Pii: s0041-1345(98)00181-x

Rapid Trabecular Bone Loss After Cardiac Transplantation Using
FK506 (Tacrolimus)-Based Immunosuppression

H.U. Stempfle, C. Werner, S. Echtler, T. Assum, B. Meiser, C.E. Angermann, K. Theisen, and R. Ga¨rtner THE MACROLIDE lactone tacrolimus (FK506) is a P Ͻ .01). No fracture was documented. There were no new immunosuppressive drug that has demonstrated significant differences in biochemical parameters of calcium to be 10 to 100 times more potent than cyclosporine A.
metabolism, intact PTH, gonadotropins, and renal function After forming a complex with the immunophilin FK506- before and shortly after HTx. Testosterone levels decreased binding protein, the complex acts in a similar fashion to the in five of six male patients, with an average of 1.7 ng/mL cyclosporine-immunophilin complex, resulting in an inhibi- (range 0.08 to 5.22 ng/mL). One patient became hypogo- tion of calcineurin, a calcium-dependent serine/threonine nadal after HTx. Luteinizing hormone increased signifi- protein phosphatase. This inhibition prevents the assembly cantly within the normal range from 3.4 Ϯ 0.9 mU/mL to of the functional transcription of interleukin 2. Although 6.2 Ϯ 1.5 mU/mL (P Ͻ .001). Follicle stimulating hormone tacrolimus has reputedly less severe side effects, recent remained unchanged within the normal range.
experimental studies have demonstrated an increase of bone formation and bone resorption, accompanied by a significant reduction in percent trabecular area.1 The present study was undertaken to assess the effects of tacrolimus-based immunosuppression on bone mineral me- Despite preexisting reduced bone density, these preliminary tabolism after orthotopic heart transplantation.
data demonstrated a rapid further reduction on bonemineral density due to a tacrolimus-based immunosuppres-sive regimen that may lead to future fractures. The precise mechanisms on bone mineral metabolism of each individual Seven patients (six male, one female; mean age: 51 Ϯ 10 yrs) were immunosuppressive agent are difficult to examine because studied before and 3 Ϯ 2 months after heart transplantation (HTx) of the combination therapy in clinical settings. Besides the to evaluate the immediate effects of tacrolimus-based immunosup- well-known negative effects of steroids on bone mineral pression on bone density, fracture rate, and disturbances in bio-chemical markers. Time interval between both examinations was metabolism, tacrolimus may have a direct toxic effect on 9 Ϯ 2 months. Aside from FK506 (mean blood level 13 to 18 bone cells and the secretion of local autocrine factors.
ng/mL, radioimmunoassay), immunosuppressive regimen included Second, the agent may have indirect effects on bone via a modulation of cytokines and gonadal dysfunction.
Bone mineral density (BMD, g/cm2) was measured at the lumbar The role of tacrolimus on steroidogenesis of Leydig cells spine (L2–L4) using dual-energy x-ray absorptiometry (DEXA, is still controversal. Eighty percent of our study population Lunar Expert-XL, Madison, Wisc). Vertebral bone density (VBD) showed a decrease of testosterone levels, which may con- was evaluated by single energy computer tomography after HTx.
tribute to trabecular bone loss. There was only a slight Results were expressed as VBD values ϮSD, BMD T-values Ϯ SD, increase in lutenizing hormone levels, which might be due and as percentage of variation from baseline. Vertebral fractures to only one hypogonadal patient. These results are in were assessed by x-rays of chest, thoracic, and lumbar spine.
Biochemical markers included gonadal hormones, gonadotro- contrast to experimental data by Tai et al who found no pins, urinary and serum parameters of calcium metabolism, intact direct inhibitory effect of tacrolimus on testosterone biosyn- PTH, 25OHD, and renal function. Data were compared between thesis in rat Leydig cells.2 Cyclosporine A, with its similar consecutive measurements as well as to age-matched controls.
From the Division of Cardiology, Division of Endocrinology, All patients showed significantly impaired bone mineral and Department of Cardiovascular Surgery, Ludwig-Maximilians density before transplantation (Ϫ1.3 Ϯ 0.7 g/cm2; 87 Ϯ 7%) This investigation was supported by a Grant awarded by the compared to normals. After HTx a further decline in BMD Ernst und Berta Grimmke Research Foundation.
(Ϫ1.6 Ϯ 0.7 g/cm2; 84 Ϯ 7%) was seen within an average of Address reprint requests to Dr H.U. Stempfle, Division of 3.1 Ϯ 1.6 months. VBD was also significantly decreased Cardiology, Medizinische Klinik, Klinikum Innenstadt, LMU after HTx (75 Ϯ 29 mg/ccm versus 125 Ϯ 25 mg/ccm, Mu¨nchen, Ziemssenstr. 1, 80336 Mu¨nchen, Germany.
655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 1132–1133 (1998) TRABECULAR BONE LOSS AFTER TRANSPLANT USING FK506 biologic action, also impairs testicular steroidogenesis and spermatogenesis in rats3 and humans4 mediated through 1. Cvetkovic M, Mann GN, Romero DF, et al: Transplantation the hypothalamic-pituitary axis and direct inhibition of 2. Tai J, Tze WT, Murase N, et al: Metabolism 43:533, 1994 In summary, these preliminary data in patients with 3. Seethalakshmi L, Flores C, Malhotra RK, et al: Transplanta- tacrolimus-based immunosuppression indicate the necessity to monitor carefully bone mineral metabolism and to 4. Stempfle HU, Ellinger M, Angermann CE, et al: J Am Coll administer a therapy to prevent further bone loss.

Source: http://www.medizin1.uk-wuerzburg.de/fileadmin/uk/medizin_1/dokumente/publikationen/angermann/cea79.pdf


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