Treatment of Tumor Hypercalcemia with Clodronate

Abstract

The association of hypercalcemia and malignant disease has been observed especially in patients with multiple myeloma and carcinomas of the lung, kidney, breast, prostate, and ovary (Myers 1960). As therapeutic regimens in the treatment of malignant disorders have been improved in recent years, resulting in prolonged survival of patients, humoral hypercalcemia of malignancy has become a more frequent and often serious complication of tumor disease, which requires additional treatment. Plasma calcium concentration can be lowered by isotonic sodium chloride infusions, calcitonin, prednisone, mithramycin, and oral phosphorus. However, congestive heart failure, escape phenomenon, or severe side effects can limit the duration of their application. Therefore, bisphosphonates such as etidronate or clodronate, which are known to inhibit osteoclast activity (Delaissé et al. 1985; Schenk et al. 1973), are under current clinical investigation to prove their effectivenes in hypercalcemia of malignancy. Etidronate, which is already used in the treatment of Paget’s disease (Holz et al. 1983) and heterotopic ossification (Garland et al. 1983), has been demonstrated to be beneficial also in tumor hypercalcemia by several authors (Kanis et al. 1987; Ringenberg and Ritch 1987). However, besides the desired inhibition of osteolysis, etidronate also causes impairment of mineralization (Schenk et al. 1973), which may cause fractures (Canfield et al. 1977). By contrast, clodronate does not induce a skeletal mineralization defect up to an oral dose of 2.4 g daily (Delmas et al. 1982), but seems to be very effective in tumor hypercalcemia (Cohen et al. 1981; Jacobs et al. 1981; Percival et al. 1985; Siris et al. 1980). In our study we evaluated the effect of intravenous and oral clodronate administration including the reaction of the calcium-regulating hormones parathyroid hormone (PTH) and 1.25-dihydroxycholecalciferol (1,25 (OH)₂D₃).