Hypercalcaemia

Hypercalcaemia is defined as an elevated serum calcium concentration above the normal range of 2.2–2.6 mmol/L. It is a common metabolic emergency in oncology, occurring in approximately 10–20% of patients with advanced cancers. The condition is most frequently associated with cancers of the breast, kidney, lung, prostate, head and neck, and multiple myeloma. Hypercalcaemia is associated with significant morbidity and is often an indicator of advanced disease and poor prognosis. Prompt recognition and immediate treatment are essential to prevent life-threatening complications.

Epidemiology

Hypercalcaemia occurs in approximately 10–20% of patients with advanced malignancy. It is most commonly seen in:

• Breast cancer

• Lung cancer

• Kidney cancer

• Prostate cancer

• Head and neck cancers

• Multiple myeloma

Severe hypercalcaemia is associated with advanced disease and poor survival.

Risk factors

Risk factors include:

• Advanced malignancy

• Bone metastases

• Multiple myeloma

• Primary hyperparathyroidism

• Prolonged immobilization

• Vitamin D excess

• Thiazide diuretic use

• Dehydration

Pathophysiology

Hypercalcaemia develops when calcium entry into the circulation exceeds renal excretion. In malignancy, the principal mechanisms include:

• Osteolytic bone destruction from skeletal metastases.

• Tumor secretion of parathyroid hormone-related peptide (PTHrP).

• Increased production of calcitriol by certain malignancies.

• Reduced renal calcium excretion due to dehydration and renal impairment.

Elevated serum calcium impairs neuromuscular, renal, gastrointestinal, cardiovascular, and central nervous system function.

Clinical presentation

Clinical manifestations depend on the severity of hypercalcaemia and the rate at which serum calcium rises. Symptoms range from mild gastrointestinal complaints to severe neurological impairment.

Symptoms

• Nausea

• Vomiting

• Constipation

• Polyuria

• Polydipsia

• Generalized weakness

• Fatigue

• Confusion

• Disorientation

• Depression

• Anxiety

• Cognitive dysfunction

• Insomnia

• Reduced level of consciousness

• Coma in severe cases

Clinical signs

• Clinical evidence of dehydration

• Volume contraction

• Dry mucous membranes

• Hypotension

• Tachycardia

• Reduced skin turgor

• Altered mental status

• Muscle weakness

• Cardiac arrhythmias

Severe hypercalcaemia (serum calcium above 3.75–4.0 mmol/L) is a medical emergency and indicates a poor prognosis.

Differential diagnosis

• Primary hyperparathyroidism

• Vitamin D intoxication

• Sarcoidosis

• Hyperthyroidism

• Multiple myeloma

• Milk-alkali syndrome

• Drug-induced hypercalcaemia (e.g., thiazides)

• Immobilization-related hypercalcaemia

Diagnostic criteria

The diagnosis of hypercalcaemia is based on elevated serum calcium levels together with compatible clinical features and evaluation of the underlying cause.

Diagnosis is established by:

• Serum calcium concentration above the normal reference range.

• Clinical manifestations consistent with hypercalcaemia.

• Laboratory investigations to determine the underlying etiology.

Investigations

• Serum calcium (corrected for albumin where appropriate)

• Parathyroid hormone (PTH)

• Renal function tests

• Serum electrolytes

• Serum phosphate

• Electrocardiogram (ECG) to detect arrhythmias

• Bone scan where metastatic bone disease is suspected

• PET-CT scan where appropriate to identify metastatic bone disease

Management

Hypercalcaemia should be treated immediately, followed by treatment of the underlying cause.

Initial management includes:

• Assess airway, breathing, and circulation.

• Assess severity of hypercalcaemia and hydration status.

• Initiate intravenous hydration promptly.

• Monitor urine output, serum electrolytes, renal function, and cardiac rhythm.

• Identify and treat the underlying cause after stabilization.

Non-pharmacological treatment

• Encourage oral hydration in patients with mild hypercalcaemia who can tolerate fluids.

• Administer intravenous fluids in moderate or severe hypercalcaemia.

• Monitor fluid balance carefully.

• Correct dehydration before administering bisphosphonates.

• Mobilize patients as tolerated to reduce bone resorption.

• Arrange dental assessment before initiation of long-term bisphosphonate or denosumab therapy where feasible.

Pharmacological treatment

Hydration and diuresis

• Normal saline (isotonic saline) – 1–2 litres – IV – over 2 hours.

Then:

• Furosemide – 30–40 mg – IV – after adequate hydration – according to clinical response.

Bisphosphonate therapy

• Zoledronic acid – 4 mg in 100 mL normal saline – IV infusion – over 15 minutes.

Normalization of serum calcium usually occurs within 4–10 days and lasts 4–6 weeks. If retreatment is required, the dose may be repeated after 7 days.

OR

• Ibandronate – 6 mg – IV infusion – over 2 hours.

Calcitonin

• Calcitonin – 4–8 IU/kg – IM or SC – every 6–8 hours.

Calcitonin produces a rapid reduction in serum calcium; however, tachyphylaxis limits its duration of effectiveness.

Management according to underlying cause

Malignancy-associated hypercalcaemia

• Immediate intravenous hydration.

• Bisphosphonate therapy.

• Calcitonin for severe symptomatic hypercalcaemia requiring rapid calcium reduction.

• Definitive treatment of the underlying malignancy after stabilization.

Hyperparathyroidism

• Treat according to the underlying endocrine disorder following confirmation of diagnosis.

Bone metastases

• Bisphosphonate therapy.

• Appropriate oncological management.

Multiple myeloma

• Manage hypercalcaemia urgently.

• Initiate definitive treatment for multiple myeloma after stabilization.

Referral

Refer all patients with moderate or severe hypercalcaemia for specialist management.

Urgent referral is indicated for patients with:

• Serum calcium above 3.75–4.0 mmol/L

• Altered mental status

• Cardiac arrhythmias

• Severe dehydration

• Acute kidney injury

• Suspected malignancy-associated hypercalcaemia

• Failure to respond to initial treatment

Complications

• Acute kidney injury

• Cardiac arrhythmias

• Severe dehydration

• Nephrolithiasis

• Nephrocalcinosis

• Pancreatitis

• Coma

• Cardiac arrest

• Osteonecrosis of the jaw associated with bisphosphonate or denosumab therapy

• Death if untreated

Prognosis

The prognosis depends largely on the underlying cause. Hypercalcaemia associated with advanced malignancy generally indicates advanced disease and carries a poor prognosis. Prompt correction of serum calcium improves symptoms and quality of life but definitive management of the underlying condition is essential to reduce recurrence.

Prevention

Prevention includes early recognition of patients at risk, maintaining adequate hydration, prompt treatment of underlying malignancy, and regular monitoring of serum calcium in high-risk patients. Patients receiving bisphosphonates or denosumab should undergo appropriate dental assessment before treatment to minimize the risk of osteonecrosis of the jaw.