Changes in osteoblast function, assessed by serial bone scans and serum alkaline phosphatase bone isoenzyme (ALP-Bl) and osteocalcin, have been studied in 53 patients receiving systemic therapy for bone metastases from advanced breast cancer. In 12/16 patients with healing of lytic disease on x-ray a paradoxical deterioration in the bone scan appearances after 3 mo treatment was seen. This was characterized by increased activity in baseline lesions and the appearance of new foci of tracer uptake; changes which are indistinguishable from progressive disease. After 6 mo successful treatment the bone scan improved with reduced tracer uptake and no new lesions since the 3-mo scan. New lesions appearing after 6 mo indicated progressive disease. These changes are attributed to a flare in osteoblast activity induced by successful systemic therapy and confirmed by a transient rise in osteocalcin and ALP-Bl. After 1 mo of treatment 15/16 responders showed a rise in both parameters compared with only 5/23 nonresponders (p = less than 0.001). The flare response is the rule rather than the exception after successful systemic therapy for bone metastases. The appearance of new lesions or increasing activity in known lesions during the first 3 mo is as likely to herald radiological response as disease progression.