Fluoride Action Network


Purpose: Previous knowledge about the relationship between voriconazole exposure and periostitis was mainly based on limited case reports and few retrospective studies. The purpose of this study was to assess the clinical characteristics, diagnosis and management of voriconazole-associated periostitis.

Methods: Case reports and case series from 1998 to November 30, 2021 on periostitis induced by voriconazole were collected for retrospective analysis.

Results: Forty four patients (18 male and 26 female) from 34 studies were included in total. The median age was 58 years (29-74). The majority of patients had undergone organ transplantation (50.0%) or suffered from hematologic malignancy (31.81%). The median onset time of symptoms was 6 months after the start of voriconazole. The most common initial symptom was diffuse skeletal pain (68.28%) which can be severe and even disabling (66.7%). Ribs (37.21%), femurs (32.56%), scapulae (25.58%), humerus (23.26%), and clavicle (23.26%) were the common involved locations. Most cases were accompanied by different degrees of elevated serum alkaline phosphatase and fluoride level, while some presented with elevated bone-specific alkaline phosphatase. The main radiological features included periosteal reaction and multifocal high radiotracer uptake on bone scintigraphy. The formation of new bone was characterized with bilateral, irregular, nodular, as well as high density. The resolution of symptoms was observed with discontinuation of voriconazole in all patients, of whom 18 patients (52.94%) were relieved within a week. Itraconazole, posaconazole or isavuconazole were safe alternatives to voriconazole in voriconazole-induced periostitis.

Conclusion: Voriconazole-induced periostitis is an infrequent complication characterized by bone inflammation involving one or multiple skeletal areas. Bony pain, elevated serum alkaline phosphatase as well as fluoride level are suspicious signs during voriconazole treatment.

Keywords: Fluoride; Periostitis; Pharmacovigilance; Voriconazole.

*Original abstract online at https://link.springer.com/article/10.1007/s15010-022-01795-x



1. Enoch DA, Yang H, Aliyu SH, Micallef C. the changing epidemiology of invasive fungal infections. Methods Mol Biol. 2017;1508:17–65. – PubMed

2. Shi C, Xiao Y, Mao Y, Wu J, Lin N. Voriconazole: a review of population pharmacokinetic analyses. Clin Pharmacokinet. 2019;58:687–703. – PubMed

3. Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet. 2006;45:649–63. – PubMed

4. Benitez LL, Carver PL. Adverse effects associated with long-term administration of azole antifungal agents. Drugs. 2019;79:833–53. – PubMed

5. Levine MT, Chandrasekar PH. Adverse effects of voriconazole: over a decade of use. Clin Transplant. 2016;30:1377–86. – PubMed

6. Wang TF, Wang T, Altman R, Eshaghian P, Lynch JR, Ross DJ, Belperio JA, Weigt SS, Saggar R, Gregson A, Kubak B, Saggar R. Periostitis secondary to prolonged voriconazole therapy in lung transplant recipients. Am J Transplant. 2009;9:2845–50. – PubMed

7. Barajas MR, McCullough KB, Merten JA, Dierkhising RA, Bartoo GT, Hashmi SK, Hogan WJ, Litzow MR, Patnaik MM, Wilson JW, Wolf RC, Wermers RA. Correlation of pain and fluoride concentration in allogeneic hematopoietic stem cell transplant recipients on voriconazole. Biol Blood Marrow Transplant. 2016;22:579–83. – PubMed

8. Moon WJ, Scheller EL, Suneja A, Livermore JA, Malani AN, Moudgal V, Kerr LE, Ferguson E, Vandenberg DM. Plasma fluoride level as a predictor of voriconazole-induced periostitis in patients with skeletal pain. Clin Infect Dis. 2014;59:1237–45. – PubMed PMC

9. Metayer B, Bode-Milin C, Ansquer C, Haloun A, Maugars Y, Berthelot J. Painful and swollen hands 3 months after lungs graft: suracute voriconazole-induced periostitis and exostosis. Joint Bone Spine. 2017;84:97–8. – PubMed

10. Becce F, Malghem J, Lecouvet FE, Vande Berg BC, Omoumi P. Voriconazole-induced periostitis deformans. Arthritis Rheum. 2012;64:3490. – PubMed

11. Fernandez AD, Diehl M, Degrave AM, Buttazzoni M, Pereira T, Aguirre MA, Basquiera AL, Scolnik M. Voriconazole-induced periostitis. Reumatismo. 2021;73:44–7.

