Biochemical markers as surrogates in clinical trials in patients with metastatic bone disease and osteoporosis.

ABSTRACT

Biochemical markers of bone turnover have been employed in phase II dose-finding trials to determine the therapeutic window of the highly potent bisphosphonate ibandronate. For intravenous dose finding in metastatic bone disease 158 patients with breast cancer were treated by single bolus injection of up to 3.0 mg and by single infusion of 4 and 6 mg of ibandronate. In the oral double-blind dose-finding trial, 108 patients received up to 50 mg of ibandronate or placebo once daily for 28 days. For dose-finding in osteoporosis 126 postmenopausal women with osteoporosis were treated in a double-blind trial by four injections of up to 2.0 mg of ibandronate or placebo every 3 months. In the phase II dose-finding trial, 180 postmenopausal women with osteoporosis received up to 5 mg of ibandronate or placebo daily for 12 months. During these trials, the bone resorption markers urinary Ca, pyridinoline (Pyd), deoxypyridinoline (Dpd), type I collagen cross-linked N-telopeptide and type I collagen cross-linked C-telopeptide revealed clear dose-dependent responses in accordance with the appropriate dose of ibandronate. The bone formation markers serum osteocalcin, carboxy-terminal propeptide of type I collagen and bone-specific alkaline phosphatase demonstrated also dose-dependent changes in long-term treatment. Thus, for dose finding and monitoring of ibandronate treatment in osteoporosis and in patients with malignant metastatic bone disease urinary type I collagen cross-linked N-telopeptide and C-telopeptide are the most responsive biochemical markers of bone resorption. For bone formation monitoring serum osteocalcin and serum bone-specific alkaline phosphatase should be employed.