In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid-hormone-related protein, which are elaborated by the tumor and circulate systemically. Humoral hypercalcemia usually occurs in squamous-cell malignancies of the lung or head and neck or in genitourinary tumors such as renal-cell carcinoma or ovarian cancer. Skeletal metastases may be absent or minimal in these patients.

Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma.

Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value for differences in albumin levels is often used in place of measurement of ionized calcium; several nomograms are in use for this type of calculation (see DOSAGE AND ADMINISTRATION).

Clinical Trials

In one double-blind clinical trial, 52 patients who had hypercalcemia of malignancy were enrolled to receive 30 mg, 60 mg, or 90 mg of Aredia as a single 24-hour intravenous infusion if their corrected serum calcium levels were ≥ 12.0 mg/dL after 48 hours of saline hydration.

The mean baseline-corrected serum calcium for the 30-mg, 60-mg, and 90-mg groups were 13.8 mg/dL,13.8 mg/dL, and 13.3 mg/dL, respectively.

The majority of patients (64%) had decreases in albumin-corrected serum calcium levels by 24 hours after initiation of treatment. Mean-corrected serum calcium levels at days 2-7 after initiation of treatment with Aredia were significantly reduced from baseline in all three dosage groups. As a result, by 7 days after initiation of treatment with Aredia, 40%, 61%, and 100% of the patients receiving 30 mg, 60 mg, and 90 mg of Aredia, respectively, had normal-corrected serum calcium levels. Many patients (33%-53%) in the 60-mg and 90-mg dosage groups continued to have normal-corrected serum calcium levels, or a partial response ( ≥ 15% decrease of corrected serum calcium from baseline), at Day 14.

In a second double-blind, controlled clinical trial, 65 cancer patients who had corrected serum calcium levels of ≥ 12.0 mg/dL after at least 24 hours of saline hydration were randomized to receive either 60 mg of Aredia as a single 24-hour intravenous infusion or 7.5 mg/kg of etidronate disodium as a 2-hour intravenous infusion daily for 3 days. Thirty patients were randomized to receive Aredia and 35 to receive etidronate disodium.

The mean baseline-corrected serum calcium for the Aredia 60-mg and etidronate disodium groups were 14.6 mg/dL and 13.8 mg/dL, respectively.

By Day 7, 70% of the patients in the Aredia group and 41% of the patients in the etidronate disodium group had normal-corrected serum calcium levels (P < 0.05). When partial responders ( ≥ 15% decrease of serum calcium from baseline) were also included, the response rates were 97% for the Aredia group and 65% for the etidronate disodium group (P < 0.01). Mean-corrected serum calcium for the Aredia and etidronate disodium groups decreased from baseline values to 10.4 and 11.2 mg/dL, respectively, on Day 7. At Day 14, 43% of patients in the Aredia group and 18% of patients in the etidronate disodium group still had normal- corrected serum calcium levels, or maintenance of a partial response. For responders in the Aredia and etidronate disodium groups, the median duration of response was similar (7 and 5 days, respectively). The time course of effect on corrected serum calcium is summarized in the following table.

Change in Corrected Serum Calcium by Time from Initiation of Treatment

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