Hypercalcemia: Symptoms and Treatment
Symptoms of Hypercalcemia
The clinical presentation of hypercalcemia varies dramatically by severity and rate of onset, ranging from completely asymptomatic in mild cases to life-threatening neurological and cardiovascular collapse in severe cases. 1, 2
Mild Hypercalcemia (10-11 mg/dL or <3 mmol/L)
- Often asymptomatic but may present with constitutional symptoms in approximately 20% of patients 3
- Fatigue and generalized weakness 3
- Constipation 3
- Polyuria and polydipsia 1, 2
Moderate Hypercalcemia (11-12 mg/dL or 5.5-6.0 mEq/L)
- Nausea and vomiting 1, 2
- Confusion and difficulty concentrating 1, 4
- Abdominal pain 1, 2
- Myalgia 5
- Dehydration 1, 2
Severe Hypercalcemia (>14 mg/dL or >3.5 mmol/L)
- Mental status changes progressing to somnolence and coma 1, 3
- Bradycardia and hypotension 2
- Acute renal failure 2
- Severe dehydration 3
Special Population: Pediatric Patients (Williams Syndrome)
- Extreme irritability 6
- Vomiting and muscle cramps 6
- Hypercalciuria and nephrocalcinosis 6
- Most common in first 2 years of life 6
Treatment of Hypercalcemia
Initial Emergency Management
Immediate IV normal saline hydration is the cornerstone of initial treatment for all symptomatic hypercalcemia, targeting urine output ≥100 mL/hour (3 mL/kg/hour in children <10 kg) to correct hypovolemia and promote calciuresis. 1, 2, 7
- Volume repletion should be aggressive, aiming for approximately 2 L/day urine output 7
- Avoid overhydration in patients with cardiac failure 7
- Do not use loop diuretics (furosemide) until after volume repletion is achieved—only indicated in patients with renal or cardiac insufficiency to prevent fluid overload 1, 5
Definitive Pharmacologic Treatment
For Moderate to Severe Hypercalcemia (especially malignancy-associated):
Administer IV bisphosphonates after initiating hydration, with zoledronic acid 4 mg IV infused over no less than 15 minutes as the preferred agent over pamidronate. 1, 5, 7, 3
- Zoledronic acid dosing: 4 mg IV over ≥15 minutes for patients with CrCl >60 mL/min 7
- Dose adjustments for renal impairment: 7
- CrCl 50-60 mL/min: 3.5 mg
- CrCl 40-49 mL/min: 3.3 mg
- CrCl 30-39 mL/min: 3.0 mg
- Monitor serum creatinine before each dose and withhold if renal deterioration occurs 5, 7
- Bisphosphonates take 2-3 days to achieve effect 4
For Immediate Short-Term Management:
Add calcitonin (100 IU subcutaneously or intramuscularly) for rapid calcium reduction while waiting for bisphosphonates to take effect, as it works within hours but has limited duration of efficacy. 1, 5, 8
- Provides rapid onset within hours but modest hypocalcemic effect 5, 9
- Can be combined with bisphosphonates to enhance rate of calcium decline 9
Cause-Specific Treatment
Vitamin D-Mediated Hypercalcemia:
Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption, including sarcoidosis, lymphomas, vitamin D intoxication, and granulomatous disorders. 1, 2, 3, 8
Refractory Hypercalcemia:
Denosumab 120 mg subcutaneously is indicated for refractory cases, especially in patients with renal impairment where bisphosphonates are contraindicated. 1, 2
- Monitor closely for hypocalcemia post-treatment 2
- Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during treatment 5
Severe Hypercalcemia with Renal Failure:
Dialysis with calcium-free or low-calcium solution is reserved for severe hypercalcemia complicated by kidney failure. 1, 5, 8
Definitive Management Based on Etiology
Primary Hyperparathyroidism:
Parathyroidectomy is indicated for patients with symptomatic disease, osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age <50 years, or calcium >0.25 mmol/L above upper normal limit. 1
- For patients >50 years with calcium <1 mg/dL above upper limit and no skeletal or kidney disease, observation may be appropriate 3
Malignancy-Associated Hypercalcemia:
Treat the underlying malignancy when possible, as this is essential for long-term control. 1, 5
Pediatric-Specific Management (Williams Syndrome):
Infants with hypercalcemia should be treated with a low-calcium diet and increased water intake under medical and nutritional supervision, with more frequent calcium monitoring. 6
- Check serum calcium every 4-6 months until age 2 years, then every 2 years 6
- Measure serum BUN, creatinine, vitamin D (25-OH and 1,25-OH), and intact PTH if hypercalcemia present 6
- Avoid multivitamin preparations containing vitamin D in early childhood 6, 1, 2
- Do not restrict calcium without medical supervision in normocalcemic patients 6, 5
Critical Pitfalls to Avoid
- Never delay bisphosphonate therapy in moderate to severe hypercalcemia—temporary measures provide only 1-4 hours of benefit 5
- Avoid NSAIDs and IV contrast media in patients with renal impairment to prevent worsening renal function 2, 5
- Do not use diuretics before correcting hypovolemia—this worsens dehydration 7, 8
- Always 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 1, 2
- Watch for bisphosphonate complications: renal toxicity and osteonecrosis of the jaw with chronic use 1
- Monitor for hypocalcemia after denosumab treatment—only treat if symptomatic (tetany, seizures) 5
Monitoring
- Monitor serum calcium, renal function, and electrolytes regularly to assess treatment effectiveness 1, 2, 5
- Measure serum creatinine before each bisphosphonate dose 5, 7
- Withhold treatment if renal deterioration occurs (increase of 0.5 mg/dL in normal baseline creatinine or 1.0 mg/dL in abnormal baseline) 7
- Resume treatment only when creatinine returns to within 10% of baseline 7