Skip to main content

Advertisement

SpringerLink
Log in

FGF23-related hypophosphatemia in patients with low bone mineral density and fragility fractures: challenges in diagnosis and management

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Purpose

Hypophosphatemia (HP) can be observed in patients evaluated for skeletal fragility. We investigated prevalence of HP among outpatients referred for low bone density or fragility fractures, HP-associated clinical and biochemical features and outcomes of recommended diagnostic algorithm in our cohort.

Methods

Chronic HP (phosphate ≤ 2.7 mg/dL over 6 months or longer) was retrospectively investigated among 2319 patients. In renal wasting-related HP, intact FGF23 was assessed; non-suppressed FGF23 prompted the performance of 68Ga-DOTATOC PET/CT in the suspicion of tumor-induced steomalacia (TIO).

Results

Renal wasting-related HP (median 2.2, range 1.6–2.6 mg/dL) was observed in 19 patients (0.82%). FGF23 levels were suppressed in two patients diagnosed with renal tubular disease, increased in one and within normal range in most patients. X-linked hypophosphatemic rickets was diagnosed in one woman. In the remaining 16 patients, highly prevalent fragility fractures (50%) and severely reduced bone mineral density were detected, though diagnostic criteria for osteomalacia were not fulfilled. 68Ga-PET was performed in nine patients and was positive in four. While intact FGF23 levels alone failed to differentiate PET’s outcomes (positive: FGF23 median 70.5 pg/mL; negative: 52 pg/mL, P = 0.462), the coexistence of multiple biochemical and radiologic alterations performed better in prediction of PET’s positivity.

Conclusion

Mild, apparently unexplained HP is observed in 0.82% of patients with low bone density or fragility fractures. In asymptomatic patients with isolated mild hypophosphatemia, the probability of finding an underlying tumor disease is very low, and utility of extensive and expensive diagnostic workup should be carefully considered in this setting.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Christov M, Jüppner H (2018) Phosphate homeostasis disorders. Best Pract Res Clin Endocrinol Metab 32:685–706. https://doi.org/10.1016/j.beem.2018.06.004

    Article  CAS  PubMed  Google Scholar 

  2. Marcucci G, Masi L, Ferrarì S, Haffner D (2018) Phosphate wasting disorders in adults. Osteoporos Int 23:2369–2387. https://doi.org/10.1007/s00198-018-4618-2

    Article  CAS  Google Scholar 

  3. Khalil R, Kim NR, Jardi F, Vanderschueren D, Claessens F, Decallonne B (2018) Sex steroids and the kidney: role in renal calcium and phosphate handling. Mol Cell Endocrinol 465:61–72. https://doi.org/10.1016/j.mce.2017.11.011

    Article  CAS  PubMed  Google Scholar 

  4. Cannata-Andía JB, Carrillo-López N, Naves-Díaz M (2010) Estrogens and bone disease in chronic kidney disease: role of FGF23. Curr Opin Nephrol Hypertens 19:21–25. https://doi.org/10.1097/MNH.0b013e328338f508

    Article  CAS  Google Scholar 

  5. Carrillo-López N, Román-García P, Rodríguez-Rebollar A, Fernández-Martín JL, Naves-Díaz M, Cannata-Andía JB (2009) Indirect regulation of PTH by estrogens may require FGF23. J Am Soc Nephrol 20:2009–2017. https://doi.org/10.1681/ASN.2008121258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Weisinger JR, Bellorín-Font E (1998) Electrolyte quintet magnesium and phosphorus. Lancet 352:391–396

    Article  CAS  Google Scholar 

  7. Gaasbeek A, Meinders AE (2005) Hypophosphatemia: an update on its etiology and treatment. Am J Med 118:1094–1101

    Article  CAS  Google Scholar 

  8. Laroche M, Boyer JF, Jahafar H, Allard J, Tack I (2009) Normal FGF23 levels in adult idiopathic phosphate diabetes. Calcif Tissue Int 84:112–117. https://doi.org/10.1007/s00223-008-9204-8

    Article  CAS  PubMed  Google Scholar 

  9. Bech AP, Hoorn EJ, Zietse R, Wetzels JFM, Nijenhuis T (2018) Yield of diagnostic tests in unexplained renal hypophosphatemia: a case series. BMC Nephrol 19:220. https://doi.org/10.1186/s12882-018-1017-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Deal C, Omizo M, Schwartz EN, Eriksen EF, Cantor P, Wang J, Glass EV, Myers SL, Krege JH (2005) Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial. J Bone Miner Res 20:1905–1911. https://doi.org/10.1359/JBMR.050714

