How to manage hypercalcemia with normal Parathyroid Hormone (PTH) levels?

Management of Hypercalcemia with Normal PTH Levels

Hypercalcemia with normal PTH levels should be thoroughly evaluated for malignancy as the most likely cause, followed by other non-parathyroid etiologies including granulomatous diseases, medications, and vitamin D intoxication. 1

Differential Diagnosis

When faced with hypercalcemia and normal PTH levels, consider the following causes:

1. Malignancy-associated hypercalcemia (most common non-PTH dependent cause)

   • Accounts for approximately 90% of hypercalcemia cases along with primary hyperparathyroidism 1
   • PTH is typically suppressed but can occasionally be normal
   • Associated with poor survival outcomes

2. Other non-PTH dependent causes:

   • Granulomatous diseases (e.g., sarcoidosis)
   • Medications (thiazide diuretics, calcium/vitamin supplements)
   • Vitamin D intoxication
   • Immobilization
   • Endocrinopathies (thyroid disease)
   • Genetic disorders
   • Newer medications: SGLT2 inhibitors, immune checkpoint inhibitors 1

Diagnostic Approach

1. Initial laboratory evaluation:

   • Confirm hypercalcemia with repeat testing
   • Check ionized calcium levels
   • Assess renal function (BUN, creatinine, GFR)
   • Measure vitamin D levels (25-OH and 1,25-OH)
   • Check alkaline phosphatase (to identify bone involvement) 2

2. Additional testing based on clinical suspicion:

   • Serum and urine protein electrophoresis (for multiple myeloma)
   • Bone scintigraphy if bone pain or very elevated alkaline phosphatase 2
   • Chest imaging (for malignancy or granulomatous disease)
   • Review medication list thoroughly

3. Important pitfall to recognize: Coexisting conditions

   • In rare cases, patients may have both primary hyperparathyroidism and malignancy-associated hypercalcemia simultaneously 3
   • This should be suspected when calcium levels are disproportionately high compared to PTH levels
   • After treatment with bisphosphonates, PTH may increase as calcium decreases, revealing underlying hyperparathyroidism 3

Treatment Algorithm

For Severe Hypercalcemia (>14 mg/dL or symptomatic)

1. Immediate management:

   • Aggressive IV hydration with normal saline
   • IV bisphosphonates (zoledronic acid or pamidronate) 1
   • Consider calcitonin for rapid but temporary effect
   • Discontinue calcium supplements, thiazide diuretics, and other contributing medications 4

2. For patients with renal failure:

   • Consider denosumab
   • Dialysis may be necessary in severe cases 1

3. For specific causes:

   • Glucocorticoids for vitamin D intoxication or granulomatous disorders 1
   • Chemotherapy for malignancy-related hypercalcemia

For Mild to Moderate Hypercalcemia (<14 mg/dL, asymptomatic)

1. Identify and treat underlying cause

   • If malignancy: appropriate cancer-directed therapy
   • If medication-induced: discontinue offending agent
   • If granulomatous disease: treat underlying condition

2. Monitoring parameters:

   • Serum calcium and phosphate levels
   • Renal function
   • Hydration status
   • Symptoms 2

Special Considerations

1. Diagnostic challenge: Normal PTH with hypercalcemia

   • While uncommon, this can represent early primary hyperparathyroidism where PTH is "inappropriately normal" rather than elevated
   • Consider malignancy workup even with normal PTH 3

2. Monitoring after initial treatment:

   • Follow calcium levels closely after treatment
   • Watch for rebound hypercalcemia
   • Monitor for treatment complications (e.g., hypocalcemia after bisphosphonates)

3. Long-term management:

   • Regular follow-up based on underlying cause
   • Repeat calcium measurements
   • Address bone health and fracture risk

Remember that hypercalcemia with normal PTH is less common than PTH-dependent hypercalcemia, and malignancy should be strongly considered as the underlying cause, particularly in hospitalized patients 5.