Current and Future Directions in Medical Therapy: Hypercalcemia

Background: Tumor-induced hypercalcemia (TIH) is essentially due to a marked stimulation of osteoclast-mediated bone resorption. An inhibition of bone formation and an enhanced tubular reabsorption of calcium play an important contributory role. These factors explain why serum calcium often rises rapidly in cancer patients and why high doses of bisphosphonates are needed to normalize bone resorption and to overcome the contributory role of the kidney.

Methods: The author provides a short review of clinical trials in hypercalcemic cancer patients, with an emphasis on the most recent trials.

Results: Rehydration and bisphosphonates now constitute the standard treatment of TIH. A single-day 1500-mg infusion of clodronate achieves normocalcemia in approximately 80% of the cases. Clodronate also can be given by subcutaneous infusion that can be particularly useful in the palliative setting. A dose of 90 mg of pamidronate achieves normocalcemia in more than 90% of the patients and has a longer-lasting effect than clodronate. Newer more potent bisphosphonates, such as ibandronate and zoledronate, may improve these results, and they certainly will simplify the therapeutic schemes. Ibandronate at the dose of 6 mg normalizes serum calcium in more than 75% of the patients with moderate or severe hypercalcemia. Of note, the same doses of pamidronate and ibandronate, repeated monthly for 1-2 years, have been shown to substantially reduce the skeletal morbidity rate in normocalcemic patients with tumor bone disease. Even lower doses of zoledronate, the most potent bisphosphonate tested so far, are able to correct TIH when administered as a 30-minute infusion.

Conclusions: Bisphosphonates have become the standard treatment for cancer hypercalcemia. Success is achieved in more than 90% of the cases. Other classes of compounds are being tested for their antiosteoclastic activity, and animal studies suggest that osteoprotegerin could be as efficient and act faster than bisphosphonates.