    Article  CAS  PubMed  Google Scholar 

  11. Anastasilakis AD, Polyzos SA, Goulis DG, Slavakis A, Efstathiadou Z, Kita M, Koukoulis G, Avramidis A (2008) Endogenous intact PTH is suppressed during teriparatide (rhPTH 1-34) administration in postmenopausal women with established osteoporosis. Endocr J 55:613–616

    Article  CAS  Google Scholar 

  12. Palmerini E, Chawla NS, Ferrari S, Sudan M, Picci P, Marchesi E, Leopardi MP, Syed I, Sankhala KK, Parthasarathy P, Mendanha WE, Pierini M, Paioli A, Chawla SP (2017) Denosumab in advanced/unresectable giant-cell tumour of bone (GCTB): for how long? Eur J Cancer 76:118–124. https://doi.org/10.1016/j.ejca.2017.01.028

    Article  CAS  PubMed  Google Scholar 

  13. Watkins KR, Rogers JE, Atkinson B (2015) Tolerability of denosumab in metastatic solid tumor patients with renal insufficiency. Support Care Cancer 23:1657–1662. https://doi.org/10.1007/s00520-014-2521-8

    Article  PubMed  Google Scholar 

  14. Stuss M, Sewerynek E, Król I, Stępień-Kłos W, Jędrzejczyk S (2016) Assessment of OPG, RANKL, bone turnover markers serum levels, and BMD after treatment with strontium ranelate and ibandronate in patients with postmenopausal osteoporosis. Endokrynol Pol 67:174–184. https://doi.org/10.5603/EP.a2016.0014

    Article  CAS  PubMed  Google Scholar 

  15. Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev N (1994) The diagnosis of osteoporosis. J Bone Miner Res 9:1137–1141

    Article  CAS  Google Scholar 

  16. Lewiecki EM, Gordon CM, Baim S, Leonard MB, Bishop NJ, Bianchi ML, Kalkwarf HJ, Langman CB, Plotkin H, Rauch F, Zemel BS, Binkley N, Bilezikian JP, Kendler DL, Hans DB, Silverman S (2008) International society for clinical densitometry 2007 adult and pediatric official positions. Bone 43:1115–1121. https://doi.org/10.1016/j.bone.2008.08.106

    Article  PubMed  Google Scholar 

  17. Genant HK, Wu CY, van Kuijk C, Nevitt MC (1993) Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8:1137–1148

    Article  CAS  Google Scholar 

  18. D’Oronzo S, Stucci S, Tucci M, Silvestris F (2015) Cancer treatment-induced bone loss (CTIBL): pathogenesis and clinical implications. Cancer Treat Rev 41:798–808. https://doi.org/10.1016/j.ctrv.2015.09.003

    Article  PubMed  Google Scholar 

  19. Fukumoto S, Ozono K, Michigami T, Minagawa M, Okazaki R, Sugimoto T, Takeuchi Y, Matsumoto T (2015) Pathogenesis and diagnostic criteria for rickets and osteomalacia-proposal by an expert panel supported by the Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research, and the Japan Endocrine Society. J Bone Miner Metab 33:467–473. https://doi.org/10.1507/endocrj.EJ15-0289

    Article  PubMed  Google Scholar 

  20. Day AL, Morgan SL, Saag KG (2018) Hypophosphatemia in the setting of metabolic bone disease: case reports and diagnostic algorithm. Ther Adv Musculoskelet Dis 10:151–156. https://doi.org/10.1177/1759720X18779761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Imel EA, Econs MJ (2012) Approach to the hypophosphatemic patient. J Clin Endocrinol Metab 97:696–706. https://doi.org/10.1210/jc.2011-1319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Walton RJ, Bijvoet OL (1975) Nomogram for derivation of renal threshold phosphate concentration. Lancet 2:309–310

    Article  CAS  Google Scholar 

  23. Souberbielle JC, Prié D, Piketty ML, Rothenbuhler A, Delanaye P, Chanson P, Cavalier E (2017) Evaluation of a new fully automated assay for plasma intact FGF23. Calcif Tissue Int 101:510–518. https://doi.org/10.1007/s00223-017-0307-y

