How should hypercalcemia be evaluated and managed based on severity and presence of symptoms, including first‑line fluid therapy, bisphosphonates, calcitonin, denosumab, glucocorticoids, dialysis, and monitoring?

Hypercalcemia: Evaluation and Management

Immediate Assessment and Severity Stratification

Begin aggressive intravenous normal saline hydration immediately for any patient with moderate-to-severe hypercalcemia (corrected calcium ≥12 mg/dL), targeting urine output of 100–150 mL/hour, followed by intravenous bisphosphonates as definitive first-line therapy. 1

Severity Classification

• Mild hypercalcemia: Corrected calcium 10.5–12 mg/dL (ionized calcium 5.6–8.0 mg/dL); usually asymptomatic but may cause fatigue and constipation in ~20% of patients 2
• Moderate hypercalcemia: Corrected calcium 12–13.5 mg/dL; presents with polyuria, polydipsia, nausea, vomiting, abdominal pain, myalgia, confusion 3
• Severe hypercalcemia: Corrected calcium ≥14 mg/dL (ionized calcium ≥10 mg/dL); associated with mental status changes, bradycardia, hypotension, severe dehydration, acute renal failure 3, 2

Calculate Corrected Calcium

• Formula: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 – Serum albumin (g/dL)] 1, 4
• Measure ionized calcium directly when available to avoid pseudo-hypercalcemia from hemolysis or improper sampling 1, 3

Diagnostic Workup

Essential Initial Laboratory Panel

Measure intact parathyroid hormone (iPTH) first—this single test distinguishes PTH-dependent from PTH-independent causes and guides all subsequent management. 1, 2

• Elevated or inappropriately normal PTH (with hypercalcemia) = primary hyperparathyroidism 3
• Suppressed PTH (<20 pg/mL) = malignancy, vitamin D intoxication, granulomatous disease, or other PTH-independent causes 3, 2

Complete Diagnostic Panel

• Intact PTH, PTH-related protein (PTHrP), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D 1, 3
• Serum calcium, albumin, magnesium, phosphorus 1
• Serum creatinine, BUN, estimated GFR 3, 4
• Complete blood count, alkaline phosphatase 4
• ECG to assess for QT interval prolongation 1, 4

Critical Measurement Considerations

• Use EDTA plasma rather than serum for PTH measurement—PTH is most stable in EDTA plasma at 4°C 3
• PTH assays vary by up to 47% between different generations; always use assay-specific reference values 3
• Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy 1, 3

First-Line Treatment: Hydration

Aggressive Fluid Resuscitation

Administer intravenous normal saline aggressively to correct hypovolemia and promote calciuresis, targeting urine output of 100–150 mL/hour. 1, 4

• Give boluses of 250–500 mL every 15 minutes until rehydration is achieved 1
• Continue hydration to maintain diuresis >2.5 L/day in adults while waiting for bisphosphonates to take effect 1
• Balanced crystalloids are preferred over 0.9% saline when possible to avoid hyperchloremic metabolic acidosis with large volumes 1

Loop Diuretics

• Use loop diuretics (furosemide) ONLY after complete volume repletion and only in patients with renal or cardiac insufficiency to prevent fluid overload 1, 5
• Avoid overhydration in patients with potential cardiac failure 6

Definitive Pharmacologic Treatment: Bisphosphonates

Zoledronic Acid (Preferred Agent)

Zoledronic acid 4 mg IV infused over no less than 15 minutes is superior to pamidronate and is the preferred bisphosphonate for moderate-to-severe hypercalcemia, normalizing calcium in 50% of patients by day 4. 1, 2

• Dose adjustments required for creatinine clearance <60 mL/min 1
• Check serum creatinine before each dose; withhold if renal deterioration occurs (increase >0.5 mg/dL from normal baseline or >1.0 mg/dL from abnormal baseline) 1, 6
• Infusion time is 15 minutes vs. 2 hours for pamidronate, offering practical benefits 1
• Mandatory baseline dental examination before initiating therapy to prevent osteonecrosis of the jaw 1

Pamidronate (Alternative)

• Moderate hypercalcemia (corrected calcium 12–13.5 mg/dL): 60–90 mg IV over 2–24 hours 6
• Severe hypercalcemia (corrected calcium >13.5 mg/dL): 90 mg IV over 2–24 hours 6
• Longer infusions (>2 hours) reduce risk of renal toxicity, particularly in patients with preexisting renal insufficiency 6
• Minimum 7 days should elapse before retreatment 6

Duration of Bisphosphonate Therapy

• Continue bone-targeting treatment for up to 2 years in patients with multiple myeloma or bone metastases 1
• Continuation beyond 2 years based on clinical judgment 1

Adjunctive Therapies

Calcitonin

Calcitonin provides rapid onset of action within hours but has limited efficacy and should be used only as a bridge until bisphosphonates take effect or in patients who cannot tolerate other treatments. 1, 7

