Treatment of Hypercalcemia
The treatment of hypercalcemia should begin with aggressive IV fluid resuscitation with normal saline, followed by bisphosphonates (preferably zoledronic acid 4 mg IV over 15 minutes) as the first-line pharmacological intervention, particularly for cancer-related hypercalcemia. 1
Initial Assessment and Classification
Severity classification:
- Mild: Total calcium <12 mg/dL (<3 mmol/L)
- Severe: Total calcium ≥14 mg/dL (≥3.5 mmol/L) 2
Essential diagnostic tests:
- Corrected calcium calculation: Total calcium + 0.8 × (4.0 - serum albumin)
- Intact parathyroid hormone (iPTH)
- Phosphorus, magnesium, renal function tests
- 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels 1
Treatment Algorithm
Step 1: Fluid Resuscitation
- Administer intravenous normal saline to:
- Correct hypercalcemia-associated hypovolemia
- Promote calciuresis
- Target urine output >2 L/day or >2 mL/kg/hour 1
- Caution: Avoid overhydration in patients with cardiac failure 1
Step 2: Bisphosphonate Therapy
- First choice: Zoledronic acid 4 mg IV over 15 minutes
- Superior efficacy (50% response by day 4 vs. 33% for pamidronate)
- Longer duration of action (30-40 days vs. 17 days for pamidronate) 1
- Alternative: Pamidronate 90 mg IV over 2 hours 1
- For refractory cases: Consider zoledronic acid 8 mg 1
Step 3: Additional Pharmacologic Options
- Denosumab: For hypercalcemia refractory to bisphosphonates or in patients with severe renal impairment (64% response rate) 1
- Calcitonin: For immediate short-term management of severe symptomatic hypercalcemia 3
- Rapid onset but short duration of effect
- Can be used while waiting for bisphosphonates to take effect 4
- Glucocorticoids: For hypercalcemia due to:
- Vitamin D toxicity
- Granulomatous disorders (e.g., sarcoidosis)
- Some lymphomas 1
- Loop diuretics: Only after adequate hydration to enhance calcium excretion 1
Special Considerations
Primary Hyperparathyroidism
- Parathyroidectomy is the definitive treatment
- Observation with monitoring may be appropriate for:
- Patients >50 years
- Serum calcium <1 mg/dL above upper normal limit
- No evidence of skeletal or kidney disease 1
Renal Impairment
- Reduce bisphosphonate dose in patients with renal impairment
- Avoid bisphosphonates in severe renal impairment
- Consider denosumab as an alternative 1
Malignancy-Associated Hypercalcemia
- More aggressive treatment typically required due to higher calcium levels and more severe symptoms 2
- Zoledronic acid is superior to both clodronate and pamidronate 5, 6
Monitoring and Follow-up
- Regular monitoring of:
- Serum calcium, phosphate, magnesium
- Renal function
- Watch for hypocalcemia after treatment (especially with denosumab)
- Retreat with bisphosphonates if calcium does not normalize 1
Common Pitfalls to Avoid
- Using diuretics before correcting hypovolemia
- Failing to correct calcium for albumin
- Inadequate hydration before bisphosphonate administration
- Treating laboratory values without addressing the underlying cause
- Delaying treatment of severe hypercalcemia
- Administering bisphosphonates too rapidly
- Failing to monitor for hypocalcemia after treatment 1
Long-term Management
- Identify and treat the underlying cause
- For patients with postmenopausal osteoporosis requiring calcitonin:
- Ensure adequate calcium (≥1000 mg elemental calcium/day)
- Ensure adequate vitamin D (≥400 IU/day) 3
- Dental examination before starting bisphosphonate therapy due to risk of osteonecrosis of the jaw 1