More than 100 genes have been discovered to be associated with osteoporosis and bone fracture. Although the effects of individual genes are relatively small, their effects en mass in the form of a “genetic signature” can help in the personalised assessment of fracture risk.
Bone fracture is a serious consequence of osteoporosis. The lifetime risk of a hip fracture for 50-year old women is about 15%, which is equivalent to that of invasive breast cancer. Almost 20% of patients with a hip fracture die within 12 months after the event. However, it is not just hip fractures that impose a great mortality and morbidity burden on both patients and the society; non-hip fractures are also associated with increased risk of mortality.
Osteoporosis and bone fractures represent one of the most challenging public problems in Australia. The challenge for both research and public health policy lies in the identification of high-risk asymptomatic individuals. Over the past 30 years, studies from our group and others have provided an important clue to the pathogenesis of osteoporotic fractures: bone strength. People sustain a bone fracture because their bone is not strong enough to bear a force exerted against it. Bone mineral density (BMD) is currently the best measure of bone strength, and people with low BMD (i.e., osteoporosis) are at significantly greater risk of fracture than people with normal or only slightly reduced BMD. Therefore, efforts to identify individuals at high risk of fracture have focused largely on factors that are associated with BMD.
Doctors and scientists have long known that the between-individuals variation in BMD is due largely to genetic factors. Studies in twins and families have found that up to 80% of differences in BMD between us are attributable to heritable factors. The risk of hip fracture in women whose mothers have sustained a hip fracture is more than 2-fold higher than women whose mothers have not had a hip fracture, because they have a deficit in bone strength. Taken together, the evidence for genetic influences on bone strength and fracture are overwhelming.
Still, it remains a great challenge to find specific genes (in the pool of millions of genetic variants in our body) that are associated with BMD — a task that is likened to finding needles in the haystack! Nevertheless, with advances in genetics and bioinformatics, after almost two decades of “gene hunting”, we and others have identified more than 60 variants associated with BMD. A more recent study based on ~142,000 individuals from the UK Biobank found 307 genetic variants that are associated with another measure of bone strength called quantitative ultrasound measurement of the heel. While these findings represent a triumph of science and technology, a small twist is that these variants explained only 10-12% of differences in BMD between individuals.
With such a small proportion of variance explained, one may ask: how can GPs utilise genes for the identification of high-risk individuals in the general community? Individually, the variants identified have little clinical utility because they have very small effects on individual fracture risk, but collectively they can be of help. One way to pull the effects of genetic variants en masse is to generate a genetic signature for each individual, which can be used in the assessment of bone health. We have created such a signature — termed as “osteogenomic profile” — and found that it predicts the risk of fracture independently of age and clinical risk factors. We have recently found that the osteogenomic profile can also help assess bone loss in elderly people. Although we are excited about these findings, it is important to emphasize that the profile is not yet ready for use in the clinic. Nevertheless, the recent findings do, however, bring us a huge step closer to a more accurate personalised fracture risk assessment.