human
***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 : Patients with monoclonal gammopathy of undetermined significance ( MGUS ) have increased rates of bone resorption , osteopenia , osteoporosis , and risk of fractures . This study was undertaken to determine the efficacy and safety of zoledronic acid for patients with MGUS and enhanced bone loss . Experimental Design : In this phase II open-label study , 54 patients with MGUS and osteopenia or osteoporosis were administered zoledronic acid 4 mg i.v . at 0 , 6 , and 12 months . The primary efficacy end point was bone mineral density , assessed using a dual-energy X-ray absorptiometry scan in the lumbar (L)-spine done at screening and at 13 months ( 1 month after the final zoledronic acid infusion ) . Results : At study end for all patients ( N = 54 ) , L-spine T-scores improved by a median of + 0.27 ( range , −0.38 to + 3.91 ) , corresponding to a median increase in bone mineral density of + 15.0 % ( range , −18.0 % to + 1,140.0 % ; P < 0.0001 ) . Hip T-scores improved by a median of + 0.10 ( range , −2.40 to + 2.03 ) , corresponding to a median increase of + 6.0 % ( range , −350.0 % to + 165.0 % ) . During the study , no new fractures , osteonecrosis of the jaw , or significant renal adverse events were reported . Conclusions : Zoledronic acid administered i.v . at a dosage of 4 mg every 6 months for three doses total was well-tolerated and substantially improved bone mineral density for patients with MGUS and bone loss .  Zoledronic acid may be effective for the prevention of new fractures in this high-risk population The Medical Research Council Myeloma IX Trial ( IS RCT NG8454111 ) examined traditional and thalidomide-based induction and maintenance regimens and IV zoledronic acid ( ZOL ) and oral clodronate ( CLO ) in 1960 patients with newly diagnosed multiple myeloma .  Overall survival ( OS ) and skeletal-related event ( SRE ) data have been reported for the overall trial population . The present analysis investigated optimal therapy regimens for different patient population s in Myeloma IX . Patients were assigned to intensive or nonintensive treatment pathways and r and omized to induction cyclophosphamide , vincristine , doxorubicin , and dexamethasone ( CVAD ) versus cyclophosphamide , thalidomide , and dexamethasone ( CTD ; intensive ) or melphalan and prednisolone versus attenuated oral CTD ( CTDa ; nonintensive ) . Patients were also r and omized to ZOL or CLO . In the nonintensive pathway , CTDa produced better responses and lower SRE rates than melphalan and prednisolone . ZOL improved OS compared with CLO independently of sex , stage , or myeloma subtype , most profoundly in patients with baseline bone disease or other SREs . In patients treated for ≥ 2 years , ZOL improved OS compared with CLO from r and omization ( median not reached for either ; P = .02 ) and also from first on- study disease progression ( median , 34 months for ZOL vs 27 months for CLO ; P = .03 ) . Thalidomide-containing regimens had better efficacy than traditional regimens , and ZOL demonstrated greater benefits than CLO A prospect i ve , multicenter , r and omized trial comparing pamidronate administration ( 60–90 mg once a month for 1 year ) versus simple observation in 177 patients with asymptomatic myeloma was performed to explore whether the administration of this drug reduces the rate of and /or the time to progression to overt , symptomatic disease . No relevant side effects were recorded in pamidronate-treated patients . With a minimum follow-up of 5 years for live patients , there were 56/89 ( 62.9 % ) progressions in the pamidronate-treated group and 55/88 ( 62.5 % ) within the controls ( p = NS ) . Median time to progression was 46 and 48 months , respectively ( p = NS ) . Overall survival was also similar between the two groups . Skeletal-related events at the time of progression were observed in 40/55 ( 72.7 % ) controls , but only in 22/56 ( 39.2 % ) pamidronate-treated patients ( p = 0.009 ) . In conclusion , the administration of pamidronate in asymptomatic myeloma , while reducing bone involvement at progression , did not decrease the risk of transformation and the time to progression into overt myeloma Background Cases of impaired renal function have been reported in patients who had been treated with both zoledronic acid and thalidomide for myeloma . Hence , we conducted a safety study of zoledronic acid and thalidomide in myeloma patients participating in a trial of maintenance therapy . Methods Twenty-four patients who were enrolled in a large r and omized trial of thalidomide vs no thalidomide maintenance therapy for myeloma , in which all patients also received zoledronic acid  , were recruited to a pharmacokinetic and renal safety sub- study , and followed for up to 16 months . Results No significant differences by Wilcoxon rank-sum statistic were found in zoledronic acid pharmacokinetics or renal safety for up to 16 months in patients r and omized to thalidomide or not . Conclusion In myeloma patients receiving maintenance therapy , the combination of zoledronic acid and thalidomide appears to confer no additional renal safety risks over zoledronic acid alone We prospect ively evaluated the effect of bortezomib , thalidomide and dexamethasone ( VTD ) consolidation on bone metabolism of 42 myeloma patients who underwent an autologous stem cell transplantation ( ASCT ) .  VTD started on day 100 post ASCT ; patients received four cycles of VTD ( first block ) , were followed without treatment for 100 days and then received another four VTD cycles ( second block ) . During this 12-month period , bisphosphonates were not administered . Best response included stringent complete remission ( sCR ) in 15 ( 35.7 % ) patients , complete response ( CR ) in 13 ( 30.9 % ) , vgPR in 7 ( 16.6 % ) , PR in 4 ( 9.5 % ) , while 3 ( 7.1 % ) patients developed a progressive disease ( PD ) . Importantly , 33.3 % and 47.6 % of patients improved their status of response after the first and second VTD block , respectively . VTD consolidation result ed in a significant reduction of circulating C-terminal cross-linking telopeptide of collagen type I ( CTX ) , soluble receptor activator of the nuclear factor-kappa B lig and ( sRANKL ) and osteocalcin ( OC ) , whereas bone-specific alkaline phosphatase ( bALP ) remained stable compared with pre-VTD values . During the study period , only one patient with a PD developed a skeletal-related event ( that is , radiation to bone ) . The median time to progression ( TTP ) after ASCT was 34 months and the median time of next treatment was 40 months . We conclude that VTD consolidation post ASCT reduces bone resorption and is associated with a very low incidence of skeletal-related events ( SREs ) despite the absence of bisphosphonates ; the later do not appear to be necessary in this context In a phase 3 trial of denosumab vs zoledronic acid in patients ( n=1776 ) with bone metastases and solid tumors or multiple myeloma , denosumab was superior to zoledronic acid for the primary end point of prevention of skeletal-related events . There was no difference in overall survival between the two groups ; however , an ad hoc overall survival analysis in the multiple myeloma subset of patients ( n=180 ) favored zoledronic acid ( hazard ratio ( HR ) 2.26 ; 95 % confidence interval ( CI ) 1.13–4.50 ; P=0.014 ) . In the present analysis , we found imbalances between the groups with respect to baseline risk characteristics . HRs with two-sided 95 % CIs were estimated using the Cox model . After adjustment in a covariate analysis , the CI crossed unity ( HR 1.86 ; 95 % CI 0.90–3.84 ; P=0.0954 ) . Furthermore , we found a higher rate of early withdrawals for the reasons of lost to follow-up and withdrawal of consent in the zoledronic acid group ; after accounting for these , the HR was 1.31 ( 95 % CI 0.80–2.15 ; P=0.278 ) . In conclusion , the survival results in multiple myeloma patients in this trial were confounded and will eventually be resolved by an ongoing phase 3 trial Summary Background Bisphosphonates reduce the risk of skeletal events in patients with malignant bone disease , and zoledronic acid has shown potential anticancer effects in pre clinical and clinical studies . We aim ed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma . Methods Patients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK . Computer-generated r and omisation sequence was used to allocate patients equally , via an automated telephone service , to receive 4 mg zoledronic acid as an infusion every 3–4 weeks or 1600 mg oral clodronic acid daily . Patients also received intensive or non-intensive induction chemotherapy . No investigators , staff , or patients were masked to treatment allocation , and bisphosphonate and maintenance therapy continued at least until disease progression . The primary endpoints were overall survival , progression-free survival , and overall response rate . We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival , and with logistic regression models for overall response rate . Analysis was by intention to treat . This trial is registered , number IS RCT N68454111 . Findings 1970 patients were enrolled between May , 2003 , and November , 2007 , of whom 1960 were eligible for intention-to-treat analysis : 981 in the zoledronic acid group ( 555 on intensive chemotherapy  , 426 on non-intensive chemotherapy ) ; and 979 on clodronic acid  ( 556 on  intensive chemotherapy , 423 on  non-intensive chemotherapy ) . The treatment cutoff was Oct 5 , 2009 , with patients receiving bisphosphonates for a median of 350 days ( IQR 137–632 ) before disease progression , with a median of 3·7 years ' follow-up ( IQR 2·9–4·7 ) . Zoledronic acid  reduced mortality by 16 % ( 95 % CI 4–26 ) versus clodronic acid ( hazard ratio [ HR ] 0·84 , 95 % CI 0·74–0·96 ; p=0·0118 ) , and extended median overall survival by 5·5 months ( 50·0 months , IQR 21·0 to not reached vs 44·5 months , IQR 16·5 to not reached ; p=0·04 ) . Zoledronic acid also significantly improved progression-free survival by 12 % ( 95 % CI 2–20 ) versus clodronic acid ( HR 0·88 , 95 % CI 0·80–0·98 ; p=0·0179 ) , and increased median progression-free survival by 2·0 months ( 19·5 months , IQR 9·0–38·0 vs 17·5 months , IQR 8·5–34·0 ; p=0·07 ) . Rates of complete , very good partial , or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy ( 432 patients [ 78 % ] vs 422 [ 76 % ] ; p=0·43 ) or non-intensive induction chemotherapy ( 215 [ 50 % ] vs 195 [ 46 % ] ; p=0·18 ) . Both bisphosphonates were generally well tolerated , with similar occurrence of acute renal failure and treatment-emergent serious adverse events , but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw ( 35 [ 4 % ] ) than was clodronic acid ( 3 [ < 1 % ] ) . Interpretation Consistent with the potential anticancer activity of zoledronic acid , overall survival improved independently of prevention of skeletal-related events , showing that zoledronic acid has treatment benefits beyond bone health . These findings support immediate treatment with zoledronic acid  in patients with newly diagnosed multiple myeloma , not only for prevention of skeletal-related events , but also for potential antimyeloma benefits . Funding Medical Research Council ( London , UK ) , with unrestricted educational grants from Novartis , Schering Health Care , Chugai , Pharmion , Celgene , and Ortho Biotech PURPOSE The reported incidence of osteonecrosis of the jaw ( ONJ ) ranges from 0.94 % to 18.6 % . This cohort study aim ed to calculate the incidence of and identify the risk factors for ONJ  in patients with cancer treated with 
    Output:
    
agent
Denosumab has shown to be noninferior to zoledronic acid for the prevention of skeletal-related events and provides an alternative .
Fewer adverse events related to renal toxicity have been noted with denosumab compared with zoledronic acid and may be preferred in this setting .
***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 : Patients with monoclonal gammopathy of undetermined significance ( MGUS ) have increased rates of bone resorption , osteopenia , osteoporosis , and risk of fractures . This study was undertaken to determine the efficacy and safety of zoledronic acid for patients with MGUS and enhanced bone loss . Experimental Design : In this phase II open-label study , 54 patients with MGUS and osteopenia or osteoporosis were administered zoledronic acid 4 mg i.v . at 0 , 6 , and 12 months . The primary efficacy end point was bone mineral density , assessed using a dual-energy X-ray absorptiometry scan in the lumbar (L)-spine done at screening and at 13 months ( 1 month after the final zoledronic acid infusion ) . Results : At study end for all patients ( N = 54 ) , L-spine T-scores improved by a median of + 0.27 ( range , −0.38 to + 3.91 ) , corresponding to a median increase in bone mineral density of + 15.0 % ( range , −18.0 % to + 1,140.0 % ; P < 0.0001 ) . Hip T-scores improved by a median of + 0.10 ( range , −2.40 to + 2.03 ) , corresponding to a median increase of + 6.0 % ( range , −350.0 % to + 165.0 % ) . During the study , no new fractures , osteonecrosis of the jaw , or significant renal adverse events were reported . Conclusions : Zoledronic acid administered i.v . at a dosage of 4 mg every 6 months for three doses total was well-tolerated and substantially improved bone mineral density for patients with MGUS and bone loss .  Zoledronic acid may be effective for the prevention of new fractures in this high-risk population The Medical Research Council Myeloma IX Trial ( IS RCT NG8454111 ) examined traditional and thalidomide-based induction and maintenance regimens and IV zoledronic acid ( ZOL ) and oral clodronate ( CLO ) in 1960 patients with newly diagnosed multiple myeloma .  Overall survival ( OS ) and skeletal-related event ( SRE ) data have been reported for the overall trial population . The present analysis investigated optimal therapy regimens for different patient population s in Myeloma IX . Patients were assigned to intensive or nonintensive treatment pathways and r and omized to induction cyclophosphamide , vincristine , doxorubicin , and dexamethasone ( CVAD ) versus cyclophosphamide , thalidomide , and dexamethasone ( CTD ; intensive ) or melphalan and prednisolone versus attenuated oral CTD ( CTDa ; nonintensive ) . Patients were also r and omized to ZOL or CLO . In the nonintensive pathway , CTDa produced better responses and lower SRE rates than melphalan and prednisolone . ZOL improved OS compared with CLO independently of sex , stage , or myeloma subtype , most profoundly in patients with baseline bone disease or other SREs . In patients treated for ≥ 2 years , ZOL improved OS compared with CLO from r and omization ( median not reached for either ; P = .02 ) and also from first on- study disease progression ( median , 34 months for ZOL vs 27 months for CLO ; P = .03 ) . Thalidomide-containing regimens had better efficacy than traditional regimens , and ZOL demonstrated greater benefits than CLO A prospect i ve , multicenter , r and omized trial comparing pamidronate administration ( 60–90 mg once a month for 1 year ) versus simple observation in 177 patients with asymptomatic myeloma was performed to explore whether the administration of this drug reduces the rate of and /or the time to progression to overt , symptomatic disease . No relevant side effects were recorded in pamidronate-treated patients . With a minimum follow-up of 5 years for live patients , there were 56/89 ( 62.9 % ) progressions in the pamidronate-treated group and 55/88 ( 62.5 % ) within the controls ( p = NS ) . Median time to progression was 46 and 48 months , respectively ( p = NS ) . Overall survival was also similar between the two groups . Skeletal-related events at the time of progression were observed in 40/55 ( 72.7 % ) controls , but only in 22/56 ( 39.2 % ) pamidronate-treated patients ( p = 0.009 ) . In conclusion , the administration of pamidronate in asymptomatic myeloma , while reducing bone involvement at progression , did not decrease the risk of transformation and the time to progression into overt myeloma Background Cases of impaired renal function have been reported in patients who had been treated with both zoledronic acid and thalidomide for myeloma . Hence , we conducted a safety study of zoledronic acid and thalidomide in myeloma patients participating in a trial of maintenance therapy . Methods Twenty-four patients who were enrolled in a large r and omized trial of thalidomide vs no thalidomide maintenance therapy for myeloma , in which all patients also received zoledronic acid  , were recruited to a pharmacokinetic and renal safety sub- study , and followed for up to 16 months . Results No significant differences by Wilcoxon rank-sum statistic were found in zoledronic acid pharmacokinetics or renal safety for up to 16 months in patients r and omized to thalidomide or not . Conclusion In myeloma patients receiving maintenance therapy , the combination of zoledronic acid and thalidomide appears to confer no additional renal safety risks over zoledronic acid alone We prospect ively evaluated the effect of bortezomib , thalidomide and dexamethasone ( VTD ) consolidation on bone metabolism of 42 myeloma patients who underwent an autologous stem cell transplantation ( ASCT ) .  VTD started on day 100 post ASCT ; patients received four cycles of VTD ( first block ) , were followed without treatment for 100 days and then received another four VTD cycles ( second block ) . During this 12-month period , bisphosphonates were not administered . Best response included stringent complete remission ( sCR ) in 15 ( 35.7 % ) patients , complete response ( CR ) in 13 ( 30.9 % ) , vgPR in 7 ( 16.6 % ) , PR in 4 ( 9.5 % ) , while 3 ( 7.1 % ) patients developed a progressive disease ( PD ) . Importantly , 33.3 % and 47.6 % of patients improved their status of response after the first and second VTD block , respectively . VTD consolidation result ed in a significant reduction of circulating C-terminal cross-linking telopeptide of collagen type I ( CTX ) , soluble receptor activator of the nuclear factor-kappa B lig and ( sRANKL ) and osteocalcin ( OC ) , whereas bone-specific alkaline phosphatase ( bALP ) remained stable compared with pre-VTD values . During the study period , only one patient with a PD developed a skeletal-related event ( that is , radiation to bone ) . The median time to progression ( TTP ) after ASCT was 34 months and the median time of next treatment was 40 months . We conclude that VTD consolidation post ASCT reduces bone resorption and is associated with a very low incidence of skeletal-related events ( SREs ) despite the absence of bisphosphonates ; the later do not appear to be necessary in this context In a phase 3 trial of denosumab vs zoledronic acid in patients ( n=1776 ) with bone