CLODRONATE IN HYPERCALCEMIA OF MALIGNANCY

Of the many compounds belonging to the diphosphonate family, clodronate has been widely used in hypercalcemia and osteolysis of malignancy. All published reports indicate that clodronate can normalize plasma calcium in the majority of hypercalcemic, rehydrated cancer patients in whom increased bone resorption is the prevailing disturbed calcium flux. In these patients, clodronate, given intravenously either as a single infusion or as repeated daily administrations, can normalize serum calcium, usually 3-5 days after the onset of therapy. In these good responders, long-term maintenance treatment should be individually adjusted since relapse appears to depend upon the type of tumor, the extent of malignancy and the administration of anticancer therapy. In a subset of well-rehydrated hypercalcemic patients in whom increased tubular calcium reabsorption represents the prevailing disturbed calcium flux, the acute effect of clodronate on plasma calcium is incomplete, despite the normalization of bone resorption. This type of therapeutic response can be experimentally reproduced in diphosphonate-treated animals receiving a constant infusion of parathyroid hormone-related peptide, a peptide isolated from lung, kidney and breast carcinomas. This indicates that, in addition to antiosteolytic drugs, such as clodronate, patients with hypercalcemia of malignancy would benefit from the development of agents that can selectively reduce the renal tubular reabsorption of calcium. In patients displaying a good response to clodronate, the fall in plasma calcium is accompanied by an increase in the calcium-regulating hormones, parathyroid hormone and 1,25-dihydroxyvitamin D3. This homeostatic reaction probably explains why hypocalcemia rarely occurs in clodronate-treated patients. No serious side effects have been reported in cancer patients receiving oral clodronate, except for the occasional occurrence of mild and transient gastrointestinal upset. A large number of clinical studies indicate that clodronate is a safe and efficacious drug in the treatment of hypercalcemia of malignancy, particularly in cases in which increased bone resorption is the major mechanism disturbing the homeostasis of extracellular calcium. © 1990 Springer-Verlag New York Inc.