Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)

  • Complicates 10%–20% of all cancers
  • Commonly the presenting feature of malignancy
  • Occurs in both solid tumors and hematologic malignancies

It is especially associated with

  • Breast cancer
  • Multiple myeloma
  • Lung cancer, especially squamous cell carcinoma

Free Ca2+ ≥3,0 mmol/L leads to multisystem dysfunction.

  • Free (ionic) Ca2+ is dependent on serum albumin and arterial pH.
  • Free (ionic) Ca2+ = measured Ca2++ [(40-albumin) x 0,02].


  • Local increased bone resorption (osteolysis) induced by bone metastases is attributed to tumor cell production of cytokines, particularly interleukins and tumor necrosis factor (TNF) activating osteoclasts.
    • It is the dominant mechanism in certain malignancies, e.g., lymphoma, non-small–cell lung cancer. Serum PO43- is usually normal.
  • There is systemic release of humoral mediators activating osteoclasts, e.g., parathyroid hormone-related peptide (PTHrP).
    • In some tumors, humoral mechanisms causing hypercalcemia are believed to dominate particularly in the absence of bony metastases, e.g., squamous cell carcinoma of the lung.
  • Often associated with low PO43– from inhibition of PO43– reabsorption

Dehydration exacerbates hypercalcemia.

  • Ca2+ is a potent diuretic causing salt and water loss.
  • As diuresis continues, Ca2+ levels increase, causing further volume depletion, etc.
  • Tumor-specific mechanisms include the following examples:
  • Multiple myeloma—secretion of an osteoclast-activating factor with or without deposition of Bence-Jones proteins leads to renal impairment and decreased Ca2+
  • Some lymphomas (usually T cell) produce active metabolites of vitamin D, increasing intestinal absorption of Ca2+.

In many cancers, more than one mechanism may contribute, e.g., osteolytic, and humoral mechanisms appear to be important in breast cancer.


  • Acute or insidious
  • May be incidental finding in an asymptomatic patient
  • Neurological features: malaise, fatigue, weakness, depression, cognitive dysfunction, coma
  • Gastrointestinal features: nausea, vomiting, anorexia, abdominal pain, constipation, pancreatitis
  • Renal signs: polydipsia, polyuria, dehydration, signs of uremia, renal calculi
  • Cardiac disorders: arrhythmias, with increased or decreased BP


  • Urea and electrolytes (U & E), corrected serum Ca2+, PO43-, Mg2+
  • Full blood count (FBC): a normal Hb in the presence of significant hypercalcemia is likely to fall once the patient is rehydrated.
  • Plasma PTH is appropriately undetectable in malignant hypercalcemia.

Nonmalignant causes of hypercalcemia are common and may coexist with a diagnosis of cancer, e.g., primary or tertiary hyperparathyroidism.


  • Establish intravenous access and monitor urine output.
  • Rehydration is given to produce volume expansion, restore glomerular function, and increase urinary Ca2+
    • Fluid deficit may be many liters.
    • Aim for 3–6 L/24 hours if cardiac function and urine output permit.
    • Reassess fluid status regularly.
  • Monitor U & E: Renal impairment should improve with fluid resuscitation. K+ and Mg2+ may fall with rehydration and require IV replacement (K+ 20–40 mmol/L, Mg2+ up to 2 mmol/L of normal saline).
    • Check Ca2+ and albumin daily.
  • Loop diuretics, e.g., furosemide po/IV, lower Ca2+ (inhibits reabsorption in the loop of Henle) and maintain diuresis once patient is rehydrated
  • Bisphosphonates: Consider if free Ca2+ remains ≥3,0 mmol/L despite rehydration
    • They cause inhibition of osteoclast activity, leading to low Ca2+.
    • Typical schedule is pamidronate 60–90 mg infused in 1 L normal saline over 2–4 hours, provided renal function is adequate following 24 hours of rehydration. Then continue fluids.
    • Onset of action is from 48 hours and patient is usually normocalemic within 3–7 days.
    • Cannot repeat dose for 7 days, i.e., the acute management of hypercalcemia is fluid resuscitation. Optimal interval is ≥3 weeks.
    • Side effects include transient fever, hypocalcemia.
    • Zolendronic acid (4 mg IV over 15 minutes) is superseding pamidronate as the bisphosphonate of choice to treat malignant hypercalcemia because of shorter infusion time and greater potency.
  • Steroids have little role. They may be helpful in treating multiple myeloma (prednisolone 30–60 mg qd).
  • Avoid immobility: Lack of weight-bearing induces increased osteoclastic activity while reducing bone formation, which may precipitate hypercalcemia.
  • Dietary Ca2+ restriction is not appropriate in most patients, as gut Ca2+ absorption is usually appropriately reduced. Rare exceptions are some patients with lymphoma associated with raised levels of vitamin D metabolites.
  • Treat the underlying malignancy if possible. Usually hypercalcemia is associated with advanced disease and treatment is palliative.
  • Salmon calcitonin leads to increased renal Ca2+ excretion and decreased bone reabsorption. Use IM or SC administration. There is a rapid onset of action but efficacy is limited to the initial 48 hours of treatment (tachyphylaxis).

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