title: Conversion of immunosuppressive monotherapy from cyclosporin a to tacrolimus reverses bone loss in rats.
abstract: Tacrolimus is used for transplant patients with refractory graft rejection and those with intolerance to cyclosporin (CsA), without the disfiguring adverse effects frequently attributed to CsA therapy. Since we have shown that CsA-associated bone loss can also affect alveolar bone, the purpose of this study was to evaluate the effects of conversion of monotherapy from CsA to tacrolimus on alveolar bone loss in rats. Groups of rats were treated with either CsA (10 mg/kg/day, s.c.), tacrolimus (1 mg/kg/day, s.c.), or drug vehicle for 60 and 120 days, and an additional group received CsA for 60 days followed by conversion to tacrolimus for a further 60-day period. Bone-specific alkaline phosphatase (BALP), tartrate-resistent acid phosphatase (TRAP-5b), calcium (Ca(2+)), interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha) concentrations were evaluated in the serum. Analyses of bone volume, bone surface, number of osteblasts, and osteoclasts were performed. Treatment with CsA for either 60 or 120 days was associated with bone resorption, represented by lower bone volume and increased number of osteoclasts; serum BALP, TRAP-5b, IL-1beta, IL-6, and TNF-alpha were also higher in these animals. After conversion from CsA to tacrolimus, all the altered serum markers returned to control values in addition to a significant increase of bone volume and a lower number of osteoclasts. This study shows that conversion from CsA to tacrolimus therapy leads to a reversal of the CsA-induced bone loss, which can probably be mediated by downregulation of IL-1beta, IL-6, and TNF-alpha production.
authors.affiliation: Department of Physiology and Pathology, Dental School of Araraquara, State University of São Paulo, Rua Humaitá 1680, CEP 14901-803, Araraquara, São Paulo, Brazil. lcs@foar.unesp.br
authors.forename: Luís C
authors.initials: LC
authors.lastname: Spolidorio
authors.forename: Patricia O
authors.initials: PO
authors.lastname: Nassar
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Nassar
authors.forename: Denise M P
authors.initials: DM
authors.lastname: Spolidorio
authors.forename: Marcelo N
authors.initials: MN
authors.lastname: Muscará
mesh_terms: D000135:Acid Phosphatase / Q000097:blood / Q000187:drug effects; D000469:Alkaline Phosphatase / Q000097:blood / Q000187:drug effects; D016301:Alveolar Bone Loss / Q000139:chemically induced* / Q000188:drug therapy* / Q000517:prevention & control; D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000502:physiology; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001857:Bone Matrix / Q000187:drug effects / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000097:blood; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D006084:Graft Rejection / Q000188:drug therapy / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007378:Interleukins / Q000097:blood; D007527:Isoenzymes / Q000097:blood / Q000187:drug effects; D008297:Male; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000627:therapeutic use*; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D050071:Bone Density Conservation Agents; D007166:Immunosuppressive Agents; D007378:Interleukins; D007527:Isoenzymes; D016572:Cyclosporine; D000469:Alkaline Phosphatase; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002118:Calcium; D016559:Tacrolimus