New mutation predisposes patients under osteoporosis treatment to atypical femur fractures, study finds

May 4 2017

A team of researchers of the University of Barcelona and the Hospital del Mar Medical Research Institute (IMIM) have discovered a new mutation that has an impact on the bone so that it is vulnerable to the bisphosphonate, a drug used to treat osteoporosis.

However, instead of strengthening the bone and prevent it from getting fractures, it would lead to a critical problem and would make the femur more likely to fracture. The new study, of great clinical importance, has been published on the journal New England Journal of Medicine, the journal with the highest scientific impact in the field of biomedicine.

The study has been carried out within the framework of a collaboration between doctors and researchers from the IMIM and the Internal Medicine Service of Hospital del Mar, belonging to the Virtual Biomedical Research Center of Fragility and Healthy Ageing (CIBERFES), and a research team led by professors Daniel Grinberg and Susana Balcells, from the Human Molecular Genetics Group of the University of Barcelona, the Institute of Biomedicine of the University of Barcelona (IBUB) and the Rare Diseases Networking Biomedical Research Centre (CIBERER). The study also counts with the external participation of teams from the University of Oxford (United Kingdom) and the University Hospital Reina Sofia in Cordova (Spain).

Osteoporosis creates fractures that affect up to the 40% of people aged over fifty. Due its low price and efficacy, bisphosphonates are among the first options for therapeutic treatments. However, its use has been associated with an atypical femur fracture. "Despite the rareness of this problem, and taking into account that there are many more prevented fractures than the induced ones, the worry about this complication has created a decrease in medical prescriptions for these drugs, in particular when it comes to long-term treatments", says Professor Adolfo Díez, head of the study and member of the Musculoskeletal Research Group of the IMIM. Consequently, most of the people at high risk of fracture due osteoporosis (the ones who already suffered from some fracture) are not receiving treatment.     

The rareness of this problem creates suspicions about a genetic predisposition that made some people more likely to show an atypical fracture. "Three cases of atypical fracture in three sisters who were treated with bisphosphonates during some years offered an opportunity that provided the possibility of analyzing a genetic basis which, in another way, would have been impossible to detect" affirms Xavier Nogués, head of the Internal Medicine Service in Hospital del Mar and coordinator of the Musculoskeletal Research Group of the IMIM.

An exhaustive genome study

An exhaustive genome study using the technique of whole exome sequencing, enabled finding -for the first time- a common mutation in the three sisters which could explain why they had the atypical fracture. This mutation harms a protein (GGPS) which is part of a metabolic chain -mevalonate pathway- and is essential for bone health. This mutation is believed to make the bone vulnerable to the drug and instead of strengthening it to prevent it from injuries, it actually makes it more likely to undergo fractures.

According to the experts Daniel Grinberg and Susana Balcells (UB-CIBERER), "the mutation -which implies the change of a single amino acid- inactivates the necessary enzyme for the geranylgeranyl pyrophosphate synthase, a lipid that holds several cytochrome proteins (from the family of GTPases) onto cell membranes. Without the lipid, these proteins are left apart and they cannot carry their functions out, which are essential for the survival of the osteoclasts, the cells in charge of reabsorbing the bone matrix".              

"In fact, bisphosphonates work following the same course because they block the mevalonate pathway in a previous reaction to the one that catalyzes the GGPPS. This block usually involves a control in the bone resorption. We understand that the dual gernaylgeranyl pirosophate depletion in the studied patients may have been more severe, and instead of resulting in a protective function it would have led to a fragility that ends up with a fracture. However, more study is needed to confirm this hypothesis" say Grinberg and Balcells.   

With this findings, broader studies would be needed in order to bring medical care the techniques of genetic analysis that allow them to detect who is more prone to atypical fractures and therefore shouldn't get treatment with bisphosphonates. This is the first step to positively prescribe a treatment that millions of people are receiving worldwide. Therefore this discovery was chosen as the study with the highest impact in the main conference on bone diseases worldwide, from the American Society for Bone and Mineral Research), now published in the prestigious journal New England Journal of Medicine.