• Dosing: Calcitonin-salmon 100 IU subcutaneously or intramuscularly every other day 1
• Alternative: 200 IU per day as nasal spray 1
• Mechanism: Inhibits osteoclastic bone resorption and increases renal calcium excretion 1
• Limitation: Tachyphylaxis develops rapidly; benefit lasts only 1–4 hours with rebound hypercalcemia 1
• Contraindication: Allergy to calcitonin-salmon 1

Glucocorticoids

Glucocorticoids are effective as primary therapy for hypercalcemia due to excessive intestinal calcium absorption: vitamin D intoxication, granulomatous diseases (especially sarcoidosis), some lymphomas, and multiple myeloma. 1, 3, 2

• Dosing: Prednisone 20–40 mg/day orally or methylprednisolone IV equivalent 1, 4
• For sarcoidosis: Start prednisone 20–40 mg/day; allow 3–6 months to demonstrate responsiveness 1
• Target lowest effective dose ≤10 mg/day to minimize toxicity 1
• If unable to wean below 10 mg/day after 3–6 months, add methotrexate as steroid-sparing agent 1

Monitoring and Prophylaxis with Glucocorticoids

• Pneumocystis pneumonia prophylaxis for patients receiving ≥20 mg methylprednisolone equivalent for ≥4 weeks 1
• GI prophylaxis with proton pump inhibitor for all patients on corticosteroids 1
• Tuberculosis screening with T-spot testing before initiating corticosteroids in granulomatous disease 1
• Calcium and vitamin D supplementation (paradoxically needed with prolonged steroid use to prevent bone loss, but carefully monitored in hypercalcemia context) 1

Denosumab

Denosumab 120 mg subcutaneously is reserved for bisphosphonate-refractory hypercalcemia or patients with impaired renal function, lowering calcium in 64% of patients within 10 days. 1, 2

• Preferred in patients with renal impairment due to lower rates of renal toxicity compared to bisphosphonates 1
• Higher risk of hypocalcemia compared to bisphosphonates; correct hypocalcemia before initiating therapy 1
• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during denosumab treatment 1
• Monitor serum calcium closely, especially with denosumab 1

Dialysis

Hemodialysis with calcium-free or low-calcium dialysate (1.25–1.50 mmol/L) is reserved for severe hypercalcemia complicated by renal insufficiency or oliguria. 1, 5, 2

• Hemodialysis effectively removes calcium through diffusive therapy 1
• Generally reserved for patients with severe hypercalcemia and kidney failure 5, 2

Etiology-Specific Management

Primary Hyperparathyroidism

• Surgical indications: Corrected calcium >1 mg/dL above upper limit of normal, age <50 years, impaired kidney function (GFR <60 mL/min/1.73 m²), osteoporosis (T-score ≤-2.5), history of nephrolithiasis or nephrocalcinosis 3
• Refer to endocrinology and experienced parathyroid surgeon for surgical evaluation 3
• For non-surgical candidates: Maintain normal calcium intake (1000–1200 mg/day), ensure adequate vitamin D (>20 ng/mL), monitor serum calcium every 3 months 3

Malignancy-Associated Hypercalcemia

• Treat underlying cancer when possible—hypercalcemia of malignancy carries poor prognosis with median survival of approximately 1 month 1, 3, 4
• Plasmapheresis as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma 1, 4
• Temporarily discontinue myeloma therapy (lenalidomide, bortezomib) until calcium normalizes 1

Chronic Kidney Disease

• Immediately discontinue all calcium-based phosphate binders in patients with hypercalcemia 1
• Stop all vitamin D analogs (calcitriol, paricalcitol) and vitamin D supplements immediately 1
• Consider lower dialysate calcium concentration (1.5–2.0 mEq/L) to stimulate PTH and increase bone turnover 1

Monitoring During Acute Treatment

Frequency

• Measure ionized calcium every 4–6 hours during the first 48–72 hours, then twice daily until stable 1
• Monitor serum calcium, creatinine, and electrolytes (especially potassium and magnesium) every 6–12 hours during acute phase 1, 4
• Reduce infusion rate once stable diuresis of 100–150 mL/hour is achieved 1

Therapeutic Targets

• Target corrected calcium of 8.4–9.5 mg/dL, preferably at lower end of range 1
• Maintain calcium-phosphorus product <55 mg²/dL² to prevent soft tissue calcification 1

Critical Pitfalls to Avoid

• Never restrict calcium intake excessively without medical supervision—this can worsen bone disease 1
• Avoid NSAIDs and intravenous contrast media in patients with renal impairment 1
• Do not use loop diuretics before complete volume repletion 1
• Do not delay bisphosphonate therapy in moderate-to-severe hypercalcemia—temporary measures like calcitonin provide only 1–4 hours of benefit 1
• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50–100 mg/kg 1
• Avoid over-correction—iatrogenic hypercalcemia can result in renal calculi and renal failure 8

Medication and Supplement Management

• Discontinue all vitamin D supplements immediately in patients with severe hypercalcemia, even when 25-OH vitamin D levels are low 1
• Stop all calcium supplements 3
• Review and discontinue thiazide diuretics, lithium (if possible) 1
• Avoid vitamin D supplementation until hypercalcemia resolves 3