Defining the genetics of osteoporosis: using the mouse to understand man

Very low bone mineral density (BMD) is now considered as diagnostic of osteoporosis. Moreover, many women who are osteopenic eventually develop osteoporotic fractures. Hence, bone density testing has occupied center stage in the diagnosis and treatment of this disorder. In addition, over the last several years, BMD has been utilized as the phenotype of choice for defining heritable markers for osteoporotic fractures. However, genetic studies in humans have been limited to some degree by the tremendous heterogeneity among populations, as well as multiple genetic, heritable and environmental determinants of the BMD phenotype. Recent advances in technology have afforded investigators the opportunity to study acquisition and maintenance of BMD in small animals. Along with newer knockout and transgenic strategies, quantification of mouse bone mass has advanced our understanding of both the biologic and genetic determinants of bone density. In this review, we will examine the use of the mouse to map the heritable factors that regulate bone acquisition. We will also examine the role of newer technology to decompose the bone density phenotype into components that are amenable to genetic studies. This review will focus on three models: (1) healthy inbred (2) recombinant inbred, and (3) congenic strains of mice. Progress in this area with these strains has been rapid, and a summary of several quantitative trait loci (QTLs) is provided. The future of the mouse as a tool to map the genes that define the osteoporosis syndrome is extremely promising.