title: The role of tacrolimus (FK506)-based immunosuppression on bone mineral density and bone turnover after cardiac transplantation: a prospective, longitudinal, randomized, double-blind trial with calcitriol.
abstract: BACKGROUND
  Tacrolimus (FK506) is a new immunosuppressive drug in organ transplantation that has demonstrated experimentally to be more deleterious on bone mineral metabolism than cyclosporine. The purpose of this clinical study was to evaluate the effects of a tacrolimus-based immunosuppression on the skeleton and to investigate in a prospective, longitudinal, randomized, double-blind, study the effect of 0.25 microg calcitriol (1,25-dihydroxyvitamin D3) versus placebo in the prevention of bone loss and fracture rate after heart transplantion (HTx).
  
  
  METHODS
  A total of 53 patients (5 female, 48 male, mean age: 53+/-11 years) were randomized to the study medication. Basic therapy included calcium and sex hormone replacement in hypogonadism. Bone mineral density of the lumbar spine (LS) and femoral neck (FN) were performed at baseline, after 12 and 24 months. Biochemical indexes of mineral metabolism were measured every 3 months.
  
  
  RESULTS
  Overall bone mineral density (BMD) was significantly decreased after HTx (T-score-LS: 89+/-13%; FN: 88+/-14%). LS-BMD (% change in g/cm2) increased significantly within the study period in the calcitriol group (12 months: 7.1+/-8.1%, P<0.01; 24 months: 14.0+/-10.1%, P<0.01) and showed a positive trend in the placebo group (12 months: 4.5+/-9.3%, NS; 24 months: 6.2+/-8.0%, NS). FN-BMD in the calcitriol group was stable (12 months: -2.1+/-4.2%; NS; 24 months: -0.9+/-3.2%, NS). FN-BMD in the placebo group decreased significantly within the first 12 month follow-up period (-7.3+/-5.4; P<0.05) and stabilized within 2 years (-8.0+/-4.1%; P < 0.05). Fracture incidence was low during the study interval (first year: 5.0%, second year: 0%). Bone resorption markers decreased significantly during calcitriol therapy.
  
  
  CONCLUSIONS
  High dose tacrolimus-based immunosuppressive regimen is associated with a rapid bone loss early after cardiac transplantation. Beyond the first 6 months after HTx, calcium, vitamin D, and hormone supplementation in hypogonadism lead sufficiently to bone mineral recovery. Besides immunosuppression, both concomitant hypogonadism and secondary hyperparathyroidism play a major role for the bone loss and should be therefore monitored and treated adequately. Low dose calcitriol should be substituted for at least 2 years as additional antiresorptive therapy.
authors.affiliation: Medizinische Klinik, Klinikum Innenstadt, Department of Cardiology, Ludwig-Maximilians University, 80336 Munich, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Stempfle
authors.forename: Christiane
authors.initials: C
authors.lastname: Werner
authors.forename: Uwe
authors.initials: U
authors.lastname: Siebert
authors.forename: Tanja
authors.initials: T
authors.lastname: Assum
authors.forename: Uli
authors.initials: U
authors.lastname: Wehr
authors.forename: Walter A
authors.initials: WA
authors.lastname: Rambeck
authors.forename: Bruno
authors.initials: B
authors.lastname: Meiser
authors.forename: Karl
authors.initials: K
authors.lastname: Theisen
authors.forename: Roland
authors.initials: R
authors.lastname: Gärtner
mesh_terms: D000328:Adult; D015519:Bone Density / Q000187:drug effects / Q000502:physiology*; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002117:Calcitriol / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D016027:Heart Transplantation / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010919:Placebos; D012016:Reference Values; D016559:Tacrolimus / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D010919:Placebos; D002117:Calcitriol; D016559:Tacrolimus