What are the causes and treatment options for hypercalcemia, particularly in older adults or individuals with a history of malignancy?

Hypercalcemia: Causes and Treatment

Major Causes of Hypercalcemia

Primary hyperparathyroidism and malignancy account for approximately 90% of all hypercalcemia cases. 1

PTH-Dependent Causes (Elevated or Normal PTH)

• Primary hyperparathyroidism is characterized by elevated or inappropriately normal PTH levels despite hypercalcemia, representing the most common cause in ambulatory patients 2, 3
• Tertiary hyperparathyroidism occurs in chronic kidney disease patients with persistent hypercalcemic hyperparathyroidism despite optimized medical therapy 4
• Familial hypocalciuric hypercalcemia should be excluded before considering parathyroid surgery 5

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

• Malignancy-associated hypercalcemia occurs in 10-25% of patients with lung cancer (most commonly squamous cell carcinoma) and carries a poor prognosis with median survival of approximately 1 month 2, 3
• Humoral hypercalcemia of malignancy is mediated by PTHrP, often seen in squamous cell carcinomas and renal cell carcinoma 3
• Granulomatous disorders (sarcoidosis, tuberculosis) cause hypercalcemia through increased 1,25-dihydroxyvitamin D production by activated macrophages 3, 1
• Vitamin D intoxication from excessive supplementation leads to increased intestinal calcium absorption 3, 4
• Medications: thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day), calcitriol, vitamin D analogues (causing hypercalcemia in 22.6-43.3% of patients), and patiromer 4, 1
• Other endocrinopathies: thyrotoxicosis 6
• Immobilization 1, 6

Clinical Presentation by Severity

Mild Hypercalcemia (10.2-12 mg/dL)

• Usually asymptomatic but may present with constitutional symptoms (fatigue, constipation) in approximately 20% of patients 1

Moderate Hypercalcemia (12-14 mg/dL)

• Polyuria, polydipsia, nausea, vomiting, abdominal pain, myalgia, and confusion 2, 3

Severe Hypercalcemia (>14 mg/dL)

• Mental status changes, bradycardia, hypotension, severe dehydration, acute renal failure, somnolence, and coma 2, 1

Diagnostic Algorithm

Step 1: Confirm True Hypercalcemia

• Measure ionized calcium (normal: 4.65-5.28 mg/dL) to avoid pseudo-hypercalcemia from hemolysis or improper sampling 2, 4
• If only total calcium available, calculate corrected calcium: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)] 2, 4

Step 2: Measure Intact PTH

• PTH is the single most important initial test to distinguish PTH-dependent from PTH-independent causes 1, 5
• Use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma at 4°C 2
• PTH assays vary up to 47% between different generations; use assay-specific reference values 2

Step 3: PTH-Dependent Hypercalcemia (Elevated or Normal PTH)

• Measure 25-hydroxyvitamin D to exclude vitamin D deficiency causing secondary hyperparathyroidism 2
• PTH reference values are 20% lower in vitamin D-replete individuals (>30 ng/mL) 2
• Measure serum phosphorus (typically low-normal in primary hyperparathyroidism) 2
• Assess 24-hour urine calcium or spot urine calcium/creatinine ratio to distinguish familial hypocalciuric hypercalcemia 2
• Measure serum creatinine and eGFR 2
• Consider renal ultrasonography for nephrocalcinosis or kidney stones 2
• Bone density scan if chronic hyperparathyroidism suspected 2

Step 4: PTH-Independent Hypercalcemia (Suppressed PTH <20 pg/mL)

• Measure both 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy 2, 4
  • Low 25-OH with elevated 1,25-(OH)₂ suggests granulomatous disease (sarcoidosis) 2
  • High 25-OH suggests vitamin D intoxication 2
• Measure PTHrP if malignancy suspected 2, 3
• Review medication history: thiazides, lithium, calcium/vitamin D supplements, calcitriol, vitamin A 4
• Evaluate for malignancy if PTHrP elevated or clinical suspicion high 3

Treatment Approach

Mild Asymptomatic Hypercalcemia (10.2-12 mg/dL)

For primary hyperparathyroidism, parathyroidectomy is indicated if ANY of the following criteria are met: 2

• Corrected calcium >1 mg/dL above upper limit of normal
• Age <50 years
• eGFR <60 mL/min/1.73 m²
• Osteoporosis (T-score ≤-2.5 at any site)
• History of nephrolithiasis or nephrocalcinosis
• Hypercalciuria (>300 mg/24hr)

If surgery not indicated or patient declines:

• Ensure adequate oral hydration 2
• Discontinue calcium supplements, vitamin D, and thiazide diuretics 2
• Maintain normal dietary calcium intake (1000-1200 mg/day); avoid high or low calcium diets 2
• Total elemental calcium intake should not exceed 2000 mg/day 2
• Monitor serum calcium every 3 months 2
• Refer to endocrinology and experienced parathyroid surgeon for evaluation 2

Moderate to Severe Hypercalcemia (≥12 mg/dL) or Symptomatic

Step 1: Aggressive IV Hydration (Cornerstone of Initial Management)

