Practice Guideline

. 2025 Jul 15;110(8):2353-2370.

doi: 10.1210/clinem/dgaf170.

X-Linked Hypophosphatemia Management in Adults: An International Working Group Clinical Practice Guideline

Aliya A Khan¹, Dalal S Ali¹, Natasha M Appelman-Dijkstra², Thomas O Carpenter³, Catherine Chaussain^{4

5

6}, Erik A Imel⁷, Suzanne M Jan de Beur⁸, Pablo Florenzano⁹, Hajar Abu Alrob¹⁰, Rana Aldabagh¹¹, R Todd Alexander¹², Farah Alsarraf¹, Signe Sparre Beck-Nielsen^{13

14}, Martin Biosse-Duplan^{4

5

6}, Martine Cohen-Solal¹⁵, Rachel K Crowley¹⁶, Karel Dandurand¹⁷, Guido Filler¹⁸, Lisa Friedlander⁴, Seiji Fukumoto¹⁹, Claudia Gagnon^{20

21}, Paul Goodyer²², Corinna Grasemann²³, Chelsey Grimbly^{24

25}, Salma Hussein¹, Muhammad K Javaid²⁶, Sarah Khan²⁷, Aneal Khan²⁸, Anna Lehman²⁹, Willem F Lems³⁰, E Michael Lewiecki³¹, Ciara McDonnell^{32

33}, Reza D Mirza¹⁰, Emmett Morgante³⁴, Archibald Morrison³⁵, Anthony A Portale³⁶, Yumie Rhee³⁷, Eric T Rush^{38

39}, Heide Siggelkow^{40

41}, Sotirios Tetradis⁴², Laura Tosi⁴³, Leanne M Ward⁴⁴, Gordon Guyatt^{10

45

46}, Maria Luisa Brandi⁴⁷

Affiliations

¹ Division of Endocrinology and Metabolism, McMaster University, Hamilton, ON L8S 4L8, Canada.
² Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden University Medical Center, Leiden 2300 ZA, the Netherlands.
³ Departments of Pediatrics (Endocrinology), and Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520, USA.
⁴ Department of Oral Medicine, Faculty of Dentistry, UMR 1333, Université Paris Cité, Paris 75006, France.
⁵ Institut Imagine, INSERM 1163, 75015 Paris, France.
⁶ Department of Oral Medicine, APHP, Paris 75006, France.
⁷ Department of Medicine and Pediatrics, Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁸ Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
⁹ Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile, Santiago 8320165, Región Metropolitana, Chile.
¹⁰ Department of Health Research Methods, Evidence, and Impact at McMaster University, Hamilton, ON L8S 4L8, Canada.
¹¹ Faculty of Dentistry, University of Toronto, Toronto, ON M5G 2L3, Canada.
¹² Faculty of Medicine & Dentistry, The University of Alberta, Edmonton, AB T6G 2R3, Canada.
¹³ Centre for Rare Diseases, Aarhus University Hospital, Aarhus N 8200, Denmark.
¹⁴ Department of Clinical Medicine, Aarhus University, Aarhus N 8200, Denmark.
¹⁵ Department of Rheumatology and reference center for Rare Bone Diseases, hopital Lariboisiere, Paris 75006, France.
¹⁶ Rare Disease Clinical Trial Network, University College Dublin, Dublin 4, D04 T6F4, Ireland.
¹⁷ Division of Internal Medicine, Endocrinology Division, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
¹⁸ London Health Sciences Centre, Children's Hospital of Western Ontario, London, ON N6A 3K7, Canada.
¹⁹ Department of Medicine, Tamaki-Aozora Hospital, Tokushima 779-3125, Japan.
²⁰ Endocrinology and Nephrology Axis, CHU de Québec-Université Laval Research Centre, Québec, QC G1V 4G2, Canada.
²¹ Department of Medicine, Université Laval, Québec, QC G1V 0A6, Canada.
²² Research Institute of the McGill University Health Centre, Montreal, QC H3H 2L9, Canada.
²³ Department of Pediatrics, Division of Rare Diseases, Katholisches Klinikum Bochum and Ruhr-University Bochum, 44791 Bochum, Germany.
²⁴ Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2R3, Canada.
²⁵ Women and Children's Health Research Institute, Edmonton, AB T6G 1C9, Canada.
²⁶ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7HE, UK.
²⁷ Trillium Health Partners, University of Toronto, Toronto, ON L5M 2N1, Canada.
²⁸ M.A.G.I.C. Clinic (Metabolics and Genetics in Canada), Calgary, AB T2E 7Z4, Canada.
²⁹ Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
³⁰ Department of Rheumatology, Amsterdam UMC, Amsterdam 1105 AZ, the Netherlands.
³¹ New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM 87106, USA.
³² Department of Pediatric Endocrinology & Diabetes, Children's Health Ireland, Dublin D12 N512, Ireland.
³³ Department of Paediatrics, School of Medicine, University of Dublin, Trinity College, Dublin D02 PN40, Ireland.
³⁴ Department of Kinesiology, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
³⁵ Citadel Oral and Facial Surgery, Halifax, NS B3L 4H7, Canada.
³⁶ Department of Pediatrics, University of California San Francisco, San Francisco, CA 94115, USA.
³⁷ Endocrine Research Institute, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.
³⁸ Division of Clinical Genetics, Children's Mercy Kansas City, Kansas City, MO 64108, USA.
³⁹ Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108-2792, USA.
⁴⁰ Department of Trauma, Orthopedics and Reconstructive Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany.
⁴¹ MVZ Endokrinologikum Goettingen, 37075 Goettingen, Germany.
⁴² Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
⁴³ Department of Orthopedics, George Washington University School of Medicine and Health Sciences, Washington, DC 20052, USA.
⁴⁴ Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
⁴⁵ Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁴⁶ MAGIC Evidence Ecosystem Foundation [www.magicevidence.org], Oslo 0456, Norway.
⁴⁷ Institute of Endocrine and Metabolic Sciences, Vita-Salute San Raffaele University and IRCCS, Milan 20132, Italy.

