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Bone Mineral Density at Forefront in Genetic Fracture Risk Meta-Analysis

NEW YORK (GenomeWeb) – A new genome-wide association meta-analysis supports the notion that bone mineral density is a crucial factor in fracture risk.

As they reported online yesterday in the British Medical Journal, researchers from 23andMe, the Genetic Factors for Osteoporosis (GEFOS) consortium, and the Genomos consortium brought together genotyping data for 37,857 bone fracture cases and 227,116 unaffected controls from dozens of prior studies to pinpoint variants with potential ties to fracture risk. After following up on suspicious loci in nearly 300,000 23andMe participants with or without fracture history, they were left with 15 significantly associated loci.

The variants at these loci overlapped with those implicated in bone mineral density previously, the team noted, while a two-stage Mendelian randomization framework indicated that the variants linked to lower bone mineral density could boost fracture risk. The latter analysis hinted that diminished grip strength also coincides with greater fracture risk, pointing to muscle strength as another potential fracture factor, though this result was not significant after testing corrections.

"Our research confirms that [bone mineral density] is the most important determinant of fracture risk and that prevention strategies aimed at increasing or maintaining bone density are the most likely to be successful," co-corresponding author Brent Richards, a genetic epidemiologist affiliated with the Jewish General Hospital's Lady Davis Institute and McGill University, said in a statement.

Both genetic and environmental factors are believed to contribute to osteoporosis, the team explained. But it remains to be seen whether clinical factors that are currently used to predict osteoporosis risk might successfully be altered to prevent such fractures.

"Understanding whether interventions aimed at clinical risk factors would reduce fracture risk is important, because clinicians often ensure that such risk factors are optimized in individuals at high risk of fracture," the authors wrote.

By considering data for more than 500,000 individuals across the discovery and validation stages of the study, the researchers aimed to get a clearer look at the biology behind fractures as well as clues to related clinical features. For example, they noted that common variants at the 15 fracture-linked loci — which each had modest effect sizes — all fell at or near sites already implicated in bone mineral density.

While the fracture risk variants were predicted to have effects on features such as bone mineral density or grip strength, the team did not see ties between variants contributing to fracture risk and features such as vitamin D or fasting glucose levels.

"One of the most important aspects of this research is the robust evidence showing that vitamin D supplementation in the general population is unlikely to be effective for the prevention of fracture," Richards said. "This will encourage clinicians to focus patients on building bone density as a more effective preventive measure against fracture."