Osteoporosis research set to improve patient targeting for TPTD treatment
May 14, 2017, SALZBURG, AUSTRIA. Press Dispensary. An international team of researchers from Edinburgh (UK), Ljubljana (Slovenia) and Aarhus (Denmark) today announced a significant step forward in identifying patients who would most benefit from the osteoporosis treatment TPTD.
TPTD (Teriparatide) is a treatment for patients with severe osteoporosis that is more effective than the more traditional oral bisphosphonates but the response differs from patient to patient. TPTD is an expensive treatment. Because the response varies a test to predict how well individual patients are likely to respond can be of great value in creating a targeted, and more personalised treatment.
The results of the research were presented by Dr Nerea Alonso from the University of Edinburgh at ECTS 2017, the 44th European Calcified Tissue Society Congress being held in Salzburg, Austria.
Dr Alonso said: "We studied 442 patients with osteoporosis from the UK, Denmark and Slovenia. Essentially, we were looking for changes in the bone mineral density (BMD) of the spine, month by month, during TPTD therapy, and comparing those changes with the genetic makeup of the patients by means of a 2-stage genome-wide association study. We found six genetic markers that were associated with response to TPTD therapy and when we combined information from these markers, we observed a very strong association with change in BMD."
This is an exciting discovery. It's the first time genetic markers have been convincingly associated with response to any osteoporosis treatment. It raises the possibility that using these markers to personalise care would be a real advance over the way we do things now.
Professor Stuart H. Ralston
Low bone mineral density is a defining feature of osteoporosis. The lower the bone density, the greater the risk of fracture. The aim of TPTD therapy is to increase bone formation, and bone density, to reduce the risk of fracture. A genome-wide association study examines the DNA of the individuals to discover associations between their genetic variations and a particular trait; in this case, the change in BMD.
The leader of the research team Professor Ralston said: "This is an exciting discovery. It's the first time genetic markers have been convincingly associated with response to any osteoporosis treatment. It raises the possibility that using these markers to personalise care would be a real advance over the way we do things now."
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Notes for editors
About the study
The study, titled "Genome-wide association analysis identifies CXCR4 gene as predictor of therapeutic response to teriparatide in severe osteoporosis" was carried out by Nerea Alonso, Omar M. Albagha, Asim Azfer, Philip Riches and Stuart H. Ralston of the University of Edinburgh; Barbara Ostanek, Tomaz Kocjan and Janja Marc of the University of Ljbljana, Slovenia; and Bente L. Langdahl of Aarhus University Hospital, Denmark.
A 2-stage genome-wide association study was performed in 442 patients with osteoporosis from UK, Denmark and Slovenia, using an Illumina OmniExpress-Exome v8 array. Primary outcome was change in spine BMD (LS-BMD). This was assessed after application of standard quality control measures using a linear regression association analysis in PLINK using residuals of percentage of change in spine BMD per month, standardised by centre, principal components, and age.
As a result, the team identified a SNP on chromosome 2 showing significant association at genome-wide level with response to TPTD therapy in the combined dataset (p=9.28x10-10,beta=-0.38, 95%CI=[-0.51--0.26]). No evidence of genomic inflation was observed (lambda=1.09). Five additional suggestive signals were identified on chromosomes 1, 5, 12 and 15, with p-values less than 2x10-5. Combined information from the top six signals showed a highly significant association of change in LS-BMD with the number of alleles carried (0.8% increase in LS-BMD at 24-month in individuals carrying more than 6 non-responder alleles compared with 18.7% increase in LS-BMD in those carrying one or none non-responder alleles (p=1.17x10-15)). The top hit was found to be an e-QTL for CXCR4 expression in peripheral blood cells (Z-score=-3.15, p=0.0016). CXCR4 encodes for a chemokine receptor specific for stromal cell-derived factor 1 expressed in osteoblasts and previously implicated in the activation of WNT signalling and bone formation.
The team concluded that it has identified a genome wide significant marker of response to TPTD and developed an allelic score that identifies patients with a 23-fold difference in treatment response. If confirmed and supported by functional studies, this could be of clinical value in personalising treatment options in patients being considered for TPTD therapy.
About ECTS 2017 (http://ects2017.org)
ECTS 2017 is the 44th European Calcified Tissue Society Congress, held from 13 to 16 May 2017 in the Austrian city of Salzburg.
ECTS serves as a forum for researchers and clinicians working in the musculoskeletal field to join forces, discover and discuss the latest advances and controversies in research and in the daily care of patients.
About The European Calcified Tissue Society (http://www.ectsoc.org/)
The European Calcified Tissue Society (ECTS) is the major organisation in Europe for researchers and clinicians working in the field of calcified tissues and related fields. ECTS acts as a forum for the dissemination of high quality research through its annual meeting, the European Symposium on Calcified Tissues, and through training courses and workshops.
Calcified tissues are central to a healthy skeleton and to bone disorders - such as osteoporosis, back pain and fractures - that make life a misery for countless people. Children can inherit some forms of bone diseases causing bone pain, shortness and deformed limbs.
For further information please contact
Roberta Mugnai, ECTS executive director
Tel: + 32 476 520 716
ECTS 2017: http://ects2017.org
Event hashtag: #ECTS2017