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      Abnormal Vitamin D Metabolism and Loss of Bone Mass after Renal Transplantation

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          Abstract

          Background/Aim: Osteoporosis is a major complication after renal transplantation. The most important causative factor is the use of corticosteroids, but abnormalities in vitamin D metabolism and persisting hyperparathyroidism could also be involved. The present study examines changes in vitamin D metabolites, intact parathyroid hormone, and bone mineral density (BMD) during the first 2 years after renal transplantation. Methods: Sixty-one patients (38 male, 23 female; age 42 ± 13 years) who received a renal transplant participated in the study. Immunosuppressive treatment consisted of ciclosporin and prednisone. Laboratory parameters and BMD (lumbar spine and hip) were measured at baseline and 1 (laboratory only), 3, 6, 12, and 24 months after transplantation. Results: At the time of transplantation, the 1,25-dihydroxyvitamin D levels were low in all patients. Although we observed a gradual increase, subnormal values were still present in 39 (64%) and 29 (47%) patients 3 and 6 months after transplantation, respectively. From 3 months after transplantation the 1,25-dihydroxyvitamin D level correlated with the creatinine clearance. After transplantation, the intact parathyroid hormone levels declined rapidly to values slightly above normal. The lumbar BMD was nearly normal at the time of transplantation, but decreased rapidly within 6 months (–6.5 ± 4.5%; p < 0.001). A smaller decrease occurred in the femoral neck (–4.1 ± 6.5%; p < 0.001), in Ward’s triangle (–2.4 ± 13.0%; p < 0.01), and in the trochanter (–5.1 ± 6.3%; p < 0.001). After 6 months, the bone mass stabilized. Conclusions: The vitamin D metabolism remains disturbed for a considerable time after renal transplantation. In nearly half of the patients, the levels of active vitamin D remain abnormal for at least 6 months. The BMD decreased during the first 6 months after transplantation and remained stable thereafter. We speculate that the observed abnormalities in vitamin D metabolism may contribute to the early bone loss after renal transplantation.

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          Prevention of corticosteroid osteoporosis. A comparison of calcium, calcitriol, and calcitonin.

          Prolonged corticosteroid therapy increases the risk of osteoporosis and fracture. We studied whether corticosteroid-induced osteoporosis could be prevented by treatment with calcium, calcitriol (1,25-dihydroxyvitamin D3), and calcitonin. One hundred three patients starting long-term corticosteroid therapy were randomly assigned to receive 1000 mg of calcium per day orally and either calcitriol (0.5 to 1.0 microgram per day orally) plus salmon calcitonin (400 IU per day intranasally), calcitriol plus a placebo nasal spray, or double placebo for one year. Data on treatment efficacy were available for 92 of these patients. Bone density was measured every four months for two years by photon absorptiometry. There were no significant differences between groups with respect to age, underlying disease, initial bone density, or corticosteroid dose during the first year. Calcitriol (mean dose, 0.6 microgram per day), with or without calcitonin, prevented more bone loss from the lumbar spine (mean rates of change, -0.2 and -1.3 percent per year, respectively) than calcium alone (-4.3 percent per year, P = 0.0035). Bone loss at the femoral neck and distal radius was not significantly affected by any treatment. In the second year, lumbar bone loss did not occur in the group previously treated with calcitonin plus calcitriol (+0.7 percent per year), but it did occur in the group given calcium alone (-2.3 percent per year). The calcitriol group also lost lumbar bone (-3.6 percent per year) but received more corticosteroid in the second year than the other two groups. Calcitriol and calcium, used prophylactically with or without calcitonin, prevent corticosteroid-induced bone loss in the lumbar spine.
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            Cyclosporine bone remodeling effect prevents steroid osteopenia after kidney transplantation.

            It is well established that prednisone above 7.5 mg/day may induce osteopenia in association with decreased bone formation. In contrast, the effect of cyclosporine on bone remodeling and bone mineral density (BMD) is controversial. Multiple confounding factors explain this controversy, especially after renal transplantation. Fifty-two renal transplanted patients never exposed to aluminum while on dialysis were selected because they had no rejection and no hypercalcemia for 24 months while being treated with low dose prednisone/cyclosporine A (daily dose at 10 mg and 4.8 mg/kg, respectively, beyond 3 months). Bone remodeling markers (BRMs; plasma osteocalcin, bone and total alkaline phosphatases for formation, and urinary pyridinolines for resorption) were sequentially measured together with plasma creatinine, intact parathyroid hormone (PTH) and 25 OH vitamin D and cyclosporine from day 0 to 24 months. BMD was measured at 3, 6, 12, and 24 months by quantitative computerized tomography (QCT) at the lumbar spine and by double-energy x-ray absorptiometry (DEXA) at this site, as well as at the femoral neck, radius shaft, and ultradistal (UD) radius. Plasma concentrations of creatinine, PTH, and 25 OH vitamin D initially decreased and stabilized beyond three months at 137 micromol/L, 1.5 the upper limit of normal (ULN) and 11 ng/mL, respectively. All BRM increased significantly above the ULN at six months and then decreased. The BMD Z score at three months was low at all sites measured by DEXA and QCT. Follow-up measurements showed stability of absolute value and of Z score at all sites measured by DEXA. A comparison of the lumbar QCT Z score, which was available in 42 patients at 3 and 24 months, showed an increase in 28 and a decrease in 14, so that the increase for the whole group was significant (P < 0.04). Compared with patients with a decreased Z score, those with an increased Z score had significantly higher cyclosporine and lower prednisone dosages and a greater BRM increase at six months, whereas age, sex ratio, and plasma creatinine, PTH and 25 OH vitamin D were comparable and stable from months 3 through 24. The mean trough level of cyclosporine for the first six months was positively correlated to osteocalcin and total alkaline phosphatase increase at six months, and both bone formation and resorption marker increases were significantly correlated to the lumbar QCT Z score increase at 24 months. Combined low-dose prednisone and cyclosporine immunosuppression are associated with a stabilization of BMD measured at all sites with DEXA 3 to 24 months after renal transplantation and with a prevention of age-related loss of vertebral trabecular bone, as shown by the significant increase in lumbar spine QCT Z score. It is suggested that cyclosporine, together with the decrease of prednisone dosage but independent of renal function, PTH, and vitamin D status, contributes to a transient stimulation of bone remodeling at six months, which counterbalances the deleterious effect of prednisone on bone formation and BMD.
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              EFFECTS OF THREE IMMUNOSUPPRESSIVE REGIMENS ON VERTEBRAL BONE DENSITY IN RENAL TRANSPLANT RECIPIENTS

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                Author and article information

                Journal
                NEC
                Nephron Clin Pract
                10.1159/issn.1660-2110
                Nephron Clinical Practice
                S. Karger AG
                1660-2110
                2003
                January 2003
                17 November 2004
                : 93
                : 1
                : c21-c28
                Affiliations
                Departments of aNephrology, bChemical Endocrinology, and cNuclear Medicine, University Medical Center, Nijmegen, The Netherlands
                Article
                66640 Nephron Clin Pract 2003;93:c21–c28
                10.1159/000066640
                12411755
                222481c4-4698-4666-bf31-bc7bed19530f
                © 2003 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 29 April 2002
                : 22 August 2002
                Page count
                Figures: 3, Tables: 3, References: 41, Pages: 1
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Bone loss,Bone mineral density,Osteoporosis,Renal transplantation,Vitamin D

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