J Bone Miner Res. 2022 Jun 11. doi: 10.1002/jbmr.4632. Online ahead of print.
New therapies may help to prevent osteoporotic fractures other than through increasing bone mineral density (BMD). Since fracture risk has an important genetic component, we aim to identify loci increasing fracture risk which do not decrease BMD, using a recently-proposed structural equation model adapted to remove genetic influences of BMD on fracture risk. We used summary statistics of the largest genome-wide association studies for BMD and for fracture in these analyses. We next estimated the genetic correlation between the non-BMD or BMD-related genetic effects and other clinical risk factors for fracture. Lastly, based on White British participants in the UK Biobank, we conducted genetic risk score analyses to assess whether the aggregated genetic effects conferred increased major osteoporotic fracture risk. We found that only three loci affecting fracture risk exhibited genetic effects not mediated by BMD: SOST, CPED1-WNT16, and RSPO3, while these three loci simultaneously conferred BMD-related effects. No strong genetic associations between non-BMD or BMD-related effects and 16 clinical risk factors were observed. However, non-BMD effects might be genetic correlated with hip bone size. In the UK Biobank, a one standard deviation increase in the non-BMD genetic risk score conferred an odds ratio of 1.17 of incident major osteoporotic fracture, compared to 1.29 for a BMD-related genetic risk score. Our study suggests that the vast majority of common genetic predisposition towards fracture risk acts upon BMD. While non-BMD genetic effects may exist, they are not strongly correlated with most traditional clinical risk factors. Risk loci harboring non-BMD genetic effects may influence other perspectives of bone quality, or confer effects that existing genome-wide association studies fail to capture, but they demonstrate weaker impact on fracture risk than BMD-related genetic effects. These findings suggest that most successful drug development programs for osteoporosis should focus on pathways identified through BMD-associated loci. This article is protected by copyright. All rights reserved.