Endocrine Abstracts

Over the past 10 years, tremendous advances have been made in understanding the role that genetic factors play in the regulation of bone metabolism and bone disease. Most bone diseases have a strong genetic component but for many of these the genetic architecture is incompletely understood. However it is clear that in some diseases, there is Mendelian inheritance of the phenotype due to alleles that have a large effect size, whereas in other diseases, the inheritance is polygenic with alleles of small effect size and additional contributions from environmental factors. Osteoporosis is the most common bone disease and is characterised by reduced bone mineral density (BMD) and increased fracture risk. The heritability of BMD is about 70% and fractures also have a heritable component although this decreases markedly with age as environmental factors assume a more important role. Multiple genes have been identified by genome wide association studies that regulate BMD and fracture risk but these have small effect sizes and (in total) so far explain only 5–6% of the genetic variance. Studies are in progress to determine if larger effect alleles also exist. Several rare bone diseases exist in which BMD levels are unusually high or low including osteopetrosis (due to mutations in genes that regulate osteoclast function) and sclerosing bone dysplasias (due to mutations in genes that regulate bone formation). Genetic analysis of families with these diseases has resulted in the identification of several key molecules that regulate bone turnover such as lipoprotein-receptor related protein 5 (LRP5), sclerostin (SOST) and Cathepsin K Paget’s disease of bone (PDB) has a frequency of about 1–2% and has a strong genetic component. Current evidence suggests that PDB is caused by a combination of rare alleles of large effect that cause Mendelian inheritance of the disease and commoner alleles of medium effect that increase disease risk by 30–50%. Causal genes include SQSTM1, TNFRSF11A, CSF1, OPTN, and TM7SF4 which are involved in regulating osteoclast differentiation and function. Advances in genetics have not only advanced our knowledge of the pathophysiology of bone disease but have also identified several molecules that are being targeted for the next generation of drug treatments for bone disease.