Hypercalcemia: Causes and Treatment
Primary Causes
The two most common causes of hypercalcemia account for approximately 90% of all cases: primary hyperparathyroidism (PHPT) in outpatients and malignancy in hospitalized patients. 1
Major Etiologies:
- Primary hyperparathyroidism - most common in ambulatory patients 1, 2
- Malignancy - most common in hospitalized patients, including multiple myeloma, bone metastases, and lymphomas 3, 1
- Granulomatous diseases - particularly sarcoidosis, causing excessive intestinal calcium absorption through unregulated 1-alpha-hydroxylase activity in activated macrophages 3, 4, 1
- Medications - thiazide diuretics, lithium, excessive calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day), vitamin A, and calcitriol/vitamin D analogs 5, 1
- Endocrinopathies - thyroid disease 1
- Immobilization - enhances bone resorption 1
- Familial hypocalciuric hypercalcemia - important to exclude before considering parathyroid surgery 2
Initial Diagnostic Workup
Measure serum intact parathyroid hormone (iPTH) immediately alongside calcium, albumin, phosphorus, magnesium, creatinine, and BUN - this single test distinguishes PTH-dependent from PTH-independent causes. 5
Diagnostic Algorithm:
- Elevated or normal iPTH (>20 pg/mL) = primary hyperparathyroidism 5
- Suppressed iPTH (<20 pg/mL) = malignancy, granulomatous disease, medications, or other causes 5, 1, 2
Additional Testing When iPTH is Suppressed:
- PTH-related protein (PTHrP) - elevated in humoral hypercalcemia of malignancy 3, 5
- 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D - both must be measured together for diagnostic accuracy 5
- Ionized calcium - preferred over corrected calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling 5
- If using total calcium, calculate: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)] 5
Treatment Algorithm by Severity
Mild Hypercalcemia (Total calcium <12 mg/dL or ionized calcium 5.6-8.0 mg/dL):
Most mild cases are asymptomatic and do not require acute intervention. 1
- For PHPT in patients >50 years with calcium <1 mg/dL above upper normal limit and no skeletal/kidney disease: observation with monitoring is appropriate 1
- For PHPT meeting surgical criteria: parathyroidectomy is definitive treatment 1, 2
- Conservative measures: saline hydration with or without loop diuretics may suffice 6
Moderate to Severe Hypercalcemia (Total calcium ≥12 mg/dL):
Initiate aggressive IV normal saline hydration immediately, targeting urine output ≥100-150 mL/hour, followed by zoledronic acid 4 mg IV as definitive pharmacologic treatment. 3, 5, 6
Step 1: Hydration
- Administer IV normal saline aggressively to correct hypovolemia and promote calciuresis 3, 5, 6
- Target urine output: 100-150 mL/hour in adults (3 mL/kg/hour in children <10 kg) 3, 5
- Maintain diuresis >2.5 L/day while waiting for bisphosphonates to take effect 3
- Avoid overhydration in patients with cardiac or renal insufficiency 3, 6
- Use loop diuretics (furosemide) ONLY after complete volume repletion and only in patients with renal or cardiac insufficiency to prevent fluid overload 3, 6
Step 2: Bisphosphonate Therapy
Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate due to superior efficacy compared to pamidronate. 3, 5, 6
- Normalizes calcium in 50% of patients by day 4, with peak effect at days 4-10 5
- Do NOT use doses >4 mg for initial treatment; reserve 8-mg dose only for relapsed/refractory cases 3
- Dose adjustments for renal impairment (CrCl <60 mL/min): CrCl 50-60 = 3.5 mg; CrCl 40-49 = 3.3 mg; CrCl 30-39 = 3.0 mg 6
- Check serum creatinine before each dose and withhold if renal deterioration occurs 3, 6
- Pamidronate IV may be used as alternative if zoledronic acid unavailable 3
Step 3: Adjunctive Therapies
Calcitonin 100 IU subcutaneously or intramuscularly provides rapid onset within hours but limited efficacy - use as bridge until bisphosphonates take effect. 3, 2
- Onset of action: within hours, but tachyphylaxis develops 3, 2
