Skip to main content

Advertisement

SpringerLink
Log in

Oncogenic osteomalacia and metastatic breast cancer: a case report and review of the literature

  • Case Report
  • Published:
Journal of Diabetes & Metabolic Disorders Aims and scope Submit manuscript

Abstract

Objectives

Oncogenic osteomalacia is a rare paraneoplastic metabolic syndrome that is characterised by severe hypophosphataemia, hyperphosphaturia and osteomalacia secondary to renal loss of phosphate. It is commonly caused by overproduction of fibroblast growth factor-23 (FGF23) from benign tumours of mesenchymal origin. Currently, there is no clear evidence on the management of oncogenic osteomalacia in patients with metastatic solid tumours.

Methods

We report a case of breast cancer-induced oncogenic osteomalacia and discuss its diagnosis and management.

Results

A 71-year-old woman with advanced breast cancer developed symptomatic oncogenic osteomalacia with raised FGF23, severe hypophosphataemia and hypocalcaemia. The electrolytic disturbances were exacerbated after the administration of bisphosphonates in the context of her oncological treatment. Systemic chemotherapy and maintenance endocrine treatment along with phosphate and calcium supplementation reduced the activity of oncogenic osteomalacia and resolved the electrolytic imbalances.

Conclusions

To our knowledge, this is the first reported case of oncogenic osteomalacia in a patient with breast cancer. Oncogenic osteomalacia constitutes a diagnostic and therapeutic challenge. Pre-clinical and clinical evidence suggest that a possible underlying mechanism is the presence of molecular alterations in the FGF/FGFR signalling pathway leading to overexpression of FGF23. In metastatic setting, anticancer treatment can potentially lead to the normalisation of the electrolytic disturbances and reduction of the activity of oncogenic osteomalacia. The use of antiresorptive therapy in patients with bone metastases can potentially trigger FGF23 overexpression. Its use should be guided by the patients’ risk of skeletal-related events and electrolytic disturbances as well as the degree of activity of oncogenic osteomalacia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Alonso G, Varsavsky M. Tumour-induced osteomalacia: an emergent paraneoplastic syndrome. Endocrinol Nutr. 2016;63(4):181–6.

    Article  PubMed  Google Scholar 

  2. Huang X, Jiang Y, Xia W. FGF23 and phosphate wasting disorders. Bone Res. 2013;1(2):120–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Florenzano P, Gafni RI, Collins MT. Tumor-induced osteomalacia. Bone Rep. 2017;7:90–7.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hu F, et al. Quantitative ELISA-like immunohistochemistry of fibroblast growth factor 23 in diagnosis of tumor-induced Osteomalacia and clinical characteristics of the disease. Dis Markers. 2016;2016:3176978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lee EK, Martinez MCR, Blakely K, Santos KD, Hoang VC, Chow A, et al. FGF23: mediator of poor prognosis in a sizeable subgroup of patients with castration-resistant prostate cancer presenting with severe hypophosphatemia? Med Hypotheses. 2014;83(4):482–7.

    Article  CAS  PubMed  Google Scholar 

  6. Jiang Y, Xia WB, Xing XP, Silva BC, Li M, Wang O, et al. Tumor-induced osteomalacia: an important cause of adult-onset hypophosphatemic osteomalacia in China: report of 39 cases and review of the literature. J Bone Miner Res. 2012;27(9):1967–75.

    Article  PubMed  Google Scholar 

  7. Larsson T, Marsell R, Schipani E, Ohlsson C, Ljunggren Ö, Tenenhouse HS, et al. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology. 2004;145(7):3087–94.

    Article  CAS  PubMed  Google Scholar 

  8. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004;19(3):429–35.

    Article  CAS  PubMed  Google Scholar 

  9. Guo YC, Yuan Q. Fibroblast growth factor 23 and bone mineralisation. Int J Oral Sci. 2015;7(1):8–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Minisola S, Peacock M, Fukumoto S, Cipriani C, Pepe J, Tella SH, et al. Tumour-induced osteomalacia. Nat Rev Dis Primers. 2017;3:17044.

