A phase 2 trial of burosumab for treatment of fibroblast growth factor-23-mediated hypophosphatemia in children and adults with fibrous dysplasia

Abstract

Fibrous dysplasia (FD) is a rare disorder associated with fractures and deformities. FD lesions produce excess phosphaturic hormone fibroblast growth factor 23 (FGF23), leading to hyperphosphaturia in most patients, and hypophosphatemia in those with high FD burden. Skeletal complications are associated with both low-normophosphatemia and frank hypophosphatemia. Burosumab is approved for other forms of FGF23 excess, but there is little evidence to inform use in FD. A phase 2 study investigated the safety and efficacy of burosumab in patients with FD. The primary endpoint was the proportion of participants achieving phosphate levels within the mid to upper part of the normal range (age and sex-adjusted Z-score –1 to +2). 12 participants (7 children, 5 adults) received burosumab for 48 weeks. Median phosphate Z-score increased from −2.88 (1.65) to 0.22 (1.37), meeting the target in 100% of participants. Alkaline phosphatase levels were elevated at baseline in 8 participants [median 846 U/L (464)] and declined by 49% at week 48, representing a median decline of −364 (244.5) U/L. PROMIS questionnaires showed trends toward improvements in all domains in children; adult scores showed no identifiable trends. Two children experienced transformational mobility gains, including advancement from full-time wheelchair use to independent ambulation. Lesion biopsies showed no changes in cellularity or composition, and ¹⁸F-NaF PET/CT scans showed no changes in tracer uptake, suggesting burosumab did not adversely impact lesional activity. Adverse events were mild, and none resulted in treatment withdrawal. Burosumab treatment in patients with FD was well-tolerated, restored phosphate homeostasis, and reduced alkaline phosphatase levels. Burosumab has the potential to lead to functional improvements and ambulation gains in severely affected patients and is a valuable tool to reduce the impact of FD-related disability.

References

[1] Boyce AM, Collins MT. Fibrous Dysplasia/McCune-Albright Syndrome: A Rare, Mosaic Disease of Gα s Activation. Endocr. Rev., 2020, 41: 345-370

[2] Riminucci M, et al.. The histopathology of fibrous dysplasia of bone in patients with activating mutations of the Gs alpha gene: site-specific patterns and recurrent histological hallmarks. J. Pathol., 1999, 187: 249-258

[3] Riminucci M, et al.. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J. Clin. Invest., 2003, 112: 683-692

[4] Geels, R. E. S. et al. Long Bone Fractures in Fibrous Dysplasia/McCune-Albright Syndrome: Prevalence, Natural History, and Risk Factors. J. Bone Miner. Res. 37, 236–243 (2022).

[5] Pan KS, Heiss JD, Brown SM, Collins MT, Boyce AM. Chiari I Malformation and Basilar Invagination in Fibrous Dysplasia: Prevalence, Mechanisms, and Clinical Implications. J. Bone, 2018, 33: 1990-1998

[6] Berglund JA, et al.. Scoliosis in Fibrous Dysplasia/McCune-Albright Syndrome: factors associated with curve progression and effects of bisphosphonates. J. Bone, 2018, 33: 1641-1648

[7] Meier ME, et al.. Coxa Vara Deformity in Fibrous Dysplasia/McCune-Albright Syndrome: Prevalence, Natural History and Risk Factors: A Two-Center Study. J. Bone, 2023, 38: 968-975

[8] Gun ZH, et al.. Serum phosphorus as a driver of skeletal morbidity in fibrous dysplasia. J. Clin. Endocrinol. Metab., 2024, 109: 1334-1340

[9] Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician’s guide to X-linked hypophosphatemia. J. Bone, 2011, 26: 1381-1388

[10] Arnold A, et al.. Hormonal regulation of biomineralization. Nat. Rev. Endocrinol., 2021, 17: 261-275

[11] Imel EA, et al.. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet, 2019, 393: 2416-2427

[12] Insogna KL, 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, 2018, 33: 1383-1393

[13] Jan de Beur SM, et al.. Burosumab for the Treatment of Tumor-Induced Osteomalacia. J. Bone, 2021, 36: 627-635

[14] Whyte MP, et al.. Efficacy and safety of burosumab in children aged 1-4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diab. Endocrinol., 2019, 7: 189-199

[15] Imanishi Y, et al.. Interim Analysis of a Phase 2 Open-Label Trial Assessing Burosumab Efficacy and Safety in Patients With Tumor-Induced Osteomalacia. J. Bone, 2021, 36: 262-270

