What is the recommended approach to evaluating and managing hypercalcemia?

Approach to Hypercalcemia

Initial Diagnostic Workup

Measure intact parathyroid hormone (PTH) immediately—this single test distinguishes PTH-dependent (primary hyperparathyroidism) from PTH-independent (malignancy, granulomatous disease, medications) hypercalcemia and directs all subsequent management. 1, 2, 3

Essential First-Line Laboratory Panel

• Obtain ionized calcium rather than relying solely on corrected total calcium to avoid misclassification from hemolysis, improper sampling, or albumin abnormalities 1, 2
• If ionized calcium is unavailable, calculate corrected calcium: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 – Serum albumin (g/dL)] 1, 4
• Measure 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D together before any supplementation—their relationship provides critical diagnostic information 2, 4
• Check serum creatinine, phosphorus, magnesium, and albumin to assess renal function and guide treatment 1, 2

PTH-Based Diagnostic Algorithm

If PTH is elevated or inappropriately normal (>20 pg/mL) with hypercalcemia:

• Confirms primary hyperparathyroidism 2, 4, 3
• Measure 25-hydroxyvitamin D to exclude vitamin D deficiency causing secondary hyperparathyroidism (target >20 ng/mL) 2, 4
• Obtain 24-hour urine calcium or spot urine calcium/creatinine ratio to assess hypercalciuria and kidney stone risk 2
• Order renal ultrasound to evaluate for nephrocalcinosis or kidney stones 2
• Consider bone density scan if chronic disease suspected 2

If PTH is suppressed (<20 pg/mL):

• Measure PTH-related protein (PTHrP) for malignancy-associated hypercalcemia—elevated in majority of cancer cases 1, 2
• Check both 25-OH and 1,25-(OH)₂ vitamin D levels: elevated 25-OH suggests vitamin D intoxication; low 25-OH with elevated 1,25-(OH)₂ indicates granulomatous disease (sarcoidosis) or lymphoma 2, 4
• Obtain serum protein electrophoresis, immunofixation, and free light chains if multiple myeloma suspected 1
• Order age-appropriate cancer screening and imaging (chest/abdomen/pelvis CT, bone scan) based on clinical suspicion 1, 4

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Severity Stratification and Immediate Management

Mild Hypercalcemia (Corrected Calcium 10.5–12 mg/dL)

Discontinue all calcium supplements, vitamin D supplements, thiazide diuretics, and lithium immediately 2, 4

• Ensure adequate oral hydration (2–3 liters daily) to promote calciuresis 2
• Review all medications for contributors including vitamin A and calcium-based phosphate binders in CKD patients 2
• Recheck calcium, creatinine, and PTH within 2–4 weeks to confirm persistent hypercalcemia 2
• Do not start bisphosphonates in the outpatient setting for mild hypercalcemia—these are reserved for moderate-to-severe or malignancy-associated cases 2

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

Initiate aggressive IV normal saline hydration immediately, targeting urine output of 100–150 mL/hour, to correct hypovolemia and promote calciuresis 1, 4, 3

• Administer 250–500 mL crystalloid boluses every 15 minutes until rehydration achieved 1
• Avoid loop diuretics (furosemide) until complete volume repletion—premature use worsens dehydration and hypercalcemia 1, 4
• Add loop diuretics only in patients with renal or cardiac insufficiency to prevent fluid overload 1, 4
• Monitor serum calcium, creatinine, and electrolytes (potassium, magnesium, phosphorus) every 6–12 hours during acute phase 1

Life-Threatening Hypercalcemia (Corrected Calcium ≥14 mg/dL or Symptomatic)

Administer zoledronic acid 4 mg IV (infused over ≥15 minutes) early as definitive treatment—do not wait for complete rehydration 1, 3

• Zoledronic acid normalizes calcium in approximately 50% of patients by day 4 and is superior to pamidronate 1, 3
• For immediate short-term management, add calcitonin 100 IU subcutaneously or intramuscularly for rapid onset (within hours), though efficacy is limited 1, 5
• Check serum creatinine before each bisphosphonate dose; withhold if renal function deteriorates (increase >0.5 mg/dL from normal baseline or >1.0 mg/dL from abnormal baseline) 1
• Measure ionized calcium every 4–6 hours during first 48–72 hours, then twice daily until stable 1
• Obtain immediate 12-lead ECG to identify shortened QT interval, arrhythmias, or other cardiac manifestations 1

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Etiology-Specific Management

Primary Hyperparathyroidism (Elevated/Normal PTH with Hypercalcemia)

Refer to endocrinology and an experienced high-volume parathyroid surgeon for surgical evaluation 2, 4

Surgical indications include: 2, 4

• Corrected calcium >1 mg/dL above upper limit of normal
• Age <50 years
• eGFR <60 mL/min/1.73 m²
• Osteoporosis (T-score ≤–2.5 at any site)
• History of nephrolithiasis or nephrocalcinosis
• 24-hour urinary calcium >300 mg/24 hours
• Disabling neuropsychiatric symptoms (depression, cognitive impairment, "brain fog")

