***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Purpose . Serum postoperative matrix metalloproteinase 2 ( MMP-2 ) level is a predictor of outcome in node positive breast cancer and can be used to stratify patients into low and high risk groups . Our aim was to determine how clodronate treatment influences MMP-2 associated clinical outcome . Patients and methods . Women with primary node-positive breast cancer were r and omized to control group or to receive oral clodronate for 3 years .  Adjuvant chemo- or endocrine therapy was given to all patients . The follow-up time for all patients was 5 years . MMP-2 and MMP-9 levels were quantitatively measured from the serum of 252 patients before and after 1 year clodronate treatment using enzyme-linked immunoassays . Results . In clodronate-treated patients , postoperative MMP-2 levels did not predict 5-year disease-free survival or overall survival ( DFS , in low MMP-2 group ( < 5.32 ng/ml , median ) 53 % versus in high MMP-2 group ( > median ) 63 % , p = NS ; OS , 68 % versus 63 % , p = NS ) . When the patients were grouped according to serum MMP-2 levels , survival rates among patients with low MMP-levels were better in control than clodronate treated patients ( DFS , 82 % versus 53 % , p = 0.003 ; OS , 91 % versus 68 % , p=0.014 ) . Among patients with high serum MMP-2 levels , no significant difference in DFS or OS was found between control and clodronate groups . In multivariate analysis of low risk patients , independent predictors for DFS were treatment , age , nodal and PgR status , and those for OS treatment together with nodal and ER status . During 12 months follow-up , MMP-2 levels increased significantly more in clodonate receiving patients than in controls ( p = 0.002 ) . In comparison , when the patients were grouped according to MMP-9 levels , clodronate also impaired DFS among patients with low MMP-9 levels ( 82 % versus 53 % , p = 0.02 ) , but no influence on OS was observed ( 83 % versus 70 % , p = 0.09 ) . Conclusions . Clodronate interferes with the prognostic value of serum MMP-2 . Clodronate has a negative impact on outcome among patients with low serum MMP-2 and MMP-9 levels , while no such influence is observed among patients with high MMP-2 and MMP-9 levels PURPOSE Adjuvant chemotherapy for breast cancer ( BC ) may be associated with increased rates of bone loss and decreased bone mineral density ( BMD ) and may lead to premature osteoporosis and increased fracture risk . We examined whether zoledronic acid ( ZA ) prevents bone loss in premenopausal women receiving chemotherapy for early-stage BC . PATIENTS AND METHODS This study is a r and omized , double-blind , multicenter , phase III trial comparing ZA ( 4 mg intravenously every 3 months ) versus placebo for 1 year . Premenopausal women underwent serial BMD measurements before initiating chemotherapy and at 6 and 12 months . The primary outcome was percent change in lumbar spine ( LS ) BMD at 6 months . Secondary outcomes were percent change at any BMD site and markers of bone turnover at 12 months . Linear mixed model analysis for repeated measures was performed . RESULTS Of 101 women who were r and omly assigned and completed baseline evaluation , 96 completed the 6-month evaluation , and 85 completed the 12-month evaluation . Baseline characteristics were comparable between the groups . Mean age was 42 years .  Placebo was associated with significant decline in LS BMD at both 6 ( 2.4 % ) and 12 ( 4.1 % ) months . Similarly , total hip BMD declined by 0.8 % at 6 months and 2.6 % at 12 months . In contrast , BMD remained stable in ZA patients ( P < .0001 compared with placebo ) . CONCLUSION Premenopausal women receiving chemotherapy  for BC sustained significant bone loss at the LS and hip , whereas BMD remained stable in women who received ZA . Administration of ZA during the first year of chemotherapy is an effective and well-tolerated strategy for preventing bone loss Purpose Zoledronic acid ( ZOL ) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway . Its benefit for the prevention of skeletal complications due to bone