12. Kelley KD, Thompson GR, Aronowitz P. Mimicking multiple myeloma: voriconazole-induced hyperfluorosis and bone lesions. J Gen Intern Med. 2020;35:932. – PubMed

13.Ladak K, Rubin L. Voriconazole-induced periostitis deformans: a mimicker of hypertrophic pulmonary osteoarthropathy. Clin Med Res. 2017;15(1–2):19–20. – PubMed PMC

14. Glushko T, Colmegna I. Voriconazole-induced periostitis. CMAJ. 2015;187:1075. – PubMed PMC

15. Rad B, Saleem M, Grant S, Florkowski C, Coates P, Gordon D, Rankin W. Fluorosis and periostitis deformans as complications of prolonged voriconazole treatment. Ann Clin Biochem. 2015;52:611–4. – PubMed

16. Khawar T, Hamann CR, Haghshenas A, Blackburn A, Torralba KD. A 31-year-old man with a fungal infection, elevated alkaline phosphatase level, and polyarthritis. Arthritis Care Res. 2020;72:601–6.

17. Baird JH, Birnbaum BK, Porter DL, Frey NV. Voriconazole-induced periostitis after allogeneic stem cell transplantation. Am J Hematol. 2015;90:574–5. – PubMed

18. Paudyal S, Dummer S, Battu P, Taylor S, Sharma S, Carbone L. Fluffy Periostitis Induced by Voriconazole. Arthritis & Rheumatology. 2015;67:3297.

19. Hirota K, Yasoda A, Fujii T, Inagaki N. Voriconazole-induced periostitis in a patient with overlap syndromes. Case Reports. 2014;2014:bcr2013203485.

20. Skaug M, Spak C, Oza U. Painful periostitis in the setting of chronic voriconazole therapy. Proc (Bayl Univ Med Cent). 2014;27:350–2.

21. Cormican S, Adams N, O Connell P, McErlean A, de Freitas D. Voriconazole-induced periostitis deformans: serial imaging in a patient with ANCA vasculitis. Skeletal Radiol. 2018;47:191–4. – PubMed

22. Skiles JL, Imel EA, Christenson JC, Bell JE, Hulbert ML. Fluorosis because of prolonged voriconazole therapy in a teenager with acute myelogenous leukemia. J Clin Oncol. 2011;29:e779–82. – PubMed

23. Malek AE, Skaff Y, Mulanovich VE. Voriconazole-induced periostitis in stem cell transplant patient. Infection. 2020;48:809–10. – PubMed

24. Hedrick J, Droz N. Voriconazole-Induced Periostitis. N Engl J Med. 2019;381:e30. – PubMed

25. Lustenberger DP, Granata JD, Scharschmidt TJ. Periostitis secondary to prolonged voriconazole therapy in a lung transplant recipient. Orthopedics. 2011;34:e793-796. – PubMed

26. Tarlock K, Johnson D, Cornell C, Parnell S, Meshinchi S, Baker KS, Englund JA. Elevated fluoride levels and periostitis in pediatric hematopoietic stem cell transplant recipients receiving long-term voriconazole. Pediatr Blood Cancer. 2015;62:918–20. – PubMed

27. Tailor TD, Richardson ML. Case 215: voriconazole-induced periostitis. Radiology. 2015;274:930–5. – PubMed

28. Raghavan M, Hayes A. Voriconazole-associated soft tissue ossification: an undescribed cause of glenohumeral joint capsulitis. Skeletal Radiol. 2014;43:1301–5. – PubMed

29. Reber JD, McKenzie GA, Broski SM. Voriconazole-induced periostitis: beyond post-transplant patients. Skeletal Radiol. 2016;45:839–42. – PubMed

