Posttransplantational bone disease : : The effect of immunosuppressive drugs on bone: clinical and experimental studies

University dissertation from Stockholm : Karolinska Institutet, Department of Surgical Science

Abstract: Osteoporosis and pathologic fractures are frequent complications ill patients with end-stage liver or kidney diseases. Although successful transplantation eliminates some factors related to poor organ function, all increased incidence of pathologic fractures was reported ill the early post-transplant period in spite of normalization of the allograft function. The aims of this thesis were to study the effect of organ transplantation oil bone density and bone mineral metabolism as well as to evaluate tile effect of immunosuppressive drugs oil bone mineral metabolism. Twenty-five patients with end-stage liver disease and candidates for liver transplantation were measured for bone mineral density (BMD) before transplantation and measurements were repeated in 9 patients at 3 months, 6 months. and 12 months after liver transplantation (Paper 1). We found that an early and accentuated bone loss occurs during the first 6 months following transplantation, predominantly in sites enriched with trabecular bone and less ill cortical bone. 'I his bone reduction seems to mainly be the result of increased bone resorption, possibly related to the immunosuppressive therapy. One hundred and twenty-eight patients with different types of' hyperparathyroidism (HPT) were included for evaluation of bone mineral density before and after parathyroidectomy (Paper 11). Bone mineral density (BMD) measurements were performed ill all patients once before parathyroidectomy and measurements were repeated longitudinally for 3 years. Regardless of the etiology, a large proportion of HPT patients [lad reduced bone density. Ill patients with primary symptomatic HPT and patients with HPT associated with hemodialysis, bone density increases after parathyroidectomy to all extent that largely restores their preoperative bone loss. Ill contrast, parathyroidectomy does riot appear to improve BMD ill patients with HPT associated with renal transplantation, possibly because ofthe adverse effects of immunosuppressive agents ill these patients. The effect of the immunosuppressant drugs cyclosporine A (CsA), Tacrolimus (FK506), and prednisolone oil bone mass ill the rat was studied ill two experiments using densitometry of femur bone and bone morphometry of decalcified tibial bone (Paper Ill. W). Bone density and histology revealed that both CsA and FK506 affect bone by different mechanisms, possibly growth retardation, and that a high dosage of CsA or FK506 alters both cortical and trabecular bone ill rats. Prednisolone reduced bone turnover without affecting bone mass, and the combined therapy of both CsA and prednisolone induced a low bone turnover osteopenia. Recent reports have indicated that statins used ill the treatment of hypercholesterolemia might substantially increase bone formation and reduce the risk of fractures. To evaluate the association between statin use and BMD ill our patient population. hospital records for all adult patients who had received a kidney transplant between 1973 and 1998 were reviewed and 59 patients were identified as receiving statins. Bone density measurements were performed in 32 renal transplant patients taking statins as well as in age- and sex- matched controls. Statins users had a higher bone density in the lumbar spine compared to their controls. In conclusion, patients undergoing organ transplantation are at high risk to develop osteoporosis and pathologic fractures due to the accentuated bone loss, which occurs during the first posttransplant year. The immunosuppressive therapy could have a contribution in the early decrease of bone mass in patients following transplantation as well as ill abolishing the anabolic effect of parathyroidectomy on bone mass ill patients with HPT associated with renal transplantation. Experimental administration of CsA and FK506 to rats ill doses comparable to those used ill human subjects provided direct evidence that both drugs have adverse effects on bone. Moreover, CsA seems to augment the effect of prednisolone oil bone when both drugs were given together. Preliminary data of the effect of statins oil bone showed a modest increment of trabecular bone density (lumbar spine) in statin users compared to controls. However, large randomized controlled studies are needed to accurately determine if statins have a salutary effect oil bone mass and bone mineral metabolism.

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