What is the management of hypercalcaemia?

Management of Hypercalcaemia

For symptomatic or severe hypercalcaemia (corrected calcium ≥12 mg/dL or ≥3 mmol/L), initiate immediate treatment with intravenous normal saline hydration followed by intravenous bisphosphonates—either zoledronic acid 4 mg over 5 minutes or pamidronate 90 mg over 2 hours—which normalizes calcium in 50-61% of patients by day 4-7. 1

Initial Assessment

Before initiating treatment, verify the diagnosis and severity:

• Measure corrected serum calcium (adjusted for albumin) or ideally ionized calcium, as total calcium may underestimate severity in patients with hypoalbuminemia, which is common in malignancy 1, 2
• Classify severity: Mild (<12 mg/dL or <3 mmol/L), moderate (12-14 mg/dL), or severe (≥14 mg/dL or ≥3.5 mmol/L) 2
• Identify the underlying cause by measuring intact parathyroid hormone (PTH): elevated or normal PTH indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) suggests malignancy or other causes 2
• In cancer patients, suspect hypercalcaemia when acute or subacute confusion, asthenia, or drowsiness develops, even if symptoms are subtle 1

Acute Management Algorithm

Step 1: Hydration (Initiate Immediately)

• Administer intravenous normal saline to correct hypovolemia and promote calciuresis 1, 2
• Volume expansion alone can reduce calcium levels in mild cases and is essential before other interventions 3
• Continue aggressive hydration throughout treatment, as hypercalcaemia causes polyuria and progressive dehydration 1, 4

Step 2: Bisphosphonates (First-Line Pharmacologic Therapy)

Zoledronic acid is preferred due to superior efficacy and convenience:

• Dose: 4 mg intravenously over 5 minutes (not 24 hours as with older protocols) 1
• Normalizes calcium in 50% of patients by day 4, compared to 33% with pamidronate 1
• Reserve the 8 mg dose for relapsed or refractory cases 1

Pamidronate is an alternative:

• Dose: 90 mg intravenously over 2 hours 1, 5
• Normalizes calcium in 61% of patients by day 7 1
• Requires longer infusion time than zoledronic acid 5

Critical timing consideration: Bisphosphonates require 2-4 days to achieve maximal effect, so administer early even if calcium is declining with hydration alone 4, 6

Step 3: Adjunctive Rapid-Acting Agents (For Severe or Symptomatic Cases)

When immediate calcium reduction is needed while awaiting bisphosphonate effect:

Calcitonin:

• Dose: Salmon calcitonin 4-8 IU/kg subcutaneously or intramuscularly every 6-12 hours 4, 3
• Onset within 4-6 hours but modest effect (reduces calcium by 1-2 mg/dL) 1, 4
• Tachyphylaxis develops within 48 hours, limiting usefulness 4, 6
• Combining calcitonin with bisphosphonates accelerates calcium decline 4, 6

Loop diuretics:

• Use furosemide only after volume repletion to avoid worsening dehydration 1, 3
• Promotes calciuresis but has limited efficacy as monotherapy 1

Step 4: Cause-Specific Therapy

For malignancy-associated hypercalcaemia:

• Hypercalcaemia indicates poor prognosis (median survival ~1 month in lung cancer) and often becomes treatment-refractory near end of life 1
• Bisphosphonates may reverse delirium in 40% of cases 1
• For bisphosphonate-refractory cases: Consider denosumab 120 mg subcutaneously, which lowers calcium in 64% of refractory patients within 10 days 1
• Monitor for hypocalcaemia after denosumab and supplement with calcium/vitamin D as needed 1
• Note: Denosumab has FDA approval for bisphosphonate-refractory hypercalcaemia of malignancy in the US but not in Europe 1

For vitamin D-mediated hypercalcaemia (sarcoidosis, lymphomas, vitamin D intoxication):

• Glucocorticoids are first-line therapy: Prednisone 40-60 mg daily orally 2, 4, 7
• Effective when hypercalcaemia results from excessive intestinal calcium absorption 2, 7
• Bisphosphonates are less effective in these conditions 4

For primary hyperparathyroidism:

• Definitive treatment is parathyroidectomy 2, 3
• In patients >50 years with calcium <1 mg/dL above normal and no skeletal or renal complications, observation is appropriate 2

Management of Mild Asymptomatic Hypercalcaemia

For corrected calcium <12 mg/dL without symptoms:

• No acute intervention required 2
• Focus on treating underlying cause 3
• Prevent complications: maintain hydration, avoid prolonged immobilization, discontinue thiazide diuretics and calcium/vitamin D supplements 4, 6
• Monitor for progression, as mild hypercalcaemia can cause long-term complications like renal calculi 7

Critical Pitfalls to Avoid

• Do not delay bisphosphonate administration while waiting for hydration alone to work—their delayed onset (2-4 days) necessitates early initiation 4, 6
• Do not use loop diuretics before adequate volume repletion, as this worsens dehydration and renal impairment 1, 3
• Do not rely on glucocorticoids for malignancy-associated hypercalcaemia—they are ineffective except in specific malignancies like lymphoma 2, 4
• Monitor electrolytes closely: Correct hypokalemia and hypomagnesemia, which commonly accompany hypercalcaemia 1, 4
• In cancer patients, recognize that hypercalcaemia is both a negative prognostic factor and potentially reversible cause of delirium, warranting aggressive treatment even in advanced disease 1

Monitoring and Follow-Up

• Measure calcium daily during acute treatment until normalized 3
• Check phosphate levels: Hypophosphatemia develops in 30% of patients after bisphosphonates; supplement if needed 5
• For recurrent hypercalcaemia: Consider maintenance bisphosphonates (pamidronate or zoledronic acid every 3-4 weeks) or denosumab for malignancy-associated cases 1, 6
• Address the underlying disease definitively—temporizing measures alone are insufficient for long-term control 6