Diffuse bone pain occurs in a wide range of conditions, and in the setting of prolonged pain associated with bony changes, careful investigation is warranted. The differential of such a presentation includes a variety of metabolic processes, but is also concerning for the possibility of a primary or metastatic neoplastic process. Classically, periosteal involvement can produce significant pain due to the abundant innervation of the periosteum,1 and thus should be a principal consideration in bone pain; imaging is central in elucidating bone pain etiology.
We encountered a 30-year-old woman with a history of double lung transplant in 2005 secondary to cystic fibrosis. She subsequently developed multiple painful bony growths. She was followed for years for these growths and was evaluated by a rheumatologist and endocrinologist. Despite her multiple comorbidities, her foremost report was pain from the bony growths.
In our patient, radiographic findings of the hands showed multifocal periostitis. The focused differential of such a presentation, in light of the patient’s presentation, includes hypertrophic osteoarthropathy2 and periostitis deformans.3
Hypertrophic osteoarthropathy is a syndrome comprising digital clubbing, periostitis, and arthritis.2 It is associated with numerous internal disease processes, including intrathoracic neoplasms and chronic pulmonary infections.2 Primary hypertrophic osteoarthropathy, known as pachydermoperiostosis, is a hereditary variety and has not been shown to indicate an underlying illness.2
The term periostitis deformans was originally introduced to describe periostitis associated with subacute fluoride poisoning, which was characterized by periosteal thickening and new bone formation in the hands and long bones.3 Periostitis associated with chronic voriconazole therapy in lung transplant patients was initially described by Wang et al,4 and periostitis deformans was recently re-examined in association with chronic voriconazole administration by Chen and Mulligan.5 In our case, similar manifestations of periostitis, particularly in the hands, were present on radiographs.
A 30-year-old woman with a history of a double lung transplant in 2005 secondary to cystic fibrosis presented with a chief complaint of bone pain. The pain started approximately 1 year after her lung transplant and progressively worsened over the 6 months prior to her presentation to the orthopedic oncology clinic. The pain was most intense in her hands and fingers. Her quality of life in the 6 months preceding presentation had deteriorated significantly due to the pain. Her medical history included hyperlipidemia, hypertension, insulin-dependent diabetes mellitus, and nephrolithiasis, in addition to her cystic fibrosis. She had a lobectomy in 1997 and a double lung transplant in 2005. Her medications included voriconazole, valsartan, fluticasonesalmeterol, prednisone, pancrelipase, losartan, hydrochlorothiazide, atorvastatin, metoprolol, insulin (aspart and glargine), omeprazole, norgestimateethinyl estradiol, cholecalciferol, tacrolimus, and azathioprine. She never used tobacco and reported no alcohol or illicit drug use.
On physical examination, she had no clubbing and no lymphadenopathy. Her right index finger, left long finger, right forearm, and bilateral clavicles had palpable nodular lesions that were tender to palpation. She had a normal range of motion in all joints and a normal gait. On her presenting radiographs, multifocal areas of periostitis were visualized involving the left hand first, second, and third proximal phalanx shafts (Figure 1). Similar periostitis was present on the left third, fourth, and fifth middle phalanx shafts. Plain radiographs of the right hand also demonstrated multifocal periostitis of the third and fourth proximal and middle phalanges. Aggressive periostitis at the level of the right fourth proximal and middle phalanges was also present. Multifocal areas of periostitis on the medial aspect of the proximal ulnar diaphysis were also present (Figure 2). Given her long-term treatment with voriconazole and a presentation consistent with periostitis deformans, voriconazole was presumed to be the offending agent and was replaced with itraconazole. The patient’s symptoms resolved shortly after withdrawal of voriconazole.
Figure 1: Plain radiograph of the left hand demonstrating voriconazole-induced periostitis that is most apparent on the middle phalanges of the third and fourth finger and the proximal phalanx of the third finger.
Figure 2: Plain radiograph of the right elbow that illustrates diffuse persiostitis of the ulnar shaft. These changes are secondary to voriconazole therapy and symptoms resolved after discontinuing treatment.
