This is a repository copy of Osteoporosis in premenopausal women: a clinical narrative review by the ECTS and the IOF. White Rose Research Online URL for this paper: https://eprints.whiterose.ac.uk/162028/ Version: Accepted Version Article: Pepe, J., Body, J.-J., Hadji, P. et al. (8 more authors) (2020) Osteoporosis in premenopausal women: a clinical narrative review by the ECTS and the IOF. The Journal of Clinical Endocrinology & Metabolism. ISSN 0021-972X https://doi.org/10.1210/clinem/dgaa306 This is a pre-copyedited, author-produced version of an article accepted for publication in Journal of Clinical Endocrinology and Metabolism following peer review. The version of record Jessica Pepe, Jean-Jacques Body, Peyman Hadji, Eugene McCloskey, Christian Meier, Barbara Obermayer-Pietsch, Andrea Palermo, Elena Tsourdi, M Carola Zillikens, Bente Langdahl, Serge Ferrari, Osteoporosis in premenopausal women: a clinical narrative review by the ECTS and the IOF, The Journal of Clinical Endocrinology & Metabolism, dgaa306 is available online at: https://doi.org/10.1210/clinem/dgaa306 Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Osteoporosis in premenopausal women: a clinical narrative review by the ECTS and the IOF 2020 June on 18 user Sheffield of by University https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaa306/5846185 from Downloaded Jessica Pepe1, Jean-Jacques Body2 , Peyman Hadji3, Eugene McCloskey4, Christian Meier5, Barbara Obermayer-Pietsch6, Andrea Palermo7, Elena Tsourdi8, M. Carola Zillikens9, Bente Langdahl10*, Serge Ferrari11* *BL and SF contributed equally to this work 1JP: Department of clinical, internal, anesthesiology and cardiovascular sciences, “Sapienza” University of Rome, Italy 2JJB: Department of Medicine, CHU Brugmann, Université Libre de Bruxelles, Brussels, Belgium 3PH: Frankfurt Certer of Bone Health, Frankfurt, Germany and Philipps-University of Marburg 4EVM: Centre for Integrated research in Musculoskleetal Ageing, Mellanby Centre for Bone Research, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK 5CM: Division of Endocrinology, Diabetology and Metabolism, University Hospital and University of Basel, Switzerland 6BOP: Division of Endocrinology and Diabetology, Department of Internal Medicine, MedicalAccepted University Graz, Austria Manuscript 7AP: Unit of Endocrinology and Diabetes, Campus Bio-Medico University, Rome, Italy 8ET: 1Department of Medicine III, 2Center for Healthy Aging, Technische Universität Dresden Medical Center, Dresden, Germany © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: [email protected] jc.2020-00709 See endocrine.org/publications for Accepted Manuscript disclaimer and additional information. 9 MCZ: Bone Center, Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands 10 BL: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 2020 June on 18 user Sheffield of by University https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaa306/5846185 from Downloaded Aarhus, Denmark. 11 SF: Service of Bone Diseases, Geneva University Hospital and Faculty of Medicine, 1211, Geneva 14, Switzerland. Corresponding author: Jessica Pepe. ORCID 0000-0002-3088-0673.Department of clinical, internal, anesthesiology and cardiovascular sciences, “Sapienza” University of Rome, Italy. [email protected] Accepted Manuscript 2 Disclosure summary: JP: has nothing to disclose. BL: research funding: Amgen, Novo Nordisk. Advisory board and lectures: Eli Lilly, UCB, Amgen. ET: research funding: MSD. Honoraria for lectures from Amgen, UCB, Shire, Kyowa Kirin and educational grants from 2020 June on 18 user Sheffield of by University https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaa306/5846185 from Downloaded Shire and UCB. JJB: research funding: UCB; honoraria for consultancy/lectures: Sandoz, Takeda, UCB. CM: research funding: Amgen, Roche Diagnostics. Advisory board and lectures: Amgen, Mylan-MEDA, Gedeon Richter, UCB. EVM: Consultant/Advisor/Speaker for AgNovos, Amgen, AstraZeneca, Consilient Healthcare, Fresenius Kabi, GSK, Hologic, Internis, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, UCB. Research support including above plus Versus Arthritis, I3 Innovus, MRC, IOF, Unilever. BOP: research funding from IDS, ViennaLab; educational grants from Gedeon Richter, IDS, Shire, Kyowa Kirin. PH: Advisory board, lectures and research funding: Amgen, Dr. Kade/Besins, Eli Lilly, Gedeon Richter, Hexal, Mylan, Novartis, UCB. MCZ: Honoraria in the past for lectures or advice from Alexion, Amgen, Eli Lilly, Kyowa Kirin, Shire and UCB. SF: Research funding from AMGEN, Agnovos, Labatec, Alexion, Consulting for AMGEN, UCB, Radius, Agnovos, Galapagos, Spirig. AP: has nothing to disclose Accepted Manuscript 3 Abstract Context: Consensus regarding diagnosis and management of osteoporosis in premenopausal women (PW) is still lacking, due to few studies carried out in this population. 