30. Rossier C, Dunet V, Tissot F, Aubry-Rozier B, Marchetti O, Boubaker A. Voriconazole-induced periostitis. Eur J Nucl Med Mol Imaging. 2012;39:375–6. – PubMed

31. Poinen K, Leung M, Wright AJ, Landsberg D. A vexing case of bone pain in a renal transplant recipient: voriconazole-induced periostitis. Transpl Infect Dis. 2018;20:e12941. – PubMed

32. Gayán Belmonte MJ, Botía González CM, GarcíaGerónimo A, MartínezFernández M, González Moreno IM. Voriconazole-Induced Periostitis. J Clin Rheumatol. 2019;25:e67. – PubMed

33. Haemels M, Pans S, Schoemans H, Goffin K, Gheysens O, Jentjens S. Voriconazole-induced periostitis after allogeneic stem cell transplantation. Clin Nucl Med. 2019;44:159–60. – PubMed

34. Gladue HS, Fox DA. Voriconazole-induced periostitis causing arthralgias mimicking a flare of granulomatosis with polyangiitis. J Clin Rheumatol. 2013;19:444–5. – PubMed

35. Chen L, Mulligan ME. Medication-induced periostitis in lung transplant patients: periostitis deformans revisited. Skeletal Radiol. 2011;40:143–8. – PubMed

36. Wermers RA, Cooper K, Razonable RR, Deziel PJ, Whitford GM, Kremers WK, Moyer TP. Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy. Clin Infect Dis. 2011;52:604–11. – PubMed

37. Gerber B, Guggenberger R, Fasler D, Nair G, Manz MG, Stussi G, Schanz U. Reversible skeletal disease and high fluoride serum levels in hematologic patients receiving voriconazole. Blood. 2012;120:2390–4. – PubMed

38. Elmore S, Wisse A, Chapin RW, Whelan TP, Silver RM. Voriconazole-associated periostitis presenting as hypertrophic osteoarthropathy following lung transplantation report of two cases and review of the literature. Semin Arthritis Rheum. 2019;49:319–23. – PubMed

39. Sircar M, Kotton C, Wojciechowski D, Safa K, Gilligan H, Heher E, Williams W, Thadhani R, Tolkoff-Rubin N. Voriconazole-induced periostitis & enthesopathy in solid organ transplant patients: case reports. J Biosci Med. 2016;04:8–17.

40. Bucknor MD, Gross AJ, Link TM. Voriconazole-induced periostitis in two post-transplant patients. J Radiol Case Rep. 2013;7:10–7. – PubMed PMC

41. Rheinboldt M, Delproposto Z, Agarwal R. Voriconazole-induced periostitis post transplant: an illustrative review of thoracic computed tomography imaging manifestations. Transpl Infect Dis. 2015;17:859–63. – PubMed

42. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45. – PubMed

43. Rana RS, Wu JS, Eisenberg RL. Periosteal reaction. AJR Am J Roentgenol. 2009;193:W259–72. – PubMed

44. Adwan MH. Voriconazole-induced periostitis: a new rheumatic disorder. Clin Rheumatol. 2017;36:609–15. – PubMed

45. Thompson GR, Bays D, Cohen SH, Pappagianis D. Fluoride excess in coccidioidomycosis patients receiving long-term antifungal therapy: an assessment of currently available triazoles. Antimicrob Agents Chemother. 2011;56:563–4. – PubMed

46. Pei J, Li B, Gao Y, Wei Y, Zhou L, Yao H, Wang J, Sun D. Fluoride decreased osteoclastic bone resorption through the inhibition of NFATc1 gene expression. Environ Toxicol. 2014;29:588–95. – PubMed

47. Allen KC, Sanchez CJ, Niece KL, Wenke JC, Akers KS. Voriconazole enhances the osteogenic activity of human osteoblasts in vitro through a fluoride-independent mechanism. Antimicrob Agents Chemother. 2015;59(12):7205–13. – PubMed PMC

48. Schumacher HJ. Hypertrophic osteoarthropathy: rheumatologic manifestations. Clin Exp Rheumatol. 1992;10:35–40. – PubMed