Mutation discovered that, linked with drug, predisposes osteoporosis patients to femur fracture

May 04, 2017

Researchers at the Hospital del Mar Medical Research Institute (IMIM) and the University of Barcelona have uncovered a mutation that makes bone vulnerable to bisphosphonates, drugs used to combat osteoporosis. Instead of strengthening bone and preventing fractures, these medicines induce a critical problem that makes the femur more prone to breaks. This discovery, enormously significant clinically, was published today in the New England Journal of Medicine, the most important biomedical journal in terms of potential impact.

Osteoporosis causes fractures that affect up to 40% of people over the age of 50. Bisphosphonates are efficient and cheap, making them the first line of treatment for this condition. Nevertheless, they have been associated with atypical fracturing of the femur. "Despite the rarity of this complication and the fact that many more fractures are prevented than induced, fear of this complication has led to the prescription of these drugs being criticised, especially for long-term treatment", explains study leader Dr. Adolf Díez, emeritus head of internal medicine at Hospital del Mar and a researcher in the musculoskeletal research group at the IMIM. The consequence of this is that the majority of people at high risk of fracture due to osteoporosis (for example, those who have already suffered fractures) do not receive treatment.

The infrequency of this problem made us suspicious that a genetic predisposition makes some people more likely to present atypical fracturing. "The opportunity offered by three cases of atypical fracture in three sisters treated with bisphosphonates over several years, gave us the possibility of looking into a genetic basis that, otherwise, would have been almost impossible to detect", says Dr. Xavier Nogués, head of internal medicine at Hospital del Mar and coordinator of IMIM's musculoskeletal research group.

An exhaustive genome study

An exhaustive study of their genome, using the whole exome sequencing technique, enabled us to find a mutation common to the three sisters that could explain why they presented this unusual fracturing. The mutation damages a protein (GGPPS) that is part of a metabolic chain essential for bone health, known as the mevalonate pathway. It is believed that this mutation makes bone vulnerable to the drug, and instead of strengthening it and preventing fractures, it makes it more prone to fractures.

Given this finding, broader studies are needed to be able to transfer genetic analysis techniques to patient care, allowing clinicians to detect people prone to this atypical fracture and who, therefore, should not receive biophosphonates. This would be the first step in confidently prescribing a treatment received by millions of people around the world. It is also the reason the discovery was chosen as the highest impact study at the world's most important conference on bone diseases, the annual meeting of the American Society for Bone and Mineral Research, and its publication in the New England Journal of Medicine.
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The work was developed thanks to collaboration between doctors and researchers from the Hospital del Mar Medical Research Institute and the internal medicine service at the same hospital, pertaining to the Centres for Biomedical Network Research on Healthy Ageing (CIBERFES), and experts from the Human Molecular Genetics group at the University of Barcelona, belonging to the Institute of Biomedicine at that university (IBUB), and the Centres for Biomedical Network Research on Rare Diseases (CIBERER) led by Dr. Daniel Grinberg and Dr. Susana Balcells. The study also involved the collaboration of the University of Oxford and Reina Sofia Hospital in Cordoba.

Reference article

"GGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates" The New England Journal of Medicine

IMIM (Hospital del Mar Medical Research Institute)

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