title: Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial.
abstract: Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain.
  
  
  
  To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks.
  
  
  
  Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014.
  
  
  
  Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years.
  
  
  
  The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels).
  
  
  
  Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of -0.3% [1-sided 95% CI, -4% to ∞]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks.
  
  
  
  Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option.
  
  
  
  clinicaltrials.gov Identifier: NCT00869206.
authors.affiliation: Helen F. Graham Cancer Center & Research Institute, Newark, Delaware.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Himelstein
authors.affiliation: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.
authors.forename: Jared C
authors.initials: JC
authors.lastname: Foster
authors.affiliation: Virginia Cancer Institute, Richmond.
authors.forename: James L
authors.initials: JL
authors.lastname: Khatcheressian
authors.affiliation: VCU Massey Cancer Center, Richmond, Virginia5Now with Yale University, New Haven, Connecticut.
authors.forename: John D
authors.initials: JD
authors.lastname: Roberts
authors.affiliation: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.
authors.forename: Drew K
authors.initials: DK
authors.lastname: Seisler
authors.affiliation: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Novotny
authors.affiliation: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota6Now with Regeneron Pharmaceuticals, Basking Ridge, New Jersey.
authors.forename: Rui
authors.initials: R
authors.lastname: Qin
authors.affiliation: Gundersen Health System, La Crosse, Wisconsin8Now with Mayo Clinic, Rochester, Minnesota.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Go
authors.affiliation: Helen F. Graham Cancer Center & Research Institute, Newark, Delaware9Now with American Society of Clinical Oncology, Alexandria, Virginia.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Grubbs
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Tracey
authors.initials: T
authors.lastname: O'Connor
authors.affiliation: Decatur Memorial Hospital, Decatur, Illinois.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Velasco
authors.affiliation: New Hampshire Oncology Hematology PA, Hooksett.
authors.forename: Douglas
authors.initials: D
authors.lastname: Weckstein
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.
authors.forename: Ann
authors.initials: A
authors.lastname: O'Mara
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Loprinzi
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shapiro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000556:secondary*; D001842:Bone and Bones / Q000528:radiation effects / Q000601:surgery; D001943:Breast Neoplasms / Q000473:pathology*; D004164:Diphosphonates / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology*; D010147:Pain Measurement; D011471:Prostatic Neoplasms / Q000473:pathology*; D018401:Sample Size; D013117:Spinal Cord Compression / Q000601:surgery; D016103:Spinal Fractures / Q000601:surgery; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid