS; Hyperparathyroidism; Hyperthyroidism; Milk-Alkali Syndrome; Rhabdomyolysis; Sarcoidosis; Tuberculosis
- Algorithm: Hypercalcemia
CODES
ICD10
E83.52 Hypercalcemia
ICD9
275.42 Hypercalcemia
SNOMED
Humoral hypercalcemia of malignancy (disorder)
CLINICAL PEARLS
- Hypercalcemia of malignancy carries with it a very poor prognosis. Left untreated, the median survival is 2 to 6 months.
- Diagnosis may be difficult unless the patient has a known malignancy. Even with a known malignancy, other causes of hypercalcemia should be ruled out.
- The mnemonic for remembering the effects of hypercalcemia: stones (kidney stones), bones (bone pain), moans (psychosis), groans (abdominal discomfort, constipation), and psychiatric overtones (including depression and confusion)
- Patients with hypercalcemia of malignancy do not need a low-calcium diet. Hypercalcemia decreases the absorption of calcium in the intestine.
- For severe hypercalcemia of malignancy, the initial treatment of choice is IV hydration. Volume depletion is the cause of many of the symptoms and the pathophysiology of hypercalcemia.