Prof. Angela Xuereb, Dean of the Faculty of Health Studies at the University of Malta, and her team of researchers, are working on unravelling the genetics of osteoporosis. 

Your team of researchers is working on unravelling the genetics of osteoporosis. Why focus on this silent bone disease in particular, of which it seems we already know a lot?

Osteoporosis is a silent progressive bone disease, affecting both women and men. The condition is diagnosed primarily through the use of bone mineral density scans.

A number of risk factors, including environmental and genetic factors, increase susceptibility to osteoporosis. Much is known about the harmful environmental factors leading to osteoporosis, such as low calcium intake, low vitamin D, malnutrition, physical inactivity, low body mass index, smoking and high alcohol consumption. Genetic research in the field of osteoporosis has unravelled an appreciable number of the genes involved in the pathogenesis of osteoporosis.

However, many other genetic risk factors still remain to be identified due to the fact that osteoporosis is a complex genetic condition. This means that multiple genetic risk factors are involved in the pathophysiology of osteoporosis, which in turn predisposes to a high fracture risk.

Moreover, such genetic risk factors might not impose the same risk across all ethnicities, making it imperative to continue searching for new genetic factors underlying this silent condition in the Maltese population.

So far, what do we know about the genetic factors underlying osteoporosis and fracture risk?

Presently, we know there are several genetic factors underlying osteoporosis and also fracture risk. These have varying degrees of harmful effects on bone. Very often, the solitary effect of these genes is not enough to result in disease, but it is the additive effect that, together with other environmental influences, culminates in pathogenesis.

Research carried out so far, using both family and population studies, has identified some genes implicated in the susceptibility to osteoporosis, all of which affect proteins important for bone development. Identified genes are further studied in animal models to confirm their role in bone biology, and moreover, replication in different ethnicities is also encouraged for confirmation of their involvement in disease pathogenesis.

What does your research aim to discover over and above that?

Our research specifically aims to identify the presence of new genetic factors contributing to osteoporosis and fracture risk using a number of Maltese family studies.

The identified genes are currently being studied further in animal models to confirm their role in bone physiology. The effect of these genes will also be tested in a case-control collection of more than 1,000 Maltese postmenopausal women to determine whether their harmful effect is also present at the population level. Furthermore, known different genetic risk factors identified from other population studies, especially European, will be replicated in the Maltese case-control collection to determine whether they also impose a risk to the Maltese community.

In fact, the Maltese case-control collection is currently involved in a collaborative study including major international research consortia, which specifically replicate their findings.

Genetic risk factors might not impose the same risk across all ethnicities, making it imperative to continue searching for new genetic factors underlying this silent condition in the Maltese population

Based on the findings, would patients be able to tell before its onset that they have a predisposition to the condition and start taking tailor-made treatment?

Genetic studies have provided valuable information on the pathogenesis of osteoporosis and fractures, which, in turn, can be applied to the identification of susceptible individuals and possibly formulation of customised treatment strategies. Individuals can be screened at a young age and, if found to possess a number of genetic risk factors for osteoporosis, can follow a number of preventive regimes focused on maintaining a healthy lifestyle.

These include increasing their dietary calcium intake, following a good healthy diet, having good vitamin D levels, performing weight-bearing physical activity, and refraining from smoking and consuming excessive alcohol. Once high-risk individuals are identified, their relatives can also be checked and monitored, especially since heritability for bone mineral density ranges from 50 per cent to 80 per cent, and individuals with a parental history of a hip fracture exhibit a twofold greater risk of sustaining an osteoporotic fracture. We hope that screening for genetic risk factors of osteoporosis will shortly become a reality and can be implemented on a local scale.

The aim of every researcher working in the field of bone is to identify the genetic make-up of high-risk individuals so as to develop and prescribe tailor-made treatment. We are already moving into this era, especially with the development of novel treatment strategies as a result of genetic studies.

Case-control studies have already been carried out and papers published. At what stage is the current research, what does it entail and when do you expect more results?

Currently, we are testing new genes identified in two extended Maltese families using next-generation sequencing. The genes are being studied in animal models to determine how they affect bone. In addition, the large case-control collection referred to earlier has been used to analyse the effect of over 20 new or known genetic risk factors in relation to bone mineral density and fracture risk. A good number of these analysed genetic risk factors have actually been found to predispose to osteoporosis and increased fracture risk in the Maltese population, confirming results reported in other population studies. More genetic risk factors are currently being analysed and will be published in international peer-reviewed journals in the coming months.

The University of Malta is collaborating with two major international consortia on the research. How does this change its scope?

We are collaborating with the international GENOMOS [Genetic Markers for Osteoporosis] and GEFOS [Genetic Factors for Osteoporosis] consortia, composed of several prominent research study groups, working to identify new and confirm known genetic risk factors underlying osteoporosis and fracture risk across different populations.

This collaboration promotes the sharing of ideas and information, and also strengthens the results obtained. In fact, the data has been published in leading science journals. This collaboration also enables the testing of important and selective genetic risk factors that might otherwise not be analysed locally due to funding restrictions.

Do you feel that enough importance is given to research projects of the sort in Malta and how important are they?

Biomedical research projects are very important since results could be used to create tailor-made treatment and to educate the community about disease prevention. Financing is an ongoing problem, but with the possibility of joining European funding programmes such as Horizon 2020, and with scholarships, such as Endeavour supporting tertiary education, and Reach High Scholars Programme financing post-doctoral projects, such research can be facilitated. The UoM also aims to promote research by financing projects through its Research Fund although resources are very limited.

Is the culture of donating to uni­versity research changing, and is the public starting to see this as another good cause that deserves philanthropic support, or not yet?

Yes, it is changing and such funding has been instrumental for a number of research projects. The university’s Research Innovation and Development Trust [RIDT] recently secured €38,000 in funding from the Malta Community Chest Fund for our new research project on the genetics of osteoporosis and fractures. As researchers, it is important for us to increase the awareness and exposure of research studies in all fields, which, in turn, can also result in more collaboration and financial help.

What else is going on behind the scenes in the university labs that the public may not be aware of?

The expansion of a new centre for biomedical research at the University of Malta, including state-of-the-art equipment, such as next-generation sequencing equipment, obtained through the European Regional Development Fund [ERDF], will help enormously in many aspects of our and other biomedical research. This will also lead to the encouragement of multi-disciplinary research, involving various researchers from different faculties across the university.

And what field could do with more research projects?

This is a difficult question to answer as many research projects are being conducted at the university in many fields, and most could do with more funding. However, one must keep in mind that despite the limited funding available, there is some excellent research being conducted in some areas, and it gets published in leading international journals.

What else would you like to focus your research on if you had the funding?

We would definitely start focusing on monogenic [controlled by a single gene] bone disorders in the Maltese population. In addition, we would aim to extend our current research studies by recruiting more individuals, including osteoporotic males, to determine the genetic risk factors leading to osteoporosis in both sexes.

We hope that screening for genetic risk factors of osteoporosis will shortly become a reality and can be implemented on a local scale

If you could pick a breakthrough in medicine, what would it be?

As a geneticist, I have to mention the completion of the Human Genome Project as a major breakthrough. This has made possible the identification of several genes involved in many diseases, and subsequently, the design of direct and appropriate treatment. The development of anti-cancer drugs is another.

In Malta, the number of people affected with osteoporosis is estimated to be around 20 per cent in women and six per cent in men aged 50 years and older. Have these figures changed over the years?

As reported by the International Osteoporosis Foundation Working Group, the number of persons suffering from osteoporosis has increased over the years, even though there have been major developments in the pharmaceutical field. This could be due to increased longevity, as well as the effect of harmful environmental influences.

The presence of coexisting medical conditions, such as premature menopause, malignancies and chronic kidney disease, as well as medications, including steroids, also predispose to osteoporosis and fracture risk. In 2010, approximately 2,600 fragility fractures in men and women over the age of 50 were estimated to have been sustained in Malta, costing the National Health Service around €17 million.

These figures are set to increase in the coming years. According to the International Osteoporosis Foundation Working Group, Malta is rated among the High Incidence Category Group for both osteoporosis and fracture incidence.

What is the major downside for sufferers of osteoporosis and what could be done to improve the condition?

The major downside is by far suffering a fracture and the consequences of such a painful event. The most common and debilitating types of fractures are those of the spine, hip and wrist.

A number of complications can delay healing, even post-operatively, especially in the elderly, and in the case of hip and spine fractures, this could possibly result in mortality. Sufferers need to adopt lifestyle changes and also require rehabilitation and secondary care.

Secondary falls are not uncommon either; so prevention strategies with optimal functional recovery and improvement in the individual’s quality of life are called for.

This article first appeared in Pink magazine, distributed with The Sunday Times of Malta