Osteoporotic fracture is due to age-related reduction in bone strength. Bone strength comprises bone mineral density, structure, quality and turnover, all of which are highly heritable. The most serious osteoporotic fracture occurs at the hip. Reduction in hip bone strength is due to a combination of low peak bone mass and age-related bone loss. Heritability of bone mass at the hip is high, but heritability of bone loss at the hip has not been studied. Women have lower bone strength and higher incidence of hip fracture than men. In men, heritability of bone strength has not been firmly established. Heritability of bone strength has been measured in 760 pairs of sisters, and a 10 cM genome screen has identified several chromosomal loci influencing bone strength. Two hypotheses will now be tested: 1. The rate of bone loss at the hip in women is genetically determined. This will be tested by remeasuring hip bone mass in 500 pairs of sisters in our current study and, if heritable, perform linkage analysis using genotypic already generated. 2. The genetic effect on bone strength in men is similar to that in women, but certain loci are sex specific. This will be tested by measuring bone strength in 700 pairs of brothers, comparing heritabilities to those in our 760 of sisters, and performing a genome screen to identify loci influencing bone strength in men. Three major goals in understanding the genetic basis of bone strength will be achieved: 1) establish if the rate of bone loss at the hip in women has a genetic component, and if so, localize the genes that underlie the loss; 2) establish heritabilities of bone strength in men and compare these with those established in women; 3) enrich our database for fine mapping bone-strength genes and establish if certain loci are sex specific. This information will lead to a much better understanding of the causes of osteoporotic hip fracture and of the difference in incidence between men and women and, ultimately, to new therapeutic and preventative treatments.
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