Hypercalcemia in Head and Neck Cancer: What It Means, How to Confirm It, and How to Manage It

A high serum calcium result in someone with head and neck cancer can suggest hypercalcemia, which is a potentially serious metabolic complication that often reflects advanced disease and requires prompt evaluation and treatment. ^[1] Hypercalcemia in this setting can arise either from cancer invading bone or from tumor‑produced “humoral” factors, most commonly parathyroid hormone–related protein (PTHrP), that increase calcium by stimulating bone resorption and reducing renal calcium excretion. ^{[2] [3]}

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Why cancer can raise calcium

• Bone involvement: Extensive invasion of bone by tumor cells can directly increase bone breakdown and release calcium into the bloodstream. ^[4]
• Humoral hypercalcemia of malignancy (HHM): Many solid tumors including squamous cell carcinomas of the head and neck can secrete PTHrP, which mimics parathyroid hormone effects and drives calcium up even without obvious bone metastases. ^{[5] [3]}
• Frequency and prognosis: Hypercalcemia appears in a notable minority of head and neck cancer cases and often signals advanced disease with poorer short‑term survival, so timely detection and treatment matter. ^{[6] [7]}

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Key symptoms to watch

Hypercalcemia can be silent or cause symptoms such as fatigue, constipation, nausea, increased urination/thirst, confusion, and bone pain; severe elevations may lead to dehydration, kidney injury, and altered consciousness. ^[1] Prompt recognition and workup help prevent complications. ^[8]

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First steps: Confirm it’s truly high calcium

• Corrected or ionized calcium: Verify true hypercalcemia by correcting total calcium for albumin or measuring ionized calcium. This ensures the elevation is real, not an artifact of protein changes. ^[9]
• Repeat measurement: Recheck calcium to confirm persistence and assess trend. ^[9]

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Diagnostic workup: Find the cause

A structured workup helps distinguish HHM from primary hyperparathyroidism and other causes:

• Serum PTH (parathyroid hormone): Low or suppressed PTH with high calcium suggests a non‑parathyroid cause (e.g., malignancy). Inappropriately normal/high PTH points toward primary hyperparathyroidism. ^[10]
• Serum PTHrP: Elevated PTHrP with high calcium supports humoral hypercalcemia of malignancy. ^{[5] [10]}
• Vitamin D levels: Check 25‑OH and sometimes 1,25‑OH vitamin D to evaluate for vitamin D excess or granulomatous disease. ^[10]
• Urine calcium: Helps characterize calcium handling and supports the differential. ^[10]
• Renal and bone assessment: Consider imaging for bone metastases and kidney evaluation if indicated by symptoms or lab abnormalities. ^[11]
• Medication and supplement review: Excess calcium or vitamin D intake can contribute to hypercalcemia. ^[1]

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Evidence-based management

Treatment depends on severity, symptoms, and the underlying driver:

• IV hydration (normal saline): Restores volume and increases urinary calcium excretion; it is the foundational acute step, especially in moderate to severe hypercalcemia. ^{[12] [13]}
• Loop diuretics (e.g., furosemide): May be used after adequate hydration to promote calciuresis; avoid over‑diuresis and monitor electrolytes. ^[13]
• IV bisphosphonates (pamidronate, zoledronic acid): Potently inhibit bone resorption and are standard for cancer‑related hypercalcemia; onset is within 24–72 hours. ^{[14] [15]}
• Denosumab: Effective when bisphosphonates are contraindicated or ineffective, especially in refractory cases. ^{[12] [16]}
• Calcitonin: Provides rapid but short‑lived lowering of calcium; useful as a bridge while antiresorptives take effect. ^[13]
• Glucocorticoids: Helpful when hypercalcemia is driven by excess vitamin D or certain hematologic malignancies. ^{[12] [17]}
• Treat the cancer: Controlling the underlying tumor is essential to prevent recurrence of hypercalcemia. ^[14]

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When to treat urgently

Very high calcium levels or significant symptoms (dehydration, confusion, arrhythmia risk, kidney dysfunction) warrant emergency management with prompt hydration and antiresorptive therapy. ^[12] Clinicians typically individualize therapy based on severity, renal function, and overall prognosis. ^[8]

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Practical workup and treatment pathway

Below is a simple pathway you can expect your care team to follow:

1. Confirm hypercalcemia: Repeat serum calcium; correct for albumin or measure ionized calcium. ^[9]
2. Initial labs: Serum PTH, PTHrP, vitamin D levels, renal function tests, and urine calcium. ^[10]
3. Supportive care: Start IV saline; consider calcitonin for rapid temporary control. ^{[12] [13]}
4. Definitive lowering: Give IV bisphosphonate; consider denosumab if refractory or contraindicated. ^{[14] [12]}
5. Search for cause: Review medications/supplements; assess for bone metastases or other contributors. ^{[1] [11]}
6. Treat the malignancy: Coordinate oncologic management to prevent recurrence. ^[14]

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Quick reference tables

Common causes of hypercalcemia in cancer

Cause	Mechanism	Typical Clues
Humoral hypercalcemia (PTHrP)	Tumor secretes PTHrP → bone resorption ↑, renal calcium excretion ↓	High calcium, low/normal PTH, elevated PTHrP, may lack bone metastases
Bone metastases	Local osteolysis and bone turnover ↑	Imaging evidence of bone lesions, bone pain
Vitamin D excess	Increased intestinal calcium absorption	Elevated vitamin D levels, history of supplements or granulomatous disease

Core diagnostic tests

Test	Purpose	Interpretation in HHM
Corrected or ionized calcium	Confirm true hypercalcemia	Elevated
Serum PTH	Differentiate parathyroid vs malignancy	Low/suppressed
Serum PTHrP	Confirm humoral mechanism	Elevated
Vitamin D (25‑OH ± 1,25‑OH)	Identify vitamin D–mediated causes	Normal or specific pattern depending on cause
Urine calcium	Assess renal handling	Variable; supports workup

First‑line treatments

Therapy	Role	Notes
IV saline	Volume repletion, calciuresis	Monitor for fluid overload
Calcitonin	Rapid temporary reduction	Tachyphylaxis within 48–72 hours
IV bisphosphonate	Inhibits bone resorption	Used widely for cancer‑related hypercalcemia
Denosumab	For refractory cases	Useful when bisphosphonates fail
Glucocorticoid	Vitamin D–mediated or hematologic causes	Short‑term use can be effective

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Take‑home points

• A high calcium in head and neck cancer often reflects either bone involvement or tumor‑driven humoral hypercalcemia via PTHrP. ^{[2] [4]}
• Confirm the elevation and promptly check PTH, PTHrP, and vitamin D to pinpoint the cause. ^{[10] [5]}
• Start hydration, then add antiresorptive therapy (bisphosphonate or denosumab) and consider calcitonin for rapid control. ^{[14] [12] [13]}
• Ongoing control depends on treating the underlying cancer. ^[14]

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Additional context on head and neck cancer

While hypercalcemia is not universal, studies show it occurs in a notable minority and often indicates advanced disease in head and neck squamous cell carcinoma, with shorter survival from the first hypercalcemic episode if not rapidly addressed. ^{[6] [7]} Early detection and systematic management can reduce distressing symptoms and hospitalizations. ^[7]