    Article  PubMed  Google Scholar 

  11. Hannan FM, Athanasou NA, Teh J, Gibbons CLMH, Shine B, Thakker RV. Oncogenic hypophosphataemic osteomalacia: biomarker roles of fibroblast growth factor 23, 1,25-dihydroxyvitamin D3 and lymphatic vessel endothelial hyaluronan receptor 1. Eur J Endocrinol. 2008;158(2):265–71.

    Article  CAS  PubMed  Google Scholar 

  12. Shimada T, Yamazaki Y, Takahashi M, Hasegawa H, Urakawa I, Oshima T, et al. Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Ren Physiol. 2005;289(5):F1088–95.

    Article  CAS  Google Scholar 

  13. Dey B, Gochhait D, Subramanian H, Ponnusamy M. Oncogenic Osteomalacia: an approach to diagnosis with a case report. J Clin Diagn Res. 2017;11(4):Ed05–ed07.

    PubMed  PubMed Central  Google Scholar 

  14. Reinert RB, Bixby D, Koenig RJ. Fibroblast growth factor 23-induced hypophosphatemia in acute leukemia. J Endocr Soc. 2018;2(5):437–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Okamiya T, Takahashi K, Kamada H, Hirato J, Motoi T, Fukumoto S, et al. Oncogenic osteomalacia caused by an occult paranasal sinus tumor. Auris Nasus Larynx. 2015;42(2):167–9.

    Article  PubMed  Google Scholar 

  16. Elderman JH, Wabbijn M, de Jongh F. Hypophosphataemia due to FGF-23 producing B cell non-Hodgkin's lymphoma. BMJ Case Rep. 2016;2016:bcr2015213954. https://doi.org/10.1136/bcr-2015-213954.

  17. Rodriguez-Velver KV, Endocrinology Division, University Hospital “Dr. Jose E. Gonzalez”, Medical School, Autonomous University of Nuevo Leon, Monterrey, Mexico, Zapata-Rivera MA, Endocrinology Division, University Hospital “Dr. Jose E. Gonzalez”, Medical School, Autonomous University of Nuevo Leon, Monterrey, Mexico, Montes-Villarreal J, Endocrinology Division, University Hospital “Dr. Jose E. Gonzalez”, Medical School, Autonomous University of Nuevo Leon, Monterrey, Mexico, et al. Tumour-induced Osteomalacia secondary to a sarcoma. Eur Endocrinol. 2016;12(2):104–6.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Abate EG, Bernet V, Cortese C, Garner HW. Tumor induced osteomalacia secondary to anaplastic thyroid carcinoma: a case report and review of the literature. Bone Rep. 2016;5:81–5.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sauder A, Wiernek S, Dai X, Pereira R, Yudd M, Patel C, et al. FGF23-associated tumor-induced Osteomalacia in a patient with small cell carcinoma: a case report and regulatory mechanism study. Int J Surg Pathol. 2016;24(2):116–20.

    Article  CAS  PubMed  Google Scholar 

  20. Mak MP, da Costa e Silva VT, Martin RM, Lerario AM, Yu L, Hoff PMG, et al. Advanced prostate cancer as a cause of oncogenic osteomalacia: an underdiagnosed condition. Support Care Cancer. 2012;20(9):2195–7.

    Article  PubMed  Google Scholar 

  21. Leaf DE, Pereira RC, Bazari H, Jüppner H. Oncogenic osteomalacia due to FGF23-expressing colon adenocarcinoma. J Clin Endocrinol Metab. 2013;98(3):887–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tanner Y, Grose RP. Dysregulated FGF signalling in neoplastic disorders. Semin Cell Dev Biol. 2016;53:126–35.

    Article  CAS  PubMed  Google Scholar 

  23. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. https://doi.org/10.1038/nature11412.

  24. Touat M, Ileana E, Postel-Vinay S, Andre F, Soria JC. Targeting FGFR signaling in Cancer. Clin Cancer Res. 2015;21(12):2684–94.

