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  • Review Article
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Parathyroid hormone receptor agonists in the management of osteoporosis

Nature Reviews Rheumatology volume 21, pages 599–611 (2025)Cite this article

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An Author Correction to this article was published on 30 September 2025

This article has been updated

Abstract

Parathyroid hormone (PTH) regulates bone homeostasis. Intermittent exposure to PTH results in bone formation being greater than bone resorption, and this effect has been harnessed through the development of agonists of the PTH and PTH-related protein type 1 receptor (PTH1R) to treat osteoporosis. Teriparatide, an analogue of the first 34 amino acids of PTH, and abaloparatide, which resembles PTH-related protein (PTHrP) in structure, are PTH1R agonists currently in clinical use. Both medications have been shown to increase bone mineral density at the lumbar spine, femoral neck and total hip. Randomized controlled trials with teriparatide or abaloparatide have also provided evidence of reduction in vertebral and non-vertebral fractures. The ACTIVE trial suggested slightly greater efficacy for major osteoporotic fractures (as an exploratory end point) for abaloparatide than for teriparatide. A similar potential superiority was suggested for hip fracture in a real-world, observational study. Side effects of these medications are usually transient, and although a risk of osteosarcoma was suggested by studies using murine models, no such risk has been observed in extensive human studies. Overall, both teriparatide and abaloparatide have demonstrated convincing clinical effectiveness and cost-effectiveness, with a reassuring safety profile. Potential differences in their effects on bone mineral density and their antifracture effects offer avenues for differentiation but require further validation in appropriately designed studies.

Key points

  • Parathyroid hormone type 1 receptor (PTH1R) agonists stimulate bone formation and effectively reduce the risk of vertebral and non-vertebral fractures.

  • The PTH1R agonists teriparatide and abaloparatide act via intermittent PTH1R stimulation, as opposed to the constant PTH1R stimulation seen in hyperparathyroidism.

  • The safety profiles of teriparatide and abaloparatide are favourable, with previous concerns regarding osteosarcoma in murine models not born out in humans, and with cardiovascular safety having been consistently demonstrated.

  • Exploratory analysis of data from the ACTIVE trial suggests that abaloparatide might have greater efficacy in reducing the risk of major osteoporotic fractures than teriparatide.

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Fig. 1: PTH and PTHrP signalling via PTH1R.
Fig. 2: Bone turnover marker profiles and anabolic windows of teriparatide and abaloparatide.

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Change history

  • 28 August 2025

    In the version of the article initially published, footnotes for equally contributing authors (now listing Nicholas Fuggle and René Rizzoli) and jointly supervising authors (now listing Jean-Yves Reginster and Nicholas C. Harvey) were incorrect and are now amended in the HTML and PDF versions of the article.

  • 30 September 2025

    A Correction to this paper has been published: https://doi.org/10.1038/s41584-025-01314-w

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Acknowledgements

This ESCEO Working Group was funded by the ESCEO. The ESCEO receives unrestricted educational grants to support its educational and scientific activities from non-governmental organisations, not-for-profit organisations, non-commercial or corporate partners. The choice of topics, participants, content and agenda of the Working Groups as well as the writing, editing, submission and reviewing of the manuscript are the sole responsibility of the ESCEO, without any influence from third parties. This work was supported by the Distinguished Scientist Fellowship Program (DSFP) of the King Saud University, Riyadh, Kingdom of Saudi Arabia.

Author information

Author notes

  1. These authors contributed equally: Nicholas Fuggle, René Rizzoli.

  2. These authors jointly supervised this work: Jean-Yves Reginster and Nicholas C Harvey.

Authors and Affiliations

  1. MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK

    Nicholas Fuggle, Elizabeth M. Curtis, Cyrus Cooper & Nicholas C. Harvey

  2. Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland

    René Rizzoli

  3. Public Health Aging Research & Epidemiology (PHARE) Group, Research Unit in Clinical Pharmacology and Toxicology (URPC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur, Namur, Belgium

    Charlotte Beaudart

  4. Department of Rheumatology, University-Hospital of Lille, Lille, France

    Bernard Cortet

  5. Department of Health Services Research, CAPHRI Care and Public Health Research Institute, Maastricht University, Maastricht, Netherlands

