Genes and Fracture Risk: A Step Closer to Personalized Medicine for Osteoporosis

An estimated 60 to 80% of bone density is inherited. Now with the ability of whole genome sequencing you would think it would be easy to identify genes for osteoporosis. Although osteoporosis and fracture risk are strongly genetic, they are very complex disorders.

A large international collaboration of prominent research groups, the GEnetic Factors for OSteoporosis consortium-GEFOS, is using advanced gene discovery tools called genome wide association analysis to identify gene variants for osteoporosis. So far of the 63 genetic factors that they have identified, these genes account only for a small approximately 6% variance in bone density.

New Osteoporotic Genetic Discovery

In Online First of the New England Journal of Medicine (October 2, 2013), Dutch researchers report an genetic link with osteoporosis fracture risk. The Dutch researcher’s strategy for identifying genetic determinants of osteoporosis started with investigating a rare gene variant. They identified a mutation in the gene for plastin 3 (PLS3) as a novel factor involved in osteoporosis. PLS3 is a bone-regulatory protein. Its function in developing bone structure was observed in zebrafish. The animal model data suggest that PLS3 may be a regulator of bone development.

They studied a total of ten families who had inherited osteoporosis and fractures. Variants in the gene PLS3 were identified as the likely contributing cause of their disease. They hypothesized that PLS3 may be involved in mechanical load sensing of bone cells called osteocytes. Mechanical loading refers to stress on the bone that occurs with activities like weight-bearing exercise. The PLS3 mutations lead to decreased mechanosensing of osteocytes, with subsequent malfunction of bone breakdown and building, which results in osteoporosis and fractures.

Next they evaluated the association of the PLS3 genetic variants with bone density and fractures in several large cohorts of elderly Dutch men and women. The researchers identified a rare PLS3 variant in women was associated with decreased bone density and double the risk of fracture compared with noncarriers. In men, no associations between carrier status and bone density or fracture risk were observed; however this result was limited by small numbers.

Future Horizons for Osteoporosis Treatment

The authors conclude that genetic variation in PLS3 is a novel factor involved in common, multifactorial osteoporosis. This research discovery of a rare gene being present in osteoporosis may be a breakthrough in the fracture and osteoporosis genetic puzzle. The hope is that this research will accelerate the timeframe of reaching personalized genetic medicine treatment for osteoporosis and reducing fracture risk.

Diane L. Schneider, MD, MSc
Author, The Complete Book of Bone Health
Medical Editor,