OSTEOLYSIS - A BIOCHEMICAL DOSE-RESPONSE STUDY

Bisphosphonates are used increasingly in normocalcemic patients for treating tumor-induced osteolysis (TIO) but little is known about the metabolic effects and the most appropriate therapeutic regimen. In 21 patients with breast cancer and TIO, we determined the biochemical effects of a single infusion of pamidronate given at 30 mg (n = 5), 60 mg (n = 5), 90 mg (n = 5), or 120 mg (n = 6). Patients received no other systemic antineoplastic therapy during the trial. We selected patients with baseline fasting urinary Ca/Creat (creatinine) >0.105 mg/mg (median value of our normal range) and they were followed weekly for up to 14 weeks. The biochemical effects were maximal at day 7. For the whole group, mean (+/- SEM) Ca/Creat levels fell from 0.208 +/- 0.018 to 0.048 +/- 0.008 mg/mg on day 7 and remained significantly (p < 0.01) lower than baseline up to day 56. Hydroxyproline excretion fell to a lesser degree, 6 om 7.0 +/- 1.2 to 4.0 +/- 0.6 mg x 100/mg of Creat. The falls in Ca/Creat and hydroxyproline excretion were dose-related (ANCOVA, p < 0.05). Changes in serum parameters of calcium metabolism were, however, not significantly dose-related. Serum Ca levels fell from 9.3 +/- 0.1 to 8.7 +/- 0.1 mg/dl on day 7, but no patients developed symptomatic hypocalcemia, and the decrease within each dose group was significant only at 120 mg. Ca2+ levels followed a similar pattern. There was a slight increase in Mg levels and a pronounced fall in P-i levels, from 3.6 +/- 0.2 to 2.8 +/- 0.1 mg/dl. Intact PTH levels increased from 29 +/- 4 to 91 +/- 13 pg/ml and remained significantly (p < 0.05) elevated up to day 28. The concentration of 1,25(OH)(2) vitamin D increased from 20 +/- 2 to 45 +/- 4 pg/ml, but the osteocalcin concentration did not change significantly. We subsequently treated 11 cancer patients with bone metastases and low urinary Ca/Creat levels (<0.105 mg/mg) with 30 or 60 mg of pamidronate. The changes in biochemical parameters of bone metabolism were similar to those described above, confirming the safety of these doses of pamidronate in patients without evidence of increased bone resorption. In summary, single pamidronate infusions, given at doses from 30 to 120 mg, dose-dependently inhibited bone resorption in patients with bone metastases. Pamidronate also induced marked but transient changes in blood parameters of calcium metabolism, especially at a dose of 120 mg. Our data suggest that 90 mg of pamidronate is adequate to inhibit bone resorption in this patient population.