    Mickaël Hiligsmann

  6. Department of Endocrinology, Ghent University Hospital, Ghent, Belgium

    Jean-Marc Kaufman

  7. Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia

    Nicola Veronese, Nasser Al-Daghri, Majed Alokail & Jean-Yves Reginster

  8. Saint Camillus International University of Health Sciences, Rome, Italy

    Nicola Veronese

  9. Espirito Santo Research and Osteoporosis Center, Federal University of Espirito Santo, Vitória, Brazil

    Ben Hur Albergaria

  10. University Vita-Salute San Raffaele, Milan, Italy

    Maria Luisa Brandi

  11. FIRMO Foundation, Florence, Italy

    Maria Luisa Brandi

  12. Research Unit in Public Health, Epidemiology and Health Economics, University of Liège, Liège, Belgium

    Olivier Bruyère

  13. The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), Liege, Belgium

    Nansa Burlet

  14. Department of Internal Medicine, Clínica Universidad de los Andes, Universidad de los Andes, Santiago, Chile

    Claudia Campusano

  15. School of Medicine, Universidad de los Andes, Santiago, Chile

    Claudia Campusano

  16. Department of Rheumatology, Parc Taulí Hospital Universitari, Universitat Autònoma de Barcelona, Sabadell, Spain

    Enrique Casado

  17. Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA). Universitat Autònoma de Barcelona, Sabadell, Spain

    Enrique Casado

  18. Department of Clinical Chemistry, CIRM, University of Liège, CHU de Liège, Liège, Belgium

    Etienne Cavalier

  19. Osteoporosis and Bone Metabolism Unit, Department of Endocrinology, Singapore General Hospital, Singapore, Singapore

    Manju Chandran

  20. DUKE NUS Medical School, Singapore, Singapore

    Manju Chandran

  21. NIHR Southampton Biomedical Research Centre, University of Southampton, Southampton, UK

    Cyrus Cooper & Nicholas C. Harvey

  22. NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK

    Cyrus Cooper

  23. Department of Geriatrics and Geriatric Rehabilitation, Lausanne University Hospital, Lausanne, Switzerland

    Patrizia D’Amelio

  24. Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA

    Bess Dawson-Hughes

  25. Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia

    Peter R. Ebeling

  26. Centre for Integrated Research in Musculoskeletal Ageing, Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK

    John A. Kanis & Eugene McCloskey

  27. Johann Wolfgang Goethe University, Frankfurt, Germany

    Andreas Kurth

  28. Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia

    Radmila Matijevic

  29. Clinic for Orthopedic Surgery and Traumatology, University Clinical Center of Vojvodina, Novi Sad, Serbia

    Radmila Matijevic

  30. Oregon Osteoporosis Center, Portland, OR, US

    Michael McClung

  31. Rheumatology Department, Ibn Roch University Hospital, Casablanca, Morocco

    Ouafa Mkinsi

  32. Department of Radiation Medicine, University of Nigeria Medical School, Nsukka, Nigeria

    Ngozi Njeze

  33. Department of Diabetes, Nutrition and Metabolic disorders, Clinical Pharmacology, University of Liège, CHU de Liège, Liège, Belgium

    Régis P. Radermecker

  34. Service de Rééducation et de Réadaptation de l’Appareil Locomoteur et des Pathologies du Rachis, Hôpital Cochin, Assistance publique – hôpitaux de Paris, Centre-Université Paris Cité, Paris, France

    François Rannou

  35. OMC Clinical Research Center, Beverly Hills, CA, USA

    Stuart Silverman

  36. Cedars-Sinai Medical Center, Beverly Hills, CA, USA

    Stuart Silverman

  37. Department of Physical Medicine and Rehabilitation, Cerrahpaşa School of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey

    Şansın Tüzün

  38. Department of Rheumatology, University of Tunis El Manar, Tunis, Tunisia

    Leith Zakraoui

Authors
  1. Nicholas Fuggle
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  2. René Rizzoli
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  3. Charlotte Beaudart
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  32. Stuart Silverman
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  33. Şansın Tüzün
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  34. Leith Zakraoui
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  35. Jean-Yves Reginster
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  36. Nicholas C. Harvey
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Contributions

N.F., N.C.H., J.Y.-R. and R.R. wrote the initial draft of the article. All authors contributed substantially to discussion of the content, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Nicholas C. Harvey.

