What are the treatment options for hypercalcemia?

Treatment of Hypercalcemia

Initiate treatment with intravenous normal saline hydration followed by bisphosphonates (zoledronic acid preferred) for moderate to severe hypercalcemia, while mild asymptomatic cases may be managed conservatively with observation and treatment of the underlying cause. 1, 2

Initial Assessment

Before initiating treatment, measure the following to determine the underlying etiology 1:

• Intact parathyroid hormone (iPTH) - distinguishes PTH-dependent (elevated/normal in primary hyperparathyroidism) from PTH-independent causes (suppressed <20 pg/mL in malignancy and other causes) 2, 3
• Parathyroid hormone-related protein (PTHrP) - elevated in malignancy-associated hypercalcemia 2
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels 1, 2
• Serum calcium, albumin, magnesium, phosphorus, and creatinine 1, 2

Evaluate for symptoms including polyuria, polydipsia, nausea, vomiting, confusion, abdominal pain, myalgia, dehydration, and mental status changes 1, 2

Treatment Algorithm by Severity

Mild Hypercalcemia (Total calcium <12 mg/dL)

Conservative management is appropriate for asymptomatic patients 3, 4:

• Oral hydration and ambulation 5
• Avoid dehydration and prolonged bed rest 6
• Treat underlying cause 3
• 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 2, 3

Moderate to Severe Hypercalcemia (Total calcium ≥12 mg/dL)

Step 1: Hydration

• Administer IV normal saline to correct hypovolemia and promote calciuresis, targeting urine output of at least 100 mL/hour (3 mL/kg/hour in children <10 kg) 1, 7
• Loop diuretics (furosemide) should only be used in patients with renal or cardiac insufficiency to prevent fluid overload, NOT before correcting hypovolemia 1, 7, 5

Step 2: Bisphosphonate Therapy (First-Line)

Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate 1, 2:

• Superior efficacy compared to pamidronate with longer duration of response (30-40 days vs 17 days) 1, 8
• Adjust dosing for renal impairment and monitor serum creatinine before each dose 1
• Onset of action is delayed (takes effect over days), so administer early 1, 6

Alternative: Pamidronate 60-90 mg IV if zoledronic acid unavailable 7, 8:

• Efficacy ranges 40-100% depending on dose and baseline calcium 8
• Indicated for moderate or severe hypercalcemia associated with malignancy 7

Critical precaution: Correct hypocalcemia before initiating bisphosphonate therapy and provide oral calcium supplement 500 mg plus vitamin D 400 IU daily during treatment 1

Step 3: Adjunctive Rapid-Acting Agents

Calcitonin-salmon for rapid effect when immediate reduction needed 1, 9:

• Dosing: 4 International Units/kg every 12 hours subcutaneously or intramuscularly, may increase to 8 IU/kg every 12 hours or maximum 8 IU/kg every 6 hours if inadequate response 9
• Provides rapid onset within hours but limited efficacy and tachyphylaxis develops 1, 8
• Use as bridge therapy until bisphosphonates take effect 1, 8
• Combining calcitonin with bisphosphonates enhances rate of calcium decline 6, 8

Cause-Specific Treatments

Vitamin D-Mediated Hypercalcemia

Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption 1, 2:

• Indicated for vitamin D intoxication, granulomatous diseases (sarcoidosis), some lymphomas, and multiple myeloma 1, 3
• Avoid vitamin D supplements in all patients with hypercalcemia 2

Malignancy-Associated Hypercalcemia

• Hydration plus zoledronic acid 4 mg IV is the cornerstone of treatment 1
• For multiple myeloma: add corticosteroids and consider plasmapheresis for symptomatic hyperviscosity 1
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1
• Treat the underlying cancer when possible 1, 2

Primary Hyperparathyroidism

Parathyroidectomy is indicated for 2:

• Symptomatic patients
• Osteoporosis, impaired kidney function, or kidney stones
• Hypercalciuria
• Age ≥50 years
• Calcium increased by >0.25 mmol/L above upper normal limit

Refractory or Severe Hypercalcemia with Renal Failure

Dialysis with calcium-free or low-calcium solution is reserved for severe hypercalcemia complicated by renal insufficiency 1, 4:

• Hemodialysis effectively removes calcium through diffusive therapy 1
• Denosumab may be considered in patients with kidney failure 3

Critical Pitfalls to Avoid

• Do NOT use loop diuretics before correcting hypovolemia - this worsens volume depletion 1, 7
• Avoid NSAIDs and IV contrast media in patients with renal impairment - prevents further kidney deterioration 1
• Do NOT delay bisphosphonate therapy in moderate to severe hypercalcemia - temporary measures provide only 1-4 hours of benefit 1
• Monitor serum creatinine before each bisphosphonate dose and withhold if renal deterioration occurs 1
• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg 1

Monitoring

Monitor serum calcium, renal function, and electrolytes regularly to assess treatment effectiveness 1, 2