. 2025 May 19;110(6):1767-1780.

doi: 10.1210/clinem/dgae890.

Systematic Review: Efficacy of Medical Therapy on Outcomes Important to Adult Patients With X-Linked Hypophosphatemia

Dalal S Ali¹, Reza D Mirza², Farah Alsarraf¹, Salma Hussein¹, Hajar Abu Alrob², Natasha M Appelman-Dijkstra³, Signe Sparre Beck-Nielsen^{4

5}, Martin Biosse-Duplan^{6

7}, Maria Luisa Brandi⁸, Thomas O Carpenter⁹, Catherine Chaussain⁶, Martine Cohen-Solal¹⁰, Rachel K Crowley¹¹, Karel Dandurand¹², Pablo Florenzano¹³, Seiji Fukumoto¹⁴, Claudia Gagnon^{15

16}, Paul Goodyer¹⁷, Corinna Grasemann¹⁸, Erik A Imel¹⁹, Suzanne M Jan de Beur²⁰, Anna Lehman²¹, E Michael Lewiecki²², Emmett Morgante²³, Leanne M Ward²⁴, Aliya A Khan¹, Gordon Guyatt^{2

25

26}

Affiliations

¹ Division of Endocrinology and Metabolism, McMaster University, Hamilton, ON, Canada L8S 4L8.
² Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada L8S 4L8.
³ Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden University Medical Center, 2300 ZA Leiden, the Netherlands.
⁴ Centre for Rare Diseases, Aarhus University Hospital, 8200 Aarhus N, Denmark.
⁵ Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark.
⁶ Department of Oral Medicine, Faculty of Dentistry, UMR 1333, Inserm and APHP, Université Paris Cité, 75006 Paris, France.
⁷ Institut Imagine, INSERM 1163, 75015 Paris, France.
⁸ Institute of Endocrine and Metabolic Sciences, Vita-Salute San Raffaele University and IRCCS, 20132 Milan, Italy.
⁹ Departments of Pediatrics (Endocrinology), and Orthopedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520, USA.
¹⁰ Department of Rheumatology and Reference Center for Rare Bone Diseases, hopital Lariboisiere, 75010 Paris, France.
¹¹ Rare Disease Clinical Trial Network, University College Dublin, Dublin 4, D04 T6F4, Ireland.
¹² Division of Internal Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada J1N 3C6.
¹³ Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile, 8320165 Santiago, Región Metropolitana, Chile.
¹⁴ Department of Medicine, Tamaki-Aozora Hospital, 779-3125 Tokushima, Japan.
¹⁵ CHU de Québec-Université Laval Research Centre, Endocrinology and Nephrology Axis, Quebec City, QC, Canada G1V 4G2.
¹⁶ Department of Medicine, Université Laval, Quebec City, QC, Canada G1V 0A6.
¹⁷ Research Institute of the McGill University Health Centre, Montreal, QC, Canada H3H 2L9.
¹⁸ Department of Pediatrics, Division of Rare Diseases, Katholisches Klinikum Bochum and Ruhr-University Bochum, 44791 Bochum, Germany.
¹⁹ Department of Medicine and Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
²⁰ Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
²¹ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
²² New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM 87106, USA.
²³ Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada N2L 3G1.
²⁴ Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada K1H 8L1.
²⁵ Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8.
²⁶ MAGIC Evidence Ecosystem Foundation, 0456 Oslo, Norway.

PMID: 39715351
PMCID: PMC12086399
DOI: 10.1210/clinem/dgae890

Systematic Review: Efficacy of Medical Therapy on Outcomes Important to Adult Patients With X-Linked Hypophosphatemia

Dalal S Ali et al. J Clin Endocrinol Metab. 2025.

. 2025 May 19;110(6):1767-1780.

doi: 10.1210/clinem/dgae890.

Authors

Affiliations

¹ Division of Endocrinology and Metabolism, McMaster University, Hamilton, ON, Canada L8S 4L8.
² Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada L8S 4L8.
³ Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden University Medical Center, 2300 ZA Leiden, the Netherlands.
⁴ Centre for Rare Diseases, Aarhus University Hospital, 8200 Aarhus N, Denmark.
⁵ Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark.
⁶ Department of Oral Medicine, Faculty of Dentistry, UMR 1333, Inserm and APHP, Université Paris Cité, 75006 Paris, France.
⁷ Institut Imagine, INSERM 1163, 75015 Paris, France.
⁸ Institute of Endocrine and Metabolic Sciences, Vita-Salute San Raffaele University and IRCCS, 20132 Milan, Italy.
⁹ Departments of Pediatrics (Endocrinology), and Orthopedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520, USA.
¹⁰ Department of Rheumatology and Reference Center for Rare Bone Diseases, hopital Lariboisiere, 75010 Paris, France.
¹¹ Rare Disease Clinical Trial Network, University College Dublin, Dublin 4, D04 T6F4, Ireland.
¹² Division of Internal Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada J1N 3C6.
¹³ Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile, 8320165 Santiago, Región Metropolitana, Chile.
¹⁴ Department of Medicine, Tamaki-Aozora Hospital, 779-3125 Tokushima, Japan.
¹⁵ CHU de Québec-Université Laval Research Centre, Endocrinology and Nephrology Axis, Quebec City, QC, Canada G1V 4G2.
¹⁶ Department of Medicine, Université Laval, Quebec City, QC, Canada G1V 0A6.
¹⁷ Research Institute of the McGill University Health Centre, Montreal, QC, Canada H3H 2L9.
¹⁸ Department of Pediatrics, Division of Rare Diseases, Katholisches Klinikum Bochum and Ruhr-University Bochum, 44791 Bochum, Germany.
¹⁹ Department of Medicine and Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
²⁰ Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
²¹ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
²² New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM 87106, USA.
²³ Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada N2L 3G1.
²⁴ Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada K1H 8L1.
²⁵ Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8.
²⁶ MAGIC Evidence Ecosystem Foundation, 0456 Oslo, Norway.