Skeletal fluorosis can be caused by excess fluoride from a number of sources. It is important to consider that, on a global scale, skeletal fluorosis is overwhelmingly due to elevated fluoride levels in drinking water.6 Many areas of India, China, and the Great Rift Valley are particularly affected by excessive fluoride levels in groundwater.6
However, in the United States, obscure sources of fluoride may have significance. Excessive consumption of tea,7–9 toothpaste,9,10 and soil11 can lead to skeletal fluorosis. Drug-induced skeletal fluorosis has been reported from abuse of methoxyflurane,12 and niflumic acid has also been associated with skeletal fluorosis.13 Nonfluoric periostitis has been reported in association with vitamin A toxicity.14
Voriconazole is a potent antifungal that received Food and Drug Administration approval in 2002.15 A derivative of fluconazole, it was created by replacing a triazole ring with a fluorinated pyrimidine, which resulted in an expanded anti-fungal spectrum.15 Voriconazole is particularly useful in immunocompromised patients with refractory fungal infections; it is the treatment of choice for invasive aspergillosis and has efficacy against emerging fungal pathogens.16,17
Voriconazole’s most common side effect is a transitory disturbance of vision.15 Less common side effects include rashes and hepatic enzyme elevations.15,16 Recently, several cases of periostitis have been reported in patients on long-term voriconazole therapy.4,5,18–20
Wang et al4 first reported periostitis in association with long-term voriconazole therapy in lung transplant recipients. Bone pain and periostitis seen on bone scans were the characteristic findings, and the symptoms resolved in all patients following voriconazole discontinuation. The authors described a presentation similar to hypertrophic osteoarthropathy, but avoided such a designation; a lack of clubbing, an absence of classic symmetric polyarthritis, and a pattern of periostitis that was proximal in long bones and nodal in nature all pointed to non-hypertrophic osteoarthropathy periostitis.4
In a series by Chen and Mulligan,5 five cases of diffuse periostitis are described in patients on long-term voriconazole, in whom the initial presentation ranged from 9 months to 3 years post-lung transplant. The authors note that the periosteal reaction was dense, irregular, and undulating or “feathery,” and involved the rib, clavicle, and phalanges of the hand, among others.5
Ayub et al18 reported a case of painful periostitis in a lung transplant recipient on long-term voriconazole therapy. The patient presented with pain in the fingers, and clubbing was absent. Radiographs of the right hand showed periosteal reaction with proliferative features involving multiple phalanges, and computed tomography scan showed nodular areas of periosteal reaction involving the bilateral ribs. Symptoms resolved after voriconazole discontinuation.18
In a study by Wermers et al,19 the authors first described a 64-year-old female heart transplant recipient who developed a painful periostitis after 6 months of voriconazole that resolved after a switch to the nonfluoride-containing itraconazole. A study was then undertaken in which fluoride levels were measured in post-transplant patients, 10 of whom received voriconazole for at least 6 months and 10 of whom received no voriconazole. All of the patients receiving voriconazole had elevated fluoride levels, and 5 of the 10 developed periostitis; 2 of those with periostitis also developed exostoses. Discontinuation of the voriconazole in those with periostitis reduced pain, alkaline phosphatase, and fluoride levels.19
A report by Wise and Wilson20 describes a 66-year-old heart transplant recipient with no prior rheumatologic disease presented with progressive bone pain voriconazole therapy for pulmonary aspergillus for 9 months. His alkaline phosphatase was elevated at 280, and a bone scan showed increased radiotracer uptake in the midthoracic ribs and discontinuous linear radiotracer uptake on the right ulna and left radius and ulna. His symptoms improved after the discontinuation of voriconazole.20
Voriconazole-induced periostitis demonstrates periosteal reaction in the proximal long bones and thoracic ribs, commonly accompanied by involvement of the phalanges of the hand.4,5,18–20 Hypertrophic osteoarthropathy, although somewhat similar in presentation, usually presents with clubbing of the digits, and periostitis is usually found in the distal diaphysis of the long bones.18 Given the cases thus far reported in the literature, it seems that periostitis deformans, originally coined to describe subacute fluorosis, may be an appropriate description.3
With fluoride as a major component, voriconazole has been associated with such painful periostitis in patients on long-term therapy after organ transplants. The cases reported thus far in the literature have been related to transplant recipients, and this association may be rooted in the appearance of periostitis only after an extended course of voriconazole, which is a therapy somewhat unique to the transplant population. Symptoms resolve after discontinuation of voriconazole, so it is particularly important that clinicians are cognizant of this association, since switching to similar, non-fluoric therapy such as itraconazole is a readily available alternative. In addition, quick recognition of this association can prevent an extended and expensive workup.
- Grönblad M, Liesi P, Korkala O, Karaharju E, Polak J. Innervation of human bone periosteum by peptidergic nerves. Anat Rec. 1984; 209(3):297–299. doi:10.1002/ar.1092090306 [CrossRef]
- Nahar I, Al-Shemmeri M, Hussain M. Secondary hypertrophic osteoarthropathy: new insights on pathogenesis and management. Gulf J Oncolog. 2007; 1(1):71–76.
