Gene polymorphisms involved in the regulation of bone quality

Abstract

Osteoporotic fractures in subjects at advanced age constitute a tremendous and growing problem. Established lifestyle risk factors can explain only a modest proportion of the liability to osteoporotic fractures. Bone mineral density (BMD) is considered the best established risk factor for osteoporotic fractures. The importance of genetic factors in the quality of bone is substantial, but no consensus exists yet on the genes that are involved. However, concomitant diseases, balance disorders and lifestyle habits are more important for fractures in elderly subjects. The abundance of common sequence variations, so-called polymorphisms, in the human genome and their high frequency in the population have made them targets to explain variation in the risk. Some genes have been identified that appear to be involved in the regulation of bone mass and in the pathogenesis of osteoporosis. Among these are those coding for the two estrogen receptors (ERα and ERβ), the androgen receptor (AR) and the vitamin D receptor (VDR). In addition, enzymes involved in the biogenesis of estrone and estradiol have attracted attention as well as polymorphisms in the regulatory region of the type I collagen gene, COLIA1, affecting the binding site for the transcription factor Specificity protein 1 (Sp1). Although evidence suggests that the quality of bone is determined to a large extent by genetic factors, research so far has not been able to unequivocally identify genes involved in this matter. Over the last years a large number of studies have pointed to the variability in many genes and their relation with BMD, bone-related symptoms or specific therapies. The findings emphasize the complexity of the genetics of bone mass and bone loss.