PMID: 39715351
PMCID: PMC12086399
DOI: 10.1210/clinem/dgae890

Abstract

Context: Understanding the effects of burosumab compared to conventional therapy or no treatment on patient-important outcomes in adults with X-linked hypophosphatemia (XLH) is essential to guide evidence-based treatment recommendations.

Objective: To examine the highest certainty evidence addressing the management of XLH in adults to inform treatment recommendations.

Methods: We searched Embase, MEDLINE, Web of Science, and Cochrane Central up to May 2023. Eligible studies included randomized controlled trials (RCTs) and observational studies of individuals aged 18+ with clinically or genetically confirmed XLH. Manuscripts comparing burosumab to no treatment or conventional therapy (phosphate and active vitamin D) and conventional therapy to no treatment were included. Two reviewers independently determined eligibility, extracted data, and assessed risk of bias (RoB). GRADE methodology was used to assess evidence certainty.

Results: We screened 4114 records, after removing duplicates, and assessed 254 full texts. One RCT and 2 observational studies were eligible. The RCT of burosumab vs no treatment had low RoB. Burosumab probably improves pain from fracture/pseudofracture healing (moderate certainty) but has little or no impact on direct pain measures (moderate certainty). Burosumab may reduce the need for parathyroidectomy (low certainty) but has little or no impact on fatigue (high certainty), stiffness (moderate certainty), and mobility (low certainty) over 24 weeks. Burosumab may increase dental abscess risk (low certainty). Indirect evidence comparing burosumab to conventional therapy provided low certainty regarding burosumab vs conventional therapy. Two observational studies on conventional therapy vs no treatment had high RoB and very low certainty regarding the impact of conventional therapy on patient-important outcomes.

Conclusion: No formal comparisons between burosumab and conventional therapy in adults exist. Evidence for conventional therapy vs no treatment is very uncertain. Our review highlights the need for more data on the long-term effects of burosumab and conventional therapy on patient-important outcomes in adult patients with XLH.

Keywords: adult XLH; burosumab; conventional therapy; efficacy; patient-important outcomes.

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Figures

**Figure 1.**
PRISMA diagram illustrating the search for the SR on the impact of burosumab compared with phosphate and active vitamin D or no treatment on patient-important outcomes.

**Figure 2.**
PRISMA diagram illustrating the search for the SR on the impact of phosphate and active vitamin D compared to no treatment on patient-important outcomes.

**Figure 3.**
Illustrates the risk of bias in the study included in the SR comparing burosumab with phosphate and active vitamin D or no treatment.

**Figure 4.**
Illustrates the risk of bias in studies included in the SR comparing phosphate and active vitamin D with no treatment.

**Figure 5.**
Meta-analysis of the effect of conventional therapy vs no treatment on serum phosphorus level.

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. Beck-Nielsen SS, Mughal Z, Haffner D, et al. FGF23 and its role in X-linked hypophosphatemia-related morbidity. Orphanet J Rare Dis. 2019;14(1):58. - PMC - PubMed
1. Holm IA, Huang X, Kunkel LM. Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets. Am J Hum Genet. 1997;60(4):790‐797. - PMC - PubMed
1. Seefried L, Dahir K, Petryk A, et al. Burden of illness in adults with hypophosphatasia: data from the global hypophosphatasia patient registry. J Bone Miner Res. 2020;35(11):2171‐2178. - PubMed
1. Hawley S, Shaw NJ, Delmestri A, et al. Prevalence and mortality of individuals with X-linked hypophosphatemia: a United Kingdom real-world data analysis. J Clin Endocrinol Metab. 2020;105(3):e871‐e878. - PMC - PubMed

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Systematic Review: Efficacy of Medical Therapy on Outcomes Important to Adult Patients With X-Linked Hypophosphatemia

Affiliations

Systematic Review: Efficacy of Medical Therapy on Outcomes Important to Adult Patients With X-Linked Hypophosphatemia

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources