Treatment of Hypercalcemia

There are two points of attack on hypercalcemia.54,55 One is to inhibit osteoclastic bone resorption, thus reducing the flux of calcium into the extracellular fluid. The other is to increase the urinary excretion of calcium, potentiating the only homeostatic mechanism to clear an excess calcium load. The urinary clearance of calcium is often impaired in patients with malignancy-associated hypercalcemia. The glomerular filtration rate is reduced both by direct effects of hypercalcemia and by the dehydration and prerenal azotemia that result from impaired urinary concentrating ability. In patients with PTHrP-induced hypercalcemia, the renal tubular reabsorption of calcium is also increased. Thus, the first line of attack on hypercalcemia is usually to correct dehydration and increase the urinary clearance of calcium by inducing a saline diuresis. If necessary, the urinary clearance of calcium can be greatly enhanced with the use of loop diuretics such as furosemide together with saline infusions to induce a massive natriuresis and calciuresis. However, close monitoring of central pressures, serum potassium, and serum magnesium and replacement of urinary losses of fluids and electrolytes are necessary to carry out this mode of therapy safely.

Several potent and effective inhibitors of bone resorption are available for acute treatment of hypercalcemia. The bis-phosphonate agent pamidronate disodium is administered in a single intravenous infusion of 60 to 90 mg over 6 to 24 hours.56'57 Normocalcemia results in 80% to 90% of patients, although the nadir of the serum calcium concentration is not reached until about 5 days after administration. The efficacy and safety of pamidronate make it the agent of first choice. The mean duration of the response is 1 to 2 weeks, and patients can be retreated on relapse. Pamidronate is considerably more potent and more effective than the older bisphosphonate etidronate disodium, but several other new bisphosphonates will prove equally effective. Among these, alendronate disodium and clodronate have had extensive trials, but neither is yet approved.

Synthetic salmon calcitonin in large doses of 200 to 800 U/day reduces the serum calcium level rapidly and is a useful adjunct to pamidronate, whose action has a delayed onset. However, refractoriness to calcitonin ensues within 2 to 4 days. In patients who are refractory to pamidronate and calcitonin, the cytotoxic antibiotic plicamycin (mithramycin) is useful. Although effective, plicamycin is no longer considered the drug of first choice because of its hepatic, renal, and bone marrow toxicity after repeated administration.

PTHrP has the same hypocalciuric effect on the kidney as PTH. For this reason, it was anticipated that patients with high levels of PTHrP might be relatively refractory to agents targeted to osteoclastic bone resorption. Several studies have shown that nonresponders to pamidronate treatment have higher serum PTHrP levels than responders.51'58'59 However, this relationship is a weak one that has not been observed consistently60; most patients with PTHrP-induced hypercalcemia respond to pamidronate treatment. Thus, the finding of a high PTHrP level should not influence the choice of therapy. In PTHrP-induced hypercalcemia, however, it is doubly important that aggressive measures to increase the urinary calcium clearance be instituted.

Definitive treatment of the underlying neoplasm is also indicated. The treatment is rarely surgical because the cancer is usually advanced and diffuse by the time hypercalcemia supervenes. Chemotherapy of breast carcinoma, multiple myeloma, lymphoma, and leukemia is usually successful in hypercalcemic patients. In solid tumors other than breast carcinoma, chemotherapy is less valuable: chemotherapy has failed in many patients before the appearance of hypercalcemia.

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