Hypercalcaemia Management

  1. Hypercalcaemia is a common disorder that necessarily involves specialised treatment, either to control symptoms or to prevent irreversible organ damage or death. Although treating the underlying cause is the best and most effective way to control hypercalcaemia in the long run, medical anti-hypercalcaemic therapy is frequently required in clinical practice, either as a stopgap measure or because the primary disease cannot be treated.
  2. The mainstays of medical anti-hypercalcaemic therapy are:
  • First, increasing calcium excretion by the kidney by restoring extracellular volume with intravenous saline
  • Second, administering pharmacological agents that inhibit bone resorption. Measures aimed at reducing intestinal calcium absorption are rarely effective.
  1. Intravenous bisphosphonates are the first-line treatment for hypercalcaemia, followed by continued oral or repeated intravenous bisphosphonates to prevent relapse. These drugs have a slow onset of action (1-3 days), but they have potent and sustained inhibitory effects on bone resorption, resulting in a long duration of action (12-30 days).
  2. Of the other agents available, calcitonin(miacalcin) has an important role in the management of severe hypercalcaemia where a rapid effect is desired. However, because of its short duration of action, calcitonin is best used in conjunction with a bisphosphonate. Intravenous phosphate (IV fluids and diuretics) has a role in the emergency management of severe hypercalcaemia, but it is probably best reserved for patients who have failed to respond to less toxic therapies. Except in rare circumstances, corticosteroids are generally ineffective and should be avoided in the routine treatment of undiagnosed hypercalcaemia.


Mechanisms Of Hypercalcaemia


Whatever the root cause, hypercalcaemia is caused by a disruption in the homeostatic mechanisms that regulate calcium levels.

Calcium exchange occurs at three locations:

  • Kidney
  • Bone
  • Intestine

The relative significance of these in hypercalcaemia pathogenesis is discussed further below.



Renal calcium homeostasis abnormalities are of concern, crucial role in pathogenesis and maintenance of the majority of hypercalcaemia types. Hypercalcaemia has an effect directly on the renal tubule to cause abnormal urinary excretion loss of sodium and water, which may or may not be substituted as a result of gastro-intestinal symptoms. The condition of volume contraction and sodium deficiency as a result of the foregoing is linked to renal sodium. This reduces urinary calcium excretion even more by increasing calcium reabsorption in the proximal kidney tubule. Calcium reabsorption in the distal renal tubule is increased in some conditions, such as primary hyperparathyroidism and many cancers, due to the effects of PTH (Para Thyroid Hormone) and PTH-related peptide (PTHrP). In addition to the renal tubular abnormalities discussed earlier in this section, impaired glomerular filtration rate is common in hypercalcaemic patients due to lack of oxygen and sodium depletion, irreversible renal tubular and glomerular damage as a result of prolonged hypercalcaemia, or in association with the excretion of specific nephrotoxic substances such as Bence-Jones protein in myeloma.



The majority of patients with severe hypercalcaemia have increased bone resorption, and in most cases, this is due to stimulation of osteoclastic activity. Osteoclasts are multinucleated cells that act during the normal process of bone remodelling to remove calcified bone matrix. Osteoclastic bone resorption is increased in many hypercalcaemic disorders, either systemically due to the action of circulating body’s immune factors (for example: PTH, PTHrP, vitamin D metabolites, thyroid hormones) or directly due to the release of osteoclast-stimulating factors by tumour metastases. While increased bone resorption alone is frequently insufficient to cause hypercalcaemia due to compensatory homeostatic mechanisms, renal function abnormalities, which are frequently present in hypercalcaemic states, impair the kidney’s ability to increase calcium excretion, allowing serum calcium levels to rise.



In a variety of hypercalcaemic disorders, including primary hyperparathyroidism, immune disorders, vitamin D intoxication, and some lymphomas, intestinal calcium absorption is increased. While this process does play a role in the pathogenesis of hypercalcaemia in some cases, it is most often overshadowed by the contributions of kidney and bone, not least because patients with hypercalcaemia severe enough to require treatment are usually anorexic and absorb little dietary calcium in any case.


Anti-hypercalcaemic treatment

  • It should be mentioned at the outset that the only sure way to control hypercalcaemia in the long run is to identify and treat the underlying cause, which may include clinical parathyroidectomy in hyperparathyroidism, chemotherapy or radiotherapy in cancer-associated hypercalcaemia, steroid therapy in sarcoidosis, and so on. However, effective therapy for the underlying disease may not be available in some patients.
  • In others, the root reason of hypercalcaemia may be unknown, or specific treatment would have to be delayed due to co-existing medical problems. Medical anti-hypercalcaemic therapy is indicated in these situations. Correcting the abnormalities in renal, skeletal, and intestinal calcium homeostasis that contribute to hypercalcaemia is essential for successful medical management. 
  • In most cases, this necessitates drug therapy to inhibit osteoclastic bone resorption and IV (intravenous) fluid therapy to promote calcium excretion through the urine. Reducing dietary calcium intake or administering agents that inhibit intestinal calcium absorption are far less effective in the treatment of hypercalcaemia, most likely because the contribution of increased intestinal absorption is often overshadowed by irregularities in renal function and bone resorption.


Other Treatment

  • Gallium nitrate is now widely used in the United States for the treatment of cancer-related hypercalcaemia, and medical trials have shown that it has an overall efficacy comparable to that of more potent bisphosphonates. It works by inhibiting osteoclastic bone resorption and, like bisphosphonates, has a slow onset of action (2-3 days) with a maximum effect 6-8 days after treatment. Although the drug may cause kidney damage, the risk is relatively low if the patient is kept hydrated and certain other nephrotoxic drugs are avoided. It is not yet approved for regular medical use in the United Kingdom. 
  • On the basis of their inhibitory action on bone resorption activated by certain experimental tumour types in vitro, prostaglandin synthetase inhibitors such as indomethacin have been used in the treatment of cancer-associated hypercalcaemia. Even though some clients with cancer-associated hypercalcaemia have responded to these agents, most workers have been disappointed by their lack of efficacy, and they cannot be recommended for the treatment of cancer-associated hypercalcaemia or other types of hypercalcaemia.
  • Octreotide, a somatostatin analogue, has recently been used successfully in the treatment of hypercalcaemia associated with certain neuroendocrine tumours. It is unknown whether this or similar drugs will be useful in the treatment of other types of hypercalcaemia.
  • The antimalarial drugs chloroquine and hydroxychloroquine can be used to treat hypercalcaemia caused by sarcoidosis, where they suppress the principal chronic illness. These medications are ineffective in treating other types of hypercalcaemia.