ESPE Abstracts

Background: Fractures are common in children, but a significant fracture history, defined as low-trauma vertebral fractures or multiple long bone fractures, is rare. Children with such history and no osteogenesis imperfecta (OI) are often presumed to have another Mendelian disease. However, in adults, multiple common risk alleles of small effect influence risk of fracture. We tested if subjects with a significant childhood fracture history have an increased burden of common risk alleles.

Methods: We generated a polygenic risk score for quantitative ultrasound speed of sound, termed "gSOS", derived from common risk alleles in 341,449 UK Biobank participants. Low gSOS predicts adult osteoporotic fracture. We tested if two cohorts with a significant childhood fracture history and no OI had lower predicted gSOS. The Canadian cohort included 94 subjects with suspected Mendelian osteoporosis. Of them 26 had positive and 68 negative OI gene panel. The Finnish cohort included 59 individuals recruited due to a significant fracture history and 25 subjects referred for suspected Mendelian osteoporosis; 5 had positive OI gene panel. 11 individuals of non-European ancestry and individuals with OI, or who failed genotyping were excluded. We computed gSOS estimates in the two cohorts and compared their gSOS to that of a UK Biobank subset. We counted the individuals with significant fracture history and identified OI and compared them to those having gSOS below the mean in excess of what would be expected by chance alone.

Results: The average gSOS in the entire cohort (n= 133) was -0.70 (standard deviation [SD]: 0.46) and was lower than that in UK Biobank (n=80,027, average gSOS: -0.48 [SD:0.45], P= 4.2 x 10^-7). The gSOS of those evaluated for Mendelian osteoporosis was lower than that of those with only significant fracture history (average gSOS osteoporosis subset (n=80): -0.83 (SD: 0.41) vs fracture-prone subset (n=53): -0.51 [SD: 0.47], P=9.8 x 10^-5). Finally, among 101 individuals with fractures tested for Mendelian disease, 31 had a mutation in an OI-related gene, while there were 21 more subjects with a gSOS below the mean than would be expected by chance alone.

Conclusions: We provide evidence for a polygenic etiology of fractures in children with significant fracture history and no OI. This suggests that patients with clinically-apparent Mendelian disease referred to specialists might have a burden of common risk alleles which could influence their risk of fracture.