July 2020 – Clinical Chemistry: Case 2

A 60 year old male reported ongoing bone and joint pain that had left him immobile. The patient had a heart transplant 11 years prior and is on an immunosuppression regimen of cyclosporine, mycophenolate, and prednisone. He also takes voriconazole for a chronic pulmonary/ocular Aspergillus infection and is prescribed intermittent topical fluorouracil for actinic keratoses.

To investigate the bone pain symptoms, a plasma fluoride test was ordered.

Which of the following medications caries a known risk for fluoride toxicity?

  • Mycophenolate
  • Cyclosporine
  • Voriconazole
  • Fluorouracil

The correct answer is...

The correct answer is Voriconazole.

Pulmonary aspergillosis, an infection of the lungs by fungi in the genus Asperillus typically requires lifelong anti-fungal therapy. Voriconazole, a triazole antifungal medication, is the first-line treatment for this disorder.1 It is thought that the fluoride atoms on voriconazole can be released into the body in some patients, leading an increase in blood fluoride level.2

High levels of fluoride increase osteoblast activity which in turn increases bone formation.3 However, the new bone that is created is more brittle and is more susceptible to fractures. The new bone is primarily fluoroapatite compared with normal bone which is composed of hydroxyapatite.4 The fluoride will also infiltrate tendons, ligaments, and muscles through mineral deposits.3 What is often seen is that patients with high fluoride levels exhibit periostitis and exostoses, which can explain this patient’s symptoms.4

When considering voriconazole-induced periostitis, three blood tests are ordered: voriconazole, alkaline phosphatase, and fluoride. High alkaline phosphatase is a good indicator of bone turnover. Interestingly, blood fluoride is one of the few blood tests that are performed using an ion-selective electrode (along with potassium, sodium, chloride, and calcium). Bone density scans may also be ordered to determine the extent of the periostitis, but may not always be performed on the areas most affecting the patient.

In this patient’s case, the alkaline phosphatase levels had been elevated for a prolonged period of time. His voriconazole levels were not higher than expected, but due to his prolonged treatment with the medication, high alkaline phosphatase, high fluoride level, and other clinical symptoms he was switched from voriconazole to itraconazole. Itraconazole, another antifungal medication useful for aspergillosis, notably does not contain any fluorine atoms in its chemical structure.5


1. Adwan, M. Voriconazole-induced periostitis: a new rheumatic disorder. Clinical Rheumatology, 2017;36:609-615
2. Wermers R, Cooper K, et al. Fluoride Excess and Periostitis in Translant Patients Receiving Long-Term Voriconazole Therapy. Clinical Infectious Diseases, 2011;52(5):604-611
3. Sellami M, Riahi H, et al. Skeletal fluorosis, don’t miss the diagnosis! Skeletal Radiology, 2020;49:345-357
4. Tan I, Lomasney L, et al. Spectrum of Voriconazole-Induced Periostitis With Review of the Differential Diagnosis. American Journal of Roentgenology, 2019;212:157-165
5. Thompson III G, Bays D, et al. Fluoride Excess in Coccidioidomycosis Patients Receiving Long-Term Antifungal Therapy: an Assessment of Currently Available Triazoles. Antimicrobial Agents and Chemotherapy, 2012;56(1):563-564

Nicholas Larkey, Ph.D.
Fellow, Clinical Chemistry
Mayo Clinic
Image of Paul Jannetto, Ph.D. Associate Professor of Laboratory Medicine and Pathology, Division of Clinical Biochemistry, Mayo Clinic, Rochester, Minnesota Paul Jannetto, Ph.D.
Consultant, Clinical Biochemistry
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

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