• Administer IV normal saline aggressively to correct hypovolemia and promote calciuresis, targeting urine output 100-150 mL/hour 2, 4
• Balanced crystalloids preferred over 0.9% saline when possible to avoid hyperchloremic metabolic acidosis 4
• Administer boluses of 250-500 mL every 15 minutes until rehydration achieved 4
• Loop diuretics (furosemide) only AFTER volume restoration and only in patients with renal or cardiac insufficiency to prevent fluid overload 2, 4
• Monitor serum calcium, creatinine, and electrolytes (especially potassium and magnesium) every 6-12 hours 4

Step 2: Bisphosphonate Therapy (First-Line Pharmacologic Treatment)

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate due to superior efficacy compared to pamidronate, normalizing calcium in 50% of patients by day 4 2, 4, 1
• Pamidronate IV is an alternative if zoledronic acid unavailable 4
• Initiate early as definitive treatment without waiting for completion of rehydration 4
• Dose adjustments required for creatinine clearance <60 mL/min 4
• Measure serum creatinine before each dose; discontinue if unexplained albuminuria >500 mg/24hr OR serum creatinine increases >0.5 mg/dL 4
• Baseline dental examination before initiating therapy to prevent osteonecrosis of the jaw 4
• Continue therapy for up to 2 years in patients with multiple myeloma or bone metastases 4

Step 3: Adjunctive Therapies

Calcitonin (for rapid but temporary effect):

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly every other day provides rapid onset within hours but limited efficacy 4, 7
• Use as bridge until bisphosphonates take effect (which require 2-4 days) 4
• Tachyphylaxis develops, limiting long-term use 5

Glucocorticoids (for specific etiologies):

• Prednisone 20-40 mg/day orally or methylprednisolone IV equivalent for vitamin D-mediated hypercalcemia 2, 3, 4
• Effective for: sarcoidosis, lymphomas, vitamin D intoxication, multiple myeloma 2, 3, 4
• Allow 3-6 months to demonstrate responsiveness 4
• Target lowest effective dose ≤10 mg/day to minimize toxicity 4
• Add methotrexate as steroid-sparing agent if unable to wean below 10 mg/day after 3-6 months 4
• Pneumocystis pneumonia prophylaxis for patients receiving ≥20 mg methylprednisolone equivalent for ≥4 weeks 4
• GI prophylaxis with proton pump inhibitor for all patients on corticosteroids 4

Denosumab (for refractory cases or renal impairment):

• Denosumab 120 mg subcutaneously for bisphosphonate-refractory hypercalcemia, lowering calcium in 64% of patients within 10 days 4
• Preferred agent for patients with impaired renal function due to lower rates of renal toxicity compared to bisphosphonates 4
• Higher rates of hypocalcemia; correct hypocalcemia before initiating and monitor closely 4
• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during treatment 4

Step 4: Dialysis (for severe refractory cases)

• Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) reserved for severe hypercalcemia complicated by renal insufficiency or oliguria 2, 4

Etiology-Specific Considerations

Malignancy-Associated Hypercalcemia:

• Treatment of underlying cancer is essential 3, 4
• Hydration, zoledronic acid (preferred), and steroids for multiple myeloma 4
• Plasmapheresis as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma 4
• Prognosis is poor with median survival approximately 1 month 2

Chronic Kidney Disease:

• Immediately discontinue all calcium-based phosphate binders and vitamin D analogs (calcitriol, paricalcitol) 4
• Consider lower dialysate calcium concentration (1.5-2.0 mEq/L) if PTH suppressed 4
• Denosumab preferred over bisphosphonates due to renal safety profile 4

Vitamin D Intoxication:

• Discontinue all forms of vitamin D therapy immediately when serum calcium exceeds 10.2 mg/dL 2
• Measure serum calcium 2-4 weeks after discontinuation 2
• Do not resume vitamin D until serum calcium consistently below 9.5 mg/dL 2
• Glucocorticoids effective as primary treatment 2, 3, 1

Critical Pitfalls to Avoid

• Do not order parathyroid imaging before confirming biochemical diagnosis; imaging is for surgical planning, not diagnosis 2
• Do not rely on corrected calcium instead of ionized calcium, as it can be inaccurate 4
• Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy 4
• Do not use loop diuretics before complete volume repletion 4
• Avoid NSAIDs and intravenous contrast media in patients with renal impairment 4
• Do not restrict calcium intake excessively without medical supervision, as this can worsen bone disease 4
• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia; temporary measures like calcitonin provide only 1-4 hours of benefit 4
• Correct hypocalcemia before initiating bisphosphonate therapy and monitor serum calcium closely, especially with denosumab 4

Monitoring and Follow-Up

• Serum calcium, renal function, and electrolytes should be monitored regularly 3
• For primary hyperparathyroidism not meeting surgical criteria: monitor serum calcium every 3 months 2
• During bisphosphonate therapy: measure serum creatinine before each dose 4
• During vitamin D supplementation: monitor serum calcium and phosphorus at least every 3 months 2