Effects of bisphosphonate treatment on bone repair under immunosuppression using cyclosporine A in adult rats.
The effect of cyclosporine A on bone turnover remains unclear. Using adult rats with vascularized bone transplantation, we show that long-term cyclosporine A administration increases bone turnover and zoledronic acid treatment enhances the reconstruction of cyclosporine A-administered skeleton. Bisphosphonates might be efficacious in human bone repair under immunosuppression using cyclosporine A.


BACKGROUND
Bisphosphonate treatment effectively prevents bone loss after transplantation. However, recent evidence from gain- and loss-of-function experiments has indicated that calcineurin inhibitors, such as cyclosporine A (CsA), reduce bone turnover, and severely suppressed bone turnover might delay the union of human fractured bone. The purpose of this study was to investigate the effects of bisphosphonate treatment on the repair of CsA-administered skeleton.


METHODS
After skeletal reconstruction by vascularized tibial grafting, adult recipient rats were treated with intramuscular CsA (10 mg/kg/day) and low-dose (0.2 microg/kg/week) or high-dose (2 microg/kg/week) subcutaneous zoledronic acid alone or in combination for 8 weeks. Biochemical parameters were measured in blood and urine. The reconstructed skeleton was analyzed using soft X-ray, histology, dual energy X-ray absorptiometry, and three-point bending test.


RESULTS
CsA induced mild renal dysfunction, hyperparathyroidism and high bone turnover. High-dose zoledronic acid delayed cortical bone union at the distal host-graft junction, but its combination with CsA did not cause such a delay. High-dose zoledronic acid prevented CsA-induced bone loss and bone fragility in the reconstructed skeleton.


CONCLUSIONS
In this rat model, long-term CsA administration increases bone turnover, at least partly, through hyperparathyroidism and high-dose zoledronic acid treatment does not impair the union of CsA-administered bone.
Matsunaga
T
T
Department of Orthopaedic Surgery, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Yamaguchi 755-8505, Japan.
Shigetomi
M
M
Hashimoto
T
T
Suzuki
H
H
Gondo
T
T
Tanaka
H
H
Sugiyama
T
T
Taguchi
T
T
D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D016723:Bone Remodeling / Q000187:drug effects* / Q000502:physiology; D001862:Bone Resorption / Q000139:chemically induced; D016025:Bone Transplantation / Q000473:pathology; D016572:Cyclosporine / Q000494:pharmacology*; D004164:Diphosphonates / Q000494:pharmacology*; D004347:Drug Interactions; D050723:Fractures, Bone / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D010012:Osteogenesis / Q000187:drug effects; D010024:Osteoporosis / Q000517:prevention & control; D051381:Rats; D011917:Rats, Inbred Lew; D013977:Tibia / Q000473:pathology / Q000637:transplantation; D000077211:Zoledronic Acid
D015415:Biomarkers; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D007166:Immunosuppressive Agents; D000077211:Zoledronic Acid; D016572:Cyclosporine