Methodology for the international working group clinical practice guidelines on X-linked hypophosphatemia in children and adults

Dalal S Ali¹, Aliya A Khan², Reza D Mirza³, Natasha M Appelman-Dijkstra⁴, Maria Luisa Brandi^{5

6}, Thomas O Carpenter⁷, Catherine Chaussain⁸, Erik A Imel⁹, Suzanne M Jan de Beur¹⁰, Pablo Florenzano¹¹, Archibald Morrison¹², Hajar Abu Alrob³, R Todd Alexander¹³, Farah Alsarraf¹, Signe Sparre Beck-Nielsen^{14

15}, Martin Biosse-Duplan^{8

16}, Martine Cohen-Solal¹⁷, Rachel K Crowley¹⁸, Karel Dandurand¹⁹, Guido Filler²⁰, Seiji Fukumoto²¹, Claudia Gagnon^{22

23}, Paul Goodyer²⁴, Corinna Grasemann²⁵, Chelsey Grimbly^{13

26}, Salma Hussein¹, Muhammad K Javaid²⁷, Sarah Khan²⁸, Aneal Khan²⁹, Anna Lehman³⁰, Willem F Lems³¹, E Michael Lewiecki³², Ciara McDonnell^{33

34}, Emmett Morgante³⁵, Anthony A Portale³⁶, Yumie Rhee³⁷, Heide Siggelkow^{38

39}, Laura Tosi⁴⁰, Leanne M Ward⁴¹, Gordon Guyatt^{3

42

43}

Affiliations

¹ Divisions of Endocrinology and Metabolism, McMaster University, 223 3075 Hospital Gate, Oakville, ON, L6M 1M1, Canada.
² Divisions of Endocrinology and Metabolism, McMaster University, 223 3075 Hospital Gate, Oakville, ON, L6M 1M1, Canada. aliya@mcmaster.ca.
³ Department of Health Research Methods, Evidence, and Impact at McMaster University, Hamilton, Canada.
⁴ Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands.
⁵ F.I.R.M.O. Onlus, Italian Foundation for the Research on Bone Diseases, Florence, Italy.
⁶ Institute of Endocrine and Metabolic Sciences, Vita-Salute San Raffaele University and IRCCS, Milan, Italy.
⁷ Departments of Pediatrics (Endocrinology), and Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA.
⁸ Department of Oral Medicine, Faculty of Dentistry, Inserm and APHP, Université Paris Cité, Paris, France.
⁹ Department of Medicine and Pediatrics, Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁰ University of Virginia School of Medicine, Charlottesville, VA, USA.
¹¹ Department of Endocrinology, School of Medicine Pontificia, Universidad Católica de Chile, Santiago, Chile.
¹² Citadel Oral and Facial Surgery, Halifax, Canada.
¹³ Department of Pediatrics, Faculty of Medicine and Dentistry, The University of Alberta, Edmonton, AB, Canada.
¹⁴ Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark.
¹⁵ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
¹⁶ Institut Imagine, INSERM 1163, Paris, France.
¹⁷ Department of Rheumatology and Reference Center for Rare Bone Diseases, Hopital Lariboisiere, Paris, France.
¹⁸ Rare Disease Clinical Trial Network, University College Dublin, Dublin, Ireland.
¹⁹ Université de Sherbrooke, Sherbrooke, QC, Canada.
²⁰ Department of Paediatrics, Western University, London, ON, Canada.
²¹ Department of Medicine, Tamaki-Aozora Hospital, Tokushima, Japan.
²² Department of Medicine, Université Laval, Quebec City, Canada.
²³ CHU de Québec-Université Laval Research Centre, Quebec City, Canada.
²⁴ Research Institute of the McGill University Health Centre, Montreal, Canada.
²⁵ Department of Pediatrics, Division of Rare Diseases, Katholisches Klinikum Bochum and Ruhr-University Bochum, Bochum, Germany.
²⁶ Women and Children's Health Research Institute, Edmonton, AB, Canada.
²⁷ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
²⁸ Trillium Health Partners, University of Toronto, Toronto, ON, Canada.
²⁹ M.A.G.I.C. Clinic (Metabolics and Genetics in Canada), Calgary, AB, Canada.
³⁰ University of British Columbia, Adult Metabolic Diseases Clinic, Vancouver, BC, Canada.
³¹ Department of Rheumatology, UMC, Amsterdam, the Netherlands.
³² New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA.
³³ Department of Pediatric Endocrinology & Diabetes, Children's Health Ireland, Dublin, Ireland.
³⁴ Department of Pediatrics, School of Medicine, University of Dublin, Trinity College, Dublin, Ireland.
³⁵ University of Waterloo, Waterloo, ON, Canada.
³⁶ Department of Pediatrics, University of California, San Francisco, San Francisco, CA, 94115, USA.
³⁷ Department of Internal Medicine, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea.
³⁸ Department of Trauma, Orthopedics and Reconstructive Surgery, University Medical Center Goettingen, Goettingen, Germany.
³⁹ MVZ Endokrinologikum Goettingen, Goettingen, Germany.
⁴⁰ District of Columbia, George Washington University School of Medicine and Health Sciences, Washington, USA.
⁴¹ Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada.
⁴² Department of Medicine, McMaster University, Hamilton, ON, Canada.
⁴³ MAGIC Evidence Ecosystem Foundation [www.magicevidence.or], Lovisenberggata 17C, 0456, Oslo, Norway.

