Over the past 10 years, many advances have been made in understanding the mechanisms by which genetic factors regulate susceptibility to osteoporosis. It has become clear from studies in man and experimental animals that different genes regulate BMD at different skeletal sites and in men and women. Linkage studies have identified several chromosomal regions that regulate BMD, but only a few causative genes have been discovered so far using this approach. In contrast, significant advances have been made in identifying the genes that cause monogenic bone diseases, and polymorphic variation in some of these genes has been found to contribute to the genetic regulation of BMD in the normal population. Other genes that have been investigated as possible candidates for susceptibility to osteoporosis because of their role in bone biology, such as vitamin D, have yielded mixed results. Many candidate gene association studies have been underpowered, and meta-analysis has been used to try to confirm or refute potential associations and gain a better estimate of their true effect size in the population. Most of the genetic variants that confer susceptibility to osteoporosis remain to be discovered. It is likely that new techniques such as whole-genome association will provide new insights into the genetic determinants of osteoporosis and will help to identify genes of modest effect size. From a clinical standpoint, genetic variants that are found to predispose to osteoporosis will advance our understanding of the pathophysiology of the disease. They could be developed as diagnostic genetic tests or form molecular targets for design of new drugs for the prevention and treatment of osteoporosis and other bone diseases.
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