- Use primarily in patients who cannot tolerate other treatments or need immediate calcium reduction 3
- Has analgesic properties for bone pain from vertebral fractures or metastases 3
Refractory or Bisphosphonate-Resistant Hypercalcemia:
Denosumab 120 mg subcutaneously lowers calcium in 64% of patients within 10 days when bisphosphonates fail. 3
- Higher risk of severe hypocalcemia compared to bisphosphonates - correct hypocalcemia before initiating and monitor closely 3
- Provide calcium supplement 500 mg plus vitamin D 400 IU daily during treatment 3, 6
Severe Hypercalcemia with Renal Failure:
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. 3, 5
- Effectively removes calcium through diffusive therapy 3
- Consider if hyperkalaemia not otherwise controlled and appropriate equipment/expertise available 7
Cause-Specific Treatments
Granulomatous Disease (Sarcoidosis, Some Lymphomas):
Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption. 3, 1
- Prednisone 20-40 mg/day orally or methylprednisolone IV equivalent 3
- Target lowest effective dose ≤10 mg/day to minimize toxicity 3
- If unable to wean below 10 mg/day after 3-6 months: add methotrexate as steroid-sparing agent 3
- Mechanism: reduces excessive intestinal calcium absorption from unregulated vitamin D production 3, 4, 1
Malignancy-Associated Hypercalcemia:
Treat the underlying cancer when possible - hypercalcemia of malignancy carries poor prognosis with median survival approximately 1 month. 3, 5
- Multiple myeloma: hydration + zoledronic acid 4 mg IV + steroids ± calcitonin 3
- Continue bisphosphonates for up to 2 years in patients with multiple myeloma or bone metastases 3
- Plasmapheresis as adjunctive therapy for symptomatic hyperviscosity 3
Primary Hyperparathyroidism:
Parathyroidectomy is definitive treatment for patients meeting surgical criteria. 1, 2
- Observation appropriate for patients >50 years with mild elevation and no complications 1
- Exclude familial hypocalciuric hypercalcemia before considering surgery 2
Tertiary Hyperparathyroidism (CKD):
Parathyroidectomy is considered for persistent hypercalcemic hyperparathyroidism despite optimized medical therapy. 3
- Immediately discontinue all calcium-based phosphate binders 3
- Stop all vitamin D analogs (calcitriol, paricalcitol) and vitamin D supplements 3
- Consider lower dialysate calcium concentration (1.5-2.0 mEq/L) 3
Critical Monitoring and Safety
Retreatment Criteria:
- Minimum 7 days must elapse before retreatment with zoledronic acid to allow full response to initial dose 6
- Renal function must be carefully monitored before each dose 6
Electrolyte Management:
- Monitor serum calcium, creatinine, and electrolytes (especially potassium and magnesium) every 6-12 hours during acute phase 3
- Correct hypomagnesemia and hypokalemia as they can worsen hypercalcemia 3
Hypocalcemia Prevention:
- Correct hypocalcemia BEFORE initiating bisphosphonates to prevent severe post-treatment hypocalcemia 3, 5
- Asymptomatic hypocalcemia following treatment does not require intervention - only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg 3
Critical Pitfalls to Avoid
Never delay bisphosphonate therapy in moderate-severe hypercalcemia while relying solely on temporary measures like calcitonin - these provide only 1-4 hours of benefit with rebound hypercalcemia. 3, 5
- Do not assume day-1 calcium levels reflect zoledronic acid failure - the drug requires 4-10 days for full effect 5
- Avoid NSAIDs and IV contrast in patients with renal impairment to prevent further kidney damage 3, 5
- Do not use loop diuretics before complete volume repletion 3, 6
- In malignant hyperthermia, use IV calcium 0.1 mmol/kg ONLY in extremis as calcium influx contributes to myoplasm calcium overload 7
- Do not rely on corrected calcium instead of ionized calcium as it can lead to inaccurate diagnosis 5
- Avoid restricting calcium intake excessively without medical supervision as this can worsen bone disease 3