PMID: 40119067
DOI: 10.1007/s00774-025-01585-z

Practice Guideline

Methodology for the international working group clinical practice guidelines on X-linked hypophosphatemia in children and adults

Dalal S Ali et al. J Bone Miner Metab. 2025 May.

. 2025 May;43(3):193-202.

doi: 10.1007/s00774-025-01585-z. Epub 2025 Mar 21.

Authors

Affiliations

¹ Divisions of Endocrinology and Metabolism, McMaster University, 223 3075 Hospital Gate, Oakville, ON, L6M 1M1, Canada.
² Divisions of Endocrinology and Metabolism, McMaster University, 223 3075 Hospital Gate, Oakville, ON, L6M 1M1, Canada. aliya@mcmaster.ca.
³ Department of Health Research Methods, Evidence, and Impact at McMaster University, Hamilton, Canada.
⁴ Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands.
⁵ F.I.R.M.O. Onlus, Italian Foundation for the Research on Bone Diseases, Florence, Italy.
⁶ Institute of Endocrine and Metabolic Sciences, Vita-Salute San Raffaele University and IRCCS, Milan, Italy.
⁷ Departments of Pediatrics (Endocrinology), and Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA.
⁸ Department of Oral Medicine, Faculty of Dentistry, Inserm and APHP, Université Paris Cité, Paris, France.
⁹ Department of Medicine and Pediatrics, Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁰ University of Virginia School of Medicine, Charlottesville, VA, USA.
¹¹ Department of Endocrinology, School of Medicine Pontificia, Universidad Católica de Chile, Santiago, Chile.
¹² Citadel Oral and Facial Surgery, Halifax, Canada.
¹³ Department of Pediatrics, Faculty of Medicine and Dentistry, The University of Alberta, Edmonton, AB, Canada.
¹⁴ Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark.
¹⁵ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
¹⁶ Institut Imagine, INSERM 1163, Paris, France.
¹⁷ Department of Rheumatology and Reference Center for Rare Bone Diseases, Hopital Lariboisiere, Paris, France.
¹⁸ Rare Disease Clinical Trial Network, University College Dublin, Dublin, Ireland.
¹⁹ Université de Sherbrooke, Sherbrooke, QC, Canada.
²⁰ Department of Paediatrics, Western University, London, ON, Canada.
²¹ Department of Medicine, Tamaki-Aozora Hospital, Tokushima, Japan.
²² Department of Medicine, Université Laval, Quebec City, Canada.
²³ CHU de Québec-Université Laval Research Centre, Quebec City, Canada.
²⁴ Research Institute of the McGill University Health Centre, Montreal, Canada.
²⁵ Department of Pediatrics, Division of Rare Diseases, Katholisches Klinikum Bochum and Ruhr-University Bochum, Bochum, Germany.
²⁶ Women and Children's Health Research Institute, Edmonton, AB, Canada.
²⁷ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
²⁸ Trillium Health Partners, University of Toronto, Toronto, ON, Canada.
²⁹ M.A.G.I.C. Clinic (Metabolics and Genetics in Canada), Calgary, AB, Canada.
³⁰ University of British Columbia, Adult Metabolic Diseases Clinic, Vancouver, BC, Canada.
³¹ Department of Rheumatology, UMC, Amsterdam, the Netherlands.
³² New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA.
³³ Department of Pediatric Endocrinology & Diabetes, Children's Health Ireland, Dublin, Ireland.
³⁴ Department of Pediatrics, School of Medicine, University of Dublin, Trinity College, Dublin, Ireland.
³⁵ University of Waterloo, Waterloo, ON, Canada.
³⁶ Department of Pediatrics, University of California, San Francisco, San Francisco, CA, 94115, USA.
³⁷ Department of Internal Medicine, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea.
³⁸ Department of Trauma, Orthopedics and Reconstructive Surgery, University Medical Center Goettingen, Goettingen, Germany.
³⁹ MVZ Endokrinologikum Goettingen, Goettingen, Germany.
⁴⁰ District of Columbia, George Washington University School of Medicine and Health Sciences, Washington, USA.
⁴¹ Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada.
⁴² Department of Medicine, McMaster University, Hamilton, ON, Canada.
⁴³ MAGIC Evidence Ecosystem Foundation [www.magicevidence.or], Lovisenberggata 17C, 0456, Oslo, Norway.

