Circulating osteocalcin (BGP), the major noncollagenous bone protein, is elevated in patients with certain metabolic bone disease while its behavior in cancer patients, particularly those with bone metastases, is unclear. We measured circulating BGP in 37 healthy females, in 13 female patients with benign breast disease, and in a group of 51 cancer patients (breast, lung, prostate, and bladder) with and without bone metastases, before and after 4'-epidoxorubicin (4'-Epidx) therapy (4'-Epidx 120 mg/m2 every 3 weeks). Under basal conditions, mean BGP levels of all of these subjects fell within the normal range of 2.0-5.0 ng/ml (mean +/- SD, 4.8 +/- 1.0 ng/ml). In cancer patients without bone metastases BGP levels measured before and after 4'-Epidx therapy were not significantly different (4.4 versus 4.6 ng/ml). Only in breast cancer patients with multiple bone metastases was circulating BGP higher after the onset of antiblastic treatment and through the entire course of therapy, accompanied by bone pain remission and regression of bone lesions (BGP = 6.7 +/- 1.3 ng/ml). Thus an increase in BGP concentration can be considered as a biological marker of recovered osteoblast activity during therapeutically induced stabilization or regression of skeletal metastatic lesions.