title: Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial.
abstract: BACKGROUND
  Zoledronic acid reduces skeletal-related events in patients with breast cancer, but concerns have been raised about prolonged monthly administration. We assessed the efficacy and safety of a reduced dosing frequency of zoledronic acid in women treated previously with monthly zoledronic acid.
  
  
  METHODS
  We did this non-inferiority, phase 3 trial in 62 centres in Italy. We enrolled patients with breast cancer who had one or more bone metastases and had completed 12-15 months of monthly treatment with zoledronic acid. Patients were randomly assigned with a permutated block (size four to eight) random list stratified by centre in a 1:1 ratio to zoledronic acid 4 mg once every 12 weeks or once every 4 weeks, and followed up for at least 1 year. Neither patients nor investigators were masked to treatment allocation. The primary outcome was skeletal morbidity rate (skeletal-related events per patient per year) in the intention-to-treat population. We used a non-inferiority margin of 0.19. The trial is registered with EudraCT, number 2005-004942-15.
  
  
  RESULTS
  We screened 430 patients and enrolled 425, of whom 209 were assigned to the 12-week group and 216 to the 4-week group. The skeletal morbidity rate was 0.26 (95% CI 0.15-0.37) in the 12-week group versus 0.22 (0.14-0.29) in the 4-week group. The between-group difference was 0.04 and the upper limit of one-tailed 97.5% CI was 0.17, which is lower than the non-inferiority margin. The most common grade 3-4 adverse events were bone pain (56 [27%] patients in the 12-week group vs 65 [30%] in the 4-week group), nausea (24 [11%] vs 33 [15%]), and asthenia (18 [9%] vs 33 [15%]). Renal adverse events occurred in one patient (<1%) in the 12-week group versus two (1%) in the 4-week group. One patient (<1%) in the 4-week group had grade 1 acute renal failure. Osteonecrosis of the jaw occurred in four patients in the 12-week group versus three in the 4-week group. No treatment-related deaths were reported. Median N-terminal telopeptide concentration changed from baseline more in the 12-week group than in the 4-week group after 12 months (12.2% vs 0.0%; p=0.011).
  
  
  CONCLUSIONS
  Our results raise the possibility of decreasing administration of zoledronic acid to a 12-weekly regimen to reduce exposure during the second year, while maintaining its therapeutic effects. However, the effects on N-terminal telopeptide should be investigated further before changing current practice.
  
  
  BACKGROUND
  Novartis Farma.
authors.affiliation: Osteoncology and Rare Tumors Center, IRCCS Scientific Institute of Romagna for the Study and Treatment of Cancer (IRST IRCCS), Meldola, Italy. d.amadori@irst.emr.it
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.forename: Massimo
authors.initials: M
authors.lastname: Aglietta
authors.forename: Barbara
authors.initials: B
authors.lastname: Alessi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Gianni
authors.forename: Toni
authors.initials: T
authors.lastname: Ibrahim
authors.forename: Gabriella
authors.initials: G
authors.lastname: Farina
authors.forename: Fernando
authors.initials: F
authors.lastname: Gaion
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoldo
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.forename: Roberta
authors.initials: R
authors.lastname: Rondena
authors.forename: Paola
authors.initials: P
authors.lastname: Bogani
authors.forename: Carla I
authors.initials: CI
authors.lastname: Ripamonti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D013997:Time Factors; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid