Response to retreatment of malignant hypercalcemia with the bisphosphonate AHPrBP (APD): Respective role of kidney and bone

Abstract

Malignant hypercalcemia is caused by both increased bone resorption and enhanced tubular reabsorption of calcium. First, the response to an infusion of APD was compared in two groups of patients: 23 with breast cancer versus 20 with squamous cell cancer. The decrease in plasma calcium was smaller in the latter group (p < 0.05 at day 14), due to increased tubular reabsorption of calcium (TmCa/GFR 2.20 ± 0.05 versus 2.58 ± 0.06 mmol/liter; p < 0.001), whereas the degree of bone resorption reflected by urinary hydroxyproline was identical. Therefore, at a given initial plasma calcium level, the type of tumor (on which TmCA/GFR depends) seems to be a determinant for the effectiveness of the treatment. Second, the response to the initial treatment was compared with that to a second treatment with the same dose in 12 patients whose malignant hypercalcemia relapsed. Within 9 days, plasma calcium decreased from 3.46 ± 0.10 to 2.50 ± 0.10 mmol/liter after the first course, but only from 3.37 ± 0.08 to 2.79 ± 0.09 mmol/liter after the second course (p < 0.01). TmCa/GFR was similar before the first and the second treatment and did not vary during the days following the infusion of APD. Initial urinary hydroxyproline was slightly but not significantly higher before the second treatment. It dropped following both APD courses, but to a lesser extent after the second treatment, reflecting higher bone resorption or possible resistance to bisphosphonate. In conclusion, both the degree of tubular reabsorption of calcium (which depends on tumor type) and that of bone resorption modify the response of malignant hypercalcemia to APD, bone resorption playing the key role for the loss of efficacy in case of retreatment.