Cyclosporine bone remodeling effect prevents steroid osteopenia after kidney transplantation.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Westeel
F P
FP
Department of Nephrology and Internal Medicine, Centre Hospitalier Universitaire d'Amiens, Hôpital Sud, Amiens, France.
Mazouz
H
H
Ezaitouni
F
F
Hottelart
C
C
Ivan
C
C
Fardellone
P
P
Brazier
M
M
El Esper
I
I
Petit
J
J
Achard
J M
JM
Pruna
A
A
Fournier
A
A
D015502:Absorptiometry, Photon; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000009:adverse effects*; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D016723:Bone Remodeling / Q000187:drug effects*; D016572:Cyclosporine / Q000008:administration & dosage*; D005260:Female; D005272:Femur Neck; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007676:Kidney Failure, Chronic / Q000601:surgery; D016030:Kidney Transplantation; D008159:Lumbar Vertebrae; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D011241:Prednisone / Q000009:adverse effects*; D011446:Prospective Studies; D011884:Radius; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011241:Prednisone