- Soriano M, Manchón F. Radiological aspects of a new type of bone fluorosis, periostitis deformans. Radiology. 1966; 87(6):1089–1094.
- Wang TF, Wang T, Altman R, et al. Periostitis secondary to prolonged voriconazole therapy in lung transplant recipients [published online ahead of print October 21, 2009]. Am J Transplant. 2009; 9(12):2845–2850. doi:10.1111/j.1600-6143.2009.02837.x [CrossRef]
- Chen L, Mulligan ME. Medication-induced periostitis in lung transplant patients: periostitis deformans revisited [published online ahead of print July 22, 2010]. Skeletal Radiol. 2011; 40(2):143–148. doi:10.1007/s00256-010-0997-y [CrossRef]
- Fewtrell L, Smith S, Kay D, Bartram J. An attempt to estimate the global burden of disease due to fluoride in drinking water. J Water Health. 2006; 4(4):533–542.
- Whyte MP, Essmyer K, Gannon FH, Reinus WR. Skeletal fluorosis and instant tea. Am J Med. 2005; 118(1):78–82. doi:10.1016/j.amjmed.2004.07.046 [CrossRef]
- Lung SC, Cheng HW, Fu CB. Potential exposure and risk of fluoride intakes from tea drinks produced in Taiwan [published online ahead of print April 4, 2007]. J Expo Sci Environ Epidemiol. 2008; 18(2):158–166. doi:10.1038/sj.jes.7500574 [CrossRef]
- Joshi S, Hlaing T, Whitford GM, Compston JE. Skeletal fluorosis due to excessive tea and toothpaste consumption [published online ahead of print October 9, 2010]. Osteoporos Int. 2011; 22(9):2557–2560. doi:10.1007/s00198-010-1428-6 [CrossRef]
- Kurland ES, Schulman RC, Zerwekh JE, Reinus WR, Dempster DW, Whyte MP. Recovery from skeletal fluorosis (an enigmatic, American case). J Bone Miner Res. 2007; 22(1):163–170. doi:10.1359/jbmr.060912 [CrossRef]
- Fisher JR, Sievers ML, Takeshita RT, Caldwell H. Skeletal fluorosis from eating soil. Ariz Med. 1981; 38(11):833–835.
- Klemmer PJ, Hadler NM. Subacute fluorosis: a consequence of abuse of an organofluoride anesthetic. Ann Intern Med. 1978; 89(5 Pt 1):607–611.
- Meunier PJ, Courpron P, Smoller JS, Briancon D. Niflumic acid-induced skeletal fluorosis: iatrogenic disease or therapeutic perspective for osteoporosis?Clin Orthop Relat Res. 1980; (148):304–309.
- Rothenberg AB, Berdon WE, Woodard JC, Cowles RA. Hypervitaminosis A-induced premature closure of epiphyses (physeal obliteration) in humans and calves (hyena disease): a historical review of the human and veterinary literature [published online ahead of print October 2, 2007]. Pediatr Radiol. 2007; 37(12):1264–1267. doi:10.1007/s00247-007-0604-0 [CrossRef]
- Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent [published online ahead of print February 10, 2003]. Clin Infect Dis. 2003; 36(5):630–637. doi:10.1086/367933 [CrossRef]
- Lazarus HM, Blumer JL, Yanovich S, Schlamm H, Romero A. Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: a dose escalation study. J Clin Pharmacol. 2002; 42(4):395–402. doi:10.1177/0091270002424005 [CrossRef]
- Shanmugam VK, Matsumoto C, Pien E, et al. Voriconazole-associated myositis. J Clin Rheumatol. 2009; 15(7):350–353. doi:10.1097/RHU.0b013e318188bea7 [CrossRef]
- Ayub A, Kenney CV, McKiernan FE. Multifocal nodular periostitis associated with prolonged voriconazole therapy in a lung transplant recipient. J Clin Rheumatol. 2011; 17(2):73–75.
- Wermers RA, Cooper K, Razonable RR, et al. Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy [published online ahead of print January 16, 2011]. Clin Infect Dis. 2011; 52(5):604–611. doi:10.1093/cid/ciq188 [CrossRef]
- Wise SM, Wilson MA. A case of periostitis secondary to voriconazole therapy in a heart transplant recipient. Clin Nucl Med. 2011; 36(3):242–244. doi:10.1097/RLU.0b013e31820902d8 [CrossRef]