Treatment of hypercalcaemia

Seek expert advice.

The underlying cause of the condition must be treated.

• general measures aimed at lowering the serum calcium
  • medications known to cause or worsen hypercalcaemia, such as thiazide diuretics, should be discontinued and immobilisation avoided
  • generous oral salt and water intake should be maintained
    • promotes calcium excretion
    • avoids ECF volume depletion, which would exacerbate hypercalcaemia

Mild Hypercalaemia (less than 3 mmol/l)

• most case caused by primary hyperparathyroidism
• management of asymptomatic patients is controversial
  • to qualify for medical, and avoid surgical, management these patients should have, besides only a mild increase in serum calcium, no previous episodes of life-threatening hypercalcaemia and normal renal function and bone density
    • patients must be monitored closely with frequent questioning about symptoms, measurement of blood pressure, serum calcium, renal function, and possibly urinary calcium excretion, abdominal radiographs, and measurements of bone density
    • specific indications for surgery in asymptomatic patients with primary hyperparathyroidism are:
      • raised serum calcium(>2·85 mmol/L or mg/dl)
      • history of episode of life threatening hypercalcaemia
      • reduced creatinine clearance(<70% of that for age-matched healthy people)
      • kidney stone(s)
      • raised 24 h uniary calcium excretion(>100µmol or 400 mg)
      • substantial reduction of bone mass
    • immediate intervention directed at the mild hypercalcaemia itself is not usually necessary
    • in outpatients with mild primary hyperparathyroidism all diuretics should be avoided
      • loop diuretics such as furosemide increase urine calcium excretion but may also induce ECF volume depletion, increasing renal calcium resorption and worsening the hypercalcaemia
      • thiazides are contraindicated because they reduce urine calcium excretion and increase the serum calcium
      • bisposphonates lower serum calcium but they are rarely required in mild hypercalcaemia

Moderate hypercalcaemia (calcium > 3mmol/l and < 3.375 mmol/l)

• treatment decisions depend on the severity of the symptoms, which generally correlate with the rate of rise of the serum calcium
  • in patients with few or mild symptoms, treatment of the underlying disorder may decrease serum calcium before symptoms become serious
  • when neurological symptoms are the sole manifestation of hypercalcaemia, other reasons for the altered mental status changes must be excluded before the symptoms are attributed to the raised serum calcium
  • if gastrointestinal or neurological symptoms are severe it may be difficult simply to provide oral salt and water, and intravenous normal saline may be required to restore intravascular volume, leading to improved GFR and enhanced renal calcium excretion
    • as the serum calcium falls the renal tubular concentrating mechanism will improve, so stabilising intravascular volume
    • gentle hydration with intravenous saline may be enough but if congestive heart failure ensues or if more rapid lowering of serum calcium is desired, a loop diuretic will enhance calcium excretion
      • ECF volume depletion must be avoided because this will worsen hypercalcaemia
      • n a setting of renal insufficiency, higher doses of loop diuretics are needed
        • thiazide diuretics must be avoided
        • intravenous saline plus a loop diuretic should decrease the serum calcium rapidly, usually by 0·25-0·75 mmol/L in 1 or 2 days
          • if this reduction is insufficient bisphosphonate may be required.

Severe hypercalcaemia (calcium level above 3·375 mmol/L)

• this requires immediate referral to the emergency department
• treatment is via a combination of measures enhancing volume repletion and renal calcium excretion, reducing bone resorption, and targeting the underlying disease proces
  • if a raised PTH then should be referred for urgent parathyroidectomy
  • the usual reason for severe hypercalcaemia is malignancy
• initial treatment for the hypercalcaemia is with intravenous normal saline and a loop diuretic
  • monitoring of haemodynamic and electrolyte status is required
    • with intravenous hydration and a loop diuretic
      • adequate rehydration with 0.9% saline e.g. 3-6 litres in 24 hr period as necessary with potassium supplements, as indicated be serum monitoring
      • serum calcium will fall rapidly - however the effect lasts only as long as the infusion and diuresis continue
      • correction of hypokalaemia and hypomagnesaemia using IV supplements
      • monitor plasma sodium, potassium, magnesium, urea, CVP
    • since osteoclast activity is usually enhanced - therefore treatments are directed at reducing bone resorption should be initiated using a bisphosphonate or other agent
      • bisphosphonates have become the principal class of agent for the management of hypercalcaemia due to enhanced osteoclastic bone resorption
        • bisphosphonates start to take effect after 48 hours to lower serum calcium, however the maximum effect may not be seen for 5 to 7 days.
      • other agents Plicamycin (mithramycin) inhibits osteoclastic RNA synthesis and decreases bone resorption
        • lower serum calcium more quickly than bisphosphonates therapy
          • mithramycin inhibits bone resorption - effective if due to hyperparathyroidism or malignancy - but toxic to liver, kidneys and platelets
        • calcitonin inhibits osteoclastic bone resorption and enhances renal calcium excretion
          • calcitonin has an acute but very short-lived hypocalcaemic effect
          • effect on calcium concentrations is modest and transient, and calcitonin alone has no place in the treatment of severe hypercalcaemia
            • in very severe cases - an excellent addition to the later- acting plicamycin or bisphosphonates
      • gallium nitrate binds to bone mineral and reduces hydroxyapatite crystal solubility
        • like bisphosphonates, takes several days before a nadir in serum calcum is reached, and this lasts about a week
        • side-effects are frequent and severe, with nephrotoxicity, hypophosphataemia, and anaemia
          • drug should be avoided in patients with renal insufficiency or those receiving another nephrotoxic agent
      • glucocorticoids are effective in hypercalcaemia associated with haematological malignancy (lymphoma, multiple myeloma) and in diseases related to 1,25(OH)2D3 excess, such as sarcoidosis and vitamin D toxicity
      • haemodialysis against low-calcium dialysate is more effective than peritoneal dialysis for the dialysis- dependent hypercalcaemic patient

Reference:

• (1) Prescribers' Journal 1999; 39 (4): 234-241.
• (2) Bushinksy DA, Monk RD. Calcium. Lancet 1998; 352 (9124): 306-311.
• (3) West Midlands Palliative Care Physicians (2012). Palliative care - guidelines for the use of drugs in symptom control.