The two most common causes of
hypercalcemia are
primary hyperparathyroidism and neoplastic disease.
Parathyroidectomy is the only curative intervention for the former condition. In the rare cases of patients with
primary hyperparathyroidism who present with clinical symptoms due to their
hypercalcemia, pharmacological treatment may be required. Fluid repletion and intravenous (IV) administration of
bisphosphonates are recommended in the literature.
Calcium receptor agonists (
calcimimetic agents) are at the present time only available for use within clinical trials.
Cancer patients usually present with symptoms of
hypercalcemia. Rapid institution of antihypercalcemic treatment is essential in preventing life-threatening deterioration. Fluid repletion and administration of
bisphosphonates are the treatment mainstays in
hypercalcemia of
malignancy. Five
bisphosphonates are currently licensed in Europe for treatment of
tumor-associated
hypercalcemia:
etidronate,
clodronate,
pamidronate,
ibandronate, and
zoledronate. In the US,
pamidronate and
zoledronate are licensed for use in this indication.
Bisphosphonates containing
nitrogen atoms (e.g.
pamidronate,
ibandronate, and
zoledronate) are more potent than those without (e.g.
etidronate,
clodronate, and
tiludronate). In patients with malignant
hypercalcemia, the efficacy of the individual
bisphosphonate depends on dose administered and initial serum
calcium concentration. At present,
pamidronate has been studied in the greatest number of investigations and in the largest number of patients. In the literature, the efficacy of
pamidronate in restoring normocalcemia ranges between 40% and 100%, depending on the dose used and baseline serum
calcium concentration. More recently, one study reported that
pamidronate was inferior to
zoledronate. In this study, the duration of response was also longer in the two
zoledronate groups (30 and 40 days) than in the
pamidronate group (17 days). The most serious adverse events of
bisphosphonates concern renal function. Increases in serum
creatinine levels have been more frequently reported following treatment of
tumor-associated
hypercalcemia with
etidronate (8%) and
clodronate (5%) than with the
nitrogen-containing
bisphosphonates pamidronate (2%) and
ibandronate (1%). The frequency of increases in serum
creatinine levels following treatment with
zoledronate is difficult to estimate. Administration of the
nitrogen-containing
bisphosphonates has been associated with transient (usually mild)
fever,
lymphocytopenia, malaise, and myalgias. These events occur within 36 hours of the first dose and are self-limiting.
Hypocalcemia occurs in up to 50% of patients treated with
bisphosphonates for
hypercalcemia of
malignancy, although symptomatic
hypocalcemia is rare. The toxicity and low efficacy of
plicamycin (
mithramycin) mean that use of this agent should be restricted to patients with
hypercalcemia of
malignancy who fail to respond to IV
bisphosphonates.
Calcitonin is characterized by good tolerability but poor efficacy in normalizing the serum
calcium level. However, a major advantage of
calcitonin is the acute onset of the hypocalcemic effect, which contrasts with the delayed but more pronounced effect of
bisphosphonates. Combination
calcitonin and
bisphosphonate treatment may therefore be of value when rapid reduction of serum
calcium is warranted.
Gallium nitrate may be a valuable treatment for
hypercalcemia of
malignancy. It is characterized by high efficacy and few adverse events apart from renal toxicity (10% of cases). However, data are very limited and further trials are necessary.