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J Bone Miner Res. 2019 Jan 23. doi: 10.1002/jbmr.3641. [Epub ahead of print]

Change in Bone Density and Reduction in Fracture Risk: A Meta-Regression of Published Trials.

Author information

1
Center for Advanced Orthopedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
2
Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK.
3
California Pacific Medical Center, San Francisco, CA, USA.
4
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
5
Merck & Co., Inc., Kenilworth, NJ, USA.
6
Amgen Inc., Thousand Oaks, CA, USA.
7
Eli Lilly and Company, Lilly Research Centre, Windlesham, UK.
8
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
9
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Abstract

Meta-analyses conducted >15 years ago reported that improvements in bone mineral density (BMD) were associated with reduction in vertebral and nonvertebral fractures in osteoporosis trials. Numerous studies have been conducted since then, incorporating new therapies with different mechanisms of action and enrolling many more subjects. To extend these prior analyses, we conducted a meta-regression of 38 placebo-controlled trials of 19 therapeutic agents to determine the association between improvements in BMD and reductions in fracture risk. We used a linear model to examine the relationship between mean percent difference in BMD change between treatment and placebo groups and the logarithm of the relative risk. We found that greater improvements in BMD were strongly associated with greater reductions in vertebral and hip fractures but not nonvertebral fractures. For vertebral fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.56, 0.54, and 0.63, respectively (p ≤ 0.0002). For a 2% or 6% improvement in total hip BMD, we might expect a 28% or 66% reduction, respectively, in vertebral fracture risk. For hip fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.48 (p = 0.01), 0.42 (p = 0.02), and 0.22 (ns), respectively. For a 2% or 6% improvement in total hip BMD, we might expect a 16% or 40% reduction in hip fracture risk. In conclusion, our results extend prior observations that larger improvements in dual-energy X-ray absorptiometry (DXA)-based BMD are associated with greater reductions in fracture risk, particularly for vertebral and hip fractures. Although these results cannot be directly applied to predict the treatment benefit in an individual patient, they provide compelling evidence that improvements in BMD with osteoporosis therapies may be useful surrogate endpoints for fracture in trials of new therapeutic agents.

KEYWORDS:

BONE MINERAL DENSITY; CLINICAL TRIAL; META-REGRESSION; OSTEOPOROSIS; SURROGATE

PMID:
30674078
DOI:
10.1002/jbmr.3641

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