metastases has been established . However , the antitumor efficacy of ZOL , although suggested by multiple pre clinical and clinical studies , has not yet been clinical ly proven . We performed the present r and omized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy ( CT ) . Methods Asian patients with HER2-negative invasive breast cancer were r and omly assigned to either the CT or CT+ZOL ( CTZ ) group . One hundred and eighty-eight patients were r and omized to either the CT group ( n = 95 ) or the CTZ group ( n = 93 ) from March 2010 to April 2012 , and 180 patients were assessed . All patients received four cycles of FEC100 ( fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 , and cyclophosphamide 500 mg/m2 ) , followed by 12 cycles of paclitaxel at 80 mg/m2 weekly . ZOL ( 4 mg ) was administered three to four times weekly for 7 weeks to the patients in the CTZ group . The primary endpoint was the pathological complete response ( pCR ) rate , which was defined as no invasive cancer in the breast tissue specimen . Safety was assessed in all patients who received at least one dose of the study drug . Results This r and omized controlled trial indicated that the rates of pCR in CTZ group ( 14.8 % ) was doubled to CT group ( 7.7 % ) , respectively ( one-sided chi-square test , p = 0.068 ) , though the additional efficacy of zoledronic acid was not demonstrated statistically . The pCR rate in postmenopausal patients was 18.4 % and 5.1 % in the CTZ and CT groups , respectively ( one-sided Fisher ’s exact test , p = 0.071 ) , and that in patients with triple-negative breast cancer was 35.3 % and 11.8 % in the CTZ and CT groups , respectively ( one-sided Fisher ’s exact test , p = 0.112 ) . Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and patients with triple-negative breast cancer . Further investigation is warranted . Trial Registration University Hospital Medical Information Network . UMIN000003261 PURPOSE Limited data are available on the efficacy of oral bisphosphonate therapy in breast cancer survivors . Our goal was to examine prevention of breast cancer-related bone loss in this cohort . PATIENTS AND METHODS Eighty-seven postmenopausal women after chemotherapy for breast cancer were r and omly assigned to once-weekly risedronate 35 mg or placebo for 24 months . Outcomes included bone mineral density ( BMD ) and turnover markers . RESULTS At study initiation , 13 % of patients were on an aromatase inhibitor ( AI ) . After 24 months , there were differences of 1.6 to 2.5 % ( P < .05 ) at the spine and hip BMD between the placebo and risedronate groups . At study completion , 44 % were on an AI . Adjusting for an AI , women on placebo plus AI had a decrease in BMD of ( mean + /- SE ) 4.8 % + /- 0.8 % at the spine and 2.8 % + /- 0.5 % at the total hip ( both P < .001 ) . In women on risedronate + AI , the spine decreased by 2.4 % + /- 1.1 % ( P < .05 ) and was stable at the hip . Women in the placebo group not on an AI , maintained BMD at the spine , and had a 1.2 % + /- 0.5 % loss at the total hip ( P < .05 ) . Women who received risedronate but no AI had the greatest improvement in BMD of 2.2 % + /- 0.9 % ( P < .05 ) at the total hip . Bone turnover was reduced with risedronate . There were no differences in adverse events between the groups . CONCLUSION We conclude that in postmenopausal women with breast cancer with or without AI therapy , once-weekly oral risedronate was beneficial for spine and hip BMD , reduced bone turnover , and was well tolerated 528 Background : The bisphosphonate clodronate ( Bonefos ) may reduce the incidence of bone metastases by inhibiting tumor-induced osteoclastic resorption of bone . METHODS This r and omized , double-blind , placebo-controlled , multicenter trial evaluated the efficacy and safety of oral clodronate in 1,069 patients with primary operable stage I-III breast cancer from 1989 - 2000 . Patients received oral clodronate ( 1600 mg/day ) or placebo for 2 years , starting within 6 months of primary treatment ( surgery , radiotherapy , and tamoxifen ) . Ad hoc analyses from this study have been published