Bone Abstracts

Genetic factors play an important role in the development of osteoporosis. Several monogenic forms of osteoporosis have been recognized. The most common of these is osteogenesis imperfecta (OI) in which mutations in the genes encoding type 1 collagen (COL1A1 and COL1A2) are responsible for ~90% of the cases. Several rare autosomal recessive forms of OI have also been described. In these the defects lie in proteins involved in posttranslational modification of type 1 collagen. Recent discoveries have further elucidated the genetic determinants of early-onset skeletal fragility and several forms not related to type 1 collagen have been identified.

The canonical WNT-signalling pathway is considered to be of key importance for skeletal health, activation leading to increase and inhibition leading to decreased bone mass. Loss-of-function mutations in LRP5, encoding a co-receptor for the pathway, cause the autosomal recessive osteoporosis–pseudoglioma syndrome. Carriers of LRP5 mutations also have reduced bone mass and present with early-onset osteoporosis and compression fractures. LRP5 polymorphisms associate with peak bone mass, BMD and fractures in the general population, highlighting the significance of this gene in bone mass development and maintenance. Recently heterozygous loss-of function mutations in the WNT1 gene were shown to lead to early-onset osteoporosis while homozygous WNT1 mutations resulted in severe infancy-onset osteoporosis. These findings suggest that WNT1 is a key ligand for the WNT-signalling pathway in the regulation of bone mass.

The first X-chromosomal form of osteoporosis, resulting from mutations in the gene encoding plastin 3 (PLS3), was described in 2013. PLS3 is involved in actin bundle formation in the cytoskeleton. PLS3–osteoporosis has its onset in childhood and is characterized by recurrent peripheral fractures, low BMD, vertebral compression fractures, and significant height loss in adulthood. Males are in general more severely affected than females. The mechanism whereby PLS3 affects bone health is unclear, but it may be linked to osteocyte dendrite function and skeletal mechanosensing.

Future studies are needed to elucidate the role of WNT1 and PLS3 in early-onset osteoporosis and to define optimal therapy for affected individuals. It is likely that further genetic studies in families with early-onset osteoporosis will identify other genes and pathways that play a role in childhood-onset osteoporosis.

Disclosure: The author declared no competing interests.