What is the treatment approach for a patient with hypercalcemia?

Treatment of Hypercalcemia

Immediately initiate aggressive IV normal saline hydration 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

Initial Assessment and Diagnostic Workup

Before initiating treatment, obtain the following laboratory tests to determine the underlying cause:

• Intact PTH (most important single test to distinguish PTH-dependent from PTH-independent causes) 2
• PTHrP (elevated in malignancy-associated hypercalcemia) 1, 3
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (both needed together for diagnostic accuracy) 1
• Serum calcium, albumin, phosphorus, magnesium 1
• Serum creatinine and BUN (to assess renal function before bisphosphonate dosing) 1
• Calculate corrected calcium: Total calcium (mg/dL) + 0.8 × [4.0 - Serum albumin (g/dL)] 1

Assess symptom severity: mild hypercalcemia (<12 mg/dL) may present with fatigue and constipation, while severe hypercalcemia (>14 mg/dL) causes nausea, vomiting, confusion, dehydration, and mental status changes. 1, 4

Treatment Algorithm by Severity

Mild Asymptomatic Hypercalcemia (<12 mg/dL)

• Conservative management with oral hydration and observation may be appropriate 5, 6
• Discontinue any causative medications (thiazides, lithium, calcium/vitamin D supplements) immediately 1, 3
• If due to primary hyperparathyroidism in patients >50 years with calcium <1 mg/dL above upper normal limit and no skeletal/renal involvement, observation is reasonable 4
• Consider parathyroidectomy if patient meets criteria: symptomatic disease, osteoporosis, impaired kidney function, kidney stones, age <50 years, or calcium >0.25 mmol/L above upper limit 2

Moderate to Severe Hypercalcemia (≥12 mg/dL)

Step 1: Aggressive Hydration

• Administer IV normal saline aggressively to correct hypovolemia and promote calciuresis 1, 2
• Target urine output of 100-150 mL/hour (or 3 mL/kg/hour in children <10 kg) 1
• Continue hydration to maintain diuresis >2.5 L/day in adults 1
• Critical pitfall: Do NOT use loop diuretics (furosemide) before complete volume repletion; only use in patients with renal or cardiac insufficiency to prevent fluid overload 1, 7

Step 2: Bisphosphonate Therapy (First-Line Definitive Treatment)

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred agent due to superior efficacy compared to pamidronate 1, 4
• Normalizes calcium in 50% of patients by day 4 1
• Dose adjustments required for creatinine clearance <60 mL/min 1
• Monitor serum creatinine before each dose; withhold if renal deterioration occurs 1
• Alternative: Pamidronate IV if zoledronic acid unavailable 1, 5

Step 3: Adjunctive Rapid-Acting Therapy

• Calcitonin 100 IU subcutaneously or intramuscularly for immediate short-term management while waiting for bisphosphonates to take effect 1, 7
• Provides rapid onset within hours but limited efficacy and duration (1-4 hours) 1
• Use as a bridge therapy only 1

Cause-Specific Treatment Modifications

Malignancy-Associated Hypercalcemia

• Hydration + zoledronic acid 4 mg IV is the cornerstone 1
• Treat underlying cancer when possible (essential for long-term control) 3, 2
• For multiple myeloma: add corticosteroids (prednisone 20-40 mg/day or methylprednisolone IV equivalent) 1
• Continue bisphosphonate therapy for up to 2 years in patients with bone metastases 1
• Prognosis: Hypercalcemia of malignancy carries poor prognosis with median survival approximately 1 month 1

Vitamin D-Mediated Hypercalcemia (Sarcoidosis, Lymphomas, Granulomatous Diseases)

• Corticosteroids are primary therapy (not bisphosphonates) 1, 4
• Prednisone 20-40 mg/day orally or methylprednisolone IV equivalent 1
• Target lowest effective dose ≤10 mg/day to minimize toxicity 1
• Allow 3-6 months to demonstrate responsiveness before escalation 1
• If unable to wean below 10 mg/day after 3-6 months, add methotrexate as steroid-sparing agent 1

Primary Hyperparathyroidism

• Parathyroidectomy is definitive treatment for symptomatic patients or those meeting surgical criteria 3, 2
• Observation with monitoring is appropriate for asymptomatic patients >50 years with mild elevation 4

Refractory or Special Situations

Bisphosphonate-Refractory Hypercalcemia

• Denosumab 120 mg subcutaneously lowers calcium in 64% of patients within 10 days 1
• Preferred in patients with impaired renal function (lower renal toxicity than bisphosphonates but higher hypocalcemia risk) 1

Severe Hypercalcemia with Renal Failure

• 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
• Effectively removes calcium through diffusive therapy 1

Chronic Kidney Disease Patients

• Immediately discontinue all calcium-based phosphate binders and vitamin D analogs (calcitriol, paricalcitol) 1
• Consider lower dialysate calcium concentration (1.5-2.0 mEq/L) if PTH is suppressed 1

Monitoring and Follow-Up

• Monitor serum calcium, renal function, and electrolytes every 6-12 hours during acute phase 1
• Correct hypocalcemia before initiating bisphosphonate therapy 1
• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia 1
• Perform baseline dental examination before initiating bisphosphonates to prevent osteonecrosis of the jaw 1
• Watch for bisphosphonate complications: renal toxicity and osteonecrosis of jaw with chronic use 2

Critical Pitfalls to Avoid

• Never use loop diuretics before complete volume repletion 1, 7
• Avoid NSAIDs and IV contrast media in patients with renal impairment (worsens kidney function) 1
• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia; temporary measures provide only 1-4 hours benefit 1
• Discontinue all vitamin D supplements immediately in hypercalcemic patients 1, 3
• Avoid overhydration in patients with cardiac or renal insufficiency 1
• Do not restrict calcium intake excessively without medical supervision (can worsen bone disease) 1