    Article  CAS  PubMed  Google Scholar 

  24. Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, Abeysinghe S, Krawczak M, Cooper DN (2003) Human gene mutation database (HGMD): 2003 update. Hum Mutat 21:577–581. https://doi.org/10.1002/humu.10212

    Article  CAS  PubMed  Google Scholar 

  25. Schwarz JM, Rödelsperger C, Schuelke M, Seelow D (2010) Mutation Taster evaluates disease-causing potential of sequence alterations. NatMethods 7:575–576. https://doi.org/10.1038/nmeth0810-575

    Article  CAS  Google Scholar 

  26. Hebsgaard SM, Korning PG, Tolstrup N, Engelbrecht J, Rouzé P, Brunak S (1996) Splice site prediction in Arabidopsis thaliana DNA by combining local and global sequence information. Nucleic Acids Res 24:3439–3452. https://doi.org/10.1093/nar/24.17.3439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rodrat M, Wongdee K, Panupinthu N, Thongbunchoo J, Teerapornpuntakit J, Krishnamra N, Charoenphandhu N (2017) Prolonged exposure to 1,25(OH)2D3 and high ionized calcium induces FGF-23 production in intestinal epithelium-like Caco-2 monolayer: a local negative feedback for preventing excessive calcium transport. Arch Biochem Biophys 640:10–16. https://doi.org/10.1016/j.abb.2017.12.022

    Article  CAS  Google Scholar 

  28. Mirams M, Robinson BG, Mason RS, Nelson AE (2004) Bone as a source of FGF23: regulation by phosphate? Bone 35:1192–1199. https://doi.org/10.1016/j.bone.2004.06.014

    Article  CAS  PubMed  Google Scholar 

  29. Liamis G, Milionis HJ, Elisaf M (2010) Medication-induced hypophosphatemia: a review. QJM 103:449–459. https://doi.org/10.1093/qjmed/hcq039

    Article  CAS  PubMed  Google Scholar 

  30. Feng J, Jiang Y, Wang O, Li M, Xing X, Huo L, Li F, Yu W, Zhong DR, Jin J, Liu Y, Qi F, Lv W, Zhou L, Meng XW, Xia WB (2017) The diagnostic dilemma of tumor induced osteomalacia: a retrospective analysis of 144 cases. Endocr J 64:675–683. https://doi.org/10.1507/endocrj.EJ16-0587

    Article  PubMed  Google Scholar 

  31. Yu WJ, He JW, Fu WZ, Wang C, Zhang ZL (2016) Reports of 17 Chinese patients with tumor-induced osteomalacia. J Bone Miner Metab 35:298–307. https://doi.org/10.1007/s00774-016-0756-9

    Article  CAS  PubMed  Google Scholar 

  32. González G, Baudrand R, Sepúlveda MF, Vucetich N, Guarda FJ, Villanueva P, Contreras O, Villa A, Salech F, Toro L, Michea L, Florenzano P (2017) Tumor-induced osteomalacia: experience from a South American academic center. Osteoporos Int 28:2187–2193. https://doi.org/10.1007/s00198-017-4007-2

    Article  CAS  PubMed  Google Scholar 

  33. Paquet M, Gauthé M, Zhang Yin J, Nataf V, Bélissant O, Orcel P, Roux C, Talbot JN, Montravers F (2018) Diagnostic performance and impact on patient management of 68 Ga-DOTA-TOC PET/CT for detecting osteomalacia-associated tumours. Eur J Nucl Med Mol Imaging 45:1710–1720. https://doi.org/10.1007/s00259-018-3971-x

    Article  PubMed  Google Scholar 

  34. Breer S, Brunkhorst T, Beil FT, Peldschus K, Heiland M, Klutmann S, Barvencik F, Zustin J, Gratz KF, Amling M (2014) 68 Ga DOTA-TATE PET/CT allows tumor localization in patients with tumor-induced osteomalacia but negative 111In-octreotide SPECT/CT. Bone 64:222–227. https://doi.org/10.1016/j.bone.2014.04.016

    Article  CAS  PubMed  Google Scholar 

  35. Agrawal K, Bhadada S, Mittal BR, Shukla J, Sood A, Bhattacharya A, Bhansali A (2015) Comparison of 18F-FDG and 68 Ga DOTATATE PET/CT in localization of tumor causing oncogenic osteomalacia. Clin Nucl Med 40:6–10. https://doi.org/10.1097/RLU.0000000000000460