PMID: 40119067
DOI: 10.1007/s00774-025-01585-z

Abstract

The guideline panel, comprising international experts in X-linked hypophosphatemia (XLH), patient partners from the XLH patient population, and guideline methodologists, held 18 teleconferences between January 2023 and July 2024 to develop comprehensive guidelines for the diagnosis and management of XLH in children and adults. For a subset of our questions, we utilized the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, assessed the certainty of evidence and formulated GRADEd recommendations. For these questions, the panelists and methodologists collaboratively framed PICO (Population, Intervention, Control, and Outcomes) questions and conducted four systematic reviews assessing the impact of medical therapy-using either burosumab or phosphate and active vitamin D-on patient-important outcomes in the XLH population as well as the impact of medical intervention compared to no treatment. We assessed the risk of bias and transparently generated summary of findings tables using MAGICApp. The panel developed three GRADEd treatment recommendations for adults and two for children. Each GRADEd recommendation was linked to an underlying body of evidence, reflecting judgments on the certainty of evidence, recommendation strength, values, preferences, and considerations of costs, feasibility, acceptability, and equity. Due to the paucity of evidence, the panel developed very low-quality GRADEd recommendations on monitoring patients with XLH based on an expert clinical practice survey. Using a rigorous narrative literature review, the panel developed non-GRADEd recommendations including guidance for pregnant women, patients with dental complications, and other areas where evidence is limited. This article summarizes the methodology utilized for the development of both GRADEd and non-GRADEd recommendations for patients with XLH.

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Conflict of interest statement

