PITTSBURGH, June 29 -- Women over age 65 who inherit a specific form of the gene for apolipoprotein E, called APOE-4, are at substantially increased risk of hip and wrist fractures, according to a University of Pittsburgh-led study published in the July issue of the Journal of Bone and Mineral Research. Impressively, APOE-4 acts independently of two important common risk factors--bone mineral density and falling.

"Our findings suggest that osteoporotic fractures may result from genes that do not influence bone mineral density directly. Identifying this new marker could improve our ability to understand how these fractures occur and allow us to identify women at increased risk," remarked Jane Cauley, Dr.P.H., associate professor of epidemiology at the University of Pittsburgh Graduate School of Public Health and lead author on the study, which also involved investigators from the University of California at San Francisco.

Applying this new genetic marker to a larger population could eventually benefit the 250,000 women who suffer life-threatening hip fractures each year in the United States, according to Dr. Cauley. One in six older white women will suffer a hip fracture sometime during her lifetime.

The APOE gene produces a combination protein-lipid that carries cholesterol to cells. This gene comes in three common forms, or alleles, called APOE-2, APOE-3 and APOE-4. Each person carries two copies of the APOE gene, and the two copies may be the same allele or two different alleles. People with one or more copies of the APOE-4 allele are known to be at increased risk of developing Alzheimer's disease.

In the -- Study of Osteoporotic Fractures,-- the researchers followed a group of 1,750 Caucasian women age 65 and older for seven years. They evaluated bone mineral density, APOE gene alleles, occurrence of wrist and hip fractures, number of falls and cognitive function. The investigators found that women with at least one copy of the APOE-4 allele were twice as likely to suffer hip and wrist fractures as those women with either APOE-2 or APOE-3 alleles. Women with the APOE-4 allele and additional risk factors were even more likely to suffer hip and wrist fractures.

"The correlation between APOE-4 and fractures among women in our study does not appear attributable to dementia, because women with APOE-4 had the same cognitive function and the same likelihood of falling as women without this allele," stated Dr. Cauley.

The researchers evaluated APOE genes in the "Study of Ostoporotic Fractures" because a previous investigation showed that patients undergoing hemodialysis who had the APOE-4 allele were more likely to suffer fractures.

The APOE-4 allele may contribute to fractures because it reduces blood levels of vitamin K, which has been shown to stimulate the formation of bone and reduce the resorption of bone, a process whereby specialized cells break down bone and release its constituents into the blood. Future studies will measure APOE allele type, vitamin K levels and bone turnover to test this hypothesis, state the researchers in the journal article. The study was supported in part by grants from the National Institutes of Health.

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