[16] Carpenter TO, et al.. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N. Engl. J. Med., 2018, 378: 1987-1998

[17] Haffner D, et al.. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat. Rev. Nephrol., 2025, 12: 330-354

[18] Jan de Beur SM, et al.. Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia. J. Intern. Med., 2023, 293: 309-328

[19] Trombetti A, et al.. Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia. Nat. Rev. Endocrinol., 2022, 18: 366-384

[20] Collins MT, et al.. An instrument to measure skeletal burden and predict functional outcome in fibrous dysplasia of bone. J. Bone Min. Res., 2005, 20: 219-226

[21] Javaid MK, et al.. Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: a consensus statement from the FD/MAS international consortium. Orphanet J. Rare Dis., 2019, 14 Article ID: 139

[22] Paul SM, et al.. Disease severity and functional factors associated with walking performance in polyostotic fibrous dysplasia. Bone, 2014, 60: 41-47

[23] Bosman A, et al.. Tumor-Induced Osteomalacia: a Systematic Clinical Review of 895 Cases. Calcif. Tissue Int., 2022, 111: 367-379

[24] Laurent, M. R., Harvengt, P., Mortier, G. R. & Böckenhauer, D. X-Linked Hypophosphatemia. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, eds. GeneReviews(®). Seattle (WA): University of Washington, Seattle Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved. (1993).

[25] Wang K, Zhang R, Chen Z, Bai Y, He Q. Meta-analysis and systematic review: burosumab as a promising treatment for children with X-linked hypophosphatemia. Front. Endocrinol., 2024, 15 Article ID: 1414509

[26] Florenzano P, et al.. Age-related changes and effects of bisphosphonates on bone turnover and disease progression in fibrous dysplasia of bone. J. Bone Min. Res., 2019, 34: 653-660

[27] Papadakis GZ, et al.. 18) F-NaF PET/CT imaging in fibrous dysplasia of bone. J. Bone, 2019, 34: 1619-1631

[28] Wang J, et al.. Increasing serum alkaline phosphatase is associated with bone deformity progression for patients with polyostotic fibrous dysplasia. J. Orthop. Surg. Res., 2020, 15: 583

[29] Hart ES, et al.. Onset, progression, and plateau of skeletal lesions in fibrous dysplasia and the relationship to functional outcome. J. Bone, 2007, 22: 1468-1474

[30] Gladding A, Szymczuk V, Auble BA, Boyce AM. Burosumab treatment for fibrous dysplasia. Bone, 2021, 150 Article ID: 116004

[31] Sawamura, K., Hamajima, T. & Kitoh, H. Improvement of fibrous dysplasia after burosumab therapy in a pediatric patient with mccune-albright syndrome: a case report. JBJS Case Connect14, https://doi.org/10.2106/JBJS.CC.24.00279 (2024).

[32] Apperley LJ, Senniappan S. Burosumab therapy in a paediatric patient with mccune-albright syndrome: a case report. Horm. Res. Paediatr., 2023, 96: 341-348

[33] Sakka SD, et al.. Burosumab treatment of a child with McCune-Albright syndrome/polyostotic fibrous dysplasia: challenges and benefits. JBMR, 2025, 9 Article ID: ziaf042

[34] Barbato A, et al.. Use of burosumab in McCune Albright syndrome: case report and review of literature in mosaic disorders with FGF23 overproduction. Front Endocrinol. (Lausanne), 2025, 16 Article ID: 1577734

[35] Kim JH, Lee SB. Evaluation of activities of daily living: current insights and future horizons. Ann. Geriatr. Med. Res., 2025, 29: 143-158

[36] Wang DXM, Yao J, Zirek Y, Reijnierse EM, Maier AB. Muscle mass, strength, and physical performance predicting activities of daily living: a meta-analysis. J. Cachexia Sarcopenia Muscle, 2020, 11: 3-25

[37] Orlando G, et al.. Longitudinal assessment of physical function in adults with X-linked hypophosphatemia following initiation of burosumab therapy. Osteoporos. Int., 2024, 35: 2055-2060

[38] Briot K, et al.. Burosumab treatment in adults with X-linked hypophosphataemia: 96-week patient-reported outcomes and ambulatory function from a randomised phase 3 trial and open-label extension. RMD Open, 2021, 7: e001714

[39] Jan de Beur SM, et al.. Burosumab improves patient-reported outcomes in adults with tumor-induced osteomalacia: mixed-methods analysis. J. Bone, 2023, 38: 1654-1664

[40] Farooq, M., Khan, A. W., Kim, M. S. & Choi, S. The role of fibroblast growth factor (fgf) signaling in tissue repair and regeneration. Cells10 (2021). [published Online First: 20211119].

[41] Zhang X, Xu J. A novel miR-466l-3p/FGF23 axis promotes osteogenic differentiation of human bone marrow mesenchymal stem cells. Bone, 2024, 185: 117123

[42] Hartley IR, Collins MT. Burosumab for tumor-induced osteomalacia: not enough of a good thing. J. Bone, 2021, 36: 2453-2454

[43] de Castro LF, Ovejero D, Boyce AM. DIAGNOSIS OF ENDOCRINE DISEASE: mosaic disorders of FGF23 excess: fibrous dysplasia/McCune-Albright syndrome and cutaneous skeletal hypophosphatemia syndrome. Eur. J. Endocrinol., 2020, 182: R83-r99

[44] da Silva PCA, Giombelli VR, Galvão Tessaro FH. Burosumab, a transformational treatment in a pediatric patient with cutaneous-skeletal hypophosphatemia syndrome. JCEM Case Rep., 2024, 2: luae184

[45] Del Pino M, et al.. Burosumab treatment in a girl with cutaneous skeletal hypophosphatemia syndrome: 2-year follow-up. Am. J. Med. Genet. A, 2025, 197: e64020

[46] Huynh C, Gillis A, Fazendin J, Abdullatif H. A case report to assess the safety and efficacy of Burosumab, an investigational antibody to FGF23, in a single pediatric patient with Epidermal Nevus Syndrome and associated hypophosphatemic rickets. Bone Rep., 2022, 17 Article ID: 101605

[47] Khadora M, Mughal MZ. Burosumab treatment in a child with cutaneous skeletal hypophosphatemia syndrome: a case report. Bone Rep., 2021, 15: 101138

[48] Merz LM, et al.. A case report: first long-term treatment with burosumab in a patient with cutaneous-skeletal hypophosphatemia syndrome. Front. Endocrinol., 2022, 13: 866831

[49] Sugarman J, et al.. The efficacy and safety of burosumab in two patients with cutaneous skeletal hypophosphatemia syndrome. Bone, 2023, 166: 116598

[50] Wu J, et al.. A child with cutaneous-skeletal hypophosphatemia syndrome caused by a mosaic hras mutation: outcome of treatment with anti-FGF23 antibody. Calcif. Tissue Int., 2025, 116: 65

[51] Wentworth KL, Park J, Yu X, Hsiao EC. Update on the medical management of fibrous dysplasia of the bone. Ther. Adv. Endocrinol. Metab., 2025, 16: 20420188251347350

[52] de Castro LF, et al.. Safety and efficacy of denosumab for fibrous dysplasia of Bone. N. Engl. J. Med., 2023, 388: 766-768

[53] Szymczuk, V. et al. Safety and efficacy of moderate-dose denosumab in fibrous dysplasia: observational results from a phase 2 clinical trial. J. Clin. Endocrinol. Metab.110, 2666–2673 (2025).

[54] de Castro LF, et al.. Activation of RANK/RANKL/OPG pathway is involved in the pathophysiology of fibrous dysplasia and associated with disease burden. J. Bone, 2019, 34: 290-294

[55] Hartley IR, et al.. Determination of FGF23 Levels for the Diagnosis of FGF23-Mediated Hypophosphatemia. J. Bone, 2022, 37: 2174-2185

[56] Adeli K, Higgins V, Trajcevski K, White-Al Habeeb N. The Canadian laboratory initiative on pediatric reference intervals: A CALIPER white paper. Crit. Rev. Clin. Lab. Sci., 2017, 54: 358-413

[57] Phosphorus (Inorganic), Serum: Mayo Clinic Laboratories, (2025).

[58] Wood SWC, et al.. Patient and public involvement to gain direct insights into the burden of fibrous dysplasia/mccune-albright syndrome (FD/MAS) with FGF23-related hypophosphataemia. Qual. Life Res., 2021, 30: S1-S177

Funding

Kyowa Hakko Kirin (Kyowa Kirin)

U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR)(DE-000758)

U.S. Department of Health & Human Services | NIH | NIH Clinical Center (Clinical Center)

RIGHTS & PERMISSIONS

This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply