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 .
Purpose To up date guideline recommendations on the role of bone-modifying agents in multiple myeloma .
First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled 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
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 .
Purpose To up date guideline recommendations on the role of bone-modifying agents in multiple myeloma .