For non-surgical candidates: 2

• Maintain normal dietary calcium intake (1,000–1,200 mg/day)—do not restrict 2
• Ensure 25-hydroxyvitamin D >20 ng/mL with supplementation if needed 2, 4
• Monitor serum calcium every 3–6 months, creatinine every 6–12 months, bone density annually 2

Malignancy-Associated Hypercalcemia (Suppressed PTH, Elevated PTHrP)

Median survival is approximately 1 month after detection—imaging and oncology consultation must proceed simultaneously with calcium-lowering measures 1, 4, 3

• Perform immediate comprehensive imaging: chest CT, abdominal/pelvic CT or MRI, and PET-CT when available 2
• Most common PTHrP-secreting tumors: squamous cell carcinoma (lung, head/neck), renal cell carcinoma, breast carcinoma, neuroendocrine tumors 2, 4
• Hydration plus zoledronic acid 4 mg IV is the cornerstone of treatment 1, 4, 3
• For bisphosphonate-refractory hypercalcemia, use denosumab 120 mg subcutaneously, which lowers calcium in 64% of patients within 10 days 1
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1
• Temporarily discontinue myeloma therapy (lenalidomide, bortezomib) until calcium normalizes if severe hypercalcemia develops 1

Granulomatous Disease/Lymphoma (Suppressed PTH, Low 25-OH, Elevated 1,25-(OH)₂ Vitamin D)

Corticosteroids are primary therapy—start prednisone 20–40 mg/day orally or methylprednisolone IV equivalent 1, 4, 3

• Corticosteroids reduce excessive intestinal calcium absorption caused by elevated 1,25-dihydroxyvitamin D 1, 4
• Allow 3–6 months to demonstrate responsiveness before escalating 1
• Target lowest effective dose ≤10 mg/day to minimize toxicity 1
• If unable to wean below 10 mg/day after 3–6 months, add methotrexate as steroid-sparing agent 1

Vitamin D Intoxication (Suppressed PTH, Markedly Elevated 25-OH Vitamin D)

Discontinue all vitamin D supplements immediately, even if 25-OH vitamin D levels are low 1, 2

• Stop all calcium-based phosphate binders 1
• Corticosteroids (prednisone 20–40 mg/day) reduce intestinal calcium absorption 1, 4
• Do not resume vitamin D until serum calcium consistently <9.5 mg/dL and 24-hour urinary calcium normalizes (<300 mg/24 hours) 4

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Special Populations and Situations

Chronic Kidney Disease (CKD)

In CKD patients with hypercalcemia, immediately discontinue all calcium-based phosphate binders and vitamin D analogs (calcitriol, paricalcitol) 1, 4

• Use denosumab 120 mg subcutaneously instead of bisphosphonates in patients with eGFR <60 mL/min/1.73 m² to minimize nephrotoxicity 1, 4
• Anticipate higher risk of hypocalcemia with denosumab; provide calcium/vitamin D supplementation as needed 1
• For severe hypercalcemia with renal failure, hemodialysis with calcium-free or low-calcium dialysate (1.25–1.50 mmol/L) is definitive treatment 1, 4
• Target corrected calcium 8.4–9.5 mg/dL, preferably at lower end of range 1
• Maintain calcium-phosphorus product <55 mg²/dL² to prevent soft tissue calcification 1

Post-Parathyroidectomy

Measure ionized calcium every 4–6 hours for first 48–72 hours to detect "hungry bone syndrome" 2

• If ionized calcium drops below 0.9 mmol/L (≈3.6 mg/dL), start IV calcium gluconate infusion at 1–2 mg elemental calcium/kg/hour 2
• Once oral intake tolerated, transition to oral calcium carbonate 1–2 g three times daily plus calcitriol up to 2 µg/day 2

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Critical Pitfalls to Avoid

• Do not order parathyroid imaging before confirming biochemical diagnosis—imaging is for surgical planning, not diagnosis 2, 4
• Do not assume hypercalcemia is benign even if asymptomatic—untreated disease causes nephrocalcinosis, kidney stones, osteoporosis, and cardiac arrhythmias 2
• Do not rely on corrected calcium instead of ionized calcium—it can lead to inaccurate diagnosis 1
• Do not use loop diuretics before complete volume repletion—premature use worsens hypercalcemia 1, 4
• Avoid NSAIDs and IV contrast media in patients with renal impairment—they worsen kidney function 1
• Do not delay bisphosphonate therapy in moderate-to-severe hypercalcemia—temporary measures like calcitonin provide only 1–4 hours of benefit 1
• Do not restrict calcium intake excessively without medical supervision—this worsens bone disease 1

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Monitoring During Acute Treatment

• Ionized calcium every 4–6 hours during first 48–72 hours, then twice daily until stable 1, 2
• Serum creatinine before each bisphosphonate dose; withhold if deterioration occurs 1
• Electrolytes (potassium, magnesium, phosphorus) every 6–12 hours in acute phase 1
• Continuous cardiac monitoring if ECG abnormalities or arrhythmias detected 1
• Daily weights, intake/output, physical exam to prevent volume overload 1