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J Bone Miner Res. 2019 Aug 12. doi: 10.1002/jbmr.3816. [Epub ahead of print]

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

Author information

1
Osteoporosis and Bone Biology, Garvan Institute of Medical Research, Sydney, Australia.
2
St Vincent's Clinical School, UNSW Sydney.
3
Máxima Medical Center, Department of Data & Analytics, MB Veldhoven, Netherlands.
4
Department of Medicine, McMaster University, Hamilton, Canada.
5
CaMos National Coordinating Centre, McGill University, Montreal, Canada.
6
Maastricht University Medical Center, Research School Nutrim, Department of Internal Medicine, Subdivision of Rheumatology, Maastricht, Netherlands.
7
VieCuri Medical Centre of Noord-Limburg, Department of Internal Medicine, Venlo, Netherlands.
8
Clinical School, St Vincent's Hospital, Faculty of Medicine, UNSW Australia, Sydney, Australia.
9
School of Medicine Sydney, University of Notre Dame Australia, Sydney, Australia.
10
University Hasselt, Biomedical Research Institute, Hasselt, Belgium.
11
Department of Medicine, McGill University, Montreal, Canada.
12
Department of Medicine, University of Calgary, Calgary, Canada.
13
Department of Medicine, University of Toronto, Toronto, Canada.
14
Department of Medicine, Dalhousie University, Halifax, Canada.
15
Faculty of Medicine, Memorial University, St. John's, Canada.
16
School of Public Health, University of Minnesota, Twin Cities, Minneapolis, MN, USA.
17
Department of Medicine and Endocrinology, University of British Columbia, Vancouver, Canada.
18
School of Biomedical Engineering, University of Technology, Sydney (UTS), Australia.

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.

KEYWORDS:

BISPHOSPHONATE; BONE LOSS; FRACTURE; MORTALITY RISK; PROSPECTIVE STUDY

PMID:
31402509
DOI:
10.1002/jbmr.3816

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