Genetic prediction of bone fracture

Dr. Will Boggs of Reuters Health (reuters.com) interviewed me about work by Nethander and colleagues [1] on the association between polygenic risk scores (PRS) and fracture. This is my research interest, and I was more than happy to entertain some ideas.

Polygenic risk score (genome.gov/Health/Genomics-and-Medicine/Polygenic-risk-scores)

Boggs: Which of these results did you find most interesting or surprising?

TVN: The most interesting result of this work, to me, is that the genetic variants associated with ultrasound measurement of the heel bone (thereby referred to as QUSGRS), but it has prognostic value for the prediction of fracture at the forearm, hip and vertebrae. Another interesting aspect of this study is that QUSGRS 'explained' about 17% of the differences in QUS between individuals, and this is high compared with those bone density-associated SNPs explains only 3-5% of differences in bone density.

2. What are the clinical implications of these findings?

TVN: The implications of this finding is manifold. First, it implies that the quantitative ultrasound measurement of bone is a valid trait to gain insight into the pathogenesis of bone fragility. Second, it seems possible to replace QUS measurement or even bone density measurement by this 'genetic signature' (QUSGRS) for assessing the risk of fracture for an individual. Third, the finding underlines the idea that 'individualized fracture risk assessment' is possible.

3. What main message should physicians take away from this report?

TVN: I guess the take-home message of this study is that genetics does contribute to and individual's propensity to fracture. Clinicians should take -- apart from bone mineral densit -- family history of fracture into account in the assessment of a patient's fracture risk. Actually, PRS can be seen as a quantitative measure of family history! However, because the contribution of QUSGRS to fracture risk is modest, it alone cannot be a reliable indicator of fracture risk; it must be used with clinical risk factors such as a history of fracture, fall, and comorbidities.

4. What other points, if any, would you like to make?

TVN: The role of ultrasound measurement of bone (QUS) in the management of osteoporosis has not been clear. At present, QUS is not used for clinical diagnosis of osteoporosis. QUS is also not used for fracture risk assessment despite the fact that QUS is associated with fracture risk. However, this study suggests that the osteoporosis community should take QUS more seriously in the assessment of fracture risk. This 'genetic signature' was developed based on genetic data collected from Caucasian populations, and it may not be applicable to non-Caucasian populations. We need more genomic studies in non-Caucasian ethnicities.

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[1] Nethander M, Pettersson-Kymmer U, Vandenput L, Lorentzon M, Karlsson M, Mellstrom D, et al. BMD-related genetic risk scores predict site-specific fractures as well as trabecular and cortical bone microstructure. J Clin Endocrinol Metab. 2020. Epub 2020/02/19. doi: 10.1210/clinem/dgaa082. PubMed PMID: 32067027.