PMID: 40243526
PMCID: PMC12261105
DOI: 10.1210/clinem/dgaf170

Practice Guideline

X-Linked Hypophosphatemia Management in Adults: An International Working Group Clinical Practice Guideline

Aliya A Khan et al. J Clin Endocrinol Metab. 2025.

. 2025 Jul 15;110(8):2353-2370.

doi: 10.1210/clinem/dgaf170.

Authors

Affiliations

¹ Division of Endocrinology and Metabolism, McMaster University, Hamilton, ON L8S 4L8, Canada.
² Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden University Medical Center, Leiden 2300 ZA, the Netherlands.
³ Departments of Pediatrics (Endocrinology), and Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520, USA.
⁴ Department of Oral Medicine, Faculty of Dentistry, UMR 1333, Université Paris Cité, Paris 75006, France.
⁵ Institut Imagine, INSERM 1163, 75015 Paris, France.
⁶ Department of Oral Medicine, APHP, Paris 75006, France.
⁷ Department of Medicine and Pediatrics, Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁸ Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
⁹ Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile, Santiago 8320165, Región Metropolitana, Chile.
¹⁰ Department of Health Research Methods, Evidence, and Impact at McMaster University, Hamilton, ON L8S 4L8, Canada.
¹¹ Faculty of Dentistry, University of Toronto, Toronto, ON M5G 2L3, Canada.
¹² Faculty of Medicine & Dentistry, The University of Alberta, Edmonton, AB T6G 2R3, Canada.
¹³ Centre for Rare Diseases, Aarhus University Hospital, Aarhus N 8200, Denmark.
¹⁴ Department of Clinical Medicine, Aarhus University, Aarhus N 8200, Denmark.
¹⁵ Department of Rheumatology and reference center for Rare Bone Diseases, hopital Lariboisiere, Paris 75006, France.
¹⁶ Rare Disease Clinical Trial Network, University College Dublin, Dublin 4, D04 T6F4, Ireland.
¹⁷ Division of Internal Medicine, Endocrinology Division, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
¹⁸ London Health Sciences Centre, Children's Hospital of Western Ontario, London, ON N6A 3K7, Canada.
¹⁹ Department of Medicine, Tamaki-Aozora Hospital, Tokushima 779-3125, Japan.
²⁰ Endocrinology and Nephrology Axis, CHU de Québec-Université Laval Research Centre, Québec, QC G1V 4G2, Canada.
²¹ Department of Medicine, Université Laval, Québec, QC G1V 0A6, Canada.
²² Research Institute of the McGill University Health Centre, Montreal, QC H3H 2L9, Canada.
²³ Department of Pediatrics, Division of Rare Diseases, Katholisches Klinikum Bochum and Ruhr-University Bochum, 44791 Bochum, Germany.
²⁴ Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2R3, Canada.
²⁵ Women and Children's Health Research Institute, Edmonton, AB T6G 1C9, Canada.
²⁶ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7HE, UK.
²⁷ Trillium Health Partners, University of Toronto, Toronto, ON L5M 2N1, Canada.
²⁸ M.A.G.I.C. Clinic (Metabolics and Genetics in Canada), Calgary, AB T2E 7Z4, Canada.
²⁹ Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
³⁰ Department of Rheumatology, Amsterdam UMC, Amsterdam 1105 AZ, the Netherlands.
³¹ New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM 87106, USA.
³² Department of Pediatric Endocrinology & Diabetes, Children's Health Ireland, Dublin D12 N512, Ireland.
³³ Department of Paediatrics, School of Medicine, University of Dublin, Trinity College, Dublin D02 PN40, Ireland.
³⁴ Department of Kinesiology, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
³⁵ Citadel Oral and Facial Surgery, Halifax, NS B3L 4H7, Canada.
³⁶ Department of Pediatrics, University of California San Francisco, San Francisco, CA 94115, USA.
³⁷ Endocrine Research Institute, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.
³⁸ Division of Clinical Genetics, Children's Mercy Kansas City, Kansas City, MO 64108, USA.
³⁹ Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108-2792, USA.
⁴⁰ Department of Trauma, Orthopedics and Reconstructive Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany.
⁴¹ MVZ Endokrinologikum Goettingen, 37075 Goettingen, Germany.
⁴² Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
⁴³ Department of Orthopedics, George Washington University School of Medicine and Health Sciences, Washington, DC 20052, USA.
⁴⁴ Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
⁴⁵ Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁴⁶ MAGIC Evidence Ecosystem Foundation [www.magicevidence.org], Oslo 0456, Norway.
⁴⁷ Institute of Endocrine and Metabolic Sciences, Vita-Salute San Raffaele University and IRCCS, Milan 20132, Italy.

