Genetic Predisposition to Stress Fractures ID’d in Healthy Individuals

Genetic predisposition may play a role in susceptibility to stress fractures, according to a study published in the March issue of Purinergic Signalling. Understanding the genetic predisposition may be important among military recruits and elite athletes who have an estimated incidence of stress fractures as high as 24 percent.

Genetic variants in the P2X7 receptor (P2X7R) gene, a key regulator of bone remodeling, have previously been tied to bone phenotypes and clinical outcomes in older populations. Variants have been tied to both gain and loss of function.

The researchers studied P2X7R in two separate cohorts—210 Israeli Defense Forces (IDF) military personnel and 518 elite athletes from the United States and the United Kingdom. Among the IDF recruits, stress fracture injury was diagnosed in 43 personnel based on symptoms, evaluation by an orthopedic surgeon, and a positive bone scan.

Among the elite athletes medical imaging-verified stress fracture injuries were seen in 125 participants. Those in both cohorts not having stress fractures confirmed by bone scans were considered controls. Participants were genotyped for 12 functional single nucleotide polymorphisms (SNPs) within the P2X7R gene using a proprietary fluorescence-based competitive allele- specific polymerase chain reaction assay.

The researchers found that the variant allele of P2X7R SNP rs3751143 (Glu496Ala— loss of function) was associated with stress fracture injury, while the variant allele of rs1718119 (Ala348Thr—gain of function) was associated with a significantly lower occurrence of stress fracture injury in IDF recruits. These findings were validated in the elite athlete cohort.

“The precise mechanism by which these mutations may influence stress fracture risk is unknown but may include decreased sensitivity of bone to mechanical loading or decreased osteoclast apoptosis,” write the authors led by Ian Varley, from Nottingham Trent University in the United Kingdom.

Takeaway: While still needing validation in a larger population, among active, healthy people there may be a genetic explanation for predisposition to stress fractures. These findings could hold importance among military recruits and elite athletes prone to repeated mechanical loading.