2020 June on 18 user Sheffield of by University https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaa306/5846185 from Downloaded Design: ECTS and IOF convened a working group to produce an updated review of literature published after 2017 on this topic. Results: Fragility fractures in PW are rare and mostly due to secondary osteoporosis, i.e. in presence of an underlying disease such as hormonal, inflammatory or digestive disorders. In absence of another disorder, low bone density (BMD) together with fragility fractures qualifies as “idiopathic osteoporosis”. In contrast, low BMD alone does not necessarily represent osteoporosis in absence of bone microarchitectural abnormalities. BMD increases in PW with osteoporosis when the underlying disease is treated. For example, in celiac disease, an increase of 9% in radius trabecular volumetric density was achieved after 1 year of gluten-free diet, while anti-TNF alfa improved BMD in PW with inflammatory bowel diseases. In amenorrhea, including anorexia nervosa, appropriately delivered estrogen replacement therapy can also improve BMD. Alternatively, antiresorptive or anabolic therapy has been shown to improve BMD in a variety of conditions, the range of improvement (3- 16%) depending on skeletal site and the nature of the secondary cause. No studies were powered to demonstrate fracture reduction. The effects of bisphosphonates in childbearing women have been scantly studied and caution is needed. ConclusionAccepted: The majority of PW with osteoporosis Manuscript have an underlying disease. Specific therapy of these diseases, as well as antiresorptive and anabolic drugs, improve BMD, but without evidence of fracture reduction. Key words: premenopausal women, osteoporosis, fracture, secondary osteoporosis, pregnancy, antiresorptive therapy 4 Introduction Downloaded from https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaa306/5846185 by University of Sheffield user on 18 June 2020 June on 18 user Sheffield of by University https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaa306/5846185 from Downloaded The epidemiology of osteoporosis and fracture rate in premenopausal women is uncertain. The prevalence of “osteoporosis” in premenopausal women varies from 0.5 to 50% depending on the population studied, the definition of osteoporosis used, and the referral center involved (1, 2). A European study in premenopausal women (mean age 34.8± 0.5) from the general population found no subjects with osteoporosis (defined as a T score ≤ -2.5) and 10.6% with osteopenia (T-score >-2.5 and ≤-1.0) (3). However such data can be misleading since a low areal bone mineral density (aBMD) alone at a young age may reflect a relatively thinner skeleton, for instance in a constitutionally lean person, but with normal volumetric BMD and no alterations of microstructure, i.e. not necessarily more fragile bones. In contrast, in premenopausal women with known causes of secondary osteoporosis, the prevalence of low bone mass (defined as Z-score ≤ -2) was recently reported as 17.3% in patients affected by systemic lupus erythematosus (4), 7.3% in rheumatoid arthritis (5), 44.5% in Cushing diseases (6), 35% in HIV (7), and 45% in cystic fibrosis (8), and these disorders are associated with an increased risk of fragilty fractures. A premenopausal woman with a prior fracture has a 35 to 75% higher risk of having a fracture in her postmenopausal years than a premenopausal woman without fracture (9). Therefore, early diagnosis and management may be beneficial, although currently no studies have investigated this strategy with respect to reducing fractures later in life (10,11). Few reviewsAccepted on osteoporosis in premenopausal womenManuscript have been published (1,2,10,12-15),