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

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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.

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Data availability

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

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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

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  1. R. Indirli
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  2. G. Guabello
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  3. M. Longhi
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  4. S. Niada
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  5. K. Maruca
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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.

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Correspondence to S. Corbetta.

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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.

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

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

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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

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