What is the treatment approach for hypercalcemia?

Treatment of Hypercalcemia

Initiate aggressive IV normal saline hydration immediately, targeting urine output of 100-150 mL/hour, followed by IV zoledronic acid 4 mg infused over at least 15 minutes as the preferred bisphosphonate for definitive treatment. 1, 2

Initial Management: Hydration

• Administer IV normal saline as the cornerstone of initial therapy to correct hypovolemia and promote calciuresis, regardless of underlying etiology 1, 2
• Target urine output of at least 100 mL/hour (or 3 mL/kg/hour in children <10 kg) 1
• Avoid overhydration in patients with cardiac or renal insufficiency; use loop diuretics (furosemide) after volume repletion to prevent fluid overload 1
• Do not employ diuretic therapy prior to correction of hypovolemia 3

Definitive Pharmacologic Treatment: Bisphosphonates

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate due to superior efficacy compared to pamidronate 1, 4
• Dose adjustments are required for creatinine clearance <60 mL/min 1
• Monitor serum creatinine before each dose and withhold treatment if renal deterioration occurs 1
• Bisphosphonates are first-line treatment for moderate to severe hypercalcemia, especially malignancy-associated 1, 5
• Pamidronate 60-90 mg IV may be used as an alternative if zoledronic acid is unavailable 1, 3
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1

Adjunctive Rapid-Acting Therapy: Calcitonin

• Calcitonin-salmon 4 International Units/kg body weight every 12 hours by subcutaneous or intramuscular injection provides rapid onset of action within hours 1, 6
• If response is unsatisfactory after 1-2 days, increase to 8 International Units/kg every 12 hours 6
• Maximum dose: 8 International Units/kg every 6 hours 6
• Use calcitonin as a bridge until bisphosphonates take effect (which have delayed action of 2-4 days) 1, 4
• Combining calcitonin with bisphosphonates enhances the rate of decline of serum calcium 1
• Calcitonin has limited efficacy for long-term control but provides rapid symptom relief 1

Cause-Specific Treatments

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

• Glucocorticoids are the primary treatment for vitamin D-mediated hypercalcemia 1, 2, 5
• Prednisone 1 mg/kg/day orally or methylprednisolone IV equivalent 1
• Taper over 2-4 months depending on response 1
• Provide pneumocystis pneumonia prophylaxis for patients receiving ≥20 mg methylprednisolone equivalent for ≥4 weeks 1
• Add GI prophylaxis with proton pump inhibitor therapy for all patients on corticosteroids 1

Malignancy-Associated Hypercalcemia

• Treat the underlying cancer with chemotherapy, as this is essential for long-term control 2, 5
• Hydration plus bisphosphonates (zoledronic acid preferred) remain the cornerstone 1
• Plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients 1
• Median survival is approximately 1 month, indicating poor prognosis 1

Primary Hyperparathyroidism

• Parathyroidectomy is indicated for symptomatic patients and those with osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age ≥50 years, or calcium increased by >0.25 mmol/L above upper limit of normal 5
• For patients >50 years with serum calcium <1 mg above upper normal limit and no skeletal or kidney disease, observation may be appropriate 4

Tertiary Hyperparathyroidism (CKD Patients)

• Parathyroidectomy is considered for persistent hypercalcemic hyperparathyroidism despite optimized medical therapy 1
• Consider lower dialysate calcium concentration (1.5-2.0 mEq/L) to stimulate PTH and increase bone turnover 1
• Allow intact PTH to rise to at least 100 pg/mL to avoid low-turnover bone disease 1

Severe or Refractory Hypercalcemia

• Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is reserved for severe hypercalcemia complicated by renal insufficiency or oliguria 1, 7
• Dialysis effectively removes calcium through diffusive therapy 1

Diagnostic Workup (Concurrent with Treatment)

• Measure intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, albumin, magnesium, phosphorus, creatinine, and BUN 1, 2
• Calculate corrected calcium: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 [4 - Serum albumin (g/dL)] 1
• Preferably measure ionized calcium directly to avoid pseudo-hypercalcemia from hemolysis or improper sampling 1
• Assess medication history: thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day) 1

Critical Pitfalls to Avoid

• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia, as temporary measures like calcitonin provide only short-term benefit 1
• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent worsening renal function 1
• Do not restrict calcium intake excessively without medical supervision, as this can worsen bone disease 1
• Avoid vitamin D supplements in patients with hypercalcemia 1, 5
• Discontinue any nephrotoxic medications to avoid worsening renal function 1

Monitoring and Follow-up

• Monitor serum calcium, renal function, and electrolytes regularly to assess treatment effectiveness 1, 2
• Provide calcium supplementation (500 mg daily) plus vitamin D (400 IU daily) during bisphosphonate treatment to prevent hypocalcemia 1
• Correct hypocalcemia before initiating bisphosphonate therapy and monitor serum calcium closely, especially with denosumab which carries higher risk of hypocalcemia 1
• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg 1
• Assess ECG changes, particularly QT interval prolongation, in patients with severe hypercalcemia 1