What is the recommended approach to manage hypercalcemia?

Management of Hypercalcemia

Immediately initiate aggressive intravenous normal saline hydration targeting urine output of 100–150 mL/hour, followed by zoledronic acid 4 mg IV infused over at least 15 minutes for moderate-to-severe hypercalcemia (corrected calcium ≥12 mg/dL). 1, 2

Initial Assessment and Diagnostic Workup

Measure ionized calcium rather than relying solely on corrected total calcium to avoid misclassification from sampling artifacts or albumin abnormalities. 1 If ionized calcium is unavailable, calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)]. 1

Obtain the following laboratory panel immediately: 1, 2

• Intact parathyroid hormone (PTH) – the single most important test to distinguish PTH-dependent from PTH-independent causes
• PTH-related protein (PTHrP) if PTH is suppressed
• 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D (measure both together for diagnostic accuracy)
• Albumin, phosphorus, magnesium
• Serum creatinine and BUN to assess renal function
• Alkaline phosphatase (elevated in high-turnover bone disease or malignancy)

Perform a 12-lead ECG immediately to identify shortened QT interval (hypercalcemia) or arrhythmias, especially if concurrent electrolyte abnormalities exist. 1

Assess for symptoms: polyuria, polydipsia, nausea, vomiting, confusion, dehydration, constipation, fatigue, abdominal pain, myalgia, and altered mental status. 1 Severe hypercalcemia (≥14 mg/dL or ionized calcium ≥10 mg/dL) causes somnolence and coma. 3

Treatment Algorithm by Severity

Mild Hypercalcemia (Corrected Calcium <12 mg/dL)

For asymptomatic primary hyperparathyroidism in patients >50 years with calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease, observation with monitoring is appropriate. 3 Otherwise, consider parathyroidectomy based on age, calcium level, and organ involvement. 3

Discontinue causative medications immediately: thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day), and vitamin A. 1

Moderate-to-Severe Hypercalcemia (Corrected Calcium ≥12 mg/dL)

Step 1: Aggressive Hydration

**Administer IV normal saline aggressively to achieve urine output of 100–150 mL/hour (3 mL/kg/hour in children <10 kg).** 1, 2 Infuse 250–500 mL boluses every 15 minutes until rehydration is achieved, targeting total diuresis >2.5 L/day in adults. 1

Do NOT use loop diuretics (furosemide) until complete volume repletion is achieved. 1, 2 Only add furosemide after full hydration in patients with cardiac or renal insufficiency to prevent fluid overload. 1, 4

Avoid Ringer's lactate in patients with severe head trauma due to risk of fluid shift to damaged brain tissue. 1

Step 2: Bisphosphonate Therapy (Definitive Treatment)

Administer zoledronic acid 4 mg IV infused over ≥15 minutes as the preferred bisphosphonate – it normalizes calcium in 50% of patients by day 4 and is superior to pamidronate (90 mg). 1, 2, 3 Zoledronic acid has a 15-minute infusion time versus 2 hours for pamidronate. 1

Initiate bisphosphonate therapy early without waiting for complete rehydration. 1, 2

Dose adjustments for renal impairment (CrCl <60 mL/min): 1

• CrCl 50–60 mL/min: zoledronic acid 3.5 mg
• CrCl 40–49 mL/min: zoledronic acid 3.3 mg
• CrCl 30–39 mL/min: zoledronic acid 3.0 mg
• CrCl <30 mL/min: use denosumab instead

For patients with impaired renal function (CrCl <60 mL/min), use denosumab 120 mg subcutaneously instead of bisphosphonates to minimize nephrotoxicity, though hypocalcemia risk is higher. 1, 2 Provide calcium 500 mg plus vitamin D 400 IU daily during treatment. 1

Check serum creatinine before each bisphosphonate dose and withhold if renal deterioration occurs (increase >0.5 mg/dL from normal baseline or >1.0 mg/dL from abnormal baseline). 1, 2

Obtain baseline dental examination before initiating bisphosphonates to prevent osteonecrosis of the jaw (ONJ); zoledronic acid carries 9.5-fold greater ONJ risk than pamidronate. 1

