WASHINGTON, DC—Common LRP5 gene variants are associated with up to a 20% increased risk for fractures and lower levels of bone mineral density (BMD) in the spine and hip across different white populations, according to a study in the March 19 issue of the Journal of the American Medical Association.1 The findings were presented Tuesday March 18 at a media briefing on genetics and genomics in Washington, DC.

"While some other common variants have been associated previously with osteoporosis phenotypes with large-scale evidence, this may be the first time that an association in this field crosses the threshold of genome-wide statistical significance,” said lead researcher Joyce B. J. van Meurs, PhD, of Erasmus MC in Rotterdam, The Netherlands, at the press conference

Earlier work has shown that genetic factors determine up to 80% of the variance in BMD, but the precise genes that contribute to differences in risk for osteoporosis and fractures are unknown. Several common gene variants are believed to be involved. Variations of LRP5 have been linked to bone mass accrual and susceptibility to osteoporosis. Moreover, some reports have suggested that some LRP5 variants contribute to change in BMD in the general population, but results have been inconclusive until now.

Prospective, collaborative study picked up on modest association

The research team examined the relationship between LRP5 and LRP6 variants, BMD, and risk of fracture using data from the full Genetic Markers for Osteoporosis consortium. The data bank includes genetic material from 37,534 individuals from 18 participating teams in Europe and North America.

The magnitude of the effects of the gene variant was modest, but consistent across studies, the researchers report. Such effects might have been missed by smaller and potentially underpowered individual studies.

A 1-standard deviation reduction in bone mass doubles the fracture rate. Based on this, "an increase of fracture risk of about 15% to 20% is expected," the researchers concluded. "This is similar to the observed effects on fracture, although adjustment for BMD only partly reduced the increase in fracture risk," they wrote.

The findings point to a role for LRP5 in determining BMD and fracture risk throughout life in the general population. "Although any single marker explains only a small portion of the phenotype risk, identification of several such osteoporosis risk variants may eventually help in improving clinical prediction," Dr, van Meurs said. "Single genetic risk variants such as LRP5 may also offer insights about mechanisms and pathways that may be useful in drug development.”

Reference
1. van Meurs JBJ, Trikalinos TA, Ralston SH, et al. Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA. 2008;299:1277-1290.