title: Skeletal morbidity rates over time in patients with bone metastases from solid tumors reported in bone modifying agents randomised trials.
abstract: OBJECTIVE
  Skeletal related events (SREs) are common in patients with bone metastases and lead to decreased quality of life and functional status. The definition of an SRE has evolved over the years and now excludes hypercalcemia of malignancy due to its low incidence. The purpose of this review was to investigate if advances in bone-targeted therapies have decreased skeletal morbidity rates (SMR) over time.
  
  
  METHODS
  A literature search was conducted in several databases to identify phase III results from bone-targeted therapy trials from 1980 through September 2011. Graphs were created to document the trends of the natural log of SMR over the mean time of enrolment for all placebo and intervention arms. Statistical hypothesis testing was employed to account for confounding factors.
  
  
  RESULTS
  A total of 14 studies were identified which reported the SMR from phase III trials from 1990 to 2007. A statistically significant downward trend was observed in the placebo arms of trials over time; a similar trend was seen in all intervention arms. In a direct comparison of intervention against placebo arms, it was found that there was a significant decreasing time trend (p<0.0001) and a significant departure in SMR from placebo to intervention arms (p=0.0348). These results were seen even after accounting for the confounding factors of histology and differences in drugs.
  
  
  CONCLUSIONS
  The decrease in SMR over time may not only be a result of advancements with bone targeted agents, but also due to better management and awareness of events associated with bone metastases.
authors.affiliation: Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Michael
authors.initials: M
authors.lastname: Poon
authors.affiliation: Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Liang
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Marko
authors.initials: M
authors.lastname: Popovic
authors.affiliation: Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Ronald
authors.initials: R
authors.lastname: Chow
authors.affiliation: Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Henry
authors.initials: H
authors.lastname: Lam
authors.affiliation: Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Gillian
authors.initials: G
authors.lastname: Bedard
authors.affiliation: Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Urban
authors.initials: U
authors.lastname: Emmenegger
authors.affiliation: St Michael Hospital, University of Toronto, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Christine
authors.initials: C
authors.lastname: Simmons
authors.affiliation: Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Edward
authors.initials: E
authors.lastname: Chow
keywords: Bisphosphonates; Bone metastases; Skeletal morbidity rates time trend; Skeletal related events