Osteoporosis or loss of bone density is associated with age and causes fractures that affect up to 40% of people over the age of 50 years.  The most common treatment is with bisphosphonates, due to their efficacy and low cost. However, their use has, in some cases, been linked to atypical femoral fractures. Dr. Adolf Diez, emeritus head of the Hospital del Mar department of internal medicine and researcher of the IMIM Musculoskeletal Research Group, together with researchers from UB, has led a study that has identified the factor responsible for these atypical fractures as a mutation that predisposes the bone to be vulnerable to bisphosphonates and, instead of strengthening the bone and preventing fractures, causes a critical problem that makes the femur more prone to fractures.

Although it is rare and many more fractures are prevented than are caused, the fear of this complication has considerably reduced prescription of these drugs, especially in long-term treatments. As a result, most people with a high risk of fractures due to osteoporosis (e.g., those who have already suffered a fracture) do not receive treatment.

A thorough study of the genome

The possibility of studying the genetic basis of this unexpected effect arose thanks to the case of three sisters who had presented atypical fractures after being treated with bisphosphonates for several years. A thorough study of their genome was carried out using a technique called whole exome sequencing, and this made it possible to find, for the first time, a mutation common to all three that could explain why they had suffered from this type of fracture.

This mutation damages a protein (GGPPS) that forms part of a metabolic chain essential for bone health, which we call the mevalonate pathway. It is thought that this mutation causes the bone to be vulnerable to the drug and, instead of strengthening it to prevent fractures, it makes it more prone to fracture.

In light of this finding, broader studies will be needed to be able to bring genetic analysis techniques to patient care to detect who is prone to atypical fracture and, therefore, should not be given bisphosphonates. This is the first step to prescribing with confidence a treatment that is being taken by millions of people throughout the world and which is highly effective at reducing the number of fractures.

Reference article

Roca-Ayats N, Balcells S, García-Giralt N, Falcó-Mascaró M, Martínez-Gil N, Abril JF, Urreizti R, Dopazo J, Quesada-Gómez JM, Nogués X, Mellibovsky L, Prieto-Alhambra D, Dunford JE, Javaid MK, Russell RG, Grinberg D, Díez-Pérez A. GGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates. New Engl J Med 2017; 376(18): 1794-1795.