previously ( Powles et al. JCO 2002 ) , and the unpublished protocol -specified results and ad hoc analysis of stage II/III patients are reported here . The protocol -specified primary endpoint was time to first bone metastasis during the 5-year study period . The secondary endpoint was overall survival . These endpoints were analyzed by unstratified Log-rank test and hazard ratio ( HR ) with 95 % CI . RESULTS Patient demographics were similar between treatment groups . Oral clodronate significantly reduced the risk of bone metastases by 45 % in all patients during the medication period ( 2 years : HR = 0.546 , P = 0.031 ) , and by 31 % during the study period ( 5 years : HR = 0.692 , P = 0.043 ) compared to placebo . Similarly , clodronate significantly reduced the risk of bone metastases in patients with stage II/III disease during the medication ( 2 years : 50 % , HR = 0.496 , P = 0.020 ) and study ( 5 years : 41 % , HR = 0.592 , P = 0.009 ) periods . Oral clodronate vs. placebo significantly improved overall survival ( 23 % reduction in risk of death : HR = 0.768 , P = 0.048 ) and survival for stage II/III patients ( 26 % reduction in risk of death : HR = 0.743 , P = 0.041 ) . Oral clodronate was well tolerated , with mild-to-moderate diarrhea being the most frequently reported adverse event . CONCLUSION In patients with primary operable breast cancer , oral clodronate significantly reduced the risk of bone metastases and significantly improved survival rates during the medication and 5-year study periods compared to placebo . Similar results were seen in stage II/III patients . [ Table : see text ] Background : Despite neoadjuvant/adjuvant chemotherapy , women with resectable stage II/III breast cancer ( BC ) have high risk of recurrent disease . Recent data suggest that zoledronic acid ( ZOL ) therapy concurrent with adjuvant treatments may improve cancer-related outcomes in patients with BC . Methods : Disease-free survival ( DFS ; secondary end point ) and overall survival ( OS ; tertiary end point ) were evaluated in 119 women with stage II/III BC r and omised to intravenous ZOL 4 mg every 3 weeks for 1 year or no ZOL ( control ) starting with the first chemotherapy cycle . Results : At 61.9 months ’ median follow-up , there was no significant difference in recurrence or survival between study arms . However , time to recurrence or death ( DFS ) was significantly different between subgroups defined by oestrogen receptor ( ER ) status ( interaction P=0.010 for DFS and 0.025 for OS ) . Hazard ratios ( HRs ) for disease recurrence and death were significantly less among patients with ER-negative ( ER− ) tumours who received ZOL vs no ZOL ( DFS : HR=0.361 , 95 % confidence interval ( CI ) 0.148 , 0.880 ; OS : HR=0.375 , 95 % CI 0.143 , 0.985 ) . Conclusion : ZOL administered with chemotherapy may improve DFS and OS in a subset of BC patients with ER− tumours . This study was not powered to compare subgroups of patients ; thus , these findings should be considered hypothesis generating PURPOSE Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer . Their effect in early breast cancer is controversial . Ib and ronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile . It therefore qualifies as potential agent for adjuvant use . PATIENTS AND METHODS The GAIN ( German Adjuvant Intergroup Node-Positive ) study was an open-label , r and omized , controlled phase III trial with a 2 × 2 factorial design . Patients with node-positive early breast cancer were r and omly assigned 1:1 to two different dose-dense chem 
    Output:
    
For women with EBC , bisphosphonates reduce the risk of bone metastases and provide an overall survival benefit compared to placebo or no bisphosphonates .
There is preliminary evidence suggestive that bisphosphonates provide an overall survival and disease-free survival benefit in postmenopausal women only when compared to placebo or no bisphosphonate .
For women with BCBM , bisphosphonates reduce the risk of developing SREs , delay the median time to an SRE , and appear to reduce bone pain compared to placebo or no bisphosphonate