Step 3: Adjunctive Rapid-Acting Therapy

For severe symptomatic hypercalcemia requiring immediate reduction, add calcitonin-salmon 100 IU subcutaneously or intramuscularly every 12 hours. 1, 2, 5 Calcitonin lowers calcium within 1–3 hours but provides only modest reduction lasting 30–60 minutes to 4 hours, with tachyphylaxis developing after 48 hours. 1, 6, 4

Combining calcitonin with bisphosphonates bridges the gap until bisphosphonates take effect (2–4 days). 1, 6, 4

Etiology-Specific Management

Hypercalcemia of Malignancy

For multiple myeloma or lymphoma-associated hypercalcemia, add corticosteroids: prednisone 20–40 mg/day orally or methylprednisolone IV equivalent, in combination with hydration and bisphosphonates. 1, 2

Plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma. 1

Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases to reduce skeletal-related events by 41%. 1

Temporarily discontinue myeloma therapy (lenalidomide, bortezomib) until calcium normalizes, as hypercalcemia indicates active disease requiring reassessment. 1

Granulomatous Disease (Sarcoidosis, Tuberculosis)

Corticosteroids are the primary treatment for hypercalcemia due to granulomatous diseases, vitamin D intoxication, or lymphoma. 1, 2, 3 Start prednisone 20–40 mg/day orally (or methylprednisolone IV equivalent). 1

Taper corticosteroids over 2–4 months depending on response, targeting the lowest effective dose ≤10 mg/day. 1 If unable to wean below 10 mg/day after 3–6 months, add methotrexate as a steroid-sparing agent. 1

Screen for tuberculosis with T-spot testing before initiating corticosteroids. 1

Provide pneumocystis pneumonia prophylaxis for patients receiving ≥20 mg methylprednisolone equivalent for ≥4 weeks. 1

Primary Hyperparathyroidism

Parathyroidectomy is curative for primary hyperparathyroidism and should be considered in patients meeting criteria: age <50 years, calcium >1 mg/dL above upper normal limit, or evidence of skeletal/kidney disease. 3, 4

For tertiary hyperparathyroidism (persistent hypercalcemic hyperparathyroidism despite optimized medical therapy), consider parathyroidectomy. 1

Chronic Kidney Disease and Dialysis Patients

Immediately discontinue all calcium-based phosphate binders and vitamin D analogs (calcitriol, paricalcitol) in CKD patients with hypercalcemia. 1

For severe hypercalcemia complicated by renal insufficiency or oliguria, use hemodialysis with calcium-free or low-calcium dialysate (1.25–1.50 mmol/L). 1, 2, 5 Hemodialysis effectively removes calcium through diffusive therapy. 1

In CKD patients with hypercalcemia and low PTH, consider lower dialysate calcium concentration (1.5–2.0 mEq/L) to stimulate PTH and increase bone turnover, allowing PTH to rise to at least 100 pg/mL to avoid low-turnover bone disease. 1

Monitoring During Acute Management

Check ionized calcium every 4–6 hours during the first 48–72 hours, then twice daily until stable. 1

Monitor serum creatinine before each bisphosphonate dose and withhold if renal function deteriorates. 1, 2

Measure electrolytes (potassium, magnesium, phosphorus) every 6–12 hours in the acute phase. 1

Target corrected calcium of 8.4–9.5 mg/dL, preferably at the lower end of this range. 1

Monitor for hypocalcemia after treatment (occurs in up to 50% of patients treated with bisphosphonates); only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50–100 mg/kg. 1, 6

Critical Pitfalls to Avoid

Never restrict calcium intake excessively without medical supervision, as this can worsen bone disease. 1

Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further kidney injury. 1, 2

Do not delay bisphosphonate therapy in moderate-to-severe hypercalcemia, as temporary measures like calcitonin provide only 1–4 hours of benefit with rebound hypercalcemia. 1, 2

Avoid using loop diuretics before complete volume repletion, as premature use worsens dehydration and aggravates hypercalcemia. 1

Do not use corticosteroids for hypercalcemia caused by solid-tumor malignancies (e.g., spindle-cell carcinomas); they are ineffective in this context. 1

Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together in suspected granulomatous disease, as activated macrophages produce excess 1,25-(OH)₂ vitamin D via extrarenal 1α-hydroxylase. 1

Stop all vitamin D supplements immediately in patients with severe hypercalcemia, even when 25-OH vitamin D levels are low, as supplementation worsens calcium elevation. 1