Treatment of tumour-induced hypercalcaemia with the bisphosphonate pamidronate: Dose-response relationship and influence of tumour type

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Abstract
Patients with humoral hypercalcaemia of malignancy appear to respond less well to biphosphonate therapy than hypercalcaemic patients with osteolytic metastases. On the other hand, pamidronate is currently the most potent of the commercially available biphosphonates and it is recommended that its dose be increased as a function of pre-treatment calcium levels. We reviewed our experience with pamidronate in 160 patients with tumour-induced hypercalcemia (TIH) persisting after rehydration, particularly the influence of the dose administered, the tumour type and the presence of bone metastatic involvement on the calcaemic and calciuric response to pamidronate therapy. Serum Ca was normalized in 92% of the cases (87% when Ca was corrected for protein levels). After therapy, 59% of the patients developed asymptomatic hypocalcaemia (30% for Corn Ca levels). A multiparameter regression analysis revealed that the response to pamidronate was significantly (P < 0.01) influenced by initial Ca levels up to days 5–7 and, thereafter, only by the dose received. To confirm the dose effect, we divided the patients into three groups according to the median dose received, namely 0.5 mg/kg (n = 35), 1.0 mg/kg (n = 52), and 1.5 mg/kg (n = 73). The differences among the three groups became significant(P < 0.05) from days 5–7 until the end of the evaluation (days 22–26). Similarly, the success rate, considering Corr. Ca levels, was 80% for the 0.5 and 1.0 mg/kg groups combined, compared to 94% for the 1.5 mg/kg group (P < 0.05). The duration of normocalcaemia was similarly more prolonged in the high-dose group. There was a dose-response relationship only in patients with Ca levels above 3.0 mmol/L and in patients with an elevated index of tubular calcium reabsorption. By contrast, the decrease in Ca levels and in fasting urinary calcium excretion, a sensitive index of bone resorption, were not significantly influenced by the primary tumour site or by the presence of bone metastatic involvement. Our data demonstrate a dose-response relationship for pamidronate in TIH over an efficient hypocalcaemic dose range, at least in patients with an elevated tubular calcium reabsorption, which helps to resolve conflicting data in the literature. We suggest that a dose of around 1.5 mg of pamidronate/kg is optimal for the treatment of TIH, except in patients with mild hypercalcaemia, for whom a dose of 1 mg/kg appears to be sufficient. At these dose levels, the efficacy of pamidronate is not significantly influenced by the tumour type or the degree of metastatic bone involvement.