Osteoporosis is a complex metabolic disease with a strong genetic component which results in a decrease in bone mineral density and deterioration in the microarchitecture of bone, leading to an increased risk of fractures. During the last decade, a number of genetic studies of the Maltese population were performed to determine a potential genetic component which increases the individual’s susceptibility to osteoporosis. Both family and population case-control approaches were used. Linkage analysis using large affected families has identified a region on chromosome 11p12, following which functional studies have shown that variations within two genes found in that region namely, TRAF6 and CD44, affect gene expression, and, more specifically, pre-mRNA splicing in the case of CD44. This is the first report of strong suggestive linkage of 11p12 to osteoporosis. Using the candidate gene approach, selected candidate genes, which had been studied in other populations and been found to increase susceptibility to osteoporosis to varying degrees in some of them, included those coding for the vitamin D and oestrogen receptors (VDR & ER1), osteoprotegerin (TNFRSF11B), collagen type 1 (COL1A1), methylenetetrahydrofolate reductase (MTHFR) and lipoprotein receptor related protein (LRP)-5. In the Maltese population, the most significant result showed that a polymorphism in the promoter region of TNFRSF11B, which codes for osteoprotegerin, had a significant effect on bone mineral density, thus increasing the susceptibility to osteoporosis. These studies have shown that variations within three different genes, namely TRAF6, CD44 and TNFRSF11B, all involved in osteoclast biology, might increase the risk of osteoporosis and could therefore serve as targets for novel therapeutic agents.peer-reviewe
