Researchers discover new strong genetic cause for osteoporosis and fractures

A large international study has identified a new rare variant lying close to the gene Engrailed homeobox 1 (EN1) which has a fourfold increased impact on bone mineral density (BMD) and fractures compared to all other previously reported variants to date.

The study was led by researchers from Montreal’s McGill University, Canada, and Rotterdam’s Erasmus University Medical Centre and The Netherlands, and which included Maltese researchers Professor Angela Xuereb and Dr Melissa Formosa, from the Department of Applied Biomedical Science, Faculty of Health Sciences,

The identified gene variant is relatively rare (1%) in the overall population, however it is more frequent among those with the disease, predisposing carriers of the variant to an unusually high risk of osteoporosis. This is the first time that the EN1 gene has been linked to osteoporosis in humans, thus making it a strong target for the development of drugs to treat the condition.

The genetic research involved the participation of more than 500,000 individuals, including those of the Malta Osteoporotic Fracture Study. Different testing methods were applied to find the rare genetic variants, including the whole-genome sequencing method, and the findings were subsequently confirmed by testing in a number of independent studies, including the Malta Osteoporotic Fracture study. The EN1 gene was also tested in mice, confirming that indeed the gene affects limb development in mice.

Osteoporosis is a silent bone disease in which bone mass significantly decreases, especially with increasing age, giving rise to an increased fracture risk. The most common and important fracture sites are the hip, spine and wrist, which are most debilitating for patients and inflict huge costs on the global economy. The prevalence of osteoporosis and fractures is on the rise as a result of the increase in the aging population.

A number of risk factors are known to increase the development of such conditions, such as a low body mass index, young age at menopause, low physical activity, smoking and high alcohol consumption, and a strong family history of osteoporosis and fragility fractures, highlighting the presence of a strong genetic component.

Hence, such genetic research studies, provide valuable information regarding bone biology, osteoporosis and skeletal fragility, which in turn help in the early identification of susceptible individuals and the implementation of preventive measures in such individuals, especially since few safe and effective treatments are currently available.

The findings of this study have been published in the prestigious journal Nature:  “Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture”, Nature, on-line September 14, 2015.