    Article  Google Scholar 

  36. Martini G, Valleggi F, Gennari L, Merlotti D, De Paola V, Valenti R, Nuti R (2012) Oncogenic osteomalacia. Clin Cases Miner Bone Metab 3:76–83

    Google Scholar 

  37. Amblee A, Uy J, Senseng C, Hart P (2014) Tumor-induced osteomalacia with normal systemic fibroblast growth factor-23 level. Clin Kidney J 7:186–189. https://doi.org/10.1093/ckj/sfu004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Endo I, Fukumoto S, Ozono K, Namba N, Tanaka H, Inoue D, Minagawa M, Sugimoto T, Yamauchi M, Michigami T, Matsumoto T (2008) Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients. Bone 42:1235–1239. https://doi.org/10.1016/j.bone.2008.02.014

    Article  CAS  PubMed  Google Scholar 

  39. Laroche M (2001) Phosphate, the renal tubule, and the musculoskeletal system. Joint Bone Spine 68:211–215

    Article  CAS  Google Scholar 

  40. Burnett-Bowie SM, Mendoza N, Leder BZ (2007) Effects of gonadal steroid withdrawal on serum phosphate and FGF-23 levels in men. Bone 40:913–918. https://doi.org/10.1016/j.bone.2006.10.016

    Article  CAS  PubMed  Google Scholar 

  41. Zhang D, Maalouf NM, Adams-Huet B, Moe OW, Sakhaee K (2013) Effects of sex and postmenopausal estrogen use on serum phosphorus levels: a cross-sectional study of the National Health and Nutrition Examination Survey (NHANES) 2003–2006. Am J Kidney Dis 63:198–205. https://doi.org/10.1053/j.ajkd.2013.07.012

    Article  CAS  PubMed  Google Scholar 

  42. Bansal N, Katz R, de Boer IH, Kestenbaum B, Siscovick DS, Hoofnagle AN, Tracy R, Laughlin GA, Criqui MH, Budoff MJ, Li D, Ix JH (2013) Influence of estrogen therapy on calcium, phosphorus, and other regulatory hormones in postmenopausal women: the MESA study. J Clin Endocrinol Metab 98:4890–4898. https://doi.org/10.1210/jc.2013-2286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rayamajhi SJ, Yeh R, Wong T, Dumeer S, Mittal BR, Remotti F, Chikeka I, Reddy AK (2019) Tumor-induced osteomalacia—current imaging modalities and a systematic approach for tumor localization. Clin Imaging 56:114–123. https://doi.org/10.1016/j.clinimag.2019.04.007

    Article  PubMed  Google Scholar 

Download references

Funding

The study was partially supported by Italian Ministry of Health (L4126) and by Gruppo San Donato Foundation (Progetto 5x1000 2016 “Osteoregistry”).

Author information

Authors and Affiliations

  1. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

    R. Indirli

  2. Endocrinology Unit, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Milan, Italy

    R. Indirli

  3. Rheumatology Unit, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy

    G. Guabello & M. Longhi

  4. Laboratory of Biotechnological Applications, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy

    S. Niada

  5. Laboratory of Pediatric Endocrinology, IRCCS San Raffaele Institute, Milan, Italy

    K. Maruca & S. Mora

  6. Pediatric Bone Densitometry Service, IRCCS San Raffaele Institute, Milan, Italy

    S. Mora

  7. Division of Pathology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy

    M. Maggioni

  8. Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy

    S. Corbetta

  9. Endocrinology and Diabetology Service, IRCCS Istituto Ortopedico Galeazzi, Via R.Galeazzi 4, 20161, Milan, Italy

    S. Corbetta

Authors
  1. R. Indirli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Guabello
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Longhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Niada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Maruca
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Mora
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Maggioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S. Corbetta
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SC designed the study and performed the critical revision of the manuscript. She is guarantor. RI was responsible for data collection, statistical analysis and manuscript preparation. GG, ML and SC performed the clinical diagnoses and patients’ follow-up. MM was responsible for histopathological examination of tissue samples. SN, KM and SM performed molecular analyses. All authors revised the paper critically for intellectual content and approved the final version. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

Corresponding author

Correspondence to S. Corbetta.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Welfare of animals

This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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

Indirli, R., Guabello, G., Longhi, M. et al. FGF23-related hypophosphatemia in patients with low bone mineral density and fragility fractures: challenges in diagnosis and management. J Endocrinol Invest 43, 787–798 (2020). https://doi.org/10.1007/s40618-019-01165-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-019-01165-9

Keywords

Search

Navigation