Enthesopathy of the Patellar Tendon Insertion Associated with Isotretinoin Therapy

Anthony J. Scuderi, Frederick L. Datz, Sonia Valdivia and Kathryn A. Morton

Division ofNuclear Medicine, University of Utah School ofMedicine, Salt Lake City, Utah

tibialtuberosityirregularities.An incisionalbiopsyandcultures A 00r@@Tc@MDPbone scan performed on a 34-yr-old female for of the left tibial tubercle mass revealed normal bone fragments suspected osteomyelitis of the proximal tibia revealed focally without evidenceof tumor or infection. Over the following year increased activity in both tibial tuberosities due to enthesop thispainfulmassrecurred.Shewasreferredfor a bonescanin athies secondary to chronic isotretinoin therapy. Physicians June 1992to rule out osteomyelitis. She denied fevers, chills or should be aware that isotretinoin therapy can cause abnor a penetrating injury. mal bone scans and not mistake these abnormalities for The patient had been treated with isotretinoin for hydraden other diseases such as osteomyelitis. Second, bone scans itis suppurativa since 1986.An initial dose of 40 mg q.i.d. (2 may be helpful in diagnosing and following isotretinoin bone mgfkg/day) was reduced after 2 yr because of a favorable re toxicity. sponse. She was taking 40 mg b.i.d. (1 mg/kg/day) at the time she presented to our department. J NucIMed1993;34:455—457 A firm, minimally tender mass was palpable on her left tibial tuberosity. There was no erythema, warmth, fluctuance or drainingsinusin thisarea. Shewas afebrileandhada normal white blood cell count, sedimentation rate, calcium and phos rreversible skeletal changes have been described in phorous levels. A bone scan was ordered for possible osteomy patients with dermatologic disorders treated with elitis. A limited three-phase bone scan was performed following the isotretinoin (13-cis-retinoic acid) [Accutane®-US, Ro intravenousadministrationof 20 mCi (740 MBq) @Tc-MDP. accutane®-UK], a synthetic vitamin A derivative (1—3). Angiographic, blood-pool and delayed images at 2 hr were ob The earliest and most common changes occur in the axial tamedofbothkneesintheanteriorandlateralprojectionsusing skeleton and consist of premature osteophyte formation a high-resolution parallel-hole collimator interfaced with a digi or hyperostosis of the cervical and thoracic spine and tal gamma camera. During the flow, blood-pool and delayed ossificationof the anteriorlongitudinalligament(4). En phases of the bone scan, there was focally increased activity thesopathy, a proliferation of bone at tendon insertions, related to both tibial tuberosities, although relatively more ac has also been described as a later and less frequent man tivity involved the symptomatic side (Fig. 1). The distal femurs ifestation of this disorder in the appendicular skeleton and proximal tibial metaphyses were normal. We suspected that (2,5). these abnormalities represented a process other than osteomy We report a patient who developed bilateral patellar elitis because of absent contiguous metaphyseal involvement tendon enthesopathy and skeletal hyperostoses as a re and the bilateral nature of this process. Plain radiographs of her left knee, cervical and thoracic spine suit of chronic isotretinoin therapy for hydradenitis sup were obtained. Enthesopathy at the patellar tendon insertion on purativa. Skeletal changes involving both tibial tuberosi the left tibial tuberosity were found which corresponded in ties were found on a limited bone scan requestedto location with the increased metabolic activity on bone scan (Fig. exclude osteomyelitis of the left knee. 2A). Anterior cervical and thoracic vertebral body osteophytes at multiple disc levels had the characteristic radiographic ap CASE REPORT pearance of hyperostoses secondary to retinoid therapy (Figs. A 33-yr-old female complained of a painful indolent mass on 2B and 2C). the anterior surface of the proximal left tibia that was unrespon sive to a 6-mo course of nonsteroidal anti-flammatory medica DISCUSSION tion. RadiographsandCT showedcalcificationof theleft patel Isotretinoin belongs to a pharmacologic class of syn lar tendon at the tibial tuberosity insertion and mild bilateral thetic vitamin A derivatives collectively known as retin oids. Isotretinoin inhibits sebaceous gland function and ReceivedSept.11, 1992;revisionacceptedOct.22, 1992. keratinization and is primarily used for the treatment of For correspondence or reprints contact: Frederick L Datz, MD, Nuclear Medicine Division, University of Utah Medical Center, Salt Lake City, UT severe recalcitrant cystic acne. Other applications for this 84132. drug include treatment of hydradenitis suppurativa and

Bilateral Patellar Tendon Enthesopathy •Scuderi et al. 455 A B C

FIGURE 1. Bonescanshowsincreasedactivityinbothanteriortibialtuberosities(arrowheads)onthelateralblood-poolimages (A) and delayed images of the knees in the anterior (B) and lateral (C) projections. disorders of keratinization, e.g., ichthyosis, epider including hyperostoses of the spine and ossification of molytic hyperkeratosis. both the anterior and posterior longitudinal ligaments, Skeletal changes secondary to vitamin A toxicity were were reported with the use of isotretinoin (8). Since that first reported in 1944 (6). Retinoids were developed in an time, multiple studies and several prospective trials have attempt to avoid toxicity associated with vitamin A. confirmed similar skeletal manifestations, including pro However, these synthetic compoundsalsoresult in a high liferative enthesopathies and diminished bone density, in prevalence of untoward skeletal changes in patients patients treated with isotretinoin (2,4,5, 9—11). treated for skin conditions not associated with prolifera The mechanism of action of isotretinoin on the skele tive skeletal lesions. In 1982, the first undesirable skeletal ton remains unknown. It is thought retinoids enhance effect of isotretinoin was described as premature closure production of interleukin-1 in bone, which in turn stimu of the proximal tibial epiphysis (7). The following year lates osteoblasts (1,12). Biochemical indices such as cal bone changes similar to those induced by vitamin A, cium and phosphorous are normal in patients treated with

FIGURE 2. Enthesopathyofthepatellartendonandhyperostosesofthespine.Lateralradiographsoftheleftknee(A),cervicalI (B) and thoracic (C) spine show calcificationat the patellartendon insertion (arrowhead)and anteriorvertebral osteophytesat the following levels: C7-T1, T2-4, 17-8, and Ti 1-12.

456 The Journal of Nuclear Medicine •Vol. 34 •No. 3 •March 1993 isotretinoin (13). There is no increased frequency of HLA ing retinoid therapy have been diagnosed and subse B27 or any other HLA antigen (8,13). quently followed with radiographs. Bone scans, however, The earliest and most frequent bone changes associ allow earlier detection of these skeletal changes and pro ated with isotretinoin therapy are small osteophytes oc vide information about their metabolic activity. The bone curling alongthe anteriormarginsof cervicaland tho scan's lower radiation exposure in comparison to skeletal racic vertebrae and ossification of the anterior survey is also beneficial. longitudinal ligament (4,14). Changes in the axial skeleton are similar to those reported in diffuse idiopathic skeletal hyperostosis (DISH), but they occur at a younger age and REFERENCES progress more rapidly (8,11, 13, 15). Anecdotal reports in 1. McOuire 3, Lawson JP. Skeletal changes associated with chronic other symptomatic individuals have described ossifica isotretinoin and etretinate administration. Der,natologica 1987;175:169— tion of the posterior longitudinal ligament causing spinal 181. cord compression (15,16). The resultant spinal stenosis 2. PennesDR. Martel W, Ellis CN, VoorheesJJ. Evolutionof skeletal hyperostoses caused by 13-cis-retinoic acid therapy. Am I Roentgenol increases the susceptibility to severe neurological conse 1988;151:967—973. quences even following minor trauma. 3. White SL, MacKie RM. Bone changes associated with oral retinoid The most prominent appendicular enthesopathies oc therapy. Pharmacol Ther 1989;40:137—144. 4. Ellis CN, PennesDR, Hermann RC, Blauvelt A, Martel W, Voorhees ii. cur in the feet at the insertions of the gastrocnemius Long-term radiographic follow-up after isotretinoin therapy. JAm Acad tendon and plantar fascia on the calcaneus. 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Retinoidhyperostosis:skeletaltoxicity associ progressively larger with continuation of retinoid therapy ated with long-termadministrationof 13-cis-retinoicacid for refractory and the earliest bone changes become the largest hyper ichthyosis. N Engi I Med 1983;308:1012—1014. 9. Torok L, Galuska L, Kasa M, Kadar L. Bone-scintigraphic examinations ostoses over the period of therapy (2). They are indepen in patients treated with retinoids: a prospective study. Br I Dermatol dent of either the daily or cumulative dose (2,4). 1989;120:31—36. In our patient, left patellar enthesopathy resulted in a 10. Kilcoyne RF. Effects of retinoids in bone. JAm Aced Dermatol 1988;19: 212—216. painful mass in the proximal tibia that recurred within 1 11.PennesDR,MartelW, EllisCN. Retinoid-mducedossificationof the yr following excision. Hyperostoses of her spine and posterior longitudinal ligament. Skeletal Radio! 1985;14:191—193. enthesopathy of her knees were typical of skeletal 12. 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