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

Dalal S Ali; Reza D Mirza; Salma Hussein; Farah Alsarraf; R Todd Alexander; Hajar Abu Alrob; Natasha M Appelman-Dijkstra; Martin Biosse-Duplan; Maria Luisa Brandi; Thomas O Carpenter; Catherine Chaussain; Karel Dandurand; Guido Filler; Pablo Florenzano; Seiji Fukumoto; Corinna Grasemann; Erik A Imel; Suzanne M Jan de Beur; Emmett Morgante; Leanne M Ward; Aliya A Khan; Gordon Guyatt

doi:10.1210/clinem/dgaf011

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

J Clin Endocrinol Metab. 2025 Jan 9:dgaf011. doi: 10.1210/clinem/dgaf011. Online ahead of print.

Authors

Dalal S Ali¹, Reza D Mirza², Salma Hussein¹, Farah Alsarraf¹, R Todd Alexander³, Hajar Abu Alrob², Natasha M Appelman-Dijkstra⁴, Martin Biosse-Duplan⁵, Maria Luisa Brandi⁶, Thomas O Carpenter⁷, Catherine Chaussain⁸, Karel Dandurand⁹, Guido Filler¹⁰, Pablo Florenzano¹¹, Seiji Fukumoto¹², Corinna Grasemann¹³, Erik A Imel¹⁴, Suzanne M Jan de Beur¹⁵, Emmett Morgante¹⁶, Leanne M Ward¹⁷, Aliya A Khan¹, Gordon Guyatt^{2

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Affiliations

¹ Division of Endocrinology and Metabolism, McMaster University, Hamilton, ON, Canada.
² Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
³ Department of Pediatrics, Faculty of Medicine & Dentistry, The University of Alberta, Edmonton, AB, Canada.
⁴ Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden University Medical Center, Leiden, the Netherlands.
⁵ Faculty of Dentistry, Université Paris Cité, Paris, France; Institut Imagine, INSERM 1163, Paris, France; APHP, Paris, France.
⁶ Vita-Salute San Raffaele University, Milan, Italy.
⁷ Departments of Pediatrics (Endocrinology), and Orthopedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA.
⁸ Faculty of Dentistry, Université Paris Cité and APHP, Paris, France.
⁹ Université de Sherbrooke, Sherbrooke, Québec, Canada.
¹⁰ Department of Paediatrics, Western University, London, Ontario, Canada.
¹¹ Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile.
¹² Tamaki-Aozora Hospital, Japan.
¹³ Department of Pediatrics, Division of Rare Diseases, Katholisches Klinikum Bochum and Ruhr-University Bochum, Bochum, Germany.
¹⁴ Department of Medicine and Pediatrics, Endocrinology, Indiana University School of Medicine, Indianapolis, Indiana.
¹⁵ University of Virginia School of Medicine, Charlottesville, VA, USA.
¹⁶ University of Waterloo, Waterloo, Ontario, Canada.
¹⁷ Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.
¹⁸ Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
¹⁹ MAGIC Evidence Ecosystem Foundation [www.magicevidence.org], Lovisenberggata 17C, 0456 Oslo, Norway.

PMID: 39787354
DOI: 10.1210/clinem/dgaf011

Abstract

Objective: To examine the evidence addressing the management of X-linked hypophosphatemia (XLH) in children to inform treatment recommendations.

Methods: We searched Embase, MEDLINE, Web of Science, and Cochrane Central up to May 2023. Eligible studies included RCTs and observational studies of individuals less than 18yrs with clinically or genetically confirmed XLH. Manuscripts comparing burosumab to either no treatment or conventional therapy (phosphate/active vitamin D) or evaluating 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 4,114 records and assessed 254 full texts. One RCT and one post-hoc study proved eligible when comparing burosumab to conventional therapy or no treatment. The open-label RCT was at high RoB, with certainty of evidence ranging from moderate to very low. Burosumab, compared to conventional therapy, probably prevents lower limb deformity and improves physical health QoL(moderate certainty). Burosumab may increase height and enhance the burden of symptoms related to chronic hypophosphatemia(low certainty). Burosumab probably increases Treatment-Emergent Adverse Events (moderate certainty) and may increase dental abscesses (low certainty). One observational study assessing conventional therapy versus no treatment was at high RoB providing very low certainty evidence regarding the impact of conventional therapy on final height.

Conclusion: Our review indicates that burosumab likely provides benefits to children by preventing lower limb deformity and improving physical health QoL while potentially increasing height. However, burosumab may also increase adverse events. Our review found limited evidence regarding the impact of conventional therapy compared to no treatment on final height. Further research is required to understand the long-term effect of medical therapy in children.

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