Ethics declarations

Competing interests

N.F. has received honoraria and speaker fees from UCB and Viatris, and travel bursaries from Eli Lilly and Pfizer. B.C. has received occasional fees as an expert or speaker from Alexion, Amgen, Aptissen, Expanscience, Lilly, Kyowa Kirin, Novartis, Theramex, UCB and Viatris. E.M.C. has received speaker fees from Eli Lilly, Thornton and Ross, and UCB, and travel bursaries or conference support from Amgen and Eli Lilly. M.H. has received research grants (paid to his institution) from Angelini Pharma and Radius Health, and lecture fees from IBSA (paid to his institution) and Mylan Pharmaceuticals, and was grant adviser for Pfizer (paid to his institution). N.V. declares personal fees from Bayer, Fidia, Nestlè and Viatris. B.H.A. reports research grants from Amgen and UCB, and honoraria from Amgen, Theramex and UCB. M.L.B. declares honoraria from Amgen, Ascendis, Bruno Farmaceutici, Calcilytix and Kyowa Kirin, grants or speaker fees from Alexion, Amgen, Amolyt, Bruno Farmaceutici, CoGeDi, Echolight, Gedeon Richter, Kyowa Kirin, Monte Rosa Therapeutics and UCB, and consultancy for Aboca, Alexion, Amolyt, Bruno Farmaceutici, Calcilytix, Echolight, Enterabio, Kyowa Kirin, Personal Genomics and Septern. O.B. has received consulting or lecture fees from Amgen, Aptissen, Biophytis, IBSA, Mylan, Novartis, Nutricia, Orifarm, Sanofi, UCB and Viatris outside the submitted work. E. Casado has received honoraria and speaker fees from FAES, Gedeon-Richter, STADA, Theramex and UCB, and travel bursaries from Amgen, Rubió, STADA and Theramex. M.C. has received honoraria and travel grants from Amgen and Promedius AI solutions. P.D'A. declares research grants and honoraria from ErreKappa, Nestlé, OM Pharma and Schwabe Pharma. P.R.E. declares research grants from Amgen, Alexion and Sanofi, and honoraria from Amgen, Alexion and Kyowa Kirin. J.A.K. is a director of Osteoporosis Research, which maintains FRAX. A.K. declares honoraria for scientific advisory board, research grants and speakers fees from AgNovos bioscience, Alexion, Amgen, Celltrion Deutschland, Echolight, Eli Lilly, Ipsen, Imaging Biopsy Lab (IBL), Kyowa Kirin, Merit Medical, new4med, Novartis, NovoNordisk, Roche, Sandoz, Servier, Stadapharm, Theramex and UCB. E.McC. is a director of Osteoporosis Research, which maintains FRAX, and has also received honoraria and research funding from Amgen, Fresenius Kabi, Lilly, ObsEva, Radius Pharma, Theramex and UCB. M.McC. declares consulting fees or honoraria from Amgen, Alexion, Pfizer and UCB. O.M. declares lecture fees or honoraria from Bottu Johnson and Johnson, Pfizer and Sanofi. J.-Y.R. declares speaker’s Bureau for Radius Health and Theramex, and consultancy agreement for Theramex. N.C.H. has received personal fees, consultancy, lecture fees or honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Internis Pharma, Kyowa Kirin, Servier, Shire, Consilient Healthcare, Theramex and UCB outside the submitted work. R.R., C.B., J.-M.K, N.A.-D., M.A., N.B., C. Campusano, E. Cavalier, C. Cooper, B.D.-H., R.M., N.N., R.P. R., F.R., S.S. S.T., and L.Z. have no competing interests to declare.

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Nature Reviews Rheumatology thanks Torben Harsløf and Bart Clarke for their contribution to the peer review of this work.

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Fuggle, N., Rizzoli, R., Beaudart, C. et al. Parathyroid hormone receptor agonists in the management of osteoporosis. Nat Rev Rheumatol 21, 599–611 (2025). https://doi.org/10.1038/s41584-025-01287-w

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