Identification of Novel Drug Targets for Osteoporosis through Characterisation of the Genetic Basis of High Bone Mass

Osteoporosis is a common condition caused by thinning of bones. It worsens with age and makes bones more likely to break (fracture). 1 in 3 women and 1 in 5 men over the age of 50 will break a bone in their lifetime because of osteoporosis. Fractures can have severe consequences on mobility, independence and life expectancy.

Most current osteoporosis treatments focus on preventing further bone loss rather than rebuilding bone. Long term use of these treatments has been found to actually increase the risk of certain types of uncommon fractures and can rarely cause damage to the jaw. There is only one treatment available in the UK (teriparatide) which helps to rebuild bone but access to it is restricted due to high costs and it can only be given as daily injections into the skin.

More effective, affordable and safe treatments are needed which can be taken by mouth to help rebuild bone and prevent fractures.

One approach to finding new osteoporosis treatments is to study people who have High Bone Mass (HBM). HBM is rare, affecting only 0.18% of the population. HBM individuals have thicker/denser bones than normal which means they are less likely to break their bones.

HBM runs in families but at present, we do not know all the genes that are responsible for causing HBM. Identifying these genes will help us to develop new treatments which mimic the actions of these genes and help rebuild bone for people suffering with osteoporosis. This approach has already been used successfully in the USA to develop a new osteoporosis treatment to rebuild bone (romosozumab).

However, it has been linked to an increased risk of heart attacks, so it is not suitable for everyone.

The UK HBM study at the University of Bristol is the largest study of extreme HBM performed to date. Data, blood samples and scans have been gathered from 355 HBM individuals and their relatives from across the UK. Their genetic code (DNA) has been examined and new variations (mutations) in the DNA of 18 families have been identified which may be directly responsible for causing HBM.

This research aims to discover these HBM-causing mutations and understand their effects on bone shape, strength and biology. I aim to:

i) Discover if the same mutations in UK HBM individuals can be found in the DNA of other people with HBM. This will involve analysing genetic data from several populations, including up to 500,000 people enrolled in the UK Biobank.

ii) Examine how the mutation affects HBM individuals and families carrying that mutation, looking in particular for any effects on their bone shape, structure and biology.

iii) Establish the function of the genes containing the mutations and their role in bone development using a range of computer-based tools and databases. I will also look at the role of these genes in the zebrafish skeleton. Zebrafish have a very similar bone structure and genetic code to humans, so can give us helpful insights into how these genes might work in humans.

iv) Determine how gene mutations might cause HBM using computer-based tools and zebrafish models. The effect on bone development will be measured to predict the likely effects in humans.

By understanding the biology of how rare gene mutations cause HBM, I will be able to find new ways to treat osteoporosis. I will work with partners at the University of Bristol, King's College London and the University of Queensland in Australia to help ensure the results of my research lead to the development of new treatments which will directly benefit patients with osteoporosis.