Osteoporosis is a common disorder characterized by reduced bone mass and increased risk of fracture (1). Evidence from family studies suggests that genetic factors have a major role in the determination of bone mass (2). Because bone mass and bone strength are complex phenotypes, their heredity is almost certainly polygenic. Among the potential candidate genes that might influence bone mass acquisition, special attention has been directed to the vitamin D receptor and estrogen receptor genes; results of these studies, however, have been contradictory (3)(4)(5). Type I collagen, a protein encoded by the collagen I α1 (COLIA1) and collagen I α2 (COLIA2) genes, is the major protein of bone matrix. Genes encoding collagen type I may be important candidates for the genetic regulation of bone density because mutations that affect their coding regions have been associated with osteogenesis imperfecta (6). A guanine-to-thymidine polymorphism at the first base of a binding site for the transcription factor Sp1 in the first intron of COLIA1 has recently been associated with low bone density and bone fractures in women from various European populations(7)(8)(9)(10)(11). In these studies, the COLIA1 genotypes were determined using a PCR assay with a mismatched primer that introduces a restriction site for the enzyme Bal I in polymorphic alleles with the thymidine substitution. The test discriminates two alleles, S and s , which correspond to the presence of guanine and thymidine, respectively. Thus, the absence of the restriction site on both alleles was defined as homozygote SS , the presence of the restriction site was defined as homozygote ss , and the combination of both was defined as heterozygote Ss (7). In this assay, the PCR products containing s alleles are cleaved by Bal I, and agarose …