Koizumi et al. BMC Cancer 2010, 10:423 http://www.biomedcentral.com/1471-2407/10/423 Page 5 of 9 Figure 2 Kaplan-Meier curves for survival (cause-specific death, CSD) in patients with and without pain. Starting point was the date of diagnosis of skeletal metastasis. CSD fractions are presented for patients without pain (black line) and with pain (gray line). A log-rank test demonstrated a statistically significant difference between the two groups (p < 0.001). Starting point was the date of diagnosis of skeletal metastasis. pain (data not shown). These findings indicate that fewer SREs and longer survival (CSD) were not due to the lead time bias. Length time bias could not be eliminated from this study even though the time from initial surgery to diagnosis of osseous metastasis was no different in patients with or without pain. Patients with painful bone metastases could have different dis- ease biology from asymptomatic individuals (more aggressive recurrence, rapid growth, higher disease burden, more lytic lesions), which could account for their poor prognosis. The results presented herein do not predict that routine bone surveys will detect more asymptomatic patients and improve their outcome. However, the results do reveal that asymptomatic patients diagnosed with skeletal metastasis had lesser SRE and CSD than symptomatic patients. Kohno et al. reported that the SRE rate was higher among patients with pathological fractures before diagnosis than in patients with no prior fracture [12], and this could relate to the fact that the SRE rate was higher in patients with bone pain at the time of diagnosis of ske- letal metastasis than in patients with no pain. Patients with skeletal metastasis but no bone pain (bone pain could be the result of micro-fractures at skeletal metastasis) should present with a lower SRE than patients with bone pain. Drawbacks with this retrospective study include using a database of breast cancer patients in our institute, where data collection began approximately 30 years ago. The records lacked several important pieces of informa- tion including tumor grade and HER2/neu status, and it employed the local (Japanese) pathological classification system. A second database was utilized for data analysis of skeletal metastasis in breast cancer patients. This database lacked information regarding the type of skele- tal metastasis (lytic, blastic, mixed type), and both data- bases lacked information regarding the pain condition of individuals. Patients’ records (cards) were checked for the presence or absence of pain at diagnosis of skeletal metastasis but there was no detailed information about the pain condition of individuals. Therapy for breast cancer has changed over time with the advancement of chemotherapeutic agents and their combination, hormones and molecular targeting agents (HER2/neu). The concept of standard therapy for skele- tal metastasis has changed with the advent of bispho- sphonates. In Japan, bisphosphonates were first approved for use in the treatment of skeletal metastasis