Abstract
BackgroundAccurately quantifying the risk of osteoporotic fracture is important for directing appropriate clinical interventions. While skeletal measures such as heel quantitative speed of sound (SOS) and dual-energy X-ray absorptiometry bone mineral density are able to predict the risk of osteoporotic fracture, the utility of such measurements is subject to the availability of equipment and human resources. Using data from 341,449 individuals of white British ancestry, we previously developed a genome-wide polygenic risk score (PRS), called gSOS, that captured 25.0% of the total variance in SOS. Here, we test whether gSOS can improve fracture risk prediction.MethodsWe examined the predictive power of gSOS in five genome-wide genotyped cohorts, including 90,172 individuals of European ancestry and 25,034 individuals of Asian ancestry. We calculated gSOS for each individual and tested for the association between gSOS and incident major osteoporotic fracture and hip fracture. We tested whether adding gSOS to the risk prediction models had added value over models using other commonly used clinical risk factors.ResultsA standard deviation decrease in gSOS was associated with an increased odds of incident major osteoporotic fracture in populations of European ancestry, with odds ratios ranging from 1.35 to 1.46 in four cohorts. It was also associated with a 1.26-fold (95% confidence interval (CI) 1.13–1.41) increased odds of incident major osteoporotic fracture in the Asian population. We demonstrated that gSOS was more predictive of incident major osteoporotic fracture (area under the receiver operating characteristic curve (AUROC) = 0.734; 95% CI 0.727–0.740) and incident hip fracture (AUROC = 0.798; 95% CI 0.791–0.805) than most traditional clinical risk factors, including prior fracture, use of corticosteroids, rheumatoid arthritis, and smoking. We also showed that adding gSOS to the Fracture Risk Assessment Tool (FRAX) could refine the risk prediction with a positive net reclassification index ranging from 0.024 to 0.072.ConclusionsWe generated and validated a PRS for SOS which was associated with the risk of fracture. This score was more strongly associated with the risk of fracture than many clinical risk factors and provided an improvement in risk prediction. gSOS should be explored as a tool to improve risk stratification to identify individuals at high risk of fracture.
Highlights
Quantifying the risk of osteoporotic fracture is important for directing appropriate clinical interventions
We demonstrated that genomic speed of sound (SOS) (gSOS) was more predictive of incident major osteoporotic fracture (area under the receiver operating characteristic curve (AUROC) = 0.734; 95% Confidence interval (CI) 0.727– 0.740) and incident hip fracture (AUROC = 0.798; 95% CI 0.791–0.805) than most traditional clinical risk factors, including prior fracture, use of corticosteroids, rheumatoid arthritis, and smoking
We showed that adding gSOS to the Fracture Risk Assessment Tool (FRAX) could refine the risk prediction with a positive net reclassification index ranging from 0.024 to 0.072
Summary
Quantifying the risk of osteoporotic fracture is important for directing appropriate clinical interventions While skeletal measures such as heel quantitative speed of sound (SOS) and dual-energy X-ray absorptiometry bone mineral density are able to predict the risk of osteoporotic fracture, the utility of such measurements is subject to the availability of equipment and human resources. In the Western world, between one third to one half of women will experience an osteoporotic fracture in their lifetime [2] The burden of this disease will increase substantially as our population ages, such that by the year 2040, the annual incidence of hip fractures is expected to surpass 500,000 in the USA and the direct medical costs of surgery for each hip fracture will exceed $65–68,000 USD [3]. Combining these clinical risk factors with femoral neck BMD in the FRAX score has become widely accepted as a method to appropriately stratify individuals for therapy [7,8,9,10]
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