Effective treatment of hyperphosphatemia with denosumab in patients with loss of function of FGF23 and high bone density: case series

Mehdi Vafadar; Elham Zarei; Sonya Dadakhani; Vahid Ziaee

doi:10.1515/jpem-2025-0272

Article

Effective treatment of hyperphosphatemia with denosumab in patients with loss of function of FGF23 and high bone density: case series

Mehdi Vafadar , Elham Zarei , Sonya Dadakhani and Vahid Ziaee

Published/Copyright: November 18, 2025

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information Explore this Subject

From the journal Journal of Pediatric Endocrinology and Metabolism Volume 38 Issue 12

Abstract

Objectives

This study evaluated denosumab for treating hyperphosphatemia in patients with loss-of-function FGF23 mutations and high bone density.

Methods

Three patients with hyperphosphatemia due to mutations in the FGF23 pathway (two FGF23, one GALNT3) were treated. Conventional therapies, including phosphate binders, dietary restriction, and teriparatide, failed to reduce phosphate in the two symptomatic FGF23 patients. Denosumab, a RANKL inhibitor that decreases bone resorption, was administered for more than two years.

Results

Denosumab result in a marked and sustained reduction in serum phosphate in all three patients. The two symptomatic patients experienced significant relief from bone pain and improved appetite and well-being. Serum calcium decreased in all patients, with asymptomatic hypocalcemia seen in two cases. Bone density decreased in one patient and was unchanged in another. No significant side effects were observed, except for hypocalcemia.

Conclusions

Denosumab effectively reduced serum phosphate and improved symptoms in patients with FGF23-related hyperphosphatemia that was resistant to standard treatments. Denosumab may represent a promising new therapy for treatment-resistant hyperphosphatemia in FGF23 pathway disorders, though further studies are needed to confirm these findings and determine optimal management strategies.

Keywords: denosumab; hyperphosphatemia; FGF23 ; RANKL

Corresponding author: Elham Zarei, Department of Radiology, Aliasghar Children’s Hospital, School of Medicine, Iran University of Medical Sciences, Zafar st., Modarres highway. Tehran, Iran, E-mail: Zarei.e@iums.ac.ir

Acknowledgements

The authors would like to thank Ali Asghar Children Hospital and Iran University of Medical Sciences for supporting the present study.

Research ethics: This study is a report of a treatment process and confidential patient information has not been disclosed.
Informed consent: Not applicable.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Use of Large Language Models, AI and Machine Learning Tools: None declared.
Conflict of interest: The authors state no conflict of interest.
Research funding: None declared.
Data availability: The datasets supporting the finding of this study are available from the corresponding author upon reasonable request.

References

1. Rodelo-Haad, C, Santamaria, R, Muñoz-Castañeda, JR, Pendón-Ruiz de Mier, MV, Martin-Malo, A, Rodriguez, M. FGF23, biomarker, or target? Toxins 2019;11:175. https://doi.org/10.3390/toxins11030175.Search in Google Scholar PubMed PubMed Central

2. Bergwitz, C, Jüppner, H. FGF23 and syndromes of abnormal renal phosphate handling. Adv Exp Med Biol 2012;728:41–64. https://doi.org/10.1007/978-1-4614-0887-1_3.Search in Google Scholar PubMed PubMed Central

3. Edmonston, D, Wolf, M. FGF23 at the crossroads of phosphate, iron economy and erythropoiesis. Nat Rev Nephrol 2020;16:7–19. https://doi.org/10.1038/s41581-019-0189-5.Search in Google Scholar PubMed

4. White, KE, Carn, G, Lorenz-Depiereux, B, Benet-Pages, A, Strom, TM, Econs, MJ, et al.. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000;26:345–8. https://doi.org/10.1038/81664.Search in Google Scholar PubMed

5. Ho, BB, Bergwitz, C. FGF23 signalling and physiology. J Mol Endocrinol 2021;66:R23–2. https://doi.org/10.1530/jme-20-0178.Search in Google Scholar PubMed PubMed Central

6. Boyce, AM, Lee, AE, Roszko, KL, Gafni, RI. Hyperphosphatemic tumoral calcinosis: pathogenesis, clinical presentation, and challenges in management. Front Endocrinol 2020;11:293. https://doi.org/10.3389/fendo.2020.00293.Search in Google Scholar PubMed PubMed Central

7. Freedman, JD, Novak, R, Bratman Morag, S, Avitan-Hersh, E, Nikomarov, D. Bone involvement in hyperphosphatemic familial tumoral calcinosis: a new phenotypic presentation. Rambam Maimonides Med J 2021;12:e0024. https://doi.org/10.5041/rmmj.10445.Search in Google Scholar PubMed PubMed Central

8. Joseph, L, Hing, SN, Presneau, N, O’Donnell, P, Diss, T, Idowu, BD, et al.. Familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are different manifestations of the same disease: novel missense mutations in GALNT3. Skelet Radiol 2010;39:63–8. https://doi.org/10.1007/s00256-009-0808-5.Search in Google Scholar PubMed

9. Specktor, P, Cooper, JG, Indelman, M, Sprecher, E. Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred. J Hum Genet 2006;51:487–90. https://doi.org/10.1007/s10038-006-0377-6.Search in Google Scholar PubMed

10. Raux, S, Bouhamama, A, Gaspar, N, Brugières, L, Entz-Werlé, N, Mallet, C, et al.. Denosumab for treating aneurysmal bone cysts in children. Orthop Traumatol Surg Res 2019;105:1181–5. https://doi.org/10.1016/j.otsr.2019.04.028.Search in Google Scholar PubMed

11. Wang, D, Tang, X, Shi, Q, Wang, R, Ji, T, Tang, X, et al.. Denosumab in pediatric bone disorders and the role of RANKL blockade: a narrative review. Transl Pediatr 2023;12:470–86. https://doi.org/10.21037/tp-22-276.Search in Google Scholar PubMed PubMed Central

12. Nakaseko, K, Asano, T. AB0784 A study of serum electrolyte levels after denosumab administration. Ann Rheum Dis 2016;75:1172. https://doi.org/10.1136/annrheumdis-2016-eular.1053.Search in Google Scholar

13. Hanley, DA, Adachi, JD, Bell, A, Brown, V. Denosumab: mechanism of action and clinical outcomes. Int J Clin Pract 2012;66:1139–46. https://doi.org/10.1111/ijcp.12022.Search in Google Scholar PubMed PubMed Central

14. Marcadet, L, Bouredji, Z, Argaw, A, Frenette, J. The roles of RANK/RANKL/OPG in cardiac, skeletal, and smooth muscles in health and disease. Front Cell Dev Biol 2022;10:903657. https://doi.org/10.3389/fcell.2022.903657.Search in Google Scholar PubMed PubMed Central

15. Boyce, BF, Xing, L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther 2007;9:1–7. https://doi.org/10.1186/ar2165.Search in Google Scholar PubMed PubMed Central

16. Boyce, AM. Denosumab: an emerging therapy in pediatric bone disorders. Curr Osteoporos Rep 2017;15:283–92. https://doi.org/10.1007/s11914-017-0380-1.Search in Google Scholar PubMed PubMed Central

17. Hoyer-Kuhn, H, Rehberg, M, Netzer, C, Schoenau, E, Semler, O. Individualized treatment with denosumab in children with osteogenesis imperfecta – follow up of a trial cohort. Orphanet J Rare Dis 2019;14:219. https://doi.org/10.1186/s13023-019-1197-z.Search in Google Scholar PubMed PubMed Central

18. Tai, R, Mouchaileh, N, Ting, C. Hypocalcaemia and hypophosphataemia following denosumab and IV ferric carboxymaltose in an older patient with normal renal function. J Pharm Pract Res 2022;52:49–52. https://doi.org/10.1002/jppr.1791.Search in Google Scholar

19. Strickling, J, Wilkowski, MJ. Severe, symptomatic hypocalcemia due to denosumab administration: treatment and cinical course. Case Rep Nephrol Dial 2019;9:33–41. https://doi.org/10.1159/000499824.Search in Google Scholar PubMed PubMed Central

20. Jacquillet, G, Unwin, RJ. Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi). Pflugers Arch Eur J Physiol 2019;471:83–98. https://doi.org/10.1007/s00424-018-2231-z.Search in Google Scholar PubMed PubMed Central

21. Ghafouri-Fard, S, Abbasi, F, Azizi, F, Javaheri, M, Mehdizadeh, M, Setoodeh, A. Hyperostosis-hyperphosphatemia syndrome (HHS): report of two cases with a recurrent mutation and review of the literature. J Pediatr Endocrinol Metab 2015;28:231–5. https://doi.org/10.1515/jpem-2014-0178.Search in Google Scholar PubMed

22. Olauson, H, Krajisnik, T, Larsson, C, Lindberg, B, Larsson, TE. A novel missense mutation in GALNT3 causing hyperostosis-hyperphosphataemia syndrome. Eur J Endocrinol 2008;158:929–34. https://doi.org/10.1530/eje-08-0011.Search in Google Scholar

23. Mikati, MA, Melhem, RE, Najjar, SS. The syndrome of hyperostosis and hyperphosphatemia. J Pediatr 1981;99:900–4. https://doi.org/10.1016/s0022-3476(81)80013-3.Search in Google Scholar PubMed

24. Melhem, RE, Najjar, SS, Khachadurian, AK. Cortical hyperostosis with hyperphosphatemia: a new syndrome? J Pediatr 1970;77:986–90. https://doi.org/10.1016/s0022-3476(70)80081-6.Search in Google Scholar PubMed

25. Ursem, SR, Diepenbroek, C, Bacic, V, Unmehopa, UA, Eggels, L, Maya‐Monteiro, CM, et al.. Localization of fibroblast growth factor 23 protein in the rat hypothalamus. Eur J Neurosci 2021;54:5261–71. https://doi.org/10.1111/ejn.15375.Search in Google Scholar PubMed PubMed Central

26. Natsuki, Y, Morioka, T, Fukumoto, S, Kakutani, Y, Yamazaki, Y, Ochi, A, et al.. Role of adiponectin in the relationship between visceral adiposity and fibroblast growth factor 23 in non-diabetic men with normal kidney function. Endocr J 2022;69:121–9. https://doi.org/10.1507/endocrj.ej21-0185.Search in Google Scholar

27. Filipski, KJ, Sammons, MF, Bhattacharya, SK, Panteleev, J, Brown, JA, Loria, PM, et al.. Discovery of orally bioavailable selective inhibitors of the sodium-phosphate cotransporter NaPi2a (SLC34A1). ACS Med Chem Lett 2018;9:440–5. https://doi.org/10.1021/acsmedchemlett.8b00013.Search in Google Scholar PubMed PubMed Central

28. Courbebaisse, M, Lanske, B. Biology of fibroblast growth factor 23: from physiology to pathology. Cold Spring Harb Perspect Med 2018;8:a031260. https://doi.org/10.1101/cshperspect.a031260.Search in Google Scholar PubMed PubMed Central

Received: 2025-05-18

Accepted: 2025-09-03

Published Online: 2025-11-18

Published in Print: 2025-12-17

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/jpem-2025-0272

Keywords for this article

denosumab; hyperphosphatemia; FGF23; RANKL