Objective. To examine the relationship between a common polymorphism within intron 1 of the COL1A1 gene and osteoporosis in a nested case-control study.Methods. We studied 185 healthy women (mean ؎ SD age 54.3 ؎ 4.6 years). Bone mineral density (BMD) was measured using dual x-ray absorptiometry, and fractures were determined radiographically. The COL1A1 genotype was assessed using the polymerase chain reaction and Bal I endonuclease digestion.Results. Genotype frequencies were similar to those previously observed and in Hardy-Weinberg equilibrium: SS 61.1%, Ss 36.2%, and ss 2.7%. Carriage of at least one copy of the "s" allele was associated with a significant reduction in lumbar spine BMD (P ؍ 0.02) and an increased risk of total fracture (P ؍ 0.04). Urinary pyridinoline levels were significantly elevated in those with the risk allele (P < 0.05).Conclusion. These data support the findings that the COL1A1 gene polymorphism is associated with low BMD and fracture risk, and suggest a possible physiologic effect on total body turnover of type I collagen.Osteoporosis is a common condition characterized by low bone mineral density (BMD), deterioration of the skeletal microarchitecture, and a consequently increased risk of fragility fracture. Family and twin studies have demonstrated that 50-85% of the population variance in BMD is attributable to genetic factors, findings that are consistent with the hypothesis that BMD is under strong genetic determination (1-5). Twin studies have also suggested that this genetic regulation of BMD may be mediated, at least in part, by an effect on bone turnover (6,7).Type I collagen is the major protein constituent in bone, and in a few individuals with severe osteoporosis, coding sequence defects similar to those observed in osteogenesis imperfecta have been demonstrated (8). These structural mutations are, however, rare and unlikely to account for more than a small portion of the clinical cases seen (9). Sequence changes in regulatory regions of the type I collagen gene, rather than gross structural mutations within the proteincoding region, may also predispose to osteoporosis, with alterations in type I collagen metabolism. A single basepair polymorphism at an Sp1 binding site within the promoter region of the type I collagen ␣1 gene (COL1A␣1) has recently been associated with low BMD and vertebral fracture risk in 2 UK patient groups (10). Association studies may, however, be confounded by population admixture, heterogeneity, or stratification (11), and experience with another candidate gene, the vitamin D receptor, suggests that such preliminary results require confirmation in other populations (12). The candidacy of the potential locus is also enhanced if a functional significance can be demonstrated. We therefore examined the relationship between the COL1A1 polymorphism and BMD, osteoporotic fracture risk, and biochemical markers of type I collagen resorption in a cross-sectional analysis of women from a UK population cohort.