Zhou et al. Journal of Experimental & Clinical Cancer Research 2011, 30:72 http://www.jeccr.com/content/30/1/72 Table 1 Characteristics of eligible trials Author (Study) Gnant (ABCSG12) Shapiro (CALGB) Hershman Coleman (AZURE) Brufsky (Z- FAST) Eidtmann (ZO-FAST) Hines (N03CC) Year Intervention Dosage of treatment 2009 Zoledronic acid 4 mg IV every 6 months No treatment 2011 Zoledronic acid 4 mg IV every 3 months No treatment 2008 Zoledronic acid 4 mg IV every 3 months Placebo 2011 Zoledronic acid 4 mg IV monthly for 6 months, then every 3 months for 8 doses No treatment and then every 6 months for 5 doses 2009 Upfront 4 mg IV every 6 months zoledronic acid Delayed zoledronci acid 2010 Upfront 4 mg IV every 6 months zoledronic acid Delayed zoledronci acid 2009 Upfront 4 mg IV every 6 months zoledronic acid Delayed zoledronci acid Duration Number of (yr) patients 3 1 5 5 5 5 899 904 70 80 50 53 1665 1675 300 300 524 536 267 274 Page 3 of 7 Follow-up (mo) 47.8 12 12 6 36 36 12 yr, year; mo, months; IV, intravenous; NA, not available 1.376, P = 0.193 for heterogeneity) (Figure 2). However, there was no significantly different risk of muscle pain between the two groups (RR: 1.198, 95% CI: 0.901-1.594, P = 0.366 for heterogeneity). Funnel plot and Egger’s test were performed to access the publication bias of the four studies. No significant publication bias (P > 0.05) existed (data not shown). Upfront versus delayed-start ZOL The main results were also showed in Table 2. Arthral- gia occurred in 12.7%-42.2% patients treated with upfront ZOL and in 11.3%-40.7% patients with delayed ZOL. There was no significantly different risk of arthral- gia between the two groups (RR: 1.022, 95% CI: 0.932- 1.120, P = 0.850 for heterogeneity). The similar results were observed about muscle pain between the two groups (RR: 1.071, 95% CI: 0.942-1.217, P = 0.422 for heterogeneity). The rates of muscle pain were 6.4%- 16.3% and 5.1%-12.1% in upfront group and delayed group, respectively. Bone pain caused by ZOL was reported in Z-FAST and ZO-FAST trials. The rate of bone pain in upfront group (119/824) was significantly higher than that in delayed group (74/836) (RR: 1.284, 95% CI: 1.135-1.453, P = 0.460 for heterogeneity) (Fig- ure 3). Since only three trials were included in this analysis of musculoskeletal disorders between upfront and delayed ZOL groups, publication bias was not accessed. Discussion Previous randomized clinical trials showed that muscu- loskeletal disorders occurred in a high rate of patients treated with ZOL. This meta-analysis suggested that patients treated with ZOL had a statistically significant higher risk of arthralgia and bone pain compared to patients without ZOL treatment. Furthermore, patients treated with upfront ZOL had a significant higher risk of bone pain than patients with delayed ZOL. Although ZOL can bypass the potential disadvantages of the oral route used by other bisphosphonates, it may cause more musculoskeletal disorders than other bisphosphonates [30-32]. A high rate of musculoskeletal disorders occurred in patients treated with ZOL. Patients treated with ZOL had a statistically significant Table 2 Summary RRs and 95% CI Complications Arthralgia Bone pain Muscle pain RR (95%CI) 1.162 (1.096-1.232)# 1.257 (1.149-1.376) 1.198 (0.901-1.594) ZOL vs no ZOL P⋆ 0.466 0.193 0.366 Number of studies 4 2 2 RR, risk ratio; CI, confidence interval; ZOL, zoledronic acid; *P value for between-study heterogeneity; #the number in AZURE trial included the number of arthralgia and muscle pain. Upfront ZOL vs delayed ZOL RR (95%CI) P⋆ Number of studies 1.022 (0.932-1.120) 1.284 (1.135-1.453) 1.071 (0.942-1.217) 0.850 0.460 0.422 3 2 3