What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

The treatment of hypercalcemia should begin with aggressive intravenous normal saline hydration followed by bisphosphonates, with specific interventions tailored to the severity, cause, and patient factors. 1

Initial Assessment and Management

Step 1: Assess Severity and Cause

• Calculate corrected calcium using formula: Corrected calcium = Total calcium + 0.8 × (4.0 - serum albumin) 1
• Obtain initial laboratory tests:
  • Intact parathyroid hormone (iPTH)
  • Phosphorus, magnesium
  • Renal function tests
  • 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels
  • Urinary calcium/creatinine ratio 1

Step 2: Hydration (First-line for all hypercalcemia)

• Begin with intravenous normal saline to:
  • Correct hypercalcemia-associated hypovolemia
  • Promote calciuresis
  • Target urine output >2 L/day or >2 mL/kg/hour 1
• Important: Avoid overhydration in patients with cardiac failure 1

Step 3: Pharmacological Management

Based on severity:

Mild Hypercalcemia (< 12 mg/dL)

• Monitor serum calcium and phosphorus at least every 3 months
• Avoid excessive calcium intake (total elemental calcium not exceeding 2,000 mg/day)
• Discontinue vitamin D supplementation if calcium levels exceed 10.2 mg/dL 1

Moderate to Severe Hypercalcemia (≥ 12 mg/dL)

1. Bisphosphonates (first-line pharmacological therapy):

   • Zoledronic acid 4 mg IV over 15 minutes (preferred due to superior efficacy and longer duration)
     • Response rate: 50% by day 4
     • Duration of response: 30-40 days 1
   • Alternative: Pamidronate 90 mg IV over 2 hours
     • Less potent than zoledronic acid
     • Duration of response: 17 days 1
   • Dose adjustments for renal impairment (see table below)

2. Denosumab (for refractory cases or severe renal impairment):

   • 120 mg subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of first month 2
   • Response rate: 64% in bisphosphonate-refractory cases 1

3. Calcitonin (for immediate short-term management):

   • Useful for rapid but short-term calcium reduction
   • Often combined with bisphosphonates for faster initial response 1

4. Loop diuretics (after adequate hydration):

   • Enhance calcium excretion
   • Caution: Do not use before correcting hypovolemia 1

5. Glucocorticoids (for specific causes):

   • Effective for hypercalcemia due to:
     • Vitamin D toxicity
     • Granulomatous disorders (sarcoidosis, tuberculosis)
     • Some lymphomas 1

Dose Adjustments for Zoledronic Acid in Renal Impairment

Baseline Creatinine Clearance (mL/min)	Zoledronic Acid Recommended Dose (mg)
>60	4
50-60	3.5
40-49	3.3
30-39	3

Cause-Specific Management

Primary Hyperparathyroidism

• For mild cases (calcium <1 mg/dL above upper limit) in patients >50 years without evidence of skeletal or kidney disease:
  • Observation with monitoring may be appropriate 1
• For symptomatic or severe cases:
  • Parathyroidectomy is definitive treatment 3

Malignancy-Related Hypercalcemia

• More aggressive approach with IV hydration and bisphosphonates
• Zoledronic acid 4 mg IV is first choice 1, 4
• Consider waiting minimum 7 days before retreatment with zoledronic acid 1

Vitamin D-Related Hypercalcemia

• Discontinue vitamin D supplementation
• Consider glucocorticoids 1
• Maintain hydration

Monitoring and Follow-up

• Regular monitoring of serum calcium, phosphate, magnesium, and renal function 1
• Watch for hypocalcemia after treatment, especially with denosumab 1
• Assess for adequate urine output (target >2 L/day) 1
• Consider retreatment if calcium does not normalize or rises again 1

Common Pitfalls to Avoid

1. Using diuretics before correcting hypovolemia 1
2. Failing to correct calcium for albumin 1
3. Inadequate hydration before bisphosphonate administration 1
4. Treating laboratory values without addressing the underlying cause 1
5. Delaying treatment of severe hypercalcemia 1
6. Administering bisphosphonates too rapidly 1
7. Failing to monitor for hypocalcemia after treatment 1

Special Considerations

• Perform dental examination before starting bisphosphonate therapy due to risk of osteonecrosis of the jaw (higher with zoledronic acid at 3.7% vs. clodronate at 0.5%) 1
• Consider familial hypocalciuric hypercalcemia, which typically requires no treatment 1
• For patients with granulomatous disorders, be aware of increased risk of hypercalcemia even with normal vitamin D levels 1