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A model of fracture risk used to examine the link between bone mineral density and the impact of different therapeutic mechanisms on fracture outcomes in patients with osteoporosis

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Abstract

A hazard model of fracture was developed using individual patient data (IPD) from the NHANES (2005–2008) database and summary-level data from an aggregate dataset (AD). The AD was built by performing a comprehensive and systematic literature search of clinical studies published from 1995 to 2015, recording fracture rate and bone mineral density (BMD) for both treatment and placebo arms. The search resulted in a metadata set comprised of 21 studies investigating the effects of various bisphosphonates, teriparatide, denosumab, and raloxifene in 65,254 patients over a cumulative 56.75 years of study. The IPD was used to augment an AD in a model-based meta-analysis (MBMA) hierarchical modeling approach. The resulting model predicts the probability of fracture events in patients with osteoporosis. The object of model building using this approach was to promote understanding of the impact of therapeutic drug effects on the probability of fracture together with, or independent of their effects on BMD. Candidate models were evaluated by deviance information criteria and posterior predictive check. The model with covariates for lumbar spine BMD with interaction with a drug effect on BMD, and patient body mass index, years post-menopause, fracture measure method (clinical or radiological) and an additional drug effect outperformed those models without interaction and without additional drug effects. The model quantitatively supports the widely held notion that changes in bone microarchitecture, which cannot be measured by areal BMD elicited by therapy contribute in a significant way to a reduction in fracture. Furthermore, this model can be used to simulate fracture risk in a clinical cohort similar to those contained in the MBMA.

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Authors and Affiliations

  1. Metrum Research Group, LLC, 2 Tunxis Road, Suite 112, Tariffville, CT, 06081, USA

    Rena J. Eudy-Byrne, William Gillespie, Matthew M. Riggs & Marc R. Gastonguay

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  1. Rena J. Eudy-Byrne
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  2. William Gillespie
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  3. Matthew M. Riggs
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Correspondence to Rena J. Eudy-Byrne.

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Eudy-Byrne, R.J., Gillespie, W., Riggs, M.M. et al. A model of fracture risk used to examine the link between bone mineral density and the impact of different therapeutic mechanisms on fracture outcomes in patients with osteoporosis. J Pharmacokinet Pharmacodyn 44, 599–609 (2017). https://doi.org/10.1007/s10928-017-9551-z

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