    Article  CAS  PubMed  Google Scholar 

  25. Martin A, David V, Quarles LD. Regulation and function of the FGF23/klotho endocrine pathways. Physiol Rev. 2012;92(1):131–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sharpe R, Pearson A, Herrera-Abreu MT, Johnson D, Mackay A, Welti JC, et al. FGFR signaling promotes the growth of triple-negative and basal-like breast cancer cell lines both in vitro and in vivo. Clin Cancer Res. 2011;17(16):5275–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Xiao L, Naganawa T, Lorenzo J, Carpenter TO, Coffin JD, Hurley MM. Nuclear isoforms of fibroblast growth factor 2 are novel inducers of hypophosphatemia via modulation of FGF23 and KLOTHO. J Biol Chem. 2010;285(4):2834–46.

    Article  CAS  PubMed  Google Scholar 

  28. Sequist LV, et al. Abstract CT326: phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors. Cancer Res. 2014;74(19 Suppl):CT326.

  29. Miller CB, et al. Response of tumor-induced osteomalacia (TIO) to the FGFR inhibitor BGJ398. J Clin Oncol 2016;34(15_suppl):e22500–e22500

  30. Miller RP, Tadagavadi RK, Ramesh G, Reeves WB. Mechanisms of cisplatin nephrotoxicity. Toxins. 2010;2(11):2490–518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chong WH, Molinolo AA, Chen CC, Collins MT. Tumor-induced osteomalacia. Endocr Relat Cancer. 2011;18(3):R53–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Martin M, Bell R, Bourgeois H, Brufsky A, Diel I, Eniu A, et al. Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid. Clin Cancer Res. 2012;18(17):4841–9.

    Article  CAS  PubMed  Google Scholar 

  33. Body JJ, Bone HG, de Boer RH, Stopeck A, van Poznak C, Damião R, et al. Hypocalcaemia in patients with metastatic bone disease treated with denosumab. Eur J Cancer. 2015;51(13):1812–21.

    Article  CAS  PubMed  Google Scholar 

  34. Liamis G, Milionis HJ, Elisaf M. Medication-induced hypophosphatemia: a review. QJM-Int J Med. 2010;103(7):449–59.

  35. Vervloet MG, van Ittersum FJ, Buttler RM, Heijboer AC, Blankenstein MA, ter Wee PM. Effects of dietary phosphate and calcium intake on fibroblast growth factor-23. Clin J Am Soc Nephrol: CJASN. 2011;6(2):383–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We appreciate the patient and her family for their cooperation in this case report.

Author information

Authors and Affiliations

  1. Cancer Sciences Unit, Centre for Cancer Immunology, Faculty of Medicine, University Of Southampton, Tremona Road, Southampton, SO16 6YD, UK

    Constantinos Savva

  2. Translational Oncology, Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, NG51 PB, UK

    Constantinos Savva, Jason Adhikaree & Srinivasan Madhusudan

  3. Department of Oncology, Nottingham University Hospitals NHS Trust, Nottingham, NG5 1PB, UK

    Jason Adhikaree & Srinivasan Madhusudan

  4. Department of Endocrinology and Metabolic Medicine, Nottingham University Hospitals NHS Trust, Nottingham, NG5 1PB, UK

    Kamal Chokkalingam

Authors
  1. Constantinos Savva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jason Adhikaree
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Srinivasan Madhusudan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kamal Chokkalingam
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CS and JA managed the patient and wrote the manuscript. SM and KC supervised the management of the case, revised critically and approved the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Constantinos Savva.

Ethics declarations

The authors declare that they did not have any industrial links of affiliations.

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Written informed consent was obtained from the patient for publication of this case report.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Savva, C., Adhikaree, J., Madhusudan, S. et al. Oncogenic osteomalacia and metastatic breast cancer: a case report and review of the literature. J Diabetes Metab Disord 18, 267–272 (2019). https://doi.org/10.1007/s40200-019-00398-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40200-019-00398-y

Keywords

Search

Navigation