How to manage hypercalcemia?

Management of Hypercalcemia

Initiate treatment with intravenous normal saline hydration followed immediately by bisphosphonate therapy (zoledronic acid 4 mg IV over 15 minutes) for moderate to severe hypercalcemia, as this combination provides the most effective and rapid correction of calcium levels. 1, 2, 3

Initial Assessment

Measure intact PTH to distinguish the underlying cause:

• Elevated or inappropriately normal PTH indicates primary hyperparathyroidism 4, 3
• Suppressed PTH (<20 pg/mL) suggests malignancy or other non-PTH-mediated causes 3

Additional diagnostic workup should include:

• PTHrP (elevated in malignancy-associated hypercalcemia, particularly squamous cell and renal cell carcinomas) 4
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels 1, 4
• Serum creatinine, albumin, magnesium, and phosphorus 1
• Assess for symptoms: polyuria, polydipsia, nausea, vomiting, confusion, dehydration, mental status changes 1, 4

Treatment Algorithm by Severity

Mild Hypercalcemia (Total calcium <12 mg/dL)

For asymptomatic patients:

• Maintain normal calcium intake (minimum 1g daily) and avoid excessive supplementation 5
• Correct any vitamin D deficiency 5
• Monitor serum calcium, renal function, and electrolytes regularly 5

For symptomatic mild hypercalcemia:

• Begin IV normal saline hydration 5
• Consider bisphosphonate therapy if symptoms persist 5

Moderate to Severe Hypercalcemia (Total calcium ≥12 mg/dL or ionized calcium ≥5.6 mg/dL)

Step 1: Immediate Hydration

• Administer IV normal saline to correct hypovolemia and promote calciuresis 1, 3
• Target urine output of at least 100 mL/hour (3 mL/kg/hour in children <10 kg) 1
• Loop diuretics should only be used in patients with renal or cardiac insufficiency to prevent fluid overload, NOT routinely 1, 6

Critical pitfall: Furosemide provides no additional benefit and may actually increase calcium levels when used without adequate hydration—a 2022 study showed furosemide increased calcium by 0.09 mmol/L in severe hyperparathyroid hypercalcemia 7

Step 2: Bisphosphonate Therapy (First-Line)

• Zoledronic acid 4 mg IV over 15 minutes is the preferred agent 1, 2, 3
• Maximum reduction in calcium occurs within 3-6 days, with mean reduction of 0.57 mmol/L 7
• Achieves normocalcemia in 60% of severe cases 7
• Do not infuse over less than 15 minutes—faster infusion increases renal toxicity risk 2

Dose adjustments for renal impairment (CrCl 30-60 mL/min):

• CrCl 50-60: 3.5 mg 2
• CrCl 40-49: 3.3 mg 2
• CrCl 30-39: 3.0 mg 2
• Contraindicated if CrCl <30 mL/min 2

Step 3: Adjunctive Calcitonin (For Rapid Effect)

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly provides rapid but modest calcium reduction within hours 1, 6
• Use as a bridge until bisphosphonates take effect (which requires 2-4 days) 1, 6
• Standard dosing: 200 IU/day nasal spray or 100 IU SC/IM every other day 1

Life-Threatening Hypercalcemia (Total calcium ≥14 mg/dL or ionized calcium ≥10 mg/dL)

Immediate interventions:

• Aggressive IV saline hydration plus immediate bisphosphonate administration 3
• Add calcitonin for rapid initial effect 6, 3
• Consider hemodialysis for patients with severe renal insufficiency or when other measures fail 1, 6, 3
• Plasmapheresis may be used as adjunctive therapy in malignancy-associated hyperviscosity 1

Cause-Specific Management

Primary Hyperparathyroidism

Parathyroidectomy is indicated for:

• Symptomatic patients 4
• Age <50 years 4
• Calcium >0.25 mmol/L above upper limit of normal 4
• Osteoporosis, impaired kidney function, kidney stones, or hypercalciuria 4

Conservative management acceptable for:

• Patients >50 years with calcium <1 mg/dL above upper limit and no skeletal or kidney disease 3

Malignancy-Associated Hypercalcemia

• Treat the underlying cancer as definitive therapy 1, 4
• Continue bisphosphonate therapy for up to 2 years in multiple myeloma or bone metastases 1
• Prognosis is poor—hypercalcemia of malignancy indicates advanced disease 3

Vitamin D-Mediated Hypercalcemia (Granulomatous Disease, Lymphoma, Intoxication)

• Glucocorticoids are the primary treatment for excessive intestinal calcium absorption 4, 6, 3
• Avoid vitamin D supplements 1, 4

Monitoring and Retreatment

Monitor before each treatment:

• Serum creatinine must be assessed prior to each bisphosphonate dose 2
• Withhold treatment if creatinine increases by 0.5 mg/dL (normal baseline) or 1.0 mg/dL (abnormal baseline) 2
• Resume only when creatinine returns to within 10% of baseline 2

Retreatment with zoledronic acid:

• Allow minimum 7 days between doses to assess full response 2
• May repeat if calcium does not normalize or remains elevated 2

Supplementation during bisphosphonate therapy:

• Administer oral calcium 500 mg daily plus vitamin D 400 IU daily to prevent hypocalcemia 2

Special Populations

Chronic kidney disease patients:

• Careful monitoring required with bisphosphonates 4, 5
• Consider denosumab as alternative in severe renal failure 3
• Dialysis may be necessary for severe hypercalcemia with renal insufficiency 1, 6

Pediatric patients (Williams syndrome):

• Low-calcium diet and increased water intake under medical supervision 4
• Avoid vitamin D supplements 1