What are the treatment options for a patient with hypercalcemia?

Treatment of Hypercalcemia

Immediate Management: Hydration First

Aggressive intravenous normal saline hydration is the cornerstone of initial treatment for all patients with symptomatic or severe hypercalcemia, targeting urine output of 100-150 mL/hour. 1, 2

• Volume repletion corrects the hypovolemia that universally accompanies hypercalcemia and promotes calciuresis through the kidneys 1, 3
• Administer boluses of 250-500 mL crystalloids every 15 minutes until rehydration is achieved, then maintain diuresis >2.5 L/day in adults 1
• Loop diuretics (furosemide) should only be used AFTER complete volume repletion, and only in patients with renal or cardiac insufficiency to prevent fluid overload 1, 4—a common pitfall is using diuretics before adequate hydration, which worsens hypercalcemia 1

Definitive Pharmacologic Treatment: Bisphosphonates

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

• Zoledronic acid normalizes calcium in 50% of patients by day 4, with a 15-minute infusion time compared to 2 hours for pamidronate 1
• The maximum dose is 4 mg—never exceed this dose for initial treatment, as higher doses increase renal toxicity without improving efficacy 1, 2
• Bisphosphonates should be initiated early without waiting for complete rehydration, as their onset of action is delayed 2-4 days 1
• Measure serum creatinine before each dose and adjust dosing for renal impairment (see Table 1 in FDA label): CrCl 50-60 mL/min use 3.5 mg, CrCl 40-49 use 3.3 mg, CrCl 30-39 use 3.0 mg 1, 2

Renal Impairment Considerations

• For patients with severe renal impairment (CrCl <30 mL/min), denosumab 120 mg subcutaneously is preferred over bisphosphonates due to lower renal toxicity, though it carries higher risk of hypocalcemia 1
• Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is reserved for severe hypercalcemia complicated by renal failure or oliguria 1, 4

Adjunctive Rapid-Acting Agents

Calcitonin 100 IU subcutaneously or intramuscularly provides rapid onset within hours but limited efficacy, best used as a bridge until bisphosphonates take effect. 1, 3, 5

• Calcitonin's effect is modest and short-lived (1-4 hours), with tachyphylaxis developing within 48 hours 1
• Standard dosing is 100 IU subcutaneously/IM every 12 hours or 200 IU daily as nasal spray 1
• Use primarily in patients who cannot tolerate other treatments or need immediate calcium reduction while awaiting bisphosphonate effect 1

Cause-Specific Treatments

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

Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption, with prednisone 20-40 mg/day orally or IV methylprednisolone equivalent. 1, 6, 3, 7

• Corticosteroids work by reducing 1,25-dihydroxyvitamin D production in activated macrophages and decreasing intestinal calcium absorption 1, 6
• Allow 3-6 months to demonstrate responsiveness before escalating therapy 1
• Target the lowest effective dose ≤10 mg/day; if unable to wean below 10 mg/day after 3-6 months, add methotrexate as steroid-sparing agent 1
• Immediately discontinue all vitamin D and calcium supplements in any patient with hypercalcemia 1, 6

Malignancy-Associated Hypercalcemia

Treat the underlying malignancy with chemotherapy, as this is essential for long-term control; hypercalcemia of malignancy carries a poor prognosis with median survival of approximately 1 month. 1, 3

• For multiple myeloma: hydration + zoledronic acid 4 mg IV + corticosteroids ± calcitonin 1
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1
• Plasmapheresis is adjunctive therapy for symptomatic hyperviscosity in multiple myeloma 1

Primary Hyperparathyroidism

Parathyroidectomy is indicated for symptomatic patients or those meeting surgical criteria: age <50 years, calcium >1 mg/dL above upper limit of normal, osteoporosis, impaired kidney function, kidney stones, or hypercalciuria. 6, 3

• Patients >50 years with calcium <1 mg/dL above normal and no skeletal or kidney disease may be observed without surgery 3
• Calcimimetics may be used when surgery is not possible or patients don't meet surgical criteria 8

Essential Monitoring and Prevention of Complications

• Correct pre-existing hypocalcemia before initiating bisphosphonates to prevent severe post-treatment hypocalcemia 1
• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia 1, 2
• Obtain baseline dental examination before starting bisphosphonates to prevent osteonecrosis of the jaw (ONJ), which occurs 9.5-fold more with zoledronic acid than pamidronate 1
• Monitor serum calcium, creatinine, and electrolytes (especially potassium and magnesium) every 6-12 hours during acute phase 1
• Withhold bisphosphonates if creatinine increases >0.5 mg/dL from baseline (or >1.0 mg/dL if abnormal baseline) and resume only when creatinine returns to within 10% of baseline 1, 2

Critical Pitfalls to Avoid

• Never use loop diuretics before complete volume repletion—this worsens hypercalcemia by increasing calcium reabsorption 1, 4
• Avoid NSAIDs and IV contrast in patients with renal impairment, as they worsen kidney function 1
• Do not restrict dietary calcium intake without medical supervision, as this can worsen bone disease 1
• Measure ionized calcium or calculate corrected calcium [Corrected Ca = Total Ca + 0.8 × (4.0 - albumin)] to avoid misdiagnosis from hypoalbuminemia 1, 6
• Retreatment with zoledronic acid requires minimum 7-day interval to allow full response to initial dose 2

Diagnostic Workup to Guide Treatment

Measure intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, albumin, phosphorus, magnesium, creatinine, and BUN to determine underlying cause. 1, 6

• Elevated or normal PTH = primary hyperparathyroidism; suppressed PTH (<20 pg/mL) = other causes 6, 3, 5
• If PTH suppressed, check PTHrP (elevated in malignancy), vitamin D metabolites (elevated in granulomatous disease/intoxication), and malignancy markers 6
• Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy 1