Zhou et al. Journal of Experimental & Clinical Cancer Research 2011, 30:72 http://www.jeccr.com/content/30/1/72 Page 2 of 7 were caused by ZOL [12]. However, the adverse effects caused by ZOL itself should not be neglected. Osteone- crosis of the jaw, an uncommon serious side effect caused by ZOL, has been paid close attention. Previous study [13] showed that osteonecrosis of the jaw occurred in only about 0.33% of patients treated with ZOL. Musculoskeletal disorders were common after ZOL administration and distressing to the patients. Up to now, no precise estimation of musculoskeletal disor- ders has been made. Previous randomized clinical trials [14-17] showed that musculoskeletal disorders occurred in more than 20% patients treated with ZOL and in more than 10% patients without ZOL treatment. Furthermore, some randomized trials [12,18,19] were conducted to evaluate the efficacy of upfront ZOL ver- sus delayed ZOL in preventing bone loss. The muscu- loskeletal disorders reported by these trials were discordant. The UK Expert Group [20] suggested that bispho- sphonates should be administrated to patients with high risk of osteoporosis. However, patients with low risk of osteoporosis might benefit little from ZOL treatment. When ZOL was considered to be administrated to patients, the benefit and adverse effects should be well balanced. We performed this meta-analysis to give a precise estimation of the musculoskeletal disorders of ZOL versus no ZOL and upfront ZOL versus delayed ZOL in adjuvant breast cancer treatment. Methods Search strategy The present study was conducted as described previously [21-23]. Relevant studies were selected by searching the electronic database PubMed (updated on May 1, 2011), using the following terms: early or adjuvant, breast can- cer or breast neoplasm, zoledronic acid or bisphospho- nates. Two investigators (Zhou WB and Liu XA) independently evaluated titles and abstracts of the identi- fied papers. References in identified articles and reviews were also reviewed for possible inclusion. Only published randomized clinical trials in English language were included in our study. Randomized clinical trials were included if they met the following criteria: (1) ZOL used in breast cancer patients in adjuvant setting; (2) ZOL used with a control group receiving no treatment or pla- cebo, or upfront ZOL (receiving ZOL immediately after randomization) versus delayed ZOL (receiving ZOL only if T-score fell below -2.0, after a nontraumatic clinical fracture, or if an asymptomatic fracture); (3) enough pub- lished data for estimated a risk ratio (RR) with 95% confi- dence interval (CI). In addition, to avoid duplication of information, only the report with longest follow-up was included for calculations when multiple reports pertained to overlapping groups of patients. Data extraction The data of musculoskeletal disorders, including arthral- gia, bone pain and muscle pain, were carefully extracted from all the eligible randomized trials independently by two investigators (Zhou WB and Liu XA). The following variables were extracted from each study: first author’s name, the name of each trial, publication year, the med- ian follow-up time, the number of total patients in every group, and the number of patients with musculoskeletal disorders in every group. All the data were reached con- sensus after discussion. Statistical analysis Crude RRs with 95% CI were used to assess the muscu- loskeletal disorders risk of ZOL. The between-study het- erogeneity was tested with Q statistics (significant differences indicated by P < 0.10) [24]. The fixed-effects model (the Mantel-Haenszel method) was used when between-study was absent [25]. Otherwise, the random- effects model (the DerSimonian and Laird method) was selected [26]. Funnel plots and Egger’s linear regression were used to test the publication bias and a P value less than 0.05 was considered significant. All analyses were performed using the software Stata version 11.0 (Stata Corporation, College Station, TX, USA). Results Eligible studies Ten randomized clinical trials, in which ZOL was used in adjuvant setting, were identified. Of these ten studies, the detail data of musculoskeletal disorders were not reported in three studies [27-29]. In all, seven studies [12,14-19] were eligible in this meta-analysis. Table 1 presented the characteristics of the seven trials. Of these seven studies, four studies [14-17] reported musculoske- letal disorders of ZOL versus placebo or no treatment, including 2684 patients treated with ZOL and 2712 patients treated with placebo or no treatment. Three studies [12,18,19] reported the complications of upfront versus delayed ZOL, including 1091 patients with upfront ZOL and 1110 patients with delayed ZOL. ZOL versus no ZOL Table 2 showed the main results of this meta-analysis. Arthralgia occurred in about 23.9%-68% patients treated with ZOL and 12.5%-60.4% patients without ZOL treat- ment. Compared to patients without ZOL treatment, patients treated with ZOL had a significantly higher risk of arthralgia (RR: 1.162, 95% CI: 1.096-1.232, P = 0.466 for heterogeneity) (Figure 1). Bone pain occurred in about 35.3%-40% patients treated with ZOL and in 24.6%-41.5% patients without ZOL treatment. Similarly, a significantly higher risk of bone pain was observed in patients with ZOL treatment (RR: 1.257, 95% CI: 1.149-