Reduced Bone Loss Is Associated With Reduced Mortality Risk in Subjects Exposed to Nitrogen Bisphosphonates: A Mediation Analysis

Dana Bliuc*, Thach Tran, Tineke van Geel, Jonathan D. Adachi, Claudie Berger, Joop van den Bergh, John A. Eisman, Piet Geusens, David Goltzman, David A. Hanley, Robert Josse, Stephanie Kaiser, Christopher S. Kovacs, Lisa Langsetmo, Jerilynn C. Prior, Tuan Nguyen, Jacqueline R. Center, CaMos Research Group

*Corresponding author for this work

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Abstract

Bisphosphonates, potent antiresorptive agents, have been found to be associated with mortality reduction. Accelerated bone loss is, in itself, an independent predictor of mortality risk, but the relationship between bisphosphonates, bone loss, and mortality is unknown. This study aimed to determine whether the association between bisphosphonates and mortality is mediated by a reduction in the rate of bone loss. Participants from the population-based Canadian Multicentre Osteoporosis Study were followed prospectively between1996 and 2011. Comorbidities and lifestyle factors were collected at baseline and bone mineral density (BMD) at baseline and at years 3 (for those aged 40 to 60 years), 5, and 10. Rate of bone loss was calculated using linear regression. Information on medication use was obtained yearly. Bisphosphonate users grouped into nitrogen bisphosphonates (nBP; alendronate or risedronate) and etidronate and non-users (NoRx) were matched by propensity score, including all baseline factors as well as time of treatment. Cox's proportional hazards models, unadjusted and adjusted for annual rate of bone loss, were used to determine the association between nBP and etidronate versus NoRx. For the treatment groups with significant mortality risk reduction, the percent of mortality reduction mediated by a reduction in the rate of bone loss was estimated using a causal mediation analysis. There were 271 pairs of nBP and matched NoRx and 327 pairs of etidronate and matched NoRx. nBP but not etidronate use was associated with significant mortality risk reduction (hazard ratios [HR] = 0.61 [95% confidence interval 0.39-0.96] and 1.35 [95% CI 0.86-2.11] for nBP and etidronate, respectively). Rapid bone loss was associated with more than 2-fold increased mortality risk compared with no loss. Mediation analysis indicated that 39% (95% CI 7%-84%) of the nBP association with mortality was related to a reduction in the rate of bone loss. This finding provides an insight into the mechanism of the relationship between nBP and survival benefit in osteoporotic patients. (c) 2019 American Society for Bone and Mineral Research.

Original languageEnglish
Pages (from-to)2001-2011
Number of pages11
JournalJournal of Bone and Mineral Research
Volume34
Issue number11
Early online date12 Aug 2019
DOIs
Publication statusPublished - Nov 2019

Keywords

  • FRACTURE
  • MORTALITY RISK
  • BISPHOSPHONATE
  • BONE LOSS
  • PROSPECTIVE STUDY
  • CANADIAN MULTICENTER OSTEOPOROSIS
  • ZOLEDRONIC ACID
  • SUBSEQUENT FRACTURE
  • MINERAL DENSITY
  • HIP FRACTURE
  • OLDER WOMEN
  • MEN
  • EFFICACY
  • FRAILTY
  • METAANALYSIS

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