What are the management options for hypercalcemia?

Hypercalcemia: Comprehensive Review for Provider Examination

Definition and Severity Classification

Hypercalcemia is classified by severity to guide urgency of intervention: mild (10-11 mg/dL), moderate (11-12 mg/dL), or severe (>14 mg/dL), with ionized calcium thresholds of 5.6-8.0 mg/dL (1.4-2 mmol/L) for mild and ≥10 mg/dL (≥2.5 mmol/L) for severe disease. 1, 2

• 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, as concomitant hypoalbuminemia commonly masks true severity 1, 3

Pathophysiology

The fundamental derangement in hypercalcemia is excessive osteoclastic bone resorption, which releases calcium into the bloodstream, triggering polyuria and gastrointestinal disturbances that lead to progressive dehydration and decreased glomerular filtration rate. 3

• This creates a vicious cycle: decreased GFR increases renal calcium resorption, worsening systemic hypercalcemia 3, 4, 3
• Breaking this cycle requires both reducing bone resorption and maintaining adequate hydration 3

Major Etiologies

PTH-Dependent Causes (Elevated or Inappropriately Normal PTH)

Primary hyperparathyroidism accounts for approximately 90% of hypercalcemia cases along with malignancy, characterized by elevated or inappropriately normal PTH levels, hypophosphatemia, and hyperchloremic metabolic acidosis. 5, 1, 2

• Typically presents with lower calcium levels (<12 mg/dL), longer duration (>6 months), kidney calculi, and osteitis fibrosa cystica 6
• No anemia is present, distinguishing it from malignancy 6

PTH-Independent Causes (Suppressed PTH <20 pg/mL)

Malignancy-associated hypercalcemia presents with rapid onset, higher calcium levels, marked anemia, elevated PTHrP, and suppressed PTH, but never causes kidney calculi or metabolic acidosis. 5, 1, 6

Two Mechanisms:

1. Humoral hypercalcemia: PTHrP secretion by squamous cell carcinomas (lung, head/neck), renal cell carcinoma, or ovarian cancer, with minimal skeletal metastases 5, 1, 3

2. Osteolytic hypercalcemia: Direct tumor invasion of bone (breast cancer, multiple myeloma) causing local osteoclast activation 5, 1, 3

Other PTH-independent causes include:

• Granulomatous disorders (sarcoidosis) producing excess 1,25-dihydroxyvitamin D 5, 1
• Vitamin D intoxication from excessive supplementation, showing elevated 25-hydroxyvitamin D 5, 1
• Medications: thiazide diuretics, calcium/vitamin D supplements, particularly in CKD patients with low-turnover bone disease 5, 2
• Williams syndrome causing idiopathic infantile hypercalcemia 5

Clinical Presentation

Mild hypercalcemia (10-11 mg/dL) is asymptomatic in 80% of patients but may cause constitutional symptoms like fatigue and constipation in 20%. 2

Moderate hypercalcemia (11-12 mg/dL) manifests with polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain, myalgia, and dehydration. 7, 5, 1

Severe hypercalcemia (>14 mg/dL) or rapidly developing hypercalcemia causes mental status changes, bradycardia, hypotension, acute renal failure, somnolence, and coma. 5, 1, 2

• In Williams syndrome infants: extreme irritability, vomiting, constipation, muscle cramps 5
• ECG changes include QT interval prolongation in severe cases 7

Diagnostic Workup

Measure intact PTH first—this single test distinguishes PTH-dependent (elevated/normal PTH = primary hyperparathyroidism) from PTH-independent causes (suppressed PTH <20 pg/mL = all other etiologies). 7, 1, 2

Complete Initial Laboratory Panel:

• Intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D 7, 5, 1
• Calcium (total and ionized), albumin, phosphorus, magnesium 7, 1
• Serum creatinine, BUN, electrolytes 7, 1
• Urinary calcium excretion 5
• Malignancy markers if PTH suppressed 7, 1

Etiology-Specific Patterns:

Primary hyperparathyroidism: Elevated/normal PTH + hypercalcemia + hypophosphatemia + hyperchloremic metabolic acidosis 1, 6

Malignancy: Suppressed PTH + elevated PTHrP + low/normal 1,25-dihydroxyvitamin D + rapid onset + anemia 1, 6

Granulomatous disease/lymphoma: Suppressed PTH + elevated 1,25-dihydroxyvitamin D 1

Vitamin D intoxication: Suppressed PTH + elevated 25-hydroxyvitamin D 1

Treatment Algorithm

Step 1: Immediate Hydration (All Patients)

Administer IV normal saline immediately to correct hypovolemia and promote calciuresis, targeting urine output ≥100 mL/hour (3 mL/kg/hour in children <10 kg). 7, 1

• This is the cornerstone of initial management for all hypercalcemia 7, 1
• Critical pitfall: Avoid overhydration in cardiac or renal insufficiency patients 7
• Use loop diuretics (furosemide) only after volume repletion in patients with renal or cardiac insufficiency to prevent fluid overload 7, 1, 6
• Furosemide alone without adequate hydration is ineffective and may worsen hypercalcemia 8

Step 2: Bisphosphonate Therapy (Moderate to Severe Hypercalcemia)

Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred first-line bisphosphonate for moderate to severe hypercalcemia, superior in efficacy to pamidronate. 7, 1, 3, 2, 9, 6

• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia 7
• Onset of action: calcium reduction begins within 24 hours, with maximal effect by day 7 4, 8
• Mean calcium reduction: 0.57 ± 0.27 mmol/L, achieving normocalcemia in 60% of patients 8
• Pamidronate 60-90 mg IV over 4 hours is an acceptable alternative if zoledronic acid unavailable 7, 1
• Continue bisphosphonate therapy for up to 2 years in multiple myeloma or bone metastases 7

Bisphosphonate Dosing and Monitoring:

Zoledronic acid:

• Standard dose: 4 mg IV over ≥15 minutes 7, 1, 3
• Never infuse over 5 minutes—this increases renal toxicity risk 3
• Never use 8 mg dose—associated with increased renal toxicity without added benefit 3
• Monitor serum creatinine before each dose; withhold if renal deterioration occurs 7
• Adjust dose for renal impairment 7

Pamidronate:

• 30 mg over 4 hours for mild hypercalcemia 4
• 60-90 mg over 4 hours for moderate to severe hypercalcemia 4, 6
• Approximately 43-47% of dose excreted in urine 4

Critical Bisphosphonate Precautions:

• Correct hypocalcemia before initiating therapy 7
• Administer oral calcium 500 mg plus vitamin D 400 IU daily during treatment to prevent hypocalcemia 7
• Denosumab carries higher hypocalcemia risk than bisphosphonates—monitor calcium closely 7
• Monitor for osteonecrosis of the jaw with chronic use 1
• Avoid NSAIDs and IV contrast in patients with renal impairment to prevent further kidney damage 7, 1

Step 3: Calcitonin (Severe Symptomatic Hypercalcemia)

Calcitonin provides rapid onset of action within hours but limited efficacy; use as a bridge until bisphosphonates take effect in severe symptomatic cases. 7, 1, 2, 6

• Dosing: 200 IU/day intranasal or 100 IU subcutaneously/intramuscularly every other day 7
• Use primarily in patients who cannot tolerate other treatments 7
• Provides only short-term benefit (1-4 hours) 7

Step 4: Cause-Specific Therapies

Vitamin D-Mediated Hypercalcemia (Granulomatous Disease, Lymphoma, Vitamin D Intoxication)

Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption from vitamin D intoxication, granulomatous diseases (sarcoidosis), some lymphomas, and multiple myeloma. 7, 5, 1, 2, 6

• Corticosteroids should be started as soon as possible if not contraindicated 10
• Avoid vitamin D supplements in all patients with hypercalcemia, particularly in early childhood 7, 5, 1

Multiple Myeloma-Specific Management

For multiple myeloma patients with hypercalcemia, use hydration + zoledronic acid (preferred) + steroids ± calcitonin. 7

• Plasmapheresis as adjunctive therapy for symptomatic hyperviscosity 7
• If on lenalidomide and bortezomib: Temporarily discontinue until calcium normalizes, as hypercalcemia indicates active disease requiring reassessment 7
• Monitor ECG for QT prolongation in severe cases 7
• Discontinue nephrotoxic medications 7

Refractory or Severe Hypercalcemia with Renal Failure

Denosumab 120 mg subcutaneously is indicated for refractory hypercalcemia, especially when bisphosphonates are contraindicated due to renal impairment. 1, 9

Dialysis with calcium-free or low-calcium solution is reserved for severe hypercalcemia complicated by renal insufficiency or oliguria. 7, 1, 6

• Hemodialysis effectively removes calcium, uric acid, and phosphate through diffusive therapy 7, 1

Step 5: Definitive Management

Primary Hyperparathyroidism

Parathyroidectomy is indicated for symptomatic primary hyperparathyroidism or patients meeting any of these criteria: osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age <50 years, or calcium >0.25 mmol/L (>1 mg/dL) above upper normal limit. 5, 1, 2

• For patients >50 years with calcium <1 mg/dL above upper limit and no skeletal/kidney disease: Observation with monitoring is appropriate 2
• Calcimimetic agents are used when surgery is not possible or patients don't meet surgical criteria 9
• Prognosis with medical or surgical management is excellent 2

Tertiary Hyperparathyroidism (CKD)

Parathyroidectomy is considered for persistent hypercalcemic hyperparathyroidism despite optimized medical therapy in CKD patients. 7

• Restrict calcium-based phosphate binders in CKD patients with hyperphosphatemia 7
• Do not routinely use calcitriol or vitamin D analogues in non-dialysis CKD patients with secondary hyperparathyroidism due to hypercalcemia risk 7

Malignancy-Associated Hypercalcemia

Treat the underlying cancer when possible—this is essential for long-term control, though prognosis is poor with median survival approximately 1 month. 7, 5, 1, 2

Monitoring and Follow-Up

Monitor serum calcium, renal function, and electrolytes regularly to assess treatment effectiveness. 7, 5, 1

• Serum phosphate typically decreases after treatment, returning toward normal within 7-10 days 4
• Urinary calcium/creatinine and hydroxyproline/creatinine ratios decrease within the first week 4
• Asymptomatic hypocalcemia following treatment does not require intervention 7
• Only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg 7

Common Pitfalls to Avoid

1. Never use furosemide before adequate volume repletion—it is ineffective and may worsen hypercalcemia 8, 10

2. Never infuse zoledronic acid over 5 minutes or use 8 mg dose—both increase renal toxicity without benefit 3

3. Never delay bisphosphonates in moderate to severe hypercalcemia—temporary measures provide only 1-4 hours of benefit 7

4. Never use NSAIDs or IV contrast in patients with renal impairment—prevents further kidney damage 7, 1

5. Never restrict calcium intake without medical supervision—can worsen bone disease 7

6. Never continue vitamin D supplements in hypercalcemic patients 7, 5, 1

7. Always correct hypocalcemia before starting bisphosphonates 7

8. Always provide calcium 500 mg + vitamin D 400 IU daily during bisphosphonate treatment to prevent treatment-induced hypocalcemia 7