metastases and solid tumors or multiple myeloma , denosumab was superior to zoledronic acid for the primary end point of prevention of skeletal-related events . There was no difference in overall survival between the two groups ; however , an ad hoc overall survival analysis in the multiple myeloma subset of patients ( n=180 ) favored zoledronic acid ( hazard ratio ( HR ) 2.26 ; 95 % confidence interval ( CI ) 1.13–4.50 ; P=0.014 ) . In the present analysis , we found imbalances between the groups with respect to baseline risk characteristics . HRs with two-sided 95 % CIs were estimated using the Cox model . After adjustment in a covariate analysis , the CI crossed unity ( HR 1.86 ; 95 % CI 0.90–3.84 ; P=0.0954 ) . Furthermore , we found a higher rate of early withdrawals for the reasons of lost to follow-up and withdrawal of consent in the zoledronic acid group ; after accounting for these , the HR was 1.31 ( 95 % CI 0.80–2.15 ; P=0.278 ) . In conclusion , the survival results in multiple myeloma patients in this trial were confounded and will eventually be resolved by an ongoing phase 3 trial Summary Background Bisphosphonates reduce the risk of skeletal events in patients with malignant bone disease , and zoledronic acid has shown potential anticancer effects in pre clinical and clinical studies . We aim ed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma . Methods Patients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK . Computer-generated r and omisation sequence was used to allocate patients equally , via an automated telephone service , to receive 4 mg zoledronic acid as an infusion every 3–4 weeks or 1600 mg oral clodronic acid daily . Patients also received intensive or non-intensive induction chemotherapy . No investigators , staff , or patients were masked to treatment allocation , and bisphosphonate and maintenance therapy continued at least until disease progression . The primary endpoints were overall survival , progression-free survival , and overall response rate . We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival , and with logistic regression models for overall response rate . Analysis was by intention to treat . This trial is registered , number IS RCT N68454111 . Findings 1970 patients were enrolled between May , 2003 , and November , 2007 , of whom 1960 were eligible for intention-to-treat analysis : 981 in the zoledronic acid group ( 555 on intensive chemotherapy  , 426 on non-intensive chemotherapy ) ; and 979 on clodronic acid  ( 556 on  intensive chemotherapy , 423 on  non-intensive chemotherapy ) . The treatment cutoff was Oct 5 , 2009 , with patients receiving bisphosphonates for a median of 350 days ( IQR 137–632 ) before disease progression , with a median of 3·7 years ' follow-up ( IQR 2·9–4·7 ) . Zoledronic acid  reduced mortality by 16 % ( 95 % CI 4–26 ) versus clodronic acid ( hazard ratio [ HR ] 0·84 , 95 % CI 0·74–0·96 ; p=0·0118 ) , and extended median overall survival by 5·5 months ( 50·0 months , IQR 21·0 to not reached vs 44·5 months , IQR 16·5 to not reached ; p=0·04 ) . Zoledronic acid also significantly improved progression-free survival by 12 % ( 95 % CI 2–20 ) versus clodronic acid ( HR 0·88 , 95 % CI 0·80–0·98 ; p=0·0179 ) , and increased median progression-free survival by 2·0 months ( 19·5 months , IQR 9·0–38·0 vs 17·5 months , IQR 8·5–34·0 ; p=0·07 ) . Rates of complete , very good partial , or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy ( 432 patients [ 78 % ] vs 422 [ 76 % ] ; p=0·43 ) or non-intensive induction chemotherapy ( 215 [ 50 % ] vs 195 [ 46 % ] ; p=0·18 ) . Both bisphosphonates were generally well tolerated , with similar occurrence of acute renal failure and treatment-emergent serious adverse events , but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw ( 35 [ 4 % ] ) than was clodronic acid ( 3 [ < 1 % ] ) . Interpretation Consistent with the potential anticancer activity of zoledronic acid , overall survival improved independently of prevention of skeletal-related events , showing that zoledronic acid has treatment benefits beyond bone health . These findings support immediate treatment with zoledronic acid  in patients with newly diagnosed multiple myeloma , not only for prevention of skeletal-related events , but also for potential antimyeloma benefits . Funding Medical Research Council ( London , UK ) , with unrestricted educational grants from Novartis , Schering Health Care , Chugai , Pharmion , Celgene , and Ortho Biotech PURPOSE The reported incidence of osteonecrosis of the jaw ( ONJ ) ranges from 0.94 % to 18.6 % . This cohort study aim ed to calculate the incidence of and identify the risk factors for ONJ  in patients with cancer treated with 
    Output:
    