Predicting Risk Of Fracture Using Polygenic Risk Score Of Speed Of Sound Through Bone

Pixabay License | Source: Dr. Manuel González Reyes , Altered aspect ratio.

As we age, the risk of bone fracture increases. Doctors developed the Fracture Risk Assessment Tool (FRAX), which takes account of age, weight, gender, smoking history, alcohol use and family history of fracture, as an initial approach for managing risk. Follow up can include a further, more authoritative, assessment including bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA).

According to MDsave, the US national average cost for DXA is $355. A speed of sound through heel bone using ultrasound (SOS) can be used to estimate BMD in place of DXA. Ultrasounds cost approximately the same as DXA.

The cost of whole genome sequencing of a single genome is still around the $1000 mark, under regular circumstances, in most laboratories. That said, some consumer sequencing providers, such as Veritas Genomics, have offered whole genome sequencing for as little as $200, for a limited time. The sequence information has many applications, one of which is the indirect estimation of bone mineral density, which can be achieved for an additional $40, according to the authors of a new report. This could serve as an alternative to DXA or SOS.

J. Brent Richards of Jewish General Hospital, McGill University, Montréal, and colleagues, developed a genetically predicted SOS (gSOS) from the UK Biobank. The sensitivity and specificity of gSOS to predict those in need of further DXA or SOS procedures (at risk of fracture during their lifetime) was tested in a further five different cohorts. The results were published in the journal PLOS Medicine.


The polygenic risk score (PRS) termed gSOS including 21,717 SNPs accounted for 23% of the variance in measured SOS in the UK Biobank. In the test validation cohorts the use of gSOS reduced the use of FRAX by 37% and the use of BMD-FRAX by 41%, overall. The overall sensitivity was 93% and the specificity was 99%. When tested in all male or all female cohorts, women derived the most benefit from gSOS which decreased BMD testing by 55%, whereas in men there was a 25% decrease. 

Overall, when using gSOS for pre-screening, only 20% of those that were predicted to require a BMD test subsequently turned out not to need it, compared with 34% of those that received a BMD test recommendation from FRAX without gSOS. Those aged 70 and over benefited the most from reductions in unnecessary BMD testing, reduced by 50%. 

Benefits from gSOS did not seem to be restricted to white British, even though they formed the majority of the training cohort, however this requires further validation in other ethnic cohorts. SOS was used as a convenient proxy for BMD, since cohorts with known BMD were not large enough, therefore future large cohorts with known BMD could increase the accuracy of PRS scores for risk of fracture.

“In summary, we have developed and tested gSOS, a polygenic risk score for SOS, which when introduced into a fracture risk screening program decreased the number of people requiring CRF-FRAX and BMD-FRAX assessments, while still maintaining a high sensitivity and specificity to identify individuals in whom an intervention should be recommended. These findings highlight the role that genetic prediction could play in screening programs that rely upon heritable risk factors,” concluded the authors.