PMID: 40243526
PMCID: PMC12261105
DOI: 10.1210/clinem/dgaf170

Abstract

Purpose: An international working group (IWG) consisting of experts in X-linked hypophosphatemia (XLH) developed global guidelines providing a comprehensive, evidence-based approach to XLH diagnosis, management, and monitoring.

Methods: The IWG, consisting of 43 members as well as methodologists and a patient partner, conducted 2 systematic reviews (SRs) and narrative reviews to address key areas. The SRs addressed the impact of burosumab compared to conventional therapy (phosphate and active vitamin D) or no therapy on patient-important outcomes in adults. They also evaluated conventional therapy compared to no therapy. GRADE methodology was applied to evaluate the certainty of evidence. Non-GRADED recommendations were made in the presence of insufficient evidence to conduct SRs. These guidelines have been reviewed and endorsed by several medical and patient societies and organizations.

Results: The diagnosis of XLH is based on integrating clinical evaluation, laboratory findings confirming renal phosphate wasting (following exclusion of conditions mimicking XLH), and skeletal imaging. Fibroblast growth factor 23 measurement and DNA analysis are of value in the diagnosis, if available. Pathogenic or likely pathogenic variants in the PHEX gene are confirmatory but not necessary for the diagnosis. Management requires a multidisciplinary team knowledgeable and experienced in XLH. Effective medical therapy with burosumab can improve fracture and pseudofracture healing.

Main conclusion: In adults with XLH and fractures or pseudofractures, burosumab is recommended over no therapy (strong recommendation, GRADEd). Additionally, burosumab is suggested as the preferred treatment compared to conventional therapy (conditional recommendation, GRADEd) in the absence of fractures or pseudofractures. If burosumab is not available, symptomatic adults should be treated with conventional therapy (Non-GRADEd recommendation).

Keywords: X-linked hypophosphatemia (XLH); adult XLH; clinical practice guidelines; consensus.

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Figures

**Figure 2.**
GRADEd initial assessment recommendations in adults with XLH.

**Figure 3.**
Workup for hypophosphatemia.

**Figure 4.**
GRADEd monitoring recommendations for follow-up in adults with XLH.

**Figure 5.**
GRADEd treatment recommendations in adult XLH.

See this image and copyright information in PMC

References

1. Liu S, Tang W, Zhou J, et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol. 2006;17(5):1305‐1315. - PubMed
1. Che H, Roux C, Etcheto A, et al. Impaired quality of life in adults with X-linked hypophosphatemia and skeletal symptoms. Eur J Endocrinol. 2016;174(3):325‐333. - PubMed
1. Biosse Duplan M, Coyac BR, Bardet C, et al. Phosphate and vitamin D prevent periodontitis in X-linked hypophosphatemia. J Dent Res. 2017;96(4):388‐395. - PubMed
1. Insogna KL, Briot K, Imel EA, et al. A randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy of burosumab, an anti-FGF23 antibody, in adults with X-linked hypophosphatemia: week 24 primary analysis. J Bone Miner Res. 2018;33(8):1383‐1393. - PubMed
1. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924‐926. - PMC - PubMed

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X-Linked Hypophosphatemia Management in Adults: An International Working Group Clinical Practice Guideline

Affiliations

X-Linked Hypophosphatemia Management in Adults: An International Working Group Clinical Practice Guideline

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