Declarations. Conflict of interest: Steering Committee: DSA: none; AAK: Speaker, advisory board (Alexion, Amgen); Speaker, advisory board, research funding (Ascendis); Advisory board, research funding (Takeda); Research funding (Amolyt, Calcilytix); RM: none; NMA: Kyowa Kirin, UCB and Amgen (Consulting & advisory boards), XLH-Network Netherlands (Patient Advisory Org), Kyowa Kirin, UCB (unrestricted research grant); MLB: Honoraria: Amgen, Bruno Farmaceutici, Calcilytix, Kyowa Kirin, UCB; Grants and/or speaker: Abiogen, Alexion, Amgen, Amolyt, Amorphical, Bruno Farmaceutici, CoGeDi, Echolight, Eli Lilly, Enterabio, Gedeon Richter, Italfarmaco, Kyowa Kirin, Menarini, Monte Rosa, SPA, Takeda, Theramex, UCB; Consultant: Aboca, Alexion, Amolyt, Bruno Farmaceutici, Calcilytix, Echolight, Kyowa Kirin, Personal Genomics, UCB; TOC: Consulting and advisory boards: Ultragenyx, Kyowa Kirin; Consulting: Viridian; Research support: Ultragenyx; Other roles: Assoc. Editor JBMR, President Ped Endo Soc, Author UpToDate (royalties), XLH-Network (Patient Advisory Org); CC: Institutional research contracts with Kyowa-Kirin and novonordisk; EAI: Ultragenyx (Research funding and consulting), Kyowa Kirin (research funding and consulting), Inozyme (consulting), Amgen (research funding); SJdB: participation in clinical trials and consulting for Ultragenyx and consulting for Kyowa Kirin; PF: Institutional Research Grants: Ultragenyx. Advisory Boards: Ultragenyx, Kyowa Kirin; AM: none; HAA: none; GG: none. Members of the IWG: RTA: Ardylex Inc. (Research grant), Ardylex Inc, Advicienne and Ultragenyx (Consultancy); FA: none; SSBN: Kyowa Kirin (Research grants/consultancy/speaker/ad. board), Inozymes (consultancy), Novo Nordisk (Consultancy); MBD: Kyowa Kirin (research grants, speaker fee), Alexion (speaker fee and advisory board); MCS: Kyowa Kirin (research grants, speaker fee); RKC: speaker and consultancy fees from Kyowa Kirin, advisory to UCB / Amgen; KD: Speaker: Amgen, Kyowa Kirin, Mantra Pharma; GF: Consultant: Kyowa Kirin, ProKidney, Ultragenyx, Alnylum, Speaker: ProKidney, Ultragenyx; SF: Kyowa Kirin (consulting); CG: Ascendis Pharma, Takeda and Shire (research funding); PG: none; CoG: Kyowa Kirin; Biomarin, Alexion, Merck, Novo Nordisk; ChG: Ultragenyx (unrestricted research grant, consultancy and advisory board), IPSEN, Alexion and Kyowa Kirin (consultancy); SH: none; MKJ: funding for consultancy and speaker fees from Kyowa Kirin unrelated to this manuscript; SK: Amgen: honoraria/advisory board, Sandoz Pharmaceuticals: honoraria/advisory board, PI for XLH disease monitoring program—funded by Ultragenyx, Co-investigator TransconPTH trial funded by Ascendis; AK: none; AL: Consulting (advisory boards): Sanofi-Genzyme, Horizon, Spark Therapeutics, Ultragenyx, Biomarin, Takeda-Shire, Amicus, Recordati, Alexion; Travel grant: Sanofi Genzyme; Research and education grants: Takeda, Sanofi, Amicus; WFL: Speakers fee/advisory Boards: UCB, Amgen, Galapagos, Pfizer; EML: Consulting: Amgen; Speaker: Amgen, Ascendis; Investigator: Amgen, Ardius, Ultragenyx; CM: Consultancy, Travel/Research Grants or Advisory boards— Kyowa Kirin, Ascendis Pharma, Pfizer, Novo Nordisk, Biomarin, Regeneron; EM: none; AAP: Kyowa Kirin (advisory board, speaker); YR: Speaker: Amgen, Dawoong; Investigator: Amgen, Kyowa Kirin, Dongguk, Dong-A, Daewoong; HS: Advisory boards and/or speaker fees: Amgen, Takeda, UCB, Kyowa Kirin, Merck/Serono, Alexion, Biomarin. Research grant: Takeda, Ascendis; LT: clinical trial fees from Ultragenyx, NIH and PCOR grants, committees member for the Osteogenesis Imperfecta Foundation, the American Orthopaedic Association and the FDA; LMW: supported by a Tier 1 (Senior) Research Chair in Pediatric Bone Disorders from the University of Ottawa and the Children’s Hospital of Eastern Ontario Research Institute; declares participation in clinical trials with Ultragenyx, and consultancy to Kyowa Kirin and Ultragenyx, and unrestricted educational grants from Ultragenyx and Kyowa Kirin (with funds to Dr. Ward’s institution).

References

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Methodology for the international working group clinical practice guidelines on X-linked hypophosphatemia in children and adults

Affiliations

Methodology for the international working group clinical practice guidelines on X-linked hypophosphatemia in children and adults

Authors

Affiliations

Abstract

Conflict of interest statement

References

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