While
osteoporosis is commonly thought of as a disease of old women, it''s really more a disease of old age. Marked by a
deterioration of bone density and strength,
osteoporosis (meaning porous bones) often goes undetected until a fateful slip results in a serious fracture of the hip, spine, or wrist. While it''s true that postmenopausal women are much more susceptible than menlargely owing to their smaller framesrisk for men increases exponentially with age. Risk factors traditionally reflect lifestyle choices, including lack of exercise and poor diet, though genetics appears to be a major determinant of low bone mineral density (BMD), a characteristic feature of osteoporosis. Genetic factors also influence an individual''s rate of bone loss, bone size, and likelihood of falling. In a large genetic study of osteoporotic Icelanders and their extended families, Unnur Styrkrsdttir and colleagues at deCODE Genetics in Reykjavik identified a
candidate gene associated with a predisposition for osteoporosis.
Linking specific genes with complex diseases like osteoporosis is a tricky business. There are likely to be several genetic causes, and to find them researchers need large populations, abundant genetic markers, and extensive patient data. In addition to powerful genetic resources, researchers at deCODE can take advantage of a nationwide genealogical database of native Icelanders stretching back to the country''s origins 1,100 years ago. By screening hundreds of affected individuals and their families, the scientists searched for candidate genes underlying osteoporosis and its harbinger, low BMD.
While low BMD is the best predictor of osteoporotic fracture, peak bone mass (mineral mass begins to diminish after young adulthood) and the rate of postmenopausal bone loss also appear to influence risk. Genetics contributes to all of these factors. Styrkrsdttir and colleagues screened the genealogical data on 207 extended families for the most clinically relevant phenotypic factorslow BMD and osteoporotic fracturesto focus their search. Screening only affected families with these attributes in a genome-wide scan, they say, seemed a reasonable method for finding susceptibility genes. They conducted a series of scans and found a significant linkage to the short arm of Chromosome 20. This region contains six known genes, including four genes involved in bone formation and osteoblast (bone-forming cell) differentiation.
To winnow the list of most likely candidate genes, Styrkrsdttir et al. screened the genomes of 705 individuals with osteoporosis in a case-control study, using closely spaced genetic markers within the region of interest. This analysis pointed to BMP2 as the most likely candidatean enticing finding, because BMP2 (bone morphogenetic protein 2) is known to be involved in bone development. Sequencing the BMP2 gene in 188 patients and 94 controls to look for functional variants that might account for a predisposition to osteoporosis flagged several possible sequence alterations (which were subsequently shown to be associated with osteoporosis in the larger cohort). Furthermore, an independent replication study with two groups of postmenopausal Danish womenone group with low BMD and one with osteoporotic fracturesfound comparable results, with a higher incidence of the BMP2 variants in the affected women compared to the controls. These variants alone can''t explain all of the results, however, because a linkage analysis run with patients who do not carry these variants still shows a likely association in the BMP2 region, implying that there may be other variants in BMP2 or adjacent genes that might be influencing osteoporosis.
These results support BMP2 as a likely gene for osteoporosis. Future studies will determine whether it increases risk through its control over peak bone mass, as the researchers suggest, or through some other mechanism. Styrkrsdttir et al. stress that other as-yet-uniden