Hypercalcemia Workup and Management
Initial Diagnostic Workup
Measure serum intact parathyroid hormone (iPTH) immediately—this single test distinguishes PTH-dependent from PTH-independent causes and directs all subsequent management. 1, 2
Essential Laboratory Tests
Calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4], or preferably measure ionized calcium directly to avoid missing true hypercalcemia masked by hypoalbuminemia 2, 3
Complete initial panel should include: iPTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, albumin, magnesium, phosphorus, creatinine, and BUN 1, 2
Interpret iPTH results algorithmically:
If iPTH is suppressed, check PTHrP to distinguish humoral malignancy (elevated PTHrP) from other causes 1, 3
Severity Classification
- Mild: 10-11 mg/dL (2.5-2.75 mmol/L) - usually asymptomatic, may have fatigue and constipation in 20% 2, 4
- Moderate: 11-12 mg/dL or 12-13.5 mg/dL (2.75-3.4 mmol/L) 2, 3
- Severe: >14 mg/dL (>3.5 mmol/L) - causes nausea, vomiting, confusion, somnolence, coma 2, 4
Symptom Assessment by Severity
- Mild/moderate: Look specifically for polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain, myalgia 1, 2
- Severe: Assess for mental status changes, bradycardia, hypotension, dehydration, acute renal failure 2
- Check ECG for QT interval prolongation in severe cases 1
Treatment Algorithm
Step 1: Immediate Hydration (All Symptomatic Cases)
Administer IV normal saline immediately to correct hypovolemia and promote calciuresis—this is the cornerstone of acute management regardless of etiology. 1, 2, 3
- Target urine output of ≥100 mL/hour (3 mL/kg/hour in children <10 kg) 1, 2
- Avoid overhydration in patients with cardiac or renal insufficiency; use loop diuretics (furosemide) after volume repletion only if needed to prevent fluid overload [1, @10@]
- Critical pitfall: Furosemide provides no additional calcium-lowering benefit beyond saline hydration alone and may worsen dehydration if used prematurely 6
Step 2: Definitive Pharmacologic Treatment
For Moderate to Severe Hypercalcemia (Especially Malignancy-Associated)
Administer zoledronic acid 4 mg IV over 15 minutes as first-line bisphosphonate therapy—it is superior to pamidronate in efficacy and duration of response. 1, 2, 3
- Zoledronic acid normalizes calcium in approximately 50% of patients by day 4 and provides longer response duration than pamidronate 3
- Dose adjustment for renal impairment: Monitor serum creatinine before each dose; withhold if creatinine increases >0.5 mg/dL (normal baseline) or >1.0 mg/dL (abnormal baseline) 1, 3
- Alternative if zoledronic acid unavailable: Pamidronate 60-90 mg IV over 2-24 hours (longer infusions reduce renal toxicity risk) [7, @10@]
Bridging Therapy for Severe Symptomatic Cases
- Calcitonin 100 IU subcutaneously or intramuscularly provides rapid onset within hours but limited efficacy; use only as bridge until bisphosphonates take effect 1, 2
For Vitamin D-Mediated Hypercalcemia
- Glucocorticoids are first-line for excessive intestinal calcium absorption (vitamin D intoxication, granulomatous diseases like sarcoidosis, some lymphomas, multiple myeloma) 1, 2, 4
Step 3: Refractory or Special Cases
For bisphosphonate-refractory hypercalcemia or patients with renal insufficiency, use denosumab 120 mg subcutaneously—it reduces calcium in 64% of refractory cases. 2, 3
- Critical warning: Denosumab carries significant risk of severe hypocalcemia; monitor calcium levels closely and supplement with oral calcium 500 mg plus vitamin D 400 IU daily 1, 2
- Correct hypocalcemia before initiating any bisphosphonate or denosumab therapy 1
For Severe Hypercalcemia with Renal Failure
- Hemodialysis with calcium-free or low-calcium dialysate is reserved for severe hypercalcemia (>14 mg/dL) complicated by renal insufficiency or oliguria [1, @10@]
Etiology-Specific Management
Primary Hyperparathyroidism (Elevated/Normal iPTH)
- Parathyroidectomy is definitive treatment for patients meeting surgical criteria: age <50 years, calcium >1 mg/dL above upper limit, or evidence of skeletal/kidney disease 1, 2
- Observation is appropriate for patients >50 years with calcium <1 mg/dL above upper limit and no skeletal or kidney involvement 4
Malignancy-Associated Hypercalcemia (Suppressed iPTH)
- Treat underlying malignancy when possible—median survival after discovery is approximately 1 month, indicating poor prognosis 1, 3
- For multiple myeloma: Hydration + zoledronic acid 4 mg IV monthly, with consideration for continuing bisphosphonates up to 2 years 1
- Temporarily discontinue nephrotoxic chemotherapy (e.g., lenalidomide, bortezomib) until calcium normalizes 1
Monitoring and Safety
- Monitor serum calcium, creatinine, and electrolytes regularly to assess treatment effectiveness 1, 2
- Baseline dental examination and ongoing monitoring for osteonecrosis of jaw with chronic bisphosphonate use 3
- Discontinue bisphosphonates if unexplained albuminuria >500 mg/24 hours or creatinine increases as defined above 3
- Avoid NSAIDs and IV contrast in patients with renal impairment to prevent further deterioration 1, 2
Critical Pitfalls to Avoid
- Never restrict calcium intake without medical supervision, as this can worsen bone disease [1, @10@]
- Do not use furosemide before adequate volume repletion—it provides no additional benefit and may worsen outcomes [6, @10@]
- Avoid vitamin D supplements in patients with active hypercalcemia, particularly in children 1, 2
- Do not delay bisphosphonate therapy in moderate to severe cases—temporary measures like calcitonin provide only 1-4 hours of benefit 1
- Asymptomatic hypocalcemia post-treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 1