What is the approach to managing hypercalcemia?

Management of Hypercalcemia

Initiate treatment with intravenous normal saline hydration followed immediately by intravenous bisphosphonates (zoledronic acid 4 mg preferred) for moderate to severe hypercalcemia, as this combination provides the most effective and rapid reduction in serum calcium levels. 1, 2, 3

Severity Classification and Initial Assessment

Classify hypercalcemia severity to guide treatment intensity:

• Mild: Total calcium >10.5 to <12 mg/dL (>2.6 to <3.0 mmol/L) 4, 3
• Moderate: Total calcium 12-14 mg/dL (3.0-3.5 mmol/L) 4, 3
• Severe: Total calcium ≥14 mg/dL (≥3.5 mmol/L) or ionized calcium ≥10 mg/dL (≥2.5 mmol/L) 4, 3

Always calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4], particularly when albumin is abnormal, as hyperalbuminemia can mask true calcium status 4, 2

Obtain the following laboratory tests to determine etiology:

• Intact parathyroid hormone (iPTH) - the single most important test 1, 4, 3
• PTH-related protein (PTHrP) if PTH is suppressed 1, 4
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D 1, 4
• Serum phosphorus, magnesium, albumin, BUN, and creatinine 1, 4
• Urine calcium/creatinine ratio 4

Assess for symptoms based on severity:

• Mild/moderate: polyuria, polydipsia, nausea, vomiting, abdominal pain, myalgia, fatigue, constipation 1, 4, 3
• Severe: confusion, mental status changes, dehydration, bradycardia, hypotension, acute renal failure, somnolence, coma 1, 4, 3

Treatment Algorithm by Severity

Mild Asymptomatic Hypercalcemia (Calcium <12 mg/dL)

Oral hydration alone is sufficient for mild asymptomatic cases 4

For primary hyperparathyroidism in patients >50 years with calcium <1 mg above upper normal limit and no skeletal or kidney disease, observation with monitoring every 2-3 months is appropriate 4, 3

Consider parathyroidectomy for younger patients, higher calcium levels, or evidence of skeletal/kidney involvement 1, 3

Moderate to Severe Hypercalcemia (Calcium ≥12 mg/dL)

Step 1: Aggressive IV Hydration

• Administer IV normal saline (not containing calcium) to correct hypovolemia and promote calciuresis 1, 4, 3
• Target urine output of at least 100 mL/hour (3 mL/kg/hour in children <10 kg) 1
• Aim for approximately 2 L/day urine output throughout treatment 2
• Critical caveat: Avoid overhydration in patients with cardiac failure 2, 5
• Loop diuretics (furosemide) should only be used if renal or cardiac insufficiency is present to prevent fluid overload - do NOT use routinely as they provide no additional calcium-lowering benefit and may worsen outcomes 1, 6

Step 2: Bisphosphonate Therapy (Do Not Delay)

• Zoledronic acid 4 mg IV is the preferred bisphosphonate over pamidronate 1, 4, 2, 3
• Infuse over no less than 15 minutes 2
• Do not delay bisphosphonate administration - temporary measures provide only 1-4 hours of benefit 1
• Expected response: calcium reduction of 0.57 ± 0.27 mmol/L with normalization in 60% of patients within 3-6 days 7, 6, 5
• Dose adjustments for renal impairment (CrCl <60 mL/min): 2
  • CrCl 50-60 mL/min: 3.5 mg
  • CrCl 40-49 mL/min: 3.3 mg
  • CrCl 30-39 mL/min: 3.0 mg
  • Contraindicated if CrCl <30 mL/min - consider denosumab instead 4

Step 3: Adjunctive Calcitonin (For Rapid Effect)

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly provides more rapid but modest calcium reduction 1, 3
• Use as a bridge until bisphosphonates take effect (onset in 3-6 days) or in patients who cannot tolerate other treatments 1, 7
• Combining calcitonin with bisphosphonates enhances the rate of calcium decline 7

Special Treatment Considerations by Etiology

Hypercalcemia of Malignancy:

• Hydration + zoledronic acid 4 mg IV is first-line 1, 2, 5
• For multiple myeloma: continue bisphosphonates for up to 2 years 1
• Denosumab is recommended for refractory hypercalcemia, especially with renal impairment 4
• Plasmapheresis for symptomatic hyperviscosity in multiple myeloma 1
• Treat underlying malignancy when possible 1

Vitamin D-Mediated Hypercalcemia (Sarcoidosis, Lymphoma, Vitamin D Intoxication):

• Glucocorticoids are the primary treatment for excessive intestinal calcium absorption 3, 5
• Avoid vitamin D supplements 1

Tertiary Hyperparathyroidism:

• Consider parathyroidectomy for persistent hypercalcemic hyperparathyroidism despite optimized medical therapy 1

Severe Hypercalcemia with Renal Failure:

• Dialysis is reserved for severe hypercalcemia complicated by renal insufficiency 1, 5
• Hemodialysis effectively removes calcium through diffusive therapy 1
• Consider denosumab as it does not require renal dose adjustment 4

Monitoring and Retreatment

Monitor serum creatinine before each bisphosphonate dose 2

Withhold treatment for renal deterioration defined as: 2

• Increase of 0.5 mg/dL in patients with normal baseline creatinine
• Increase of 1.0 mg/dL in patients with abnormal baseline creatinine
• Resume only when creatinine returns to within 10% of baseline 2

Retreatment with zoledronic acid 4 mg may be considered if calcium does not normalize, with a minimum 7-day interval between doses 2

Supplement all patients receiving bisphosphonates with: 2

• Oral calcium 500 mg daily
• Vitamin D 400 IU daily

Monitor for treatment complications: 4

• Renal toxicity and osteonecrosis of jaw with bisphosphonates
• Hypocalcemia post-treatment with denosumab

Critical Pitfalls to Avoid

Do not use loop diuretics before correcting hypovolemia - they provide no additional calcium-lowering benefit beyond saline alone and may worsen outcomes 2, 6

Do not restrict calcium intake without medical supervision, particularly in pediatric patients 1

Avoid NSAIDs and IV contrast media in patients with renal impairment 1

Do not delay bisphosphonate therapy waiting for hydration alone to work - hydration rarely normalizes calcium levels without bisphosphonates 6