Efficacy and safety of the bisphosphonate tiludronate for the treatment of tumor-associated hypercalcemia.

Tiludronate is a new bisphosphonate whose efficacy has already been reported for the prevention of postmenopausal bone loss. We have evaluated its efficacy and tolerance by a dose-finding study in 19 hypercalcemic cancer patients after adequate intravenous (iv) rehydration. Treatment consisted of 3 days of iv tiludronate given at doses of 3.0 mg/kg/day (n = 3), 4.5 mg/kg/day (n = 3), or 6.0 mg/kg/day (n = 13); this iv therapy was followed by 17 days of oral tiludronate, 400 mg (n = 13) or 800 mg (n = 6) daily. Treatment had to be discontinued in 9 patients, including 3 because of evident treatment failure and 1 because of severe toxicity. After iv tiludronate, 13/18 patients had a normal Ca level, including 10/12 who had received 6.0 mg/kg/day, but Ca2+ levels were fully normalized in only 4/18 and 3/12 patients, respectively. After 6.0 mg/kg/day, Ca levels had fallen from 12.1 +/- 0.3 to 10.0 +/- 0.4 mg/dl (P less than 0.0005), whereas fasting urinary calcium excretion went from 0.639 +/- 0.099 to 0.272 +/- 0.054 mg Ca/mg creatinine on d4 (P less than 0.001). On the other hand, oral tiludronate was unable to normalize Ca in patients who were still hypercalcemic after the iv course, although the daily administration of 800 mg appeared to be more efficient than the 400 mg daily dosage. The administration of tiludronate caused an increase in serum phosphate levels, from 2.9 +/- 0.2 to 3.7 +/- 0.2 mg/dl after the iv course, probably through an increase in the TmP/GFR index, which went from 2.3 +/- 0.2 to 3.6 +/- 0.4 mg/dl (P less than 0.05). Three patients had an increase in serum creatinine levels after the iv course, one obese patient developing an acute renal insufficiency; during oral tiludronate therapy, 5 other patients also presented an increase in serum creatinine levels. Oral tiludronate administration was also associated with occasional nausea and vomiting. In summary, compared with aminobisphosphonates, tiludronate is not indicated for the treatment of tumor-associated hypercalcemia because of the need for high iv doses which are potentially nephrotoxic.