What are the diagnosis and management options for hypercalcaemia?

From the Guidelines

Hypercalcaemia should be treated with hydration, bisphosphonates, denosumab, steroids, and/or calcitonin, with zoledronic acid being the preferred bisphosphonate for treatment of hypercalcemia. The diagnosis of hypercalcaemia is made when serum calcium levels exceed 2.6 mmol/L (10.5 mg/dL), with severity classified as mild (2.6-3.0 mmol/L), moderate (3.0-3.5 mmol/L), or severe (>3.5 mmol/L) 1. Management depends on calcium levels, symptoms, and underlying cause. For severe or symptomatic hypercalcaemia, immediate treatment includes aggressive intravenous fluid rehydration with normal saline at 200-300 mL/hour to restore intravascular volume and enhance renal calcium excretion.

Some key points to consider in the management of hypercalcaemia include:

• Bisphosphonates are first-line medications, with zoledronic acid 4mg IV over 15 minutes being most effective, or pamidronate 60-90mg IV over 2-4 hours as an alternative 1.
• Calcitonin 4-8 IU/kg SC/IM every 12 hours provides rapid but short-term calcium reduction and works well with bisphosphonates.
• For refractory cases, denosumab 120mg SC can be used, particularly in renal impairment.
• Glucocorticoids (prednisolone 40-60mg daily) are effective for vitamin D-mediated or hematologic malignancy-related hypercalcaemia.
• Loop diuretics like furosemide should only be used after adequate rehydration.
• Hemodialysis may be necessary in severe cases with renal failure.

Long-term management requires treating the underlying cause, which commonly includes primary hyperparathyroidism (requiring parathyroidectomy), malignancy (treating the primary cancer), or medication effects (discontinuing offending agents like thiazide diuretics or excessive calcium/vitamin D supplements) 1. Regular monitoring of calcium levels, renal function, and electrolytes is essential during treatment to prevent complications like renal failure, cardiac arrhythmias, and neurological symptoms. Excess bone resorption from myeloma bone disease can lead to excessive release of calcium into the blood, contributing to hypercalcemia, and symptoms include polyuria and gastrointestinal disturbances, with progressive dehydration and decreases in glomerular filtration rate 1.

From the FDA Drug Label

Hypercalcemia of Malignancy Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in metastatic bone disease and hypercalcemia of malignancy Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. Correction of excessive bone resorption and adequate fluid administration to correct volume deficits are therefore essential to the management of hypercalcemia

Diagnosis and Management of Hypercalcaemia:

• Diagnosis: Total serum calcium levels may not reflect the severity of hypercalcemia due to concomitant hypoalbuminemia. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions.
• Management: Correction of excessive bone resorption and adequate fluid administration to correct volume deficits are essential.
  • Pamidronate disodium 2 can be used to manage hypercalcemia of malignancy.
  • Denosumab 3 can be used to treat hypercalcemia of malignancy refractory to bisphosphonate therapy.
  • Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.

From the Research

Diagnosis of Hypercalcaemia

• Hypercalcaemia is a condition characterized by elevated calcium levels in the blood, affecting approximately 1% of the worldwide population 4.
• The diagnosis of hypercalcaemia involves measuring serum intact parathyroid hormone (PTH) levels, which distinguishes PTH-dependent from PTH-independent causes 4, 5.
• Other diagnostic tests include plasma phosphorus level, vitamin D, and calculated creatinine clearance 6.
• Primary hyperparathyroidism (PHPT) and malignancy are responsible for greater than 90% of all cases of hypercalcaemia 4, 5.

Management of Hypercalcaemia

• Mild hypercalcaemia usually does not require acute intervention, but severe hypercalcaemia requires immediate treatment 4, 5.
• Initial therapy for symptomatic or severe hypercalcaemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate 4, 5, 7, 8.
• Glucocorticoids may be used as primary treatment when hypercalcaemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas) 4, 5, 7.
• Treatment of the underlying cause, such as employing chemotherapy for malignancy or parathyroidectomy for hyperparathyroidism, is also essential 4, 5, 8.
• Loop diuretics may be required in individuals with renal insufficiency or heart failure to prevent fluid overload 5, 6.
• Calcitonin is administered for the immediate short-term management of severe symptomatic hypercalcaemia 5, 7.

Treatment Options

• Parathyroidectomy may be considered for patients with PHPT, depending on age, serum calcium level, and kidney or skeletal involvement 4.
• Observation may be appropriate for patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease 4.
• Denosumab and dialysis may be indicated in patients with kidney failure 4.
• Oral or parenteral bisphosphonates can be used to maintain normocalcemia 7.