Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy.
BACKGROUND
We describe a heart transplant patient with painful periostitis and exostoses who was receiving long-term therapy with voriconazole, which is a fluoride-containing medication. Elevated plasma and bone fluoride levels were identified. Discontinuation of voriconazole therapy led to improvement in pain and reduced fluoride and alkaline phosphatase levels.


METHODS
To determine whether voriconazole is a cause of fluoride excess, we measured plasma fluoride levels in 10 adult post-transplant patients who had received voriconazole for at least 6 months and 10 post-transplant patients who did not receive voriconazole. To assess the effect of renal insufficiency on fluoride levels in subjects receiving voriconazole, half were recruited on the basis of a serum creatinine level of ≥1.4 mg/dL on their most recent measurement, whereas the other 5 subjects receiving voriconazole had serum creatinine levels <1.4 mg/dL. All control subjects had serum creatinine levels of ≥1.4 mg/dL. Patients were excluded from the study if they received a fluorinated pharmaceutical other than voriconazole.


RESULTS
All subjects who received voriconazole had elevated plasma fluoride levels, and no subjects in the control group had elevated levels (14.32 μmol/L ± 6.41 vs 2.54 ± 0.67 μmol/L; P<.001). Renal function was not predictive of fluoride levels. Plasma fluoride levels remained significantly higher in the voriconazole group after adjusting for calcineurin inhibitor levels and doses. Half of the voriconazole group subjects had evidence of periostitis, including exostoses in 2 patients. Discontinuation of voriconazole therapy in patients with periostitis resulted in improvement of pain and a reduction in alkaline phosphatase and fluoride levels.


CONCLUSIONS
Voriconazole is associated with painful periostitis, exostoses, and fluoride excess in post-transplant patients with long-term voriconazole use.
Department of Internal Medicine, Division of Endocrinology, Diabetes, Nutrition, and Metabolism, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA. wermers.robert@mayo.edu
Robert A
RA
Wermers
Kay
K
Cooper
Raymund R
RR
Razonable
Paul J
PJ
Deziel
Gary M
GM
Whitford
Walter K
WK
Kremers
Thomas P
TP
Moyer
D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D000935:Antifungal Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D005096:Exostoses / Q000139:chemically induced; D005260:Female; D005459:Fluorides / Q000097:blood*; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010522:Periostitis / Q000139:chemically induced*; D010949:Plasma / Q000737:chemistry; D011743:Pyrimidines / Q000009:adverse effects* / Q000627:therapeutic use*; D014180:Transplantation; D014230:Triazoles / Q000009:adverse effects* / Q000627:therapeutic use*; D065819:Voriconazole
D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D000469:Alkaline Phosphatase; D065819:Voriconazole; D005459:Fluorides