What are the treatment options for hypercalcemia?

Management of Hypercalcemia

Initiate treatment with aggressive intravenous normal saline hydration followed by intravenous zoledronic acid 4 mg infused over at least 15 minutes, as this combination represents the cornerstone of therapy for moderate to severe hypercalcemia. 1, 2

Initial Assessment and Diagnostic Workup

Before initiating treatment, obtain the following laboratory studies to determine the underlying etiology:

• Measure ionized calcium directly rather than relying solely on corrected calcium, as pseudo-hypercalcemia from hemolysis or improper sampling can lead to inaccurate diagnosis 1
• If ionized calcium is unavailable, calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 [4 - Serum albumin (g/dL)] 1
• Intact parathyroid hormone (PTH) is the single most important test—elevated or inappropriately normal PTH indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) points to other causes 1, 3
• PTH-related protein (PTHrP), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, magnesium, creatinine, and BUN 1
• Assess for symptoms: polyuria, polydipsia, nausea, vomiting, confusion, abdominal pain, dehydration, and mental status changes 1

Treatment Algorithm by Severity

Mild Hypercalcemia (Total calcium <12 mg/dL or ionized calcium 5.6-8.0 mg/dL)

• Conservative management with oral hydration and treatment of the underlying cause is appropriate for asymptomatic patients 3
• Avoid prolonged bed rest, volume contraction, thiazide diuretics, and excessive calcium/vitamin D supplementation 1
• For primary hyperparathyroidism in patients >50 years with calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease, observation with monitoring is reasonable 3

Moderate to Severe Hypercalcemia (Total calcium ≥12 mg/dL or ionized calcium >8.0 mg/dL)

Step 1: Aggressive Hydration

• Administer IV normal saline to correct hypovolemia and promote calciuresis, targeting urine output ≥100 mL/hour (or 3 mL/kg/hour in children <10 kg) 1
• Vigorous saline hydration should be initiated promptly with an attempt to restore urine output to approximately 2 L/day 2
• Avoid overhydration in patients with cardiac or renal insufficiency; use loop diuretics (furosemide) only after adequate volume repletion to prevent fluid overload 1
• Critical pitfall: Do not use diuretics before correcting hypovolemia, as this worsens hypercalcemia 2

Step 2: Bisphosphonate Therapy

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred agent due to superior efficacy compared to pamidronate 1, 2
• For patients with creatinine clearance (CrCl) 50-60 mL/min: reduce dose to 3.5 mg 2
• For CrCl 40-49 mL/min: reduce dose to 3.3 mg 2
• For CrCl 30-39 mL/min: reduce dose to 3.0 mg 2
• Do not use in severe renal impairment (CrCl <30 mL/min) without considering alternative therapies 2
• Monitor serum creatinine before each dose and withhold treatment if renal deterioration occurs (increase of 0.5 mg/dL in normal baseline or 1.0 mg/dL in abnormal baseline) 2
• Onset of action is delayed (2-4 days), so administer early in the treatment course 1

Step 3: Adjunctive Calcitonin (for rapid effect)

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly every 12 hours provides rapid onset within hours but limited efficacy 1
• Use as a bridge until bisphosphonates take effect, particularly when rapid calcium reduction is needed 1
• Tachyphylaxis develops within 48 hours, limiting long-term utility 3

Step 4: Retreatment if Needed

• If serum calcium does not normalize after initial zoledronic acid dose, retreatment with 4 mg may be considered after a minimum of 7 days 2

Cause-Specific Definitive Treatment

Primary Hyperparathyroidism

• Parathyroidectomy is indicated for symptomatic patients and those with osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age <50 years, or calcium >0.25 mmol/L above upper normal limit 4
• Calcimimetic agents (cinacalcet) may be used when surgery is contraindicated or patients do not meet surgical criteria 5

Malignancy-Associated Hypercalcemia

• Treat the underlying malignancy with chemotherapy or appropriate antineoplastic therapy, as this is essential for long-term control 1, 4
• Hypercalcemia of malignancy carries a poor prognosis with median survival of approximately 1 month 1
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1
• For multiple myeloma specifically: hydration, zoledronic acid, corticosteroids, and/or calcitonin 1
• Plasmapheresis is adjunctive therapy for symptomatic hyperviscosity in multiple myeloma 1

Granulomatous Diseases and Vitamin D-Mediated Hypercalcemia

• Glucocorticoids are the primary treatment for hypercalcemia due to sarcoidosis, lymphomas, or vitamin D intoxication 1, 4, 3
• Prednisone 1 mg/kg/day orally or methylprednisolone IV equivalent 1
• Taper over 2-4 months depending on response 1
• These conditions involve unregulated 1-alpha-hydroxylase activity producing excess 1,25-dihydroxyvitamin D 6

Severe Hypercalcemia with Renal Failure

• Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is reserved for severe hypercalcemia complicated by renal insufficiency or oliguria 1
• Denosumab may be considered in patients with kidney failure who cannot receive bisphosphonates 3

Essential Supportive Measures

Calcium and Vitamin D Supplementation During Bisphosphonate Therapy

• Paradoxically, provide oral calcium 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia 1, 2
• Correct pre-existing hypocalcemia before initiating bisphosphonates 1
• Monitor serum calcium closely, especially with denosumab which carries higher hypocalcemia risk 1

Medications to Avoid

• Discontinue thiazide diuretics, lithium, excessive calcium supplements (>500 mg/day), and vitamin D supplements (>400 IU/day) 1
• Avoid NSAIDs and IV contrast media in patients with renal impairment 1

Monitoring and Follow-up

• Monitor serum calcium, renal function (creatinine, BUN), and electrolytes regularly to assess treatment effectiveness 1
• Assess ECG for QT interval prolongation in severe hypercalcemia 1
• Rebound hypercalcemia can occur, requiring ongoing surveillance 1
• Only treat symptomatic hypocalcemia (tetany, seizures) following bisphosphonate therapy; asymptomatic hypocalcemia does not require intervention 1

Critical Pitfalls to Avoid

• Never delay bisphosphonate therapy in moderate to severe hypercalcemia while waiting for diagnostic workup to complete 1
• Do not use doses greater than 4 mg zoledronic acid, as renal toxicity increases without additional benefit 2
• Do not restrict calcium intake excessively without medical supervision, as this can worsen bone disease 1
• Avoid relying on corrected calcium alone—measure ionized calcium when possible for accurate assessment 1
• Do not use bisphosphonates in hyperparathyroidism or non-tumor-related hypercalcemia without careful consideration, as safety and efficacy are not established 2