Novel Genetic Score Could Reduce Unnecessary Fracture Risk Screenings


A novel polygenic risk score could help identify patients at a low-risk of fracture from osteoporosis or fragility without need for additional screenings.

Eugene McCloskey, MD

Eugene McCloskey, MD

Results of a new study from an international team of investigators indicate genetic testing could improve clinicians’ ability to predict fracture risk due to osteoporosis or fragility.

Investigators estimate using the score could reduce the need for Fracture Risk Assessment Tool (FRAX) tests and bone mineral density (BMD)-based FRAX tests by 37% and 41%, respectively, if incorporated into standard screening practices.

“As the population ages, the urgency of improving preventive measures becomes all the more intense. Bone strength, a key component underlying fracture risk, is highly heritable and is therefore a strong candidate for assessment through genetic screening,” said Eugene McCloskey, MD, a professor in Adult Bone Diseases at the University of Sheffield, in a statement.

With current screening programs for identifying patients at increased risk of fracture failing to address the current need, McCloskey and a team of colleagues sought to develop a more effective measure for identifying patients who can be safely excluded from undergoing additional, unnecessary fracture risk screenings. To do so, they designed a 3-phase study to understand if genetic prescreening could reduce the number of tests needed to identify individuals with increased fracture risk.

The first 2 phases of the investigators' study involved training and selection of the polygenic risk score for heel qualitative speed of sound, which is a heritable risk factor for osteoporotic fracture. Investigators named the top-performing prediction model gSOS and tested its validity in 5 cohorts using data from the National Osteoporosis Guideline Group.

Of note, the average range of these 5 cohorts ranged from 57-75 years, 54% of those included were women, all individuals had measured fracture risk factors, and all individuals underwent genome-wide genotyping.

The main outcomes of the investigators’ analysis were the sensitivity and specificity to identify individuals requiring treatment with and without genetic prescreening. The reference standard used in the study was a BMD-based FRAX score. Secondary outcome measures for the study were the proportions of screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX screening.

Results of the analysis indicated gSOS was strangely correlated with measured SOS (R2=23.2%; 95% CI, 22.7-23.7%).

When assessed without genetic prescreening, guideline recommendations achieved a sensitivity of 99.6% and a specificity of 97.1% in the validation cohorts. Investigators pointed out 81% of the population required CRF-FRAX screening and 37% required BMD-FRAX screening to achieve this level of accuracy.

Using gSOS in prescreening and limiting further assessment to those with a low gSOS score resulted in a sensitivity of 93.4% and a specificity of 98.5%. However, investigates noted the proportions of individuals requiring CRF-FRAX screening decreased by 37% and the proportion needing BMD-FRAX screening decreased by 41%.

“While the impact of this research is not immediate as it requires each individual’s genome to be available for calculation of their gSOS, it is of great importance for the future of medical practice,” McCloskey added in the aforementioned statement.

This study, “Development of a polygenic risk score to improve screening for fracture risk: A genetic risk prediction study,” was published in Plos Medicine.

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