Koizumi et al. BMC Cancer 2010, 10:423 http://www.biomedcentral.com/1471-2407/10/423 Page 4 of 9 Figure 1 Kaplan-Meier curves for skeletal-related events (SRE) in patients with and without pain. Starting point was the date of diagnosis of skeletal metastasis. SRE fractions are shown for skeletal metastasis 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. bone lesion and those with multiple bone lesions were analyzed separately. This analysis was performed using SRE and CSD as events and the date of diagnosis of bone metastasis as the starting point. In patients with a solitary bone lesion, individuals with pain showed a sig- nificantly higher incidence of SRE than those without pain but showed no significant differences in terms of CSD. In patients with multiple bone lesions, individuals with pain showed a significantly higher incidence of SRE and CSD than those with no pain but CSD incidence was less than that of SRE. Discussion Bone pain is commonly associated with skeletal metasta- sis. However, in this study approximately 60% of patients did not complain of bone pain at diagnosis. Patients who developed skeletal metastasis without pain had fewer SREs and longer survival (CSD) than those with pain; these differences were statistically significant. The results were consistent irrespective of the analysis method used (Kaplan-Meier, log-rank test and Cox’s proportional hazard model analysis). Cox’s proportional hazards regression analysis using SRE and CSD as end- points demonstrated that hazard ratios (univariate) of all significant factors were higher in value for CSD than for bone pain; this was also the case in multivariable analysis. Hazard ratio of bone pain was 2.331 for the SRE event, 1.441 for the CSD event (univariable analy- sis), 2.243 for SRE and 1.535 for CSD (multivariable). The presence of bone pain predicted SRE more accu- rately than CSD. Bone pain could be an important fac- tor in predicting SRE, and other factors could be of more use in predicting CSD. This research was a cohort study in a single institute that compared SRE and CSD of asymptomatic and symptomatic patients who had developed osseous metastasis. This type of comparison can be biased by lead time (early detection simply increases the period during which osseous metastasis is observed) and length time (patients with a long preclinical phase and therefore presumably less aggressive metastasis are likely to be detected by periodic bone survey). Differ- ences in SREs and survival (CSD) could be due to the lead time bias. However, additional analysis taking the starting point as the date of surgery produced similar results. There was no difference in the chronological period of diagnosis of skeletal metastasis between patients with or without pain (data not shown), indi- cating that therapy after the diagnosis of skeletal metastasis did not differ between these groups of patients. There was no difference in the use of bispho- sphonates for patients without pain and those with