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.

Sirolimus and tacrolimus rather than cyclosporine A cause bone loss in healthy adult male rats

“…According to these authors, this dose would be equivalent to 3.2 mg/kg orally, which is the dose we employed in the present work. Spolidorio et al (2007) found an increase in the resorption marker FATR following administration of CsA (a finding we did not reach with the CTX/TRAP marker) in rats treated with 10 mg/kg/day of CsA (a dose 5 times higher than ours). Another important point is that these authors used 50 g rats, many of which were younger than ours, a fact which could have caused the different effects of immunosuppressants on bone remodeling.…”

“…Folwarczna et al (2009) administering a low dose of FK-506 (0.3 mg/kg/day) to adult male rats, found that this dose increased bone formation. Results that differed from ours were found by Spolidorio et al (2007). These authors administered 10 mg/kg/day of CsA subcutaneously to one group of rats and 1 mg/kg/day of FK-506 to another group.…”

Effects of Alendronate Therapy on Cyclosporine Induced Alveolar Bone Loss : A Morpho-Metric and Bio-Chemical Study in Rats

“…A significant decrease in serum calcium level in the Cs-A treated group which was statistically significant when compared to the other groups was observed in our study. These findings are in concordance with previous studies 10,33,34 who suggested that the decreased levels of serum calcium can be attributed to the non specific effect of cyclosporin-A due to increased excretion by kidney and/or increased bone uptake. Cs-A has also shown to induce a change in the calcium flux via cellular membrane permeability.…”

Evaluation of Alveolar Bone Mandibular of Rats Obese Induced at Monosodium Glutamate Undergoing Modified Duodenal-Jejunal Bypass Surgery

“…A great quantity of osteocytes indicates bone maturity [38]. The increase in the quantity of osteoclasts is associated with bone resorption [39]. The present research found a high quantity of mandibular alveolar bone osteocytes in all the groups and a small quantity of osteoclasts, but no significant difference was found among the groups, which indicates that neither MSGinduced obesity nor bariatric surgery significantly caused changes in the number of bone cells.…”