Zhou et al. Journal of Experimental & Clinical Cancer Research 2011, 30:72 http://www.jeccr.com/content/30/1/72 Page 5 of 7 Figure 3 Forest plot for meta-analysis of bone pain of patients treated with upfront zoledronic acid (ZOL) versus delayed ZOL. higher risk of arthralgia and bone pain than patients without ZOL treatment. These adverse effects bring anxiety to patients and may threaten patients’ life quality in some conditions. These adverse effects generally resolve within 48 hours and respond well to nonsteroi- dal anti-inflammatory drugs [33]. Of these patients, some suffered serious musculoskeletal disorders from ZOL treatment, which exist longer and respond worse to anti-inflammatory drugs. Sometimes, serious muscu- loskeletal disorders cause treatment withdrawal. Although most musculoskeletal disorders will disappear spontaneously, we should take more attentions to patients treated with ZOL. The dose, frequency, and speed of infusion are all important determinants of these adverse effects [33]. When patients with high risk of osteoporosis suffered serious musculoskeletal disor- ders from ZOL, the risk-reducing measures should be considered. These measures included reducing the dose, slowing the infusion rate and prolonging the interval between infusions. When the patients can not tolerate these adverse effects, other oral bisphosphonates should be considered [33]. When ZOL was administrated to patients with low risk of osteoporosis, little benefit but additional musculoskeletal disorders would be brought to these patients. Three randomized clinical trials [12,18,19] were con- ducted to compare upfront ZOL with delayed ZOL for prevention of bone loss in postmenopausal women. These studies suggested that upfront ZOL was more effective in preserving bone mineral density than delayed ZOL, but no significant difference in fracture rate was observed. The UK Expert Group [20] sug- gested that patients with low risk of osteoporosis did not need a special treatment, while patients with high risk should be treated with bisphosphonates. Our results suggested more musculoskeletal disorders were observed in patients treated with upfront ZOL. Since not all patients need upfront ZOL treatment, delayed ZOL may be considered preferentially in some condi- tions. In addition, although ZO-FAST trial showed that upfront ZOL led to improved DFS, further rando- mized trials are required to investigate the survival and adverse effects between upfront ZOL and delayed ZOL. Several limitations of this meta-analysis should be considered when interpreting these results. First, of these seven studies, most subjects were Caucasians, while seldom Asians were included. Second, the present results were based on unadjusted RRs. More precise estimation may be adjusted by other potential covariates. Third, due to lack of data on musculoskeletal disorders, three trials were excluded. Since these studies were with small sample size, they were unlikely to change signifi- cantly our results.