Evaluation and Management of Elevated Serum Calcium
For any patient with elevated calcium, immediately obtain a fasting ionized calcium level and intact PTH to confirm true hypercalcemia and determine the underlying cause—this single step directs all subsequent management. 1, 2
Initial Diagnostic Workup
Confirm True Hypercalcemia
- Obtain fasting ionized calcium rather than relying solely on total calcium, as non-fasting samples, prolonged tourniquet use, exercise, and recent calcium intake can falsely elevate total calcium levels 1
- Hypercalcemia is confirmed when ionized calcium exceeds 5.6 mg/dL (1.4 mmol/L) or total calcium exceeds 10.3 mg/dL 2, 3
- Calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)] 4
Essential Laboratory Panel
Measure the following to determine etiology and guide treatment 4, 2:
- Intact PTH (most critical test—distinguishes PTH-dependent from PTH-independent causes)
- 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D
- PTH-related protein (PTHrP) if PTH is suppressed
- Serum albumin, phosphorus, magnesium
- Renal function (creatinine, BUN)
- Complete blood count (anemia suggests malignancy) 5
Interpret PTH Results
- Elevated or normal PTH = primary hyperparathyroidism (90% of outpatient hypercalcemia) 2, 5
- **Suppressed PTH (<20 pg/mL)** = malignancy or other non-PTH-mediated causes (accounts for >90% of cases with primary hyperparathyroidism) 2, 5
Severity Classification and Immediate Actions
Mild Hypercalcemia (Total Ca <12 mg/dL or ionized Ca 5.6-8.0 mg/dL)
- Usually asymptomatic but may cause fatigue and constipation in 20% of patients 2
- Stop all calcium-raising agents immediately: calcium supplements, vitamin D, calcium-based phosphate binders, thiazide diuretics 6, 4
- If due to primary hyperparathyroidism in patients >50 years with calcium <1 mg above upper limit and no skeletal/renal involvement, observation with monitoring is appropriate 2
- Otherwise, consider parathyroidectomy for definitive treatment 2
Moderate Hypercalcemia (Total Ca 12-14 mg/dL)
- Begin aggressive IV normal saline hydration targeting urine output 100-150 mL/hour 6, 4
- Administer zoledronic acid 4 mg IV over 15 minutes (preferred bisphosphonate—superior to pamidronate with 50% normalization by day 4) 6, 4, 2
- Monitor serum calcium every 12-24 hours and renal function closely 6
Severe Hypercalcemia (Total Ca ≥14 mg/dL or ionized Ca ≥10 mg/dL)
This is a medical emergency requiring immediate intervention 6, 2:
Immediate hydration: Aggressive IV normal saline to maintain diuresis >2.5 L/day in adults 6, 4
Bisphosphonate therapy: Administer zoledronic acid 4 mg IV over 15 minutes early—do not wait for complete rehydration 6, 4
Calcitonin for rapid effect: Calcitonin-salmon 100 IU subcutaneously/IM every 12 hours provides rapid onset (within hours) but limited duration 4, 2
Monitor continuously: Check calcium, renal function, and electrolytes every 6-12 hours 4
Etiology-Specific Management
Primary Hyperparathyroidism
- Parathyroidectomy is definitive treatment 2, 5
- Observation acceptable if: age >50 years, calcium <1 mg above upper limit, no skeletal/renal disease 2
- Prognosis is excellent with either surgical or medical management 2
Malignancy-Associated Hypercalcemia
- Treat underlying cancer when possible 4, 2
- Hydration plus zoledronic acid 4 mg IV is cornerstone therapy 4
- Consider continuing bisphosphonates for up to 2 years in multiple myeloma or bone metastases 4
- Prognosis is poor with median survival approximately 1 month 4
- For multiple myeloma specifically: add corticosteroids (prednisone 20-40 mg/day) 4
Granulomatous Disease (Sarcoidosis, TB)
- Corticosteroids are primary therapy: Prednisone 20-40 mg/day orally or methylprednisolone IV equivalent 4, 2
- Mechanism: reduces excessive intestinal calcium absorption from elevated 1,25-dihydroxyvitamin D 4
- Taper over 2-4 months based on response 4
Vitamin D Intoxication
- Stop all vitamin D supplements immediately 6, 4
- Corticosteroids (prednisone 20-40 mg/day) reduce intestinal calcium absorption 4, 2
- Hydration and bisphosphonates as needed 2
Refractory Hypercalcemia
When Standard Therapy Fails
If calcium remains >10.2 mg/dL (2.54 mmol/L) despite medication adjustments and bisphosphonates 6:
Denosumab 120 mg subcutaneously for bisphosphonate-refractory cases (lowers calcium in 64% within 10 days) 4
Dialysis with low-calcium dialysate (1.5-2.0 mEq/L) for 3-4 weeks if severe hypercalcemia complicated by renal failure 6, 4, 5
Critical Monitoring Parameters
During Acute Treatment
- Serum calcium every 12-24 hours 6
- Renal function (creatinine) to detect nephrotoxicity 6, 4
- Volume status to prevent fluid overload 6
- ECG for QT prolongation and dysrhythmias 4
Long-Term Management
- Target corrected calcium 8.4-9.5 mg/dL (preferably lower end) 6
- Maintain calcium-phosphorus product <55 mg²/dL² to prevent soft tissue calcification 6
- Limit total elemental calcium intake to ≤2,000 mg/day once stabilized 6
- Check serum calcium every 3 months in chronic management 7
Common Pitfalls to Avoid
- Never rely on non-fasting total calcium alone—obtain fasting ionized calcium for diagnostic accuracy 1
- Do not use loop diuretics before complete volume repletion—this worsens hypercalcemia 4, 5
- Avoid NSAIDs and IV contrast in patients with renal impairment—prevents further kidney damage 4
- Do not delay bisphosphonate therapy in moderate-severe hypercalcemia—temporary measures like calcitonin provide only 1-4 hours of benefit 4
- Never restrict calcium intake without medical supervision in normocalcemic patients—can worsen bone disease 4
- Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together—measuring only one reduces diagnostic accuracy 4
- Perform baseline dental examination before